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Khallaf WAI, Sharata EE, Attya ME, Rofaeil RR, Khalaf MM, Hemeida RAM, Abo-Youssef AM. Buspirone ameliorates premature ovarian insufficiency evoked by cyclophosphamide in female rats; attention to AMPK/Nrf2/HO-1, α-Klotho/NLRP3/Caspase-1, and Caspase-3-mediated apoptosis interplay. Toxicol Appl Pharmacol 2025; 500:117373. [PMID: 40345558 DOI: 10.1016/j.taap.2025.117373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 04/11/2025] [Accepted: 05/02/2025] [Indexed: 05/11/2025]
Abstract
This study aims to investigate the protective impact of buspirone (BUS) against cyclophosphamide (CPA)-induced premature ovarian insufficiency (POI) by focusing on pyroptosis, apoptosis, and the AMPK/Nrf2/HO-1 signaling pathway. POI was achieved by i.p. injection of CPA in female Wistar albino rats. CPA toxicity was evaluated using biochemical analysis of the serum hormones (AMH, FSH, inhibin B, and estrogen) and histopathological examination. Oxidative stress markers (MDA, SOD) were also evaluated. Levels of inflammatory indicators (TNF-α, IL-1β, and IL-18), apoptotic marker (caspase-3), ovarian p-AMPK, ovarian NF-κB, Nrf2, and HO-1 were evaluated. RT-qPCR was used to measure Bax and Bcl-2 mRNA expression. A western blot assay was used to determine the expression of α-Klotho, NLRP3, and caspase 1. The estrous cycle and the weights of the body and ovaries were also observed. BUS, in a dose-dependent manner, attenuated CPA-induced ovarian toxicity by regulating hormonal and estrous cycle irregularities and alleviating the histopathological aberrations. It also lowered MDA levels and increased SOD activity. Furthermore, it reduced NF-κB, TNF-α, IL-1β, and IL-18 levels, as well as BAX and caspase-3 expression, while raising Bcl-2 levels. Additionally, BUS enhanced Nrf2 and HO-1 expression and boosted the protein levels of p-AMPK and α-Klotho. As well, it diminished pyroptosis by decreasing NLRP3 and caspase-1 expression. BUS attenuated POI induced by CPA, showing potential for effective protection via increasing the activity of Nrf2/HO-1 and reducing the activity of NLRP3/Caspase-1 through the participation of α-Klotho and p-AMPK, as well as inhibiting caspase-3-driven apoptosis.
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Affiliation(s)
- Waleed A I Khallaf
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
| | - Ehab E Sharata
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Deraya University, Minia 61111, Egypt.
| | - Mina Ezzat Attya
- Department of Pathology, Faculty of Medicine, Minia University, Minia 61519, Egypt.
| | - Remon Roshdy Rofaeil
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Deraya University, Minia 61111, Egypt; Department of Medical Pharmacology, Faculty of Medicine, Minia University, Minia 61519, Egypt.
| | - Marwa M Khalaf
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
| | - Ramadan A M Hemeida
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Deraya University, Minia 61111, Egypt.
| | - Amira M Abo-Youssef
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
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Rofaeil RR, Sharata EE, Attya ME, Abo-Youssef AM, Hemeida RA, Khalaf MM. Repurposing levomilnacipran to attenuate premature ovarian insufficiency induced by cyclophosphamide in female Wistar albino rats through modulation of TLR4/p38-MAPK/NF-κB p65, caspase-3-driven apoptosis, and Klotho protein expression. Food Chem Toxicol 2025; 200:115406. [PMID: 40154831 DOI: 10.1016/j.fct.2025.115406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Revised: 03/06/2025] [Accepted: 03/21/2025] [Indexed: 04/01/2025]
Abstract
AIM This study aims to explore the mitigative impact of levomilnacipran (LVM) against cyclophosphamide (CPA)-induced premature ovarian insufficiency by targeting TLR4/p38 MAPK/NF-κB p65, and klotho expression. METHODS Rats were allocated into five groups as follows: control, LVM, CPA, CPA + LVM, and CPA + TRI. Serum hormones and histopathological examination were performed. To assess oxidative stress, ovarian MDA, GSH, and SOD were evaluated. The ovarian contents of caspase-3 and inflammatory markers were assessed using the ELISA method. The expression of ovarian NF-κB p65 was examined using an immunohistochemical technique. RT-qPCR was used to measure Bax and Bcl-2 mRNA expression. Utilizing a Western blot, the TLR4, p38 MAPK, α-Klotho, and cleaved caspase-3 levels were estimated. The estrous cycle was also monitored. FINDINGS LVM attenuated CPA-induced ovarian toxicity by regulating hormones and alleviating histopathological aberrations. It also raised SOD and GSH levels and lowered MDA's ovarian content. Moreover, Bcl-2 levels were raised, Bax and caspase-3 expression levels were reduced, and IL-18, IL-1β, and TNF-α levels were all reduced. LVM-induced ovarian protection by diminishing TLR4/p38 MAPK/NF-κB p65 expression and boosting the protein levels of α-Klotho. SIGNIFICANCE LVM mitigated POI caused by CPA by downregulating TLR4/p38 MAPK/NF-κB p65, enhancing the α-Klotho level and attenuating caspase-3 derived apoptosis.
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Affiliation(s)
- Remon Roshdy Rofaeil
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Deraya University, Minia, 61111, Egypt; Department of Medical Pharmacology, Faculty of Medicine, Minia University, Minia, 61519, Egypt.
| | - Ehab E Sharata
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Deraya University, Minia, 61111, Egypt.
| | - Mina Ezzat Attya
- Department of Pathology, Faculty of Medicine, Minia University, Minia, 61519, Egypt.
| | - Amira M Abo-Youssef
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt.
| | - Ramadan Am Hemeida
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Deraya University, Minia, 61111, Egypt.
| | - Marwa M Khalaf
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt.
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Kapoor M, Swamy AM, Sundriyal D, Khanna M, Sinha N, J K, Rajaram S, Sehrawat A. Effects of Chemotherapy on Fertility and Fertility Preservation Strategies for the Women of Childbearing Potential Undergoing Chemotherapy: A Comprehensive Review. Indian J Surg Oncol 2025; 16:401-407. [PMID: 40337032 PMCID: PMC12052606 DOI: 10.1007/s13193-024-02103-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 09/19/2024] [Indexed: 01/18/2025] Open
Abstract
Cancer incidence among women of childbearing potential (WCBP) underscores the need for effective fertility preservation strategies. Advances in cancer treatment have significantly improved survival rates, highlighting survivorship issues, particularly fertility concerns in younger patients. Chemotherapy, while a crucial treatment for cancer, often brings with it unintended consequences, particularly regarding fertility. Chemotherapy induces gonadotoxicity through mechanisms such as DNA damage, follicular apoptosis, and hormonal disruption, compromising ovarian function and fertility. The risk of infertility may be low, intermediate, or high depending upon the drug used, the dose, and the duration of use. Quantifying chemotherapy's impact is challenging due to diverse agents and variable effects. Guidelines recommend discussing fertility preservation options with WCBP before treatment, using biomarkers like anti-Mullerian hormone (AMH) to assess ovarian reserve. Strategies include cryopreservation of ovarian tissue, embryos, and oocytes, each with distinct advantages and considerations. Pharmacological interventions like GnRH agonists aim to mitigate gonadotoxic effects, although their efficacy is debated. Surgical approaches like oophoropexy protect ovaries during pelvic radiation but pose logistical challenges. Fertility preservation involves ethical and psychosocial dimensions, including informed consent, financial considerations, and ethical dilemmas, necessitating comprehensive patient counselling. Future research focuses on enhancing techniques such as in vitro maturation, developing artificial ovaries, and refining cryopreservation methods to optimize outcomes.
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Affiliation(s)
- Mayank Kapoor
- Department of Medical Oncology, Hematology All India Institute of Medical Sciences (AIIMS), Rishikesh, India
| | - Anusha Mruthyunjaya Swamy
- Department of Medical Oncology, Hematology All India Institute of Medical Sciences (AIIMS), Rishikesh, India
| | - Deepak Sundriyal
- Department of Medical Oncology, Hematology All India Institute of Medical Sciences (AIIMS), Rishikesh, India
| | - Mridul Khanna
- Department of Medical Oncology, Hematology All India Institute of Medical Sciences (AIIMS), Rishikesh, India
| | - Nishant Sinha
- Department of Medical Oncology, Hematology All India Institute of Medical Sciences (AIIMS), Rishikesh, India
| | - Karthik J
- Department of Medical Oncology, Hematology All India Institute of Medical Sciences (AIIMS), Rishikesh, India
| | - Shalini Rajaram
- Department of Obstretrics and Gynecology, All India Institute of Medical Sciences (AIIMS), Rishikesh, India
| | - Amit Sehrawat
- Department of Medical Oncology, Hematology All India Institute of Medical Sciences (AIIMS), Rishikesh, India
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Vaid AK, Pagani O, Ramesh A, Bharthuar A, Desai C, Biswas G, Wadhwa J, Mohapatra PN, Gulia S, Prasad S, Sahoo TP, Agarwal V, Desai RR, Kotak BP, Dawer F. Optimizing Premenopausal Hormone Receptor-Positive Human Epidermal Growth Factor Receptor 2-Negative Early Breast Cancer Management in India: Insights From Expert Consensus. Cureus 2024; 16:e76392. [PMID: 39867062 PMCID: PMC11763344 DOI: 10.7759/cureus.76392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/24/2024] [Indexed: 01/28/2025] Open
Abstract
This research aims to optimize adjuvant ovarian function suppression (OFS) for premenopausal Indian women with hormone receptor-positive (HR+) /human epidermal growth factor receptor 2-negative (HER2-) early breast cancer (eBC). To address specific challenges identified in clinical practice, a comprehensive questionnaire consisting of 21 statements was developed. These statements were reviewed and validated by a scientific committee, ensuring their accuracy and relevance to the study's objectives. A panel of 46 Indian experts and one global expert in the field of eBC were asked to rate their level of agreement/disagreement with each statement. Consensus was defined as achieving ≥80% agreement among participants. Following two rounds of the modified Delphi technique, a consensus was achieved on 19 out of 21 statements addressing critical aspects of premenopausal HR+ HER2- eBC management. The expert panel strongly recommended comprehensive risk stratification for premenopausal patients with HR+ HER2- eBC, highlighting age ≤40 as a high-risk factor and advising composite assessments for patients ≥40 years. For high-risk patients, OFS coupled with an aromatase inhibitor emerged as the recommended therapeutic strategy. The panel recommended a potential duration of up to five years for OFS, provided tolerability is maintained. For patients under 40, simultaneous OFS and chemotherapy is advised when needed. For those over 40, sequential initiation is acceptable. Triptorelin is preferred among luteinizing hormone-releasing hormone analogs, though all options have similar efficacies. The outcomes of this consensus offer valuable clinical guidance, enabling individualized and evidence-based approaches for OFS in Indian patients with HR+ HER2- eBC.
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Affiliation(s)
- Ashok K Vaid
- Department of Medical Oncology, Medanta Cancer Institute, Gurugram, IND
| | - Olivia Pagani
- Department of Medical Oncology, Interdisciplinary Cancer Service, Hôpital Riviera-Chablais, Vaud, CHE
| | - Anita Ramesh
- Department of Medical Oncology, Kauvery Hospital, Chennai, IND
| | - Anubha Bharthuar
- Department of Medical Oncological Sciences and Hematology, Patel Hospital, Jalandhar , IND
| | - Chirag Desai
- Department of Medical Oncology, Hemato Oncology Clinic, Vedanta Hospital, Ahmedabad, IND
| | - Ghanashyam Biswas
- Department of Medical Oncology, Sparsh Hospital and Critical Care, Bhubaneswar, IND
| | - Jyoti Wadhwa
- Department of Medical Oncology, Paras Healthcare, Gurugram, IND
| | | | - Seema Gulia
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai, IND
| | - Svss Prasad
- Department of Hematology, Apollo Hospitals, Hyderabad, Hyderabad, IND
| | - Tarini P Sahoo
- Department of Medical Oncology, Silverline Hospital, Bhopal, IND
| | - Vijay Agarwal
- Department of Medical Oncology, Apollo Hospital, Bengaluru, IND
| | - Rohit R Desai
- Department of Medical Affairs, Dr. Reddy's Laboratories, Hyderabad, IND
| | - Bhavesh P Kotak
- Department of Medical Affairs, Dr. Reddy's Laboratories, Hyderabad, IND
| | - Femina Dawer
- Department of Medical Affairs, Dr. Reddy's Laboratories, Hyderabad, IND
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Arecco L, Borea R, Magaton IM, Janković K, Mariamizde E, Stana M, Scavone G, Ottonello S, Spinaci S, Genova C, de Azambuja E, Lambertini M. Current practices in oncofertility counseling: updated evidence on fertility preservation and post-treatment pregnancies in young women affected by early breast cancer. Expert Rev Anticancer Ther 2024; 24:803-817. [PMID: 38913581 DOI: 10.1080/14737140.2024.2372337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 06/21/2024] [Indexed: 06/26/2024]
Abstract
INTRODUCTION Anticancer treatments have significantly contributed to increasing cure rates of breast cancer in the last years; however, they can also lead to short- and long-term side effects, including gonadotoxicity, and compromised fertility in young women. Oncofertility is a crucial issue for young patients who have not yet completed their family planning at the time of cancer diagnosis. AREAS COVERED This review aims to cover all the latest available evidence in the field of oncofertility, including the gonadotoxicity of currently adopted anticancer therapies in the curative breast cancer setting, the available strategies for fertility preservation and the feasibility of achieving a pregnancy following anticancer treatment completion. EXPERT OPINION Over the past years, a significant progress has been made in oncofertility care for young women with breast cancer. In the context of the currently available evidence, every young woman with newly diagnosed breast cancer should receive a proper and complete oncofertility counseling before starting any anticancer treatment to increase her chances of future pregnancies.
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Affiliation(s)
- Luca Arecco
- Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genova, Genova, Italy
- Academic Trials Promoting Team, Institut Jules Bordet, Université Libre de Bruxelles (U.L.B.), Hôpital Universitaire de Bruxelles (HUB), Brussels, Belgium
| | - Roberto Borea
- Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genova, Genova, Italy
- Department of Medical Oncology, U.O.C. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Isotta Martha Magaton
- Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genova, Genova, Italy
- Division of Gynaecological Endocrinology and Reproductive Medicine, University Women's Hospital, Bern, Switzerland
| | | | - Elene Mariamizde
- Department of Medical Oncology, U.O.C. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy
- Department of Oncology and Hematology, Todua Clinic, Tbilisi, Georgia
| | - Mihaela Stana
- Department of Medical Oncology, Elysee Hospital, Alba Iulia, Romania
| | - Graziana Scavone
- Department of Medical Oncology, U.O.C. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Silvia Ottonello
- Department of Experimental Medicine (DIMES), University of Genova, Genova, Italy
| | - Stefano Spinaci
- ASL3 Breast Unit Department, Division of Breast Surgery, Ospedale Villa Scassi, Genova, Italy
| | - Carlo Genova
- Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genova, Genova, Italy
- Department of Medical Oncology, U.O.C. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Evandro de Azambuja
- Academic Trials Promoting Team, Institut Jules Bordet, Université Libre de Bruxelles (U.L.B.), Hôpital Universitaire de Bruxelles (HUB), Brussels, Belgium
| | - Matteo Lambertini
- Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genova, Genova, Italy
- Department of Medical Oncology, U.O.C. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy
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Roof KA, Andre KE, Modesitt SC, Schirmer DA. Maximizing ovarian function and fertility following chemotherapy in premenopausal patients: Is there a role for ovarian suppression? Gynecol Oncol Rep 2024; 53:101383. [PMID: 38633671 PMCID: PMC11021951 DOI: 10.1016/j.gore.2024.101383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 03/28/2024] [Accepted: 03/29/2024] [Indexed: 04/19/2024] Open
Abstract
As more premenopausal patients undergo fertility preserving cancer treatments, there is an increased need for fertility counseling and ovarian sparing strategies. Many patients receive gonadotoxic chemotherapeutic agents which can put them at risk of primary ovarian insufficiency or profoundly diminished ovarian reserve. Traditionally, estradiol and follicle stimulating hormone (FSH) values have been used to evaluate ovarian function but more recently, reproductive endocrinologists have been proponents of anti-mullerian hormone (AMH) as a validated measure of ovarian potential. While the gold standard for fertility preservation remains oocyte cryopreservation, data suggest there may be additional interventions that can mitigate the gonadotoxic effects of chemotherapeutic agents. The main objectives of this focused review were to quantify the risk of primary ovarian failure associated with the most common chemotherapies used in treatment of gynecologic cancers and to evaluate and recommend potential interventions to mitigate toxic effects on ovarian function. Chemotherapeutic agents can cause direct loss of oocytes and primordial follicles as well as stromal and vascular atrophy and the extent is dependent upon mechanism of action and age of the patient. The risk of ovarian failure is the highest with alkylating agents (42.2 %), anthracyclines (<10-34 % in patients under 40 years versus 98 % in patients aged 40-49), taxanes (57.1 %) and platinum agents (50 %). Multiple trials demonstrate that gonadotropin releasing hormone (GnRH) agonists, when administered concurrently with chemotherapy, may have protective effects, with more patients experiencing resumption of a regular menstruation pattern and recovering ovarian function more quickly post-treatment. Premenopausal patients receiving chemotherapy for the treatment of gynecologic cancers should receive adequate counseling on the potential adverse effects on their fertility. Although oocyte cryopreservation remains the gold standard for fertility preservation, there is some evidence to suggest that GNRH agonists could help maintain and preserve ovarian function and should be considered.
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Affiliation(s)
- Kelsey A. Roof
- Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA, United States
| | - Kerri E. Andre
- Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA, United States
| | - Susan C. Modesitt
- Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA, United States
| | - D. Austin Schirmer
- Division of Reproductive Endocrinology, Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA, United States
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Molinelli C, Jacobs F, Nader-Marta G, Borea R, Scavone G, Ottonello S, Fregatti P, Villarreal-Garza C, Bajpai J, Kim HJ, Puglisi S, de Azambuja E, Lambertini M. Ovarian Suppression: Early Menopause and Late Effects. Curr Treat Options Oncol 2024; 25:523-542. [PMID: 38478329 PMCID: PMC10997548 DOI: 10.1007/s11864-024-01190-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/07/2024] [Indexed: 04/06/2024]
Abstract
OPINION STATEMENT Around 90% of breast tumours are diagnosed in the early stage, with approximately 70% being hormone receptor-positive. The cornerstone of adjuvant therapy for early-stage hormone receptor-positive breast cancer is endocrine therapy, tailored according to disease stage, biological characteristics of the tumour, patient's comorbidities, preferences and age. In premenopausal patients with hormone receptor-positive breast cancer, ovarian function suppression is a key component of the adjuvant endocrine treatment in combination with an aromatase inhibitor or tamoxifen. Moreover, it can be used during chemotherapy as a standard strategy for ovarian function preservation in all breast cancer subtypes. In the metastatic setting, ovarian function suppression should be used in all premenopausal patients with hormone receptor-positive breast cancer to achieve a post-menopausal status. Despite its efficacy, ovarian function suppression may lead to several side effects that can have a major negative impact on patients' quality of life if not properly managed (e.g. hot flashes, depression, cognitive impairment, osteoporosis, sexual dysfunction, weight gain). A deep knowledge of the side effects of ovarian function suppression is necessary for clinicians. A correct counselling in this regard and proactive management should be considered a fundamental part of survivorship care to improve treatment adherence and patients' quality of life.
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Affiliation(s)
- Chiara Molinelli
- Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Genoa, Italy
- Department of Medical Oncology, U.O. Clinical Di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132, Genoa, Italy
| | - Flavia Jacobs
- Humanitas Clinical and Research Center - IRCCS, Humanitas Cancer Center, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - Guilherme Nader-Marta
- Academic Trials Promoting Team, Institut Jules Bordet and l'Université Libre de Bruxelles (U.L.B), 90, Rue Meylemeersch, 1070, Anderlecht, Brussels, Belgium
| | - Roberto Borea
- Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Genoa, Italy
- Department of Medical Oncology, U.O. Clinical Di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132, Genoa, Italy
| | - Graziana Scavone
- Department of Medical Oncology, U.O. Clinical Di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132, Genoa, Italy
| | - Silvia Ottonello
- Department of Medical Oncology, U.O. Clinical Di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132, Genoa, Italy
| | - Piero Fregatti
- Department of Surgery, U.O. Senologia Chirurgica, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Department of Surgical Sciences and Integrated Diagnostic (DISC), School of Medicine, University of Genoa, 16132, Genoa, Italy
| | - Cynthia Villarreal-Garza
- Breast Cancer Center, Hospital Zambrano Hellion - TecSalud, Tecnologico de Monterrey, Monterrey, Mexico
| | - Jyoti Bajpai
- Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Ernest Borges Rd, Parel East, Parel, Mumbai, Maharashtra, 400012, India
| | - Hee Jeong Kim
- Division of Breast Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, South Korea
| | - Silvia Puglisi
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132, Genoa, Italy
| | - Evandro de Azambuja
- Academic Trials Promoting Team, Institut Jules Bordet and l'Université Libre de Bruxelles (U.L.B), 90, Rue Meylemeersch, 1070, Anderlecht, Brussels, Belgium
| | - Matteo Lambertini
- Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Genoa, Italy.
- Department of Medical Oncology, U.O. Clinical Di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132, Genoa, Italy.
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Li Y, Zhang H, Cai C, Mao J, Li N, Huang D, Li S, Yang J, Zhou J, Wang H, Zhu Y, Ding L, Sun H. Microfluidic Encapsulation of Exosomes Derived from Lipopolysaccharide-Treated Mesenchymal Stem Cells in Hyaluronic Acid Methacryloyl to Restore Ovarian Function in Mice. Adv Healthc Mater 2024; 13:e2303068. [PMID: 37972286 DOI: 10.1002/adhm.202303068] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 10/25/2023] [Indexed: 11/19/2023]
Abstract
Premature ovarian failure (POF) features an upward incidence nowadays, and the human umbilical cord mesenchymal stem cells (hUC-MSCs)-derived exosomes (MSC-Exos) have shown applied values in the recovery of ovarian function. Here, a novel exosome-encapsulated microcarrier prepared by microfluidic technology for ovarian repair after chemotherapy damage is presented. The exosomes derived from lipopolysaccharide (LPS)-preconditioned hUC-MSCs are encapsulated with hyaluronic acid methacryloyl (HAMA) via microfluidic electrospray, which is named HAMA/MSC-Exos. Attributing to the biocompatibility and semipermeable property of HAMA, the encapsulated exosomes show great viability and controllable release behavior from HAMA. It is demonstrated that in situ transplantation of HAMA/MSC-Exos can rescue ovarian functions of cyclophosphamide-induced ovarian failure in mice by increasing ovarian volume, improving the number of antral follicles and restoring fertility. It is believed that the transplantation of HAMA/MSC-Exos will provide a new concept for the treatment of POF in clinical practice.
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Affiliation(s)
- Yifan Li
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, 210008, China
| | - Hui Zhang
- School of Life Science and Technology, Southeast University, Nanjing, 210000, China
| | - Changjun Cai
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, 210008, China
| | - Jialian Mao
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, China
| | - Ning Li
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, China
| | - Danqing Huang
- Institute of Translational Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210002, China
| | - Shiyuan Li
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, 210008, China
- Department of Vascular Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Jun Yang
- Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Jidong Zhou
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, 210008, China
| | - Huan Wang
- The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518033, China
| | - Yujuan Zhu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325001, China
| | - Lijun Ding
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, 210008, China
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, China
- Center for Clinical Stem Cell Research, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- State Key Laboratory of Analytic Chemistry for Life Science, Nanjing University, Nanjing, 210093, China
| | - Haixiang Sun
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, 210008, China
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Rodriguez-Wallberg KA, Nilsson HP, Bergh J, Malmros J, Ljungman P, Foukakis T, Stragliotto CL, Friman EI, Linderholm B, Valachis A, Andersson A, Harrysson S, Vennström L, Frisk P, Mörse H, Eloranta S. ProFertil study protocol for the investigation of gonadotropin-releasing hormone agonists (GnRHa) during chemotherapy aiming at fertility protection of young women and teenagers with cancer in Sweden-a phase III randomised double-blinded placebo-controlled study. BMJ Open 2023; 13:e078023. [PMID: 38070906 PMCID: PMC10728964 DOI: 10.1136/bmjopen-2023-078023] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 10/31/2023] [Indexed: 12/18/2023] Open
Abstract
BACKGROUND Gonadotropin-releasing hormone agonists (GnRHa) cotreatment used to transiently suppress ovarian function during chemotherapy to prevent ovarian damage and preserve female fertility is used globally but efficacy is debated. Most clinical studies investigating a beneficial effect of GnRHa cotreatment on ovarian function have been small, retrospective and uncontrolled. Unblinded randomised studies on women with breast cancer have suggested a beneficial effect, but results are mixed with lack of evidence of improvement in markers of ovarian reserve. Unblinded randomised studies of women with lymphoma have not shown any benefit regarding fertility markers after long-term follow-up and no placebo-controlled study has been conducted so far. The aim of this study is to investigate if administration of GnRHa during cancer treatment can preserve fertility in young female cancer patients in a double-blind, placebo-controlled clinical trial. METHODS AND ANALYSIS A prospective, randomised, double-blinded, placebo-controlled, phase III study including 300 subjects with breast cancer. In addition, 200 subjects with lymphoma, acute leukemias and sarcomas will be recruited. Women aged 14-42 will be randomised 1:1 to treatment with GnRHa (triptorelin) or placebo for the duration of their gonadotoxic chemotherapy. Follow-up until 5 years from end of treatment (EoT). The primary endpoint will be change in anti-Müllerian hormone (AMH) recovery at follow-up 12 months after EoT, relative to AMH levels at EoT, comparing the GnRHa group and the placebo group in women with breast cancer. ETHICS AND DISSEMINATION This study is designed in accordance with the principles of Good Clinical Practice (ICH-GCP E6 (R2)), local regulations (ie, European Directive 2001/20/EC) and the ethical principles of the Declaration of Helsinki. Within 6 months of study completion, the results will be analysed and the study results shall be reported in the EudraCT database. STUDY REGISTRATION The National Institutional review board in Sweden dnr:2021-03379, approval date 12 October 2021 (approved amendments 12 June 2022, dnr:2022-02924-02 and 13 December 2022, dnr:2022-05565-02). The Swedish Medical Product Agency 19 January 2022, Dnr:5.1-2021-98927 (approved amendment 4 February 2022). Manufacturing authorisation for authorised medicinal products approved 6 December 2021, Dnr:6.2.1-2020-079580. Stockholm Medical Biobank approved 22 June 2022, RBC dnr:202 253. TRIAL REGISTRATION NUMBER NCT05328258; EudraCT number:2020-004780-71.
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Affiliation(s)
- Kenny A Rodriguez-Wallberg
- Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden
- Department of Reproductive Medicine, Karolinska University Hospital, Stockholm, Sweden
| | | | - Jonas Bergh
- Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden
- Theme cancer, Karolinska Comprehensive Cancer Center and University Hospital, Stockholm, Sweden
| | - Johan Malmros
- Pediatric Theme Astrid Lindgren's Pediatric Hospital, Stockholm, Sweden
| | - Per Ljungman
- Department of Cellular Therapy and Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden
- Division of Hematology, Department of Medicine Huddinge, Karolinska Institute, Huddinge, Sweden
| | - Theodoros Foukakis
- Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden
- Theme cancer, Karolinska Comprehensive Cancer Center and University Hospital, Stockholm, Sweden
| | | | | | - Barbro Linderholm
- Department of Oncology, Sahlgrenska University Hospital, Goteborg, Sweden
| | - Antonis Valachis
- Oncology, Örebro universitet Fakulteten för medicin och hälsa, Orebro, Sweden
| | - Anne Andersson
- Department of Oncology, Norrlands University Hospital, Umeå, Sweden
| | - Sara Harrysson
- Department of Hematology, Cancer Theme, Karolinska University Hospital, Stockholm, Sweden
| | - Lovisa Vennström
- Department of Hematology and Coagulation, Sahlgrenska University Hospital, Goteborg, Sweden
| | - Per Frisk
- Akademiska Hospital, Uppsala, Sweden
| | - Helena Mörse
- Center for Pediatric Oncology, Skåne University Hospital, Lund, Sweden
| | - Sandra Eloranta
- Department of Medicine, Karolinska Institute, Solna, Sweden
- Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden
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10
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Han R, Song Z, Li H, Wang C, Zhang L, Yang X. Analysis of the benefit of gonadotropin-releasing hormone agonist treatment in premenopausal women undergoing hematopoietic cell transplantation. Sci Rep 2023; 13:14497. [PMID: 37666835 PMCID: PMC10477207 DOI: 10.1038/s41598-023-40778-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 08/16/2023] [Indexed: 09/06/2023] Open
Abstract
Gonadotropin-releasing hormone agonist (GnRHa) appears to exhibit ovarian protection during chemotherapy for malignant tumors. The purpose of this study was to analyze the benefits of GnRHa in premenopausal women undergoing hematopoietic cell transplantation (HSCT). Candidates for myeloablative chemotherapy HSCT requiring fertility preservation in the Gynecological Endocrinology Clinic of Peking University People's Hospital from December 2011 to December 2021 were retrospectively analyzed. Patients who chose to receive GnRHa treatment were given at least 2 courses of a 3.75-mg dose of a GnRHa before myeloablative chemotherapy, and patients who chose not to receive GnRHa treatment were included in the control group. All patients were monitored for menstruation return and menopause-related symptoms, and ovarian function tests [follicle-stimulating hormone (FSH), luteinizing hormone, and estradiol] were performed 6-12 months after HSCT. In addition, we assessed the vaginal bleeding of patients in the laminar air-flow room (LAFR). A total of 234 cases were included in this study: 77 cases in the treatment group and 157 cases in the control group. The incidence of vaginal bleeding in the LAFR in the treatment group was significantly lower than that in the control group (24.68% vs. 79.62%, P < 0.001). The menopausal symptoms of the patients in the treatment group were reduced after transplantation (46.75% vs. 19.75%, P < 0.001). There was no difference in visible follicles by follow-up ultrasound in the two groups after HSCT (16.88% vs. 13.38%, P = 0.474). The level of FSH at 6-12 months after transplantation was lower (98.00 mIU/ml vs. 117.53 mIU/ml, P = 0.001). The proportion of patients with FSH < 40 mIU/ml did not differ between the two groups. One patient in the treatment group recovered spontaneous menstruation, while none recovered spontaneous menstruation in the control group (1.30% vs. 0%, P = 0.329). The use of GnRHa may relieve menopause-related symptoms and reduce vaginal bleeding in the LAFR and breakthrough bleeding after transplantation. GnRHa treatment can reduce the level of FSH after myeloablative chemotherapy, but it cannot reduce the incidence of premature ovarian failure in women of reproductive age following myeloablative HSCT.
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Affiliation(s)
- Ruxue Han
- Department of Gynecology and Obstetrics, Peking University People's Hospital, Beijing, China
| | - Ziyi Song
- Department of Gynecology and Obstetrics, Peking University People's Hospital, Beijing, China
| | - Huiling Li
- Department of Gynecology and Obstetrics, Peking University People's Hospital, Beijing, China
| | - Chaohua Wang
- Department of Gynecology and Obstetrics, Peking University People's Hospital, Beijing, China.
| | - Leping Zhang
- Department of Pediatrics, Peking University People's Hospital, Beijing, China
| | - Xin Yang
- Department of Gynecology and Obstetrics, Peking University People's Hospital, Beijing, China.
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11
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Yuan Y, Zhang C, Lei X, Ren T, Chen H, Zhao Q. Gonadotropin-Releasing Hormone Agonists during Gonadal Chemotherapy for the Effect on Pregnancy Outcome and Ovarian Function in Premenopausal Patients with Breast Cancer: A Systematic Review and Meta-Analysis. Breast Care (Basel) 2023; 18:270-278. [PMID: 37900550 PMCID: PMC10601703 DOI: 10.1159/000528028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 11/07/2022] [Indexed: 10/31/2023] Open
Abstract
Objectives The aim of this study was to evaluate the effects of gonadotropin-releasing hormone agonists (GnRHas) on pregnancy outcomes, premature ovarian failure (POF), menstrual recovery, disease-free survival (DFS), and adverse events in premenopausal breast cancer patients during gonadal chemotherapy. Methods We systematically searched PubMed, Cochrane Library, and Embase databases. The trials were eligible if they included premenopausal breast cancer patients treated with chemotherapy alone or with concurrent GnRHa and reported ovarian function recovery data. Heterogeneity for the eligible data was assessed, and a pooled risk ratio (RR) with 95% confidence interval (CI) was calculated. A meta-analysis was conducted using a fixed-effect model. Results Fifteen randomized controlled trials were included in this analysis. The results indicated that GnRHa combined with chemotherapy significantly increased pregnancy rates compared with chemotherapy alone (RR = 1.76; 95% CI: 1.16-2.67) and decreased rates of POF (RR = 0.42; 95% CI: 0.35-0.51). For secondary endpoints, the GnRHa group improved menstrual recovery rates (RR = 1.20; 95% CI: 1.11-1.30) and decreased the rate of amenorrhea 1-2 years after chemotherapy (RR = 0.50; 95% CI: 0.40-0.63). Furthermore, the 5-year DFS and overall survival (OS) rates were significantly improved in the GnRHa group. Conclusion For premenopausal breast cancer patients receiving gonadal toxic chemotherapy, adjuvant chemotherapy with GnRHa can better protect the ovarian function of patients, reduce the rate of POF and amenorrhea, and improve the pregnancy rate, menstrual recovery rate, DFS rate, and OS rate of patients.
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Affiliation(s)
- Yuan Yuan
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, China
| | - Chu Zhang
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Xueli Lei
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Tianshu Ren
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, China
| | - Han Chen
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, China
| | - Qingchun Zhao
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, China
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12
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White R, Wilson A, Bechman N, Keay SD, McAvan L, Quenby S, Odendaal J. Fertility preservation, its effectiveness and its impact on disease status in pre-menopausal women with breast cancer: A systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol 2023; 287:8-19. [PMID: 37269752 DOI: 10.1016/j.ejogrb.2023.05.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 05/14/2023] [Accepted: 05/21/2023] [Indexed: 06/05/2023]
Abstract
INTRODUCTION Preservation of reproductive function is a key concern for many premenopausal women with breast cancer, given the known gonadotoxic effects of treatments. The present systematic review aimed to investigate the effectiveness and safety of fertility preservation strategies in pre-menopausal women with breast cancer. METHODS Primary research assessing fertility preservation strategies of any type was identified. Markers of preservation of fertility including return of menstrual function, clinical pregnancy rates and live birth rates were selected as main outcome measures. An additional analysis of safety data was also performed. RESULTS Fertility preservation interventions were overall associated with higher fertility outcomes: with a pooled odds ratio 4.14 (95% CI 3.59-4.77) for any kind of fertility preservation intervention. This was seen both for return of menstruation and for clinical pregnancy rate, but not for live birth rates. Fertility preservation was associated with a reduced rate of disease recurrence (OR 0.63 (95% CI 0.49-0.81)), while there was no significant difference in disease free survival (OR 0.88 (95% CI 0.74-1.05)) or in overall survival (OR 0.9 (95% CI 0.74-1.10)) between the fertility preservation group and those who had not undergone fertility preservation. CONCLUSION Fertility preservation is both effective in preserving reproductive function, and safe with regard to disease recurrence, disease free survival and overall survival in premenopausal women with breast cancer.
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Affiliation(s)
- Rhiannon White
- Division of Biomedical Sciences, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, Coventry CV2 2DX, United Kingdom
| | - Anna Wilson
- Division of Biomedical Sciences, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, Coventry CV2 2DX, United Kingdom
| | - Natasha Bechman
- Division of Biomedical Sciences, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, Coventry CV2 2DX, United Kingdom
| | - Stephen D Keay
- University Hospitals Coventry & Warwickshire, Coventry CV2 2DX, United Kingdom
| | - Lucy McAvan
- University Hospitals Coventry & Warwickshire, Coventry CV2 2DX, United Kingdom
| | - Siobhan Quenby
- Division of Biomedical Sciences, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, Coventry CV2 2DX, United Kingdom; University Hospitals Coventry & Warwickshire, Coventry CV2 2DX, United Kingdom
| | - Joshua Odendaal
- Division of Biomedical Sciences, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, Coventry CV2 2DX, United Kingdom; University Hospitals Coventry & Warwickshire, Coventry CV2 2DX, United Kingdom.
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13
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Khallaf WAI, Sharata EE, Attya ME, Abo-Youssef AM, Hemeida RAM. LCZ696 (sacubitril/valsartan) mitigates cyclophosphamide-induced premature ovarian failure in rats; the role of TLR4/NF-κB/NLRP3/Caspase-1 signaling pathway. Life Sci 2023; 326:121789. [PMID: 37201697 DOI: 10.1016/j.lfs.2023.121789] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 05/06/2023] [Accepted: 05/15/2023] [Indexed: 05/20/2023]
Abstract
AIM Cyclophosphamide (CP) is used to treat a variety of cancers and autoimmune illnesses. CP has been found to frequently cause premature ovarian failure (POF). The study's objective was to assess LCZ696's potential for protection against CP-induced POF in a rat model. MAIN METHODS Rats were randomly assigned into seven groups as follows: control, valsartan (VAL), LCZ696, CP, CP + VAL, CP + LCZ696, and CP + triptorelin (TRI). Ovarian malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), interleukin-18 (IL-18), IL-1β, and tumor necrosis factor-alpha (TNF-α) were assessed using ELISA. Serum anti-mullerian hormone (AMH), estrogen, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were also measured using ELISA. The expression of NLRP3/Caspase-1/GSDMD C-NT and TLR4/MYD88/NF-B P65 proteins was estimated using western blot assay. The histopathology of the ovaries was also investigated. The estrous cycle, body, and ovarian weights were also monitored. KEY FINDINGS CP treatment significantly elevated levels of MDA, IL-18, IL-1β, TNF-α, FSH, LH, and up-regulated TLR4/NF-κB/NLRP3/Caspase-1 proteins, as compared to the control group, however, ovarian follicles count, and levels of GSH, SOD, AMH, and estrogen were reduced with CP administration. All the aforementioned biochemical and histological abnormalities were considerably alleviated by the LCZ696 therapy compared to valsartan alone. SIGNIFICANCE LCZ696 effectively mitigated CP-induced POF, offering promising protection that could be related to its suppression power on NLRP3-induced pyroptosis and TLR4/NF-B P65 pathway.
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Affiliation(s)
- Waleed A I Khallaf
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
| | - Ehab E Sharata
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Deraya University, Minia 61111, Egypt.
| | - Mina Ezzat Attya
- Department of Pathology, Faculty of Medicine, Minia University, Minia 61519, Egypt.
| | - Amira M Abo-Youssef
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
| | - Ramadan A M Hemeida
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Deraya University, Minia 61111, Egypt; Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut branch, Assiut 71524, Egypt.
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14
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Ciccarone M, Cavaceppi P, Tesei C, Brunetti S, Pulsoni A, Annibali O, Gasparoli C, Battistini R, Hohaus S, Pelliccia S, Tafuri A, Cox MC, Cantonetti M, Rigacci L, Abruzzese E. Effects of ABVD chemotherapy on ovarian function: epidemiology, hormonal dosages and ultrasound morphologic analyses in 270 patients with Hodgkin's disease. Front Oncol 2023; 13:1059393. [PMID: 37152067 PMCID: PMC10160490 DOI: 10.3389/fonc.2023.1059393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 03/27/2023] [Indexed: 05/09/2023] Open
Abstract
INTRODUCTION Classical Hodgkin Lymphoma (HL) is a lymphoproliferative disease typically diagnosed in the young. The excellent results obtained with current treatment lead to long survival with age-related complications affecting patients' survival and quality of life. One issue affecting HL patients is infertility. This problem can be easily overcome in males with seminal liquid cryopreservation, however, in females it is more complex either in terms of the quality of the cryopreserved material or the patients' age at diagnosis. Moreover, not all chemo- or radio-therapies have the same negative impact on fertility.The main objectives of this study was to collect epidemiological information on HL patients involved in fertility preservation counseling and to analyze the impact of ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine), the standard treatment for HL, on ovarian function, hormonal levels and ovarian and uterine tissue morphologies. Patterns of fertility preservation were also reported. METHODS Data were obtained from 270 female patients at HL onset who were interested in fertility counseling prior to therapy initiation. Each patient was assessed at HL diagnosis for levels of Anti-Mullerian Hormone (AMH), Follicle Stimulating Hormone (FSH), and 17β-oestradiol (17β-oe), with additional assessments at 6 and 12 months after chemotherapy. Patients were evaluated with ultrasound scans to study the number of ovarian follicles and the degree of uterine thickness at the same timepoints. RESULTS The average patient AMH level showed a statistically significant reduction at 6 months after chemotherapy (p=0.05) and by the 12 month time point returned to near pre-chemotherapy values. FSH and 17β-oe levels did not significantly vary throughout the study period. ABVD chemotherapy was associated with a significant reduction of both ovarian follicles and endometrial thickness at the 6 month time point followed by a recovery at the 12 time point in both ovaries. Different results were observed when patients changed treatment to a more intensive one. DISCUSSION Based on the results from the hormonal measurements and the follicle echography, it appears that the toxic effect of ABVD on fertility is transient, whereas, in contrast, more intensive therapies may potentially be more harmful and long-lasting.
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Affiliation(s)
- Mariavita Ciccarone
- Associazione Gemme Dormienti Organizzazione Non Lucrativa di Utilità Sociale (ONLUS), Rome, Italy
- Gynecologic Unit , San Carlo di Nancy Hospital, Rome, Italy
| | - Paola Cavaceppi
- Associazione Gemme Dormienti Organizzazione Non Lucrativa di Utilità Sociale (ONLUS), Rome, Italy
- LabAurelia, Rome, Italy
| | - Cristiano Tesei
- Associazione Gemme Dormienti Organizzazione Non Lucrativa di Utilità Sociale (ONLUS), Rome, Italy
| | - Stefania Brunetti
- Associazione Gemme Dormienti Organizzazione Non Lucrativa di Utilità Sociale (ONLUS), Rome, Italy
| | - Alessandro Pulsoni
- Department of Cellular Biotechnology and Haematology, Sapienza University, Rome, Italy
| | - Ombretta Annibali
- UOC Haematology Stem Cell Transplantation, University Campus Bio Medico, Rome, Italy
| | | | - Roberta Battistini
- UOC Ematologia e Trapianti CSE, Azienda Ospedaliera (AO) San Camillo Forlanini, Rome, Italy
| | - Stefan Hohaus
- Policlinico Gemelli Foundation, Catholic University of the Sacred Heart, Rome, Italy
| | - Sabrina Pelliccia
- Haematology Unit, Azienda Ospedaliera‐ Universitaria Sant’Andrea, Rome, Italy
| | - Agostino Tafuri
- Haematology Unit, Azienda Ospedaliera‐ Universitaria Sant’Andrea, Rome, Italy
| | | | | | - Luigi Rigacci
- UOC Ematologia e Trapianti CSE, Azienda Ospedaliera (AO) San Camillo Forlanini, Rome, Italy
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15
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Investigation of the female infertility risk associated with anti-cancer therapy. CLINICAL & TRANSLATIONAL ONCOLOGY : OFFICIAL PUBLICATION OF THE FEDERATION OF SPANISH ONCOLOGY SOCIETIES AND OF THE NATIONAL CANCER INSTITUTE OF MEXICO 2023:10.1007/s12094-023-03087-8. [PMID: 36689055 DOI: 10.1007/s12094-023-03087-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 01/11/2023] [Indexed: 01/24/2023]
Abstract
Female infertility is a significant health issue worldwide with a rising incidence. Anti-cancer therapy is one of the most important reasons for increasing infertility. Although anti-cancer treatment increases the rate of survival, it decreases the quality of life through its side effects. The most substantial side effects are sexual dysfunction and infertility. Breast cancer is the most common cancer. The first-line treatment of breast cancer is chemotherapy by alkylating agents like cyclophosphamide, which leads to infertility. For instance, persistent chemotherapy-induced amenorrhea among breast cancer patients could affect almost half of the patients that undergo such therapy. However, some agents or therapeutic methods can ameliorate these intoxicating effects. Chemotherapy plus gonadotropin-releasing hormone agonist, in breast cancer patients, can not only improve overall survival but also reduce ovarian toxicity. Age plays an essential role in chemotherapy-induced amenorrhea. Chemotherapy at a younger age can reduce the risk of infertility. Gynecological cancers including uterine and ovarian cancer, which have high mortality rates, are the most related cancers to infertility. Surgery is the primary treatment of gynecological cancers. Studies demonstrated that fertility-sparing surgery is a better option than radical surgery. In addition, neoadjuvant chemotherapy is mostly a better option than primary cytoreductive surgery in terms of survival and fertility. Immune checkpoint inhibitors (ICIs) have recently played a major role in treating various cancer types. However, ICIs are associated with hypophysitis, which affects ovaries and can lead to infertility. There are some options for ovarian preservation such as embryo cryopreservation, oocyte cryopreservation, ovarian transposition, ovarian tissue cryopreservation, and ovarian suppression by GnRH agonists. Anti-müllerian hormone level can be utilized to monitor the ovarian reserve. Moreover, to avoid fertility loss, approaches such as using transplantation of human placenta mesenchymal stem cells, administrating anti-inflammatory agents and hormone therapy are under investigation.
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Ovarian Reserve Disorders, Can We Prevent Them? A Review. Int J Mol Sci 2022; 23:ijms232315426. [PMID: 36499748 PMCID: PMC9737352 DOI: 10.3390/ijms232315426] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 11/28/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022] Open
Abstract
The ovarian reserve is finite and begins declining from its peak at mid-gestation until only residual follicles remain as women approach menopause. Reduced ovarian reserve, or its extreme form, premature ovarian insufficiency, stems from multiple factors, including developmental, genetic, environmental exposures, autoimmune disease, or medical/surgical treatment. In many cases, the cause remains unknown and resulting infertility is not ultimately addressed by assisted reproductive technologies. Deciphering the mechanisms that underlie disorders of ovarian reserve could improve the outcomes for patients struggling with infertility, but these disorders are diverse and can be categorized in multiple ways. In this review, we will explore the topic from a perspective that emphasizes the prevention or mitigation of ovarian damage. The most desirable mode of fertoprotection is primary prevention (intervening before ablative influence occurs), as identifying toxic influences and deciphering the mechanisms by which they exert their effect can reduce or eliminate exposure and damage. Secondary prevention in the form of screening is not recommended broadly. Nevertheless, in some instances where a known genetic background exists in discrete families, screening is advised. As part of prenatal care, screening panels include some genetic diseases that can lead to infertility or subfertility. In these patients, early diagnosis could enable fertility preservation or changes in family-building plans. Finally, Tertiary Prevention (managing disease post-diagnosis) is critical. Reduced ovarian reserve has a major influence on physiology beyond fertility, including delayed/absent puberty or premature menopause. In these instances, proper diagnosis and medical therapy can reduce adverse effects. Here, we elaborate on these modes of prevention as well as proposed mechanisms that underlie ovarian reserve disorders.
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Xie Y, Duan H, Wang D, Li H, Jia J, Zhang J, Li L. Gonadotropin-releasing hormone agonist protects ovarian function in young patients with ovarian malignancy undergoing platinum-based chemotherapy: A prospective study. Front Oncol 2022; 12:986208. [DOI: 10.3389/fonc.2022.986208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 10/03/2022] [Indexed: 11/13/2022] Open
Abstract
PurposeWe aimed to ascertain the effectiveness of gonadotropin-releasing hormone (GnRH) agonist co-therapy for the preservation of ovarian function in patients with ovarian malignancy who underwent unilateral salpingo-oophorectomy and platinum-based chemotherapy.MethodsWe enrolled 158 patients with ovarian malignancy who underwent fertility preservation surgery and postoperative platinum-based chemotherapy between January 2018 and December 2020. Patients were divided into two groups based on the use of GnRH agonist (GnRHa) during chemotherapy. Two patients withdrew from the study. Laboratory tests (serum follicle-stimulating hormone [FSH], serum luteinizing hormone [LH], and serum anti-Müllerian hormone [AMH]) were performed pre-chemotherapy and one year post-chemotherapy. Data on menstruation resumption, perimenopausal symptoms (modified Kupperman Menopausal Index [KMI]), health-related quality of life (Medical Outcomes Study Short Form-36 [MOS SF-36]), and obstetric outcomes were collected.ResultsOne year post-chemotherapy, the serum AMH level in the GnRHa group was higher than that in the control group (P<0.001), while the serum FSH and FSH/LH levels in the GnRHa group were lower than those in the control group (P<0.001). The mean period from last chemotherapy to menstrual resumption was 3.86 and 5.78 months in the GnRHa and control groups (P<0.001), respectively. The rate of menstrual resumption post-chemotherapy was 93.5% and 82.3% in the GnRHa and control groups (P<0.05), respectively. GnRHa co-administration during chemotherapy reduced the likelihood of low AMH levels post-chemotherapy and was significant in the multivariate analysis (P<0.05). The modified KMI scores and MOS SF-36 scores were better in the GnRHa group than in the control group (both P<0.001).ConclusionGnRHa protects ovarian function during platinum-based adjuvant chemotherapy in young patients with ovarian malignancy. This study provides a therapeutic reference for gynecologists, especially for those in economically and medically underdeveloped areas.Trial registrationChinese Clinical Trial Registry (chiCTR1800019114; October 26, 2018; http://www.chictr.org.cn/index.aspx)
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Sella T, Zheng Y, Tan-Wasielewski Z, Rosenberg SM, Poorvu PD, Tayob N, Ruddy KJ, Gelber SI, Tamimi RM, Schapira L, Come SE, Peppercorn JM, Borges VF, Partridge AH, Ligibel JA. Body weight changes and associated predictors in a prospective cohort of young breast cancer survivors. Cancer 2022; 128:3158-3169. [PMID: 35775874 DOI: 10.1002/cncr.34342] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 01/23/2022] [Accepted: 02/14/2022] [Indexed: 11/07/2022]
Abstract
BACKGROUND Weight gain after a breast cancer diagnosis is common and is associated with inferior outcomes. Young survivors may be especially susceptible to weight changes given the impact of treatment on menopausal status. METHODS The authors identified women who were diagnosed with stage 0 to III breast cancer at age 40 years or younger between 2006 and 2016 from a multicenter prospective cohort. Self-reported weight was collected at diagnosis and at 1 year and 3 years postdiagnosis. Tumor and treatment data were obtained from medical records and patient surveys. Multinomial logistic regression was used to identify the factors associated with weight gain (≥5%) or weight loss (≥5%) versus stable weight at 1 year and 3 years postdiagnosis. RESULTS The cohort included 956 women with a median age of 37 years at diagnosis. Mean weight significantly increased over time from 66.54 ± 14.85 kg at baseline to 67.33 ± 15.53 and 67.77 ± 14.65 kg at 1 year and 3 years, respectively (p ≤ .001 for both comparisons). The proportion of women experiencing ≥5% weight gain increased from 24.8% at 1 year to 33.9% at 3 years. At 1 year, less self-perceived financial comfort, Black race, and stage III disease were significantly associated with weight gain; at 3 years, only less self-perceived financial comfort remained significant. Baseline overweight or obesity was significantly associated with weight loss at both time points. Chemotherapy, endocrine therapy, and treatment-related menopause were not associated with weight change. CONCLUSIONS One third of young breast cancer survivors experienced clinically significant weight gain 3 years after diagnosis; however, treatment-related associations were not observed. Age-appropriate lifestyle interventions, including the reduction of financial barriers, are needed to prevent weight gain in this high-risk population.
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Affiliation(s)
- Tal Sella
- Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Yue Zheng
- Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | | | - Shoshana M Rosenberg
- Department of Population Health Sciences, Weill Cornell Medicine, New York, New York, USA
| | | | - Nabihah Tayob
- Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Kathryn J Ruddy
- Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA
| | - Shari I Gelber
- Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Rulla M Tamimi
- Department of Population Health Sciences, Weill Cornell Medicine, New York, New York, USA
| | | | - Steven E Come
- Breast Cancer Program, Beth Israel Deaconess Medical Center and Dana-Farber/Harvard Cancer Center, Boston, Massachusetts, USA
| | - Jeffrey M Peppercorn
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Virginia F Borges
- Department of Medical Oncology, University of Colorado Cancer Center, Aurora, Colorado, USA
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Jiang M, Wang J, Yu R, Hu R, Li J. A narrative review on the research progress of gonadal function protection in children with cancer. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:374. [PMID: 35434006 PMCID: PMC9011244 DOI: 10.21037/atm-22-681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 03/04/2022] [Indexed: 11/06/2022]
Abstract
Background and Objective The global incidence of malignant tumors in children (0-14 years) and adolescents (15-19 years) ranges between 95 per 1 million and 255 per 1 million, which seriously affects the survival of patients. In the past 30 years, with the application of comprehensive treatments (including surgery, chemotherapy, radiotherapy, and bone marrow transplantation), great progress has been made in the treatment of malignant tumors in children and adolescents. The 5-year survival rate now exceeds 80%, and most patients can smoothly enter adolescence or the reproductive period. However, due to the particular age of patients with malignant tumors in children and adolescents, treatment may cause abnormal growth of the patient's height, bones, and some vital organs (such as the pituitary gland and reproductive organs). Treatment may also cause abnormal secretion of growth hormones, thyroid hormones, and sex hormones. These complications seriously affect the quality of life of tumor patients. In the past ten years, countries have established long-term follow-up specifications for children with tumors. These programs have found that, in adulthood, 67% to 75% of children who survived having tumors have at least one treatment-related complication. Among patients receiving chemotherapy, gonadal dysfunction is the most common related endocrine dysfunction. Methods This paper reviews the literature on fertility protection services for cancer patients in foreign countries was conducted to provide a reference for developing gonadal protection services for cancer patients and for establishing consensus or guidelines on gonadal protection in China. Key Content and Findings In the treatment of childhood cancer, the assistance of reproductive technology can effectively reduce the occurrence of complications from treatment. Conclusions Therefore, minimizing the effects of radiotherapy and chemotherapy on the growth and endocrine of children and adolescents while treating tumors is a new challenge for oncologists.
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Affiliation(s)
- Mingyan Jiang
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Jialing Wang
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Ruixin Yu
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Ruolan Hu
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Jinrong Li
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
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Valsamakis G, Valtetsiotis K, Charmandari E, Lambrinoudaki I, Vlahos NF. GnRH Analogues as a Co-Treatment to Therapy in Women of Reproductive Age with Cancer and Fertility Preservation. Int J Mol Sci 2022; 23:2287. [PMID: 35216409 PMCID: PMC8875398 DOI: 10.3390/ijms23042287] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 02/10/2022] [Accepted: 02/16/2022] [Indexed: 11/17/2022] Open
Abstract
In this review, we analyzed existing literature regarding the use of Gonadotropin-releasing Hormone (GnRH) analogues (agonists, antagonists) as a co-treatment to chemotherapy and radiotherapy. There is a growing interest in their application as a prophylaxis to gonadotoxicity caused by chemotherapy and/or radiotherapy due to their ovarian suppressive effects, making them a potential option to treat infertility caused by such chemotherapy and/or radiotherapy. They could be used in conjunction with other fertility preservation options to synergistically maximize their effects. GnRH analogues may be a valuable prophylactic agent against chemotherapeutic infertility by inhibiting rapid cellular turnover on growing follicles that contain types of cells unintentionally targeted during anti-cancer treatments. These could create a prepubertal-like effect in adult women, limiting the gonadotoxicity to the lower levels that young girls have. The use of GnRH agonists was found to be effective in hematological and breast cancer treatment whereas for ovarian endometrial and cervical cancers the evidence is still limited. Studies on GnRH antagonists, as well as the combination of both agonists and antagonists, were limited. GnRH antagonists have a similar protective effect to that of agonists as they preserve or at least alleviate the follicle degradation during chemo-radiation treatment. Their use may be preferred in cases where treatment is imminent (as their effects are almost immediate) and whenever the GnRH agonist-induced flare-up effect may be contra-indicated. The combination treatment of agonists and antagonists has primarily been studied in animal models so far, especially rats. Factors that may play a role in determining their efficacy as a chemoprotective agent that limits gonadal damage, include the type and stage of cancer, the use of alkylating agents, age of patient and prior ovarian reserve. The data for the use of GnRH antagonist alone or in combination with GnRH agonist is still very limited. Moreover, studies evaluating the impact of this treatment on the ovarian reserve as measured by Anti-Müllerian Hormone (AMH) levels are still sparse. Further studies with strict criteria regarding ovarian reserve and fertility outcomes are needed to confirm or reject their role as a gonadal protecting agent during chemo-radiation treatments.
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Affiliation(s)
- Georgios Valsamakis
- Second University Department of Obstetrics and Gynecology, Aretaieion University Hospital, Athens Medical School, Ethnikon and Kapodistriakon University of Athens, 115 28 Athens, Greece; (K.V.); (I.L.); (N.F.V.)
| | - Konstantinos Valtetsiotis
- Second University Department of Obstetrics and Gynecology, Aretaieion University Hospital, Athens Medical School, Ethnikon and Kapodistriakon University of Athens, 115 28 Athens, Greece; (K.V.); (I.L.); (N.F.V.)
| | - Evangelia Charmandari
- First University Department of Paediatrics, Aghia Sophia Childrens Hospital, Athens Medical School, Ethnikon and Kapodistriakon University of Athens, 152 33 Athens, Greece;
| | - Irene Lambrinoudaki
- Second University Department of Obstetrics and Gynecology, Aretaieion University Hospital, Athens Medical School, Ethnikon and Kapodistriakon University of Athens, 115 28 Athens, Greece; (K.V.); (I.L.); (N.F.V.)
| | - Nikolaos F. Vlahos
- Second University Department of Obstetrics and Gynecology, Aretaieion University Hospital, Athens Medical School, Ethnikon and Kapodistriakon University of Athens, 115 28 Athens, Greece; (K.V.); (I.L.); (N.F.V.)
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21
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Torrisi R, Basilico V, Giordano L, Caruso M, Musolino A, Monari MN, Carnaghi C, Santoro A. Is Anti-Müllerian Hormone a Marker of Ovarian Reserve in Young Breast Cancer Patients Receiving a GnRH Analog during Chemotherapy? Breast Care (Basel) 2022; 17:10-15. [PMID: 35355699 PMCID: PMC8914273 DOI: 10.1159/000514445] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 01/14/2021] [Indexed: 02/03/2023] Open
Abstract
Introduction Anti-Müllerian hormone (AMH) is the most reliable biomarker of ovarian reserve; however, its role in predicting ovarian recovery after chemotherapy is unclear. Administration of a GnRH analog (GnRHa) during chemotherapy significantly reduces the ovarian failure rate and increases the pregnancy rate. The available data on the behavior of AMH during concurrent administration of chemotherapy and GnRHa are inconsistent. We investigated whether concurrent administration of triptorelin and adjuvant chemotherapy might reduce the expected drop of AMH. Methods Eligible patients were premenopausal women aged <40 years, with a diagnosis of early breast cancer, and candidates to 4-8 cycles of adjuvant chemotherapy. Triptorelin (3.75 mg i.m.) was started before chemotherapy and administered every 4 weeks thereafter. The principal endpoint was the proportion of patients with an AMH percent change ≤50% between 12 months after chemotherapy and basal levels. The secondary endpoint was the proportion of patients achieving postchemotherapy AMH levels above the threshold of 0.2 ng/mL. Results Fifty patients were enrolled, 31 of whom had blood samples available at baseline and 1 year after the end of chemotherapy. AMH decreased to nearly undetectable levels after chemotherapy and recovered after 12 months, but they did not exceed 1 tenth of the pretreatment levels. As for the secondary endpoint, 15 of the 31 patients recovered AMH levels above the threshold. Conclusions This study did not reach its principal endpoint; however, the rate of 48% of patients who recovered AMH above threshold levels favorably compared with those in studies without concurrent GnRHa, supporting a better recovery of AMH with triptorelin.
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Affiliation(s)
- Rosalba Torrisi
- IRCCS Humanitas Research Hospital Medical Oncology Unit, Rozzano, Italy,*Rosalba Torrisi, IRCCS Humanitas Research Hospital Medical Oncology Unit, Department of Medical Oncology and Hematology, Via Manzoni 56, IT–20089 Rozzano (Italy),
| | - Vera Basilico
- Medical Oncology Unit, Istituto Clinico Mater Domini Humanitas, Castellanza, Italy
| | - Laura Giordano
- IRCCS Humanitas Research Hospital Medical Oncology Unit, Rozzano, Italy
| | - Michele Caruso
- Medical Oncology Humanitas Centro Catanese di Oncologia, Catania, Italy
| | | | - Marta Noemi Monari
- Laboratory of Clinical Analysis, Humanitas Clinical and Research Center, IRCCS, Rozzano, Italy
| | - Carlo Carnaghi
- Medical Oncology Unit, Istituto Clinico Mater Domini Humanitas, Castellanza, Italy,Medical Oncology Humanitas Centro Catanese di Oncologia, Catania, Italy
| | - Armando Santoro
- IRCCS Humanitas Research Hospital Medical Oncology Unit, Rozzano, Italy,Department of Biomedical Sciences, Humanitas University, Rozzano, Italy
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22
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Zong X, Yu Y, Yang H, Chen W, Ding X, Liu S, Li X, Chen X, Jiang C, Xia X, Huang R, Zhu M, Hu J, Liang C. Effects of Gonadotropin-Releasing Hormone Analogs on Ovarian Function Against Chemotherapy-Induced Gonadotoxic Effects in Premenopausal Women With Breast Cancer in China: A Randomized Clinical Trial. JAMA Oncol 2022; 8:252-258. [PMID: 34967844 PMCID: PMC8719274 DOI: 10.1001/jamaoncol.2021.6214] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
IMPORTANCE Studies of the use of gonadotropin-releasing hormone analogs (GnRHa) to protect ovarian function have shown mixed results. OBJECTIVE To determine whether administering GnRHa during chemotherapy in premenopausal women with breast cancer can reduce ovarian impairment. DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial, conducted at the Shanghai Jiao Tong University Affiliated Shanghai Sixth People's Hospital and Zhejiang Cancer Hospital in China, was an open-label trial involving premenopausal women aged 18 to 49 years with operable stage I to III breast cancer for which treatment with adjuvant or neoadjuvant cyclophosphamide-containing chemotherapy was planned in 2 parallel groups: treatment with chemotherapy with or without GnRHa. Enrollment occurred from September 2015 to August 2017, and follow-up ended December 2020. The data were analyzed in March 2021. A total of 405 patients were enrolled in the study, among whom 27 patients (6.7%) quit participation voluntarily, 33 (8.1%) did not meet the inclusion criteria and were excluded, and 15 (3.7%) were lost to follow-up. Ultimately 330 patients were included in the primary analysis, including 29 patients with baseline anti-Müllerian hormone levels less than 0.5ng/ mL. INTERVENTIONS Eligible patients were randomly assigned (1:1) to receive chemotherapy with (n = 165) or without (n = 165) GnRHa. In patients randomized to receive GnRHa, 3.6 mg of goserelin or 3.75 mg of leuprorelin was injected subcutaneously once every 28 days from 1 to 2 weeks before the first cycle of chemotherapy to 4 weeks after the last cycle of chemotherapy. MAIN OUTCOMES AND MEASURES The primary end point was the rate of premature ovarian insufficiency (POI) at 12 months after chemotherapy. Premature ovarian insufficiency was defined as anti-Müllerian hormone levels of less than 0.5 ng/mL in this study. The secondary end point was overall survival (OS) and tumor-free survival (TFS). RESULTS A total of 330 eligible patients could be evaluated with complete data, among whom 301 patients (91.2%; GnRHA group: mean [SD] age, 40.6 [6.7] years; control group: mean [SD] age, 40.2 [5.9] years) were eligible for primary end point analysis. At 12 months after the completion of chemotherapy, the POI rate was 10.3% (15 of 146) in the GnRHa group and 44.5% (69 of 155) in the control group (odds ratio, 0.23; 95% CI, 0.14-0.39; P < .001). Anti-Müllerian hormone resumption in the GnRHa group was significantly better than that in the control group (15 of 25 vs 6 of 44; odds ratio, 4.40; 95% CI, 1.96-9.89; P < .001). After a median follow-up of 49 months (range, 25-60 months), the differences in 4-year OS and TFS between the 2 groups were not significant. A post hoc analysis showed that in patients younger than 35 years, the TFS was higher in the GnRHa group than in the control group (93% vs 62%; P = .004; hazard ratio, 0.15; 95% CI, 0.03-0.82; P = .03). CONCLUSIONS AND RELEVANCE This randomized clinical trial found that administering GnRHa in treatment with chemotherapy for premenopausal patients with breast cancer reduces the risk of POI, which promotes the recovery of ovarian function. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02518191.
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Affiliation(s)
- Xiangyun Zong
- Department of Breast Surgery, Shanghai Jiao Tong University Affiliated Shanghai Sixth People’s Hospital, Shanghai, China
| | - Yang Yu
- Cancer Hospital of the University of Chinese Academy of Science (Zhejiang Cancer Hospital), Hangzhou, China
| | - Hongjian Yang
- Cancer Hospital of the University of Chinese Academy of Science (Zhejiang Cancer Hospital), Hangzhou, China
| | - Wenhu Chen
- Cancer Hospital of the University of Chinese Academy of Science (Zhejiang Cancer Hospital), Hangzhou, China
| | - Xiaowen Ding
- Cancer Hospital of the University of Chinese Academy of Science (Zhejiang Cancer Hospital), Hangzhou, China
| | - Sixuan Liu
- Department of Breast Surgery, Shanghai Jiao Tong University Affiliated Shanghai Sixth People’s Hospital, Shanghai, China
| | - Xiaolin Li
- Department of Breast Surgery, Shanghai Jiao Tong University Affiliated Shanghai Sixth People’s Hospital, Shanghai, China,Cancer Hospital of the University of Chinese Academy of Science (Zhejiang Cancer Hospital), Hangzhou, China
| | - Xuan Chen
- Department of Breast Surgery, Shanghai Jiao Tong University Affiliated Shanghai Sixth People’s Hospital, Shanghai, China
| | - Chuner Jiang
- Cancer Hospital of the University of Chinese Academy of Science (Zhejiang Cancer Hospital), Hangzhou, China
| | - Xianghou Xia
- Cancer Hospital of the University of Chinese Academy of Science (Zhejiang Cancer Hospital), Hangzhou, China
| | - Run Huang
- Department of Breast Surgery, Shanghai Jiao Tong University Affiliated Shanghai Sixth People’s Hospital, Shanghai, China
| | - Meizhen Zhu
- Cancer Hospital of the University of Chinese Academy of Science (Zhejiang Cancer Hospital), Hangzhou, China
| | - Jiejie Hu
- Cancer Hospital of the University of Chinese Academy of Science (Zhejiang Cancer Hospital), Hangzhou, China
| | - Chenlu Liang
- Cancer Hospital of the University of Chinese Academy of Science (Zhejiang Cancer Hospital), Hangzhou, China
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Wu C, Wu T, Chen D, Wei S, Tang W, Xue L, Xiong J, Huang Y, Guo Y, Chen Y, Wu M, Wang S. The effects and mechanism of taxanes on chemotherapy-associated ovarian damage: A review of current evidence. Front Endocrinol (Lausanne) 2022; 13:1025018. [PMID: 36531475 PMCID: PMC9756165 DOI: 10.3389/fendo.2022.1025018] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 11/09/2022] [Indexed: 11/25/2022] Open
Abstract
Chemotherapy is often a cause of premature ovarian insufficiency and infertility since the ovarian follicles are extremely sensitive to the effects of chemotherapeutic agents. Different chemotherapeutic agents with varying mechanisms of action may damage ovarian function differently. Taxanes are widely used in clinical cancer treatment, but the specific reproductive toxicological information is still controversial. This review described the impact and duration of taxanes on ovarian function in women and analyzed the possible reasons for different conclusions. Furthermore, the toxicity of taxanes on ovarian function and its possible mechanisms were discussed. The potential protective strategies and agents against ovarian damage induced by taxanes are also reviewed.
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Affiliation(s)
- Chuqing Wu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
| | - Tong Wu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
| | - Dan Chen
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
| | - Simin Wei
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
| | - Weicheng Tang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
| | - Liru Xue
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
| | - Jiaqiang Xiong
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Yibao Huang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
| | - Yican Guo
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
| | - Ying Chen
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
| | - Meng Wu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
- *Correspondence: Shixuan Wang, ; Meng Wu,
| | - Shixuan Wang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
- *Correspondence: Shixuan Wang, ; Meng Wu,
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24
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Lambertini M, Boni L, Michelotti A, Magnolfi E, Cogoni AA, Mosconi AM, Giordano M, Garrone O, Arpino G, Poggio F, Cinacchi P, Bighin C, Fregatti P, Pronzato P, Blondeaux E, Del Mastro L. Long-Term Outcomes with Pharmacological Ovarian Suppression during Chemotherapy in Premenopausal Early Breast Cancer Patients. J Natl Cancer Inst 2021; 114:400-408. [PMID: 34850043 DOI: 10.1093/jnci/djab213] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 07/26/2021] [Accepted: 09/27/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Although use of gonadotropin-releasing hormone agonist (GnRHa) during chemotherapy is an established strategy to protect ovarian function in premenopausal breast cancer patients, no long-term safety data are available raising some concerns in women with hormone receptor-positive disease. There are controversial data on its fertility preservation potential. METHODS The PROMISE-GIM6 is a multicenter, randomized, open-label, phase III superiority trial conducted at 16 Italian centers from October 2003 to January 2008. Eligible patients were randomized to (neo)adjuvant chemotherapy alone (control arm) or combined with the GnRHa triptorelin (GnRHa arm). Primary planned endpoint was incidence of chemotherapy-induced premature ovarian insufficiency (POI). Post-hoc endpoints were disease-free survival (DFS), overall survival (OS), and post-treatment pregnancies. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. RESULTS Of 281 randomized patients, 80.4% had hormone receptor-positive breast cancer. Median follow-up was 12.4 years (interquartile range = 11.3-13.2 years). No differences in 12-year DFS (65.7% [95% CI = 57.0% to 73.1%] in GnRHa arm vs. 69.2% [95% CI = 60.3% to 76.5%] in control arm; HR = 1.16, 95% CI = 0.76 to 1.77) nor in 12-year OS (81.2% [95% CI = 73.6% to 86.8%] in GnRHa arm vs. 81.3% [95% CI = 73.1% to 87.2%] in control arm; HR = 1.17, 95% CI = 0.67 to 2.03) were observed. In patients with hormone receptor-positive disease, the HR was 1.02 (95% CI = 0.63 to 1.63) for DFS and 1.12 (95% CI = 0.59 to 2.11) for OS. In the GnRHa and control arms, 9 and 4 patients had a post-treatment pregnancy, respectively (HR = 2.14, 95% CI = 0.66 to 6.92). CONCLUSIONS Final analysis of the PROMISE-GIM6 trial provides reassuring results on the safety of GnRHa use during chemotherapy as a strategy to preserve ovarian function in premenopausal patients with early breast cancer, including those with hormone receptor-positive disease.
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Affiliation(s)
- Matteo Lambertini
- Department of Medical Oncology, Breast Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy.,Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Genova, Italy
| | - Luca Boni
- Clinical Trial Center, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Andrea Michelotti
- UO Oncologia Medica I, Ospedale S. Chiara, Dipartimento di oncologia, dei trapianti e delle nuove tecnologie, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
| | | | | | - Anna Maria Mosconi
- S.C. Oncologia Medica, Ospedale Santa Maria della Misericordia, Perugia, Italy
| | | | - Ornella Garrone
- Dipartimento di Oncologia, Ospedale di Insegnamento S. Croce e Carle, Cuneo, Italy
| | - Grazia Arpino
- Department of Medical Oncology, Università di Napoli Federico II, Napoli, Italy
| | - Francesca Poggio
- Department of Medical Oncology, IRCCS Ospedale Policlinico San Martino, Genova, U.O. Oncologia Medica 2, Italy
| | - Paola Cinacchi
- UO Oncologia Medica I, Ospedale S. Chiara, Dipartimento di oncologia, dei trapianti e delle nuove tecnologie, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
| | - Claudia Bighin
- Department of Medical Oncology, IRCCS Ospedale Policlinico San Martino, Genova, U.O. Oncologia Medica 2, Italy
| | - Piero Fregatti
- Department of Surgery, U.O.C. Clinica di Chirurgia Senologica, IRCCS Ospedale Policlinico San Martino, Genova, Italy.,Department of Integrated Diagnostic Surgical Sciences, School of Medicine, University of Genova, Genova, Italy
| | - Paolo Pronzato
- Department of Medical Oncology, IRCCS Ospedale Policlinico San Martino, Genova, U.O. Oncologia Medica 2, Italy
| | - Eva Blondeaux
- Department of Medical Oncology, IRCCS Ospedale Policlinico San Martino, Genova, U.O. Oncologia Medica 2, Italy
| | - Lucia Del Mastro
- Department of Medical Oncology, Breast Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy.,Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Genova, Italy
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25
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Odeh OM, Awwad J, Khalife D, Ghunaim S. The use of GnRH analogs in preserving ovarian function during chemotherapy. MIDDLE EAST FERTILITY SOCIETY JOURNAL 2021. [DOI: 10.1186/s43043-021-00088-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
The literature has always been controversial on the use of gonadotropin-releasing hormone agonists in preserving fertility in women of childbearing age after chemotherapy; thereby, in this article, we will be discussing its use in preserving fertility.
Main body of abstract
When it comes to preserving fertility, it is crucial to consider all available options in this topic due to its very sensitive nature, thereby we have found that while a lot of trials favor the use of gonadotropin-releasing hormone agonists, the lack of proper follow-up and long-term trials renders its use highly debatable, and since the longest follow-up trial showed non-significant results, it also opens the floor for debate on whether this short-term benefit is worth adding another drug to the regimen or not.
Short conclusion
As described in this review, while the use of gonadotropin-releasing hormone agonists is beneficial in a lot of studies, the lack of long-term reports still makes its use debatable, thereby more trials should be done.
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Lu YS, Wong A, Kim HJ. Ovarian Function Suppression With Luteinizing Hormone-Releasing Hormone Agonists for the Treatment of Hormone Receptor-Positive Early Breast Cancer in Premenopausal Women. Front Oncol 2021; 11:700722. [PMID: 34595110 PMCID: PMC8477635 DOI: 10.3389/fonc.2021.700722] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 08/04/2021] [Indexed: 01/08/2023] Open
Abstract
Chemotherapy and endocrine therapies are mainstays of treatment for early and advanced hormone receptor-positive (HR+) breast cancer. In premenopausal women with HR+ tumors, the benefits of adding ovarian function suppression (OFS) to endocrine therapy have been debated. Consequently, for many years, tamoxifen monotherapy has been the standard of care for endocrine treatment in the adjuvant setting. Recent studies have, however, provided new evidence that, in some premenopausal patients, OFS in combination with tamoxifen or aromatase inhibitors (AIs) can significantly increase survival versus tamoxifen alone. Luteinizing hormone-releasing hormone agonists (LHRHa), including goserelin, triptorelin, and leuprorelin, achieve OFS through sustained suppression of the release of follicle-stimulating hormone and luteinizing hormone from the pituitary. In turn, this suppresses production and secretion of estradiol, an ovarian hormone that supports cancer cell growth, survival, and proliferation. In this review, we discuss the clinical evidence supporting the addition of LHRHa to adjuvant endocrine therapies, including tamoxifen and AIs, for premenopausal women with breast cancer. We also discuss the role of LHRHa use in combination with adjuvant chemotherapy to preserve ovarian function and fertility in young patients with breast cancer. Finally, we discuss important practical aspects of the use of LHRHa in breast cancer treatment, including side-effects, patient adherence to treatment, and the use of slow-release, long-acting drug formulations.
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Affiliation(s)
- Yen-Shen Lu
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Andrea Wong
- Department of Haematology-Oncology, Cancer Science Institute, National University of Singapore, Singapore, Singapore
| | - Hee-Jeong Kim
- Department of Surgery, College of Medicine, Asan Medical Center, Seoul, South Korea
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Lei YY, Yeo W. The risk of menopausal symptoms in premenopausal breast cancer patients and current pharmacological prevention strategies. Expert Opin Drug Saf 2021; 20:1163-1175. [PMID: 33951990 DOI: 10.1080/14740338.2021.1926980] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 05/04/2021] [Indexed: 10/21/2022]
Abstract
Introduction: For young premenopausal breast cancer (BC) patients, adjuvant chemotherapy and other anti-cancer treatments can increase the risk of menopausal symptoms and may cause chemotherapy-related amenorrhea (CRA), infertility and premature ovarian insufficiency (POI).Areas covered: In this report, menopausal symptoms related to anti-cancer treatment are described. Menstrual disturbances associated with the use of adjuvant chemotherapy, endocrine therapy, and targeted therapy against human epidermal growth factor receptor 2 (HER2) in premenopausal women withBC are discussed. To prevent menopausal symptoms, CRA and POI, data on the efficacy of temporary ovarian suppression with gonadotropin-releasing hormone analogues (GnRHa) during chemotherapy are highlighted. Pooled analyses have confirmed that concurrent administration of GnRHa during chemotherapy could significantly reduce the risk of developing chemotherapy-induced POI in premenopausal women with early-stageBC. In addition, reports have suggested that embryo/oocyte cryopreservation may increase the chance of pregnancy after the diagnosis ofBC, although such data remain limited.Expert opinion: Commonly experienced by pre-menopausal women withBC, anti-cancer treatment could cause severe menopausal symptoms. Temporary ovarian suppression with GnRHa during chemotherapy provided asafe and efficient strategy to reduce the likelihood of chemotherapy-induced POI in premenopausal patients with early-stageBC undergoing (neo)-adjuvant chemotherapy.
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Affiliation(s)
- Yuan-Yuan Lei
- Department of Clinical Oncology, Prince of Wales Hospital, the Chinese University of Hong Kong, New Territories, Hong Kong SAR, China
| | - Winnie Yeo
- Department of Clinical Oncology, Prince of Wales Hospital, the Chinese University of Hong Kong, New Territories, Hong Kong SAR, China
- Hong Kong Cancer Institute, State Key Laboratory in Oncology in South China, Faculty of Medicine, The Chinese University of Hong Kong, New Territories, Hong Kong SAR, China
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Arecco L, Ruelle T, Martelli V, Boutros A, Latocca MM, Spinaci S, Marrocco C, Massarotti C, Lambertini M. How to Protect Ovarian Function before and during Chemotherapy? J Clin Med 2021; 10:jcm10184192. [PMID: 34575299 PMCID: PMC8467797 DOI: 10.3390/jcm10184192] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 08/29/2021] [Accepted: 09/03/2021] [Indexed: 12/22/2022] Open
Abstract
A significant number of women receive a cancer diagnosis before their age of natural menopause. Among these patients, the most frequent neoplasms are breast cancer, gynecological, and hematological malignancies. Premature ovarian insufficiency and infertility are among the most feared short- to long-term consequences of anticancer treatments in premenopausal patients. Both patient- and treatment-related characteristics are key factors in influencing the risk of gonadotoxicity with the use of chemotherapy. The cryopreservation of oocytes/embryos is a standard strategy for fertility preservations offered to young women interested in future family planning, but it does not allow gonadal function protection during chemotherapy. Ovarian suppression with gonadotropin-releasing hormone agonist (GnRHa) during chemotherapy is now recommended as an option to reduce the risk of gonadotoxicity in order to avoid the negative consequences of premature ovarian insufficiency in premenopausal women receiving cytotoxic therapy, including those not interested in fertility preservation. This review summarizes the risk of treatment-induced gonadotoxicity in premenopausal patients and the evidence available on the protective role of administering GnRHa during chemotherapy to preserve ovarian function.
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Affiliation(s)
- Luca Arecco
- U.O. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (L.A.); (M.M.L.); (C.M.)
- Department of Internal Medicine and Medical Sciences (DiMI), School of Medicine, University of Genova, 16132 Genova, Italy; (T.R.); (V.M.); (A.B.)
| | - Tommaso Ruelle
- Department of Internal Medicine and Medical Sciences (DiMI), School of Medicine, University of Genova, 16132 Genova, Italy; (T.R.); (V.M.); (A.B.)
- U.O. Oncologia Medica 2, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy
| | - Valentino Martelli
- Department of Internal Medicine and Medical Sciences (DiMI), School of Medicine, University of Genova, 16132 Genova, Italy; (T.R.); (V.M.); (A.B.)
- U.O. Oncologia Medica 1, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy
| | - Andrea Boutros
- Department of Internal Medicine and Medical Sciences (DiMI), School of Medicine, University of Genova, 16132 Genova, Italy; (T.R.); (V.M.); (A.B.)
- U.O. Oncologia Medica 2, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy
| | - Maria Maddalena Latocca
- U.O. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (L.A.); (M.M.L.); (C.M.)
- Department of Internal Medicine and Medical Sciences (DiMI), School of Medicine, University of Genova, 16132 Genova, Italy; (T.R.); (V.M.); (A.B.)
| | - Stefano Spinaci
- Division of Breast Surgery, Ospedale Villa Scassi ASL3, 16149 Genova, Italy;
| | - Camilla Marrocco
- U.O. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (L.A.); (M.M.L.); (C.M.)
| | - Claudia Massarotti
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), School of Medicine, University of Genova, 16132 Genova, Italy;
- Academic Unit of Obstetrics and Gynaecology, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy
| | - Matteo Lambertini
- U.O. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (L.A.); (M.M.L.); (C.M.)
- Department of Internal Medicine and Medical Sciences (DiMI), School of Medicine, University of Genova, 16132 Genova, Italy; (T.R.); (V.M.); (A.B.)
- Correspondence: ; Tel.: +39-010-555-4254; Fax: +39-010-555-6536
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Hong L, Yan L, Xin Z, Hao J, Liu W, Wang S, Liao S, Wang H, Yang X. Protective effects of human umbilical cord mesenchymal stem cell-derived conditioned medium on ovarian damage. J Mol Cell Biol 2021; 12:372-385. [PMID: 31742349 PMCID: PMC7288746 DOI: 10.1093/jmcb/mjz105] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2019] [Revised: 08/31/2019] [Accepted: 09/15/2019] [Indexed: 02/06/2023] Open
Abstract
Chemotherapeutic agents are extensively used to treat malignancies. However, chemotherapy-induced ovarian damage and reduced fertility are severe side effects. Recently, stem cell transplantation has been reported to be an effective strategy for premature ovarian insufficiency (POI) treatment, but safety can still be an issue in stem cell-based therapy. Here, we show the protective effects of human umbilical cord mesenchymal stem cell-derived conditioned medium (hUCMSC-CM) on a cisplatin (Cs)-induced ovarian injury model. hUCMSC-CM can relieve Cs-induced depletion of follicles and preserve fertility. In addition, hUCMSC-CM can decrease apoptosis of oocytes and granulosa cells induced by Cs. RNA sequencing analysis reveals the differentially expressed genes of ovaries after Cs and hUCMSC-CM treatments, including genes involved in cell apoptosis. Furthermore, we show that the granulocyte colony-stimulating factor (G-CSF)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway plays an important role in protecting granulosa cells from Cs-induced apoptosis. Together, we confirm the protective effects of hUCMSC-CM on ovarian reserve and fertility in mice treated with Cs, highlighting the remarkable therapeutic effects of hUCMSC-CM.
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Affiliation(s)
- Liming Hong
- Department of Human Reproductive Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, China
| | - Long Yan
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Zhimin Xin
- Department of Human Reproductive Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, China
| | - Jie Hao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Wenjing Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Shuyu Wang
- Department of Human Reproductive Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, China
| | - Shujie Liao
- Department of Gynaecology and Obstetrics, Reproductive Medical Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Hongmei Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Xiaokui Yang
- Department of Human Reproductive Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, China
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Song Y, Liu H. A review on the relationship between anti-mullerian hormone and fertility in treating young breast cancer patients. BMC WOMENS HEALTH 2021; 21:295. [PMID: 34376160 PMCID: PMC8353739 DOI: 10.1186/s12905-021-01420-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 07/06/2021] [Indexed: 11/18/2022]
Abstract
Despite the fact that the long-term survival rate of breast cancer patients had been significantly improved owing to the systemic breast cancer therapies, there are still some side effects such as amenorrhea and fertility retention to be resolved, leaving it an important thing to understand the possible side effects on fertility and fertility preservation strategies while undergoing breast cancer treatment, due to the fact that most young patients hope to become pregnant and have children after breast cancer treatment. With anti-müllerian hormone (AMH) being the most sensitive marker for predicting ovarian function in young premenopausal women with breast cancer, this review is aimed to provide the additional guidance for clinical application of AMH by exploring the impacts of AMH on the fertility of young breast cancer patients, the relationship between AMH and metabolism, and the relationship between BRAC gene mutation and fertility protection strategies.
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Affiliation(s)
- Yixuan Song
- The Second Surgical Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Hong Liu
- The Second Surgical Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
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Kim S, Kim SW, Han SJ, Lee S, Park HT, Song JY, Kim T. Molecular Mechanism and Prevention Strategy of Chemotherapy- and Radiotherapy-Induced Ovarian Damage. Int J Mol Sci 2021; 22:ijms22147484. [PMID: 34299104 PMCID: PMC8305189 DOI: 10.3390/ijms22147484] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 07/12/2021] [Indexed: 12/14/2022] Open
Abstract
Fertility preservation is an emerging discipline, which is of substantial clinical value in the care of young patients with cancer. Chemotherapy and radiation may induce ovarian damage in prepubertal girls and young women. Although many studies have explored the mechanisms implicated in ovarian toxicity during cancer treatment, its molecular pathophysiology is not fully understood. Chemotherapy may accelerate follicular apoptosis and follicle reservoir utilization and damage the ovarian stroma via multiple molecular reactions. Oxidative stress and the radiosensitivity of oocytes are the main causes of gonadal damage after radiation treatment. Fertility preservation options can be differentiated by patient age, desire for conception, treatment regimen, socioeconomic status, and treatment duration. This review will help highlight the importance of multidisciplinary oncofertility strategies for providing high-quality care to young female cancer patients.
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Affiliation(s)
- Seongmin Kim
- Gynecologic Cancer Center, CHA Ilsan Medical Center, CHA University College of Medicine, 1205 Jungang-ro, Ilsandong-gu, Goyang-si 10414, Korea;
| | - Sung-Woo Kim
- Department of Obstetrics and Gynecology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea; (S.-W.K.); (S.-J.H.)
| | - Soo-Jin Han
- Department of Obstetrics and Gynecology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea; (S.-W.K.); (S.-J.H.)
| | - Sanghoon Lee
- Department of Obstetrics and Gynecology, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, Korea; (H.-T.P.); (J.-Y.S.); (T.K.)
- Correspondence: ; Tel.: +82-2-920-6773
| | - Hyun-Tae Park
- Department of Obstetrics and Gynecology, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, Korea; (H.-T.P.); (J.-Y.S.); (T.K.)
| | - Jae-Yun Song
- Department of Obstetrics and Gynecology, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, Korea; (H.-T.P.); (J.-Y.S.); (T.K.)
| | - Tak Kim
- Department of Obstetrics and Gynecology, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, Korea; (H.-T.P.); (J.-Y.S.); (T.K.)
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Blondeaux E, Massarotti C, Fontana V, Poggio F, Arecco L, Fregatti P, Bighin C, Giannubilo I, Ruelle T, Razeti MG, Boni L, Anserini P, Del Mastro L, Lambertini M. The PREgnancy and FERtility (PREFER) Study Investigating the Need for Ovarian Function and/or Fertility Preservation Strategies in Premenopausal Women With Early Breast Cancer. Front Oncol 2021; 11:690320. [PMID: 34150661 PMCID: PMC8210666 DOI: 10.3389/fonc.2021.690320] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 04/26/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Offering ovarian function and/or fertility preservation strategies in premenopausal women with newly diagnosed breast cancer candidates to undergo chemotherapy is standard of care. However, few data are available on uptake and main reasons for refusing these options. METHODS The PREFER study (NCT02895165) is an observational, prospective study enrolling premenopausal women with early breast cancer, aged between 18 and 45 years, candidates to receive (neo)adjuvant chemotherapy. Primary objective is to collect information on acceptance rates and reasons for refusal of the proposed strategies for ovarian function and/or fertility preservation available in Italy. RESULTS At the study coordinating center, 223 patients were recruited between November 2012 and December 2020. Median age was 38 years (range 24 - 45 years) with 159 patients (71.3%) diagnosed at ≤40 years. Temporary ovarian suppression with gonadotropin-releasing hormone agonists (GnRHa) was accepted by 58 out of 64 (90.6%) patients aged 41-45 years and by 151 out of 159 (95.0%) of those aged ≤40 years. Among patients aged ≤40 years, 57 (35.8%) accepted to access the fertility unit to receive a complete oncofertility counseling and 29 (18.2%) accepted to undergo a cryopreservation technique. Main reasons for refusal were fear of delaying the initiation of antineoplastic treatments and contraindications to the procedure or lack of interest in future childbearing. Patients with hormone-receptor positive breast cancer had a tendency for a higher acceptance rates of ovarian function and/or fertility preservation strategies than those with hormone-receptor negative disease. CONCLUSIONS More than 90% of premenopausal women with early breast cancer, and particularly those with hormone receptor-positive disease, were concerned about the potential risk of chemotherapy-induced premature ovarian insufficiency and/or infertility and accepted GnRHa administration. Less than 1 out of 5 women aged ≤40 years accepted to undergo cryopreservation strategies.
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Affiliation(s)
- Eva Blondeaux
- Department of Internal Medicine and Medical Sciences (DiMI), School of Medicine, University of Genova, Genova, Italy
- Breast Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Claudia Massarotti
- Physiopathology of Human Reproduction Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Valeria Fontana
- Clinical Epidemiology Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Francesca Poggio
- Breast Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Luca Arecco
- Department of Medical Oncology, U.O. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Piero Fregatti
- U.O.C. Clinica di Chirurgia Senologica, Department of Surgery, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Claudia Bighin
- U.O.C. Oncologia Medica 2, Department of Medical Oncology, Ospedale Policlinico San Martino, Genova, Italy
| | - Irene Giannubilo
- Breast Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Tommaso Ruelle
- Breast Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Maria Grazia Razeti
- Department of Medical Oncology, U.O. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Luca Boni
- Clinical Epidemiology Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Paola Anserini
- Physiopathology of Human Reproduction Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Lucia Del Mastro
- Department of Internal Medicine and Medical Sciences (DiMI), School of Medicine, University of Genova, Genova, Italy
- Breast Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Matteo Lambertini
- Department of Internal Medicine and Medical Sciences (DiMI), School of Medicine, University of Genova, Genova, Italy
- Department of Medical Oncology, U.O. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy
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Brancati S, Gozzo L, Longo L, Vitale DC, Russo G, Drago F. Fertility Preservation in Female Pediatric Patients With Cancer: A Clinical and Regulatory Issue. Front Oncol 2021; 11:641450. [PMID: 33796467 PMCID: PMC8008167 DOI: 10.3389/fonc.2021.641450] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 01/29/2021] [Indexed: 12/22/2022] Open
Abstract
Fertility preservation represents one important goal of cancer patients’ management due to the high impact on health and quality of life of survivors. The available preventive measures cannot be performed in all patients and are not feasible in all health-care facilities. Therefore, the pharmacological treatment with GnRHa has become a valuable non-invasive and well-tolerated alternative, especially in those who cannot access to cryopreservation options due to clinical and/or logistic issues. Supporting data demonstrate a significant advantage for the survivors who received GnRHa in the long-term maintenance of ovarian function and preservation of fertility. The prevention of the risk of ovarian failure with GnRHa is a typical off-label use, defined as the administration of a medicinal product not in accordance with the authorized product information. Italy has officially recognized the off-label use of GnRHa in adult women at risk of premature and permanent menopause following chemotherapy. However, fertility preservation still represents an unmet medical need in adolescents who cannot access to other treatment options.
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Affiliation(s)
- Serena Brancati
- Clinical Pharmacology Unit/Regional Pharmacovigilance Centre, University Hospital of Catania, Catania, Italy
| | - Lucia Gozzo
- Clinical Pharmacology Unit/Regional Pharmacovigilance Centre, University Hospital of Catania, Catania, Italy.,Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Laura Longo
- Clinical Pharmacology Unit/Regional Pharmacovigilance Centre, University Hospital of Catania, Catania, Italy
| | - Daniela Cristina Vitale
- Clinical Pharmacology Unit/Regional Pharmacovigilance Centre, University Hospital of Catania, Catania, Italy
| | - Giovanna Russo
- Pediatric Onco-Hematology, University Hospital of Catania, Catania, Italy
| | - Filippo Drago
- Clinical Pharmacology Unit/Regional Pharmacovigilance Centre, University Hospital of Catania, Catania, Italy.,Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.,Centre for Research and Consultancy in HTA and drug Regulatory Affairs (CERD), University of Catania, Catania, Italy
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Severe ovarian hyperstimulation syndrome associated with long-acting GnRH agonist in oncofertility patients. J Assist Reprod Genet 2021; 38:751-756. [PMID: 33471229 DOI: 10.1007/s10815-020-02051-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 12/28/2020] [Indexed: 10/22/2022] Open
Abstract
PURPOSE To report three cases of severe ovarian hyperstimulation syndrome (OHSS) among oncofertility patients receiving a long-acting GnRH agonist for ovarian suppression after controlled ovarian hyperstimulation (COH) with a GnRH antagonist protocol METHODS: Chart abstraction was completed for three patients at a single academic medical center. Patients included were undergoing fertility preservation prior to gonadotoxic chemotherapy. All patients underwent COH with GnRH antagonist protocol and embryo cryopreservation immediately followed by ovarian suppression with long-acting GnRH agonist. Main outcome measure was development of OHSS. RESULTS Despite using GnRH agonist trigger and freezing all embryos, patients developed ascites, intermittent hyponatremia and hemoconcentration consistent with severe early-onset OHSS after receiving long-acting GnRH agonist immediately following oocyte retrieval for ovarian preservation. CONCLUSIONS Risk of severe OHSS may be increased when a long-acting GnRH agonist is used for ovarian suppression immediately following oocyte retrieval. A delay in initiating long-acting GnRH agonist after oocyte retrieval in patients at high risk for developing OHSS should be considered.
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Jin Z, Griffith MA, Rosenthal AC. Identifying and Meeting the Needs of Adolescents and Young Adults with Cancer. Curr Oncol Rep 2021; 23:17. [PMID: 33449203 DOI: 10.1007/s11912-020-01011-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/17/2020] [Indexed: 12/24/2022]
Abstract
PURPOSE OF REVIEW Adolescents and young adults (AYAs) with cancer are a vulnerable population with unique needs that are under-recognized and often overlooked by healthcare providers. This review focuses on identifying and meeting some of those needs including adherence to treatment, financial implications, impact on fertility and intimacy, issues with work/school, isolation, challenges with re-entry, and long-term side effects and survivorship. RECENT FINDINGS Survival rates have not improved in adolescents and young adults with cancer at the same rate as in children and older adults (the so called "AYA gap"). Restricted or delayed access to care and inconsistent cancer treatment and follow-up care contribute to this. Importantly, fertility preservation options have broadened and efforts to provide age appropriate counseling prior to treatment have improved. Additionally, AYAs face a variety of psychosocial issues while dealing with a cancer diagnosis during critical developmental years, and yet data pertaining to the successful identification and management of these issues is lacking. As a result, there has been recent increasing awareness that this patient population warrants strong advocates, additional research, and requires age group specific resources to be successful in navigating their cancer experience during treatment and into survivorship care. Members of the healthcare team should familiarize themselves with the unique needs of AYA cancer patients to provide optimal patient care. In order to build upon early progress, this group calls for additional study particularly when it comes to barriers to enrollment for AYA-specific research (including clinical trials), recognizing psychosocial needs (both during and after treatment), transition planning for returning to life after cancer, and managing long-term effects of treatment (including neuro cognitive changes). In addition, access to financial resources and appropriate mental health support needs to be improved.
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Affiliation(s)
- Zhaohui Jin
- Division of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
| | - Melody A Griffith
- Division of Hematology/Oncology, Mayo Clinic, Phoenix, AZ, 85054, USA
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Michalczyk K, Cymbaluk-Płoska A. Fertility Preservation and Long-Term Monitoring of Gonadotoxicity in Girls, Adolescents and Young Adults Undergoing Cancer Treatment. Cancers (Basel) 2021; 13:E202. [PMID: 33429908 PMCID: PMC7827074 DOI: 10.3390/cancers13020202] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 01/03/2021] [Accepted: 01/07/2021] [Indexed: 11/23/2022] Open
Abstract
Chemo- and radio-therapy can often affect reproductive organs impairing hormonal regulation, fertility, and sexual function. As cancer treatments become more effective and many patients have long term survival, concerns related to patient's quality of life and reproductive health become relevant. It is especially important for girls and young females facing cancer therapy who have not yet started family planning. Chemotherapy protocols using alkylating agents and abdominal radiotherapy, which are frequently used in the treatment of childhood and adolescent cancer, can cause gonadal injury. The most common clinical manifests are ovarian hormone insufficiency, premature ovarian insufficiency, early menopause and infertility. In this review we assess current literature and summarize current recommendations on the reproductive function of girls and young females undergoing cancer treatment and their follow-up. Fertility preservation methods are discussed, including psychological and ethical considerations and barriers. Improvement of reproductive health and quality of life of adolescents and young adults (AYA) undergoing cancer treatment is an important issue. Further research should be continued to develop efficient and accessible methods for fertility preservation in young patients. An expert panel including oncologists, radiation oncologists, endocrinologists and gynecologists should always consider fertility preservation in pediatric, adolescent and AYA cancer patients, minding patients' medical condition, cancer staging and potential risk of treatment-related gonadotoxicity.
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Affiliation(s)
- Kaja Michalczyk
- Department of Gynecological Surgery and Oncology of Adults and Adolescents, Pomeranian Medical University, al. Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland;
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Qu J, Li Y, Liao S, Yan J. The Effects of Negative Elements in Environment and Cancer on Female Reproductive System. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1300:283-313. [PMID: 33523439 DOI: 10.1007/978-981-33-4187-6_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
With the development of human society, factors that contribute to the impairment of female fertility is accumulating. Lifestyle-related risk factors, occupational risk factors, and iatrogenic factors, including cancer and anti-cancer treatments, have been recognized with their negative effects on the function of female reproductive system. However, the exact influences and their possible mechanism have not been elucidated yet. It is impossible to accurately estimate the indexes of female fertility, but many researchers have put forward that the general fertility has inclined through the past decades. Thus the demand for fertility preservation has increased more and more dramatically. Here we described some of the factors which may influence female reproductive system and methods for fertility preservation in response to female infertility.
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Affiliation(s)
- Jiangxue Qu
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
| | - Yuehan Li
- Department of Gynaecology and Obstetrics, Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shujie Liao
- Department of Gynaecology and Obstetrics, Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
| | - Jie Yan
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.
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Blondeaux E, Massarotti C, Fontana V, Poggio F, Arecco L, Fregatti P, Bighin C, Giannubilo I, Ruelle T, Razeti MG, Boni L, Anserini P, Del Mastro L, Lambertini M. The PREgnancy and FERtility (PREFER) Study Investigating the Need for Ovarian Function and/or Fertility Preservation Strategies in Premenopausal Women With Early Breast Cancer. Front Oncol 2021. [PMID: 34150661 DOI: 10.3389/fonc.2021.690320/full] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2023] Open
Abstract
BACKGROUND Offering ovarian function and/or fertility preservation strategies in premenopausal women with newly diagnosed breast cancer candidates to undergo chemotherapy is standard of care. However, few data are available on uptake and main reasons for refusing these options. METHODS The PREFER study (NCT02895165) is an observational, prospective study enrolling premenopausal women with early breast cancer, aged between 18 and 45 years, candidates to receive (neo)adjuvant chemotherapy. Primary objective is to collect information on acceptance rates and reasons for refusal of the proposed strategies for ovarian function and/or fertility preservation available in Italy. RESULTS At the study coordinating center, 223 patients were recruited between November 2012 and December 2020. Median age was 38 years (range 24 - 45 years) with 159 patients (71.3%) diagnosed at ≤40 years. Temporary ovarian suppression with gonadotropin-releasing hormone agonists (GnRHa) was accepted by 58 out of 64 (90.6%) patients aged 41-45 years and by 151 out of 159 (95.0%) of those aged ≤40 years. Among patients aged ≤40 years, 57 (35.8%) accepted to access the fertility unit to receive a complete oncofertility counseling and 29 (18.2%) accepted to undergo a cryopreservation technique. Main reasons for refusal were fear of delaying the initiation of antineoplastic treatments and contraindications to the procedure or lack of interest in future childbearing. Patients with hormone-receptor positive breast cancer had a tendency for a higher acceptance rates of ovarian function and/or fertility preservation strategies than those with hormone-receptor negative disease. CONCLUSIONS More than 90% of premenopausal women with early breast cancer, and particularly those with hormone receptor-positive disease, were concerned about the potential risk of chemotherapy-induced premature ovarian insufficiency and/or infertility and accepted GnRHa administration. Less than 1 out of 5 women aged ≤40 years accepted to undergo cryopreservation strategies.
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Affiliation(s)
- Eva Blondeaux
- Department of Internal Medicine and Medical Sciences (DiMI), School of Medicine, University of Genova, Genova, Italy
- Breast Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Claudia Massarotti
- Physiopathology of Human Reproduction Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Valeria Fontana
- Clinical Epidemiology Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Francesca Poggio
- Breast Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Luca Arecco
- Department of Medical Oncology, U.O. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Piero Fregatti
- U.O.C. Clinica di Chirurgia Senologica, Department of Surgery, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Claudia Bighin
- U.O.C. Oncologia Medica 2, Department of Medical Oncology, Ospedale Policlinico San Martino, Genova, Italy
| | - Irene Giannubilo
- Breast Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Tommaso Ruelle
- Breast Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Maria Grazia Razeti
- Department of Medical Oncology, U.O. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Luca Boni
- Clinical Epidemiology Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Paola Anserini
- Physiopathology of Human Reproduction Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Lucia Del Mastro
- Department of Internal Medicine and Medical Sciences (DiMI), School of Medicine, University of Genova, Genova, Italy
- Breast Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Matteo Lambertini
- Department of Internal Medicine and Medical Sciences (DiMI), School of Medicine, University of Genova, Genova, Italy
- Department of Medical Oncology, U.O. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy
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Cho HW, Lee S, Min KJ, Hong JH, Song JY, Lee JK, Lee NW, Kim T. Advances in the Treatment and Prevention of Chemotherapy-Induced Ovarian Toxicity. Int J Mol Sci 2020; 21:E7792. [PMID: 33096794 PMCID: PMC7589665 DOI: 10.3390/ijms21207792] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 10/20/2020] [Indexed: 12/24/2022] Open
Abstract
Due to improvements in chemotherapeutic agents, cancer treatment efficacy and cancer patient survival rates have greatly improved, but unfortunately gonadal damage remains a major complication. Gonadotoxic chemotherapy, including alkylating agents during reproductive age, can lead to iatrogenic premature ovarian insufficiency (POI), and loss of fertility. In recent years, the demand for fertility preservation has increased dramatically among female cancer patients. Currently, embryo and oocyte cryopreservation are the only established options for fertility preservation in women. However, there is growing evidence for other experimental techniques including ovarian tissue cryopreservation, oocyte in vitro maturation, artificial ovaries, stem cell technologies, and ovarian suppression. To prevent fertility loss in women with cancer, individualized fertility preservation options including established and experimental techniques that take into consideration the patient's age, marital status, chemotherapy regimen, and the possibility of treatment delay should be provided. In addition, effective multidisciplinary oncofertility strategies that involve a highly skilled and experienced oncofertility team consisting of medical oncologists, gynecologists, reproductive biologists, surgical oncologists, patient care coordinators, and research scientists are necessary to provide cancer patients with high-quality care.
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Affiliation(s)
| | - Sanghoon Lee
- Department of Obstetrics and Gynecology, Korea University College of Medicine, Seoul 02841, Korea; (H.-W.C.); (K.-J.M.); (J.H.H.); (J.Y.S.); (J.K.L.); (N.W.L.); (T.K.)
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Mandelbaum RS, Klar M, Takiuchi T, Bainvoll L, Matsuzaki S, Paulson RJ, Matsuo K. Fertility-sparing treatment for early-stage epithelial ovarian cancer: Contemporary oncologic, reproductive and endocrinologic perspectives. J Obstet Gynaecol Res 2020; 46:1263-1281. [PMID: 32500605 DOI: 10.1111/jog.14302] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 04/21/2020] [Accepted: 04/30/2020] [Indexed: 12/11/2022]
Abstract
AIM Epithelial ovarian cancer (EOC) can be a devastating diagnosis in women of reproductive age who desire future fertility. However, in early-stage disease, fertility-sparing surgery (FSS) can be considered in appropriately selected patients. METHODS This is a narrative descriptive review of the recent literature on FSS for EOC from oncologic, reproductive and endocrinologic perspectives. RESULTS The recurrence rate following FSS performed for stage I EOC in published retrospective studies collectively is 13% but ranges from 5 to 29%, while mortality ranges from 0 to 18%. Five-year disease-free survival following FSS is over 90% but decreases with higher stage and grade. Recurrences following FSS are more likely to be localized with a more favorable prognosis compared to recurrences following radical surgery. Adjuvant chemotherapy is recommended in women with high-risk disease, and strategies to minimize gonadotoxicity during chemotherapy such as gonadotropin-releasing hormone (GnRH) agonists may be considered. Oocyte, embryo and/or ovarian cryopreservation can also be offered to patients desiring future biologic children. Reproductive outcomes following FSS, including pregnancy and miscarriage rates, resemble those of the general population, with a chance of successful pregnancy of nearly 80%. CONCLUSION In retrospective data, FSS appears to be oncologically safe in stage IA and IC grade 1-2 non-clear cell EOC. In patients with grade 3 tumors or clear cell histology, treatment can be individualized, weighing a slightly higher risk of recurrence with fertility goals. A multidisciplinary approach with oncology and reproductive endocrinology may be of utility to help these patients achieve their fertility goals.
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Affiliation(s)
- Rachel S Mandelbaum
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California, USA.,Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California, USA
| | - Maximilian Klar
- Department of Obstetrics and Gynecology, University of Freiburg, Freiburg, Germany
| | - Tsuyoshi Takiuchi
- Department of Obstetrics and Gynecology, Osaka University, Osaka, Japan
| | - Liat Bainvoll
- Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Shinya Matsuzaki
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California, USA
| | - Richard J Paulson
- Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California, USA
| | - Koji Matsuo
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California, USA.,Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA
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NSAS-BC02 substudy of chemotherapy-induced amenorrhea (CIA) in premenopausal patients who received either taxane alone or doxorubicin(A) cyclophosphamide(C) followed by taxane as postoperative chemotherapy. Breast Cancer Res Treat 2020; 182:325-332. [PMID: 32462261 DOI: 10.1007/s10549-020-05692-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Accepted: 05/13/2020] [Indexed: 01/07/2023]
Abstract
BACKGROUND Chemotherapy-induced amenorrhea (CIA) is one of the critical side effects from the chemotherapy in premenopausal patients with breast cancer. The goals of our study are the following: (1) to investigate the factors affecting the incidence of CIA; and (2) to evaluate the prognostic role of CIA in premenopausal patients with breast cancer. METHODS We conducted a post hoc retrospective substudy to examine the incidence of the CIA and the relationship between CIA and prognosis in NSAS-BC02 that compared taxane alone to Doxorubicin(A) Cyclophosphamide(C) followed by taxane in postoperative patients with node-positive breast cancer RESULTS: Of 395 premenopausal women, 287 (72.7%) had CIA due to protocol treatment. Regarding type of protocol regimen, proportion of CIA was 76.9% in AC Paclitaxel(P), 75.2% in AC Docetaxel(D), 62.8% in PTX, and 75.2% in DTX. Predictive factors of CIA were age increase by 5 years (OR 1.50), ER positivity (OR 2.08), and HER2 3 + ( OR 0.40) according to logistic regression analysis. According to the log rank test and the Cox proportional hazards model, CIA group had significantly better disease-free survival than non-CIA group (P < .0001). However, according to time-dependent Cox model that was used to reduce guarantee-time bias, CIA was not a statistically significant prognostic factor in both ER-positive and ER-negative patients. CONCLUSION Treatment with taxane alone caused high frequency of CIA in premenopausal women with breast cancer. CIA did not turn out to be an independent prognostic factor, taking guarantee-time bias into consideration. Further clinical studies are needed to validate these findings.
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Ghunaim S, Ghazeeri G, Khalife D, Azim HA. Fertility preservation in patients with BRCA mutation. Ecancermedicalscience 2020; 14:1033. [PMID: 32419845 PMCID: PMC7221131 DOI: 10.3332/ecancer.2020.1033] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Indexed: 12/27/2022] Open
Abstract
Evidence suggests a likely negative impact of deleterious BRCA mutations on female fertility. Hence, different studies have aimed to address the reproductive potential and performance of fertility preservation strategies in BRCA-mutated breast cancer patients with a prime focus on their safety and efficacy. However, several uncertainties exist in many domains of this field. The aim of the current paper is to overview the reproductive potential and fertility preservation options in breast and ovarian cancer patients harbouring a BRCA mutation. We also discuss pre-implantation genetic testing in an attempt to help physicians during oncofertility counselling of these patients.
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Affiliation(s)
- Suleiman Ghunaim
- Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Haifa Idriss-ART Unit, American University of Beirut Medical Center, PO Box 11-0236, Riad El Solh, Beirut 1107 2020, Lebanon
| | - Ghina Ghazeeri
- Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Haifa Idriss-ART Unit, American University of Beirut Medical Center, PO Box 11-0236, Riad El Solh, Beirut 1107 2020, Lebanon
| | - Dalia Khalife
- Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Haifa Idriss-ART Unit, American University of Beirut Medical Center, PO Box 11-0236, Riad El Solh, Beirut 1107 2020, Lebanon
| | - Hatem A Azim
- Breast Cancer Centre, Hospital Zambrano Hellion, Tecnologico de Monterrey, San Pedro Garza Garcia, Mexico
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Çelebi F, Ordu Ç, Ilgün S, Oztürk A, Erdoğan Iyigün Z, Alço G, Duymaz T, Aktepe F, Soybir G, Baysal B, Özmen V. The Effect of Systemic Chemotherapy on Ovarian Function: A Prospective Clinical Trial. Eur J Breast Health 2020; 16:177-182. [PMID: 32656517 DOI: 10.5152/ejbh.2020.5114] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 11/25/2019] [Indexed: 11/22/2022]
Abstract
Objective Premenopausal women with breast cancer are at risk of developing ovarian failure after chemotherapy. The aim of this study was to investigate the negative effects of systemic chemotherapy on ovarian function in premenoupausal women with breast cancer. Materials and Methods Thirty-one premenopausal women with operable breast cancer aged between 26-48 years were enrolled in this prospective cohort study to investigate preliminary results. Additional 69 patients' data will be included after the completion of all five measurements. The change in serum Antimullerian Hormone (AMH) levels, mean ovarian volumes (MOV) and antral follicle counts (AFCs) at 3-month intervals were recorded to evaluate ovarian function. Women who had at least one pretreatment and four post-treatment measurements in one year follow-up period were included in the study. Decision of chemotherapy regimen was taken by the Tumor Board. Results Thirty-one patients had all five AMH, MOV and AFCs results. There was a statistically significant negative correlation between 1st - 5th AMH levels (p=0.006) and 1st - 5th AFCs during the follow-up period (p<0.0001). However pre- and post-chemotherapy measurements of MOVs did not demonstrate any significant correlation (p=0.799). BMI, parity, lactation, histopathology and molecular subtypes of breast cancer, alcohol intake, smoking and type of chemotherapy regimen were not significantly correlated with AMH, AFC and MOV. Conclusion Pretreatment AMH levels and AFC were shown to have a significant role in early prediction of ovarian-reserve after chemotherapy.
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Affiliation(s)
- Filiz Çelebi
- Department of Radiology, Gayrettepe Florence Nightingale Hospital, İstanbul, Turkey
| | - Çetin Ordu
- Department of Oncology, Gayrettepe Florence Nightingale Hospital, İstanbul, Turkey
| | - Serkan Ilgün
- Department of General Surgery, Demiroğlu Bilim University School of Medicine, İstanbul, Turkey
| | - Alper Oztürk
- Department of General Surgery, Biruni University Hospital, İstanbul, Turkey
| | - Zeynep Erdoğan Iyigün
- Department of Physical Therapy and Rehabilitation, Demiroğlu Bilim University School of Medicine, İstanbul, Turkey
| | - Gül Alço
- Department of Radiation Oncology, Gayrettepe Florence Nightingale Hospital, İstanbul, Turkey
| | - Tomris Duymaz
- Department of Physical Therapy and Rehabilitation, Bilgi University, İstanbul, Turkey
| | - Fatma Aktepe
- Department of Pathology, Gayrettepe Florence Nightingale Hospital, İstanbul, Turkey
| | - Gürsel Soybir
- Department of General Surgery, Memorial Etiler Hospital, İstanbul, Turkey
| | - Bülent Baysal
- Department of Obstetrics and Gynecology, İstanbul Florence Nightingale Hospital, İstanbul, Turkey
| | - Vahit Özmen
- Department of General Surgery, İstanbul Florence Nightingale Hospital, İstanbul, Turkey
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Klipstein S, Fallat ME, Savelli S. Fertility Preservation for Pediatric and Adolescent Patients With Cancer: Medical and Ethical Considerations. Pediatrics 2020; 145:peds.2019-3994. [PMID: 32071259 DOI: 10.1542/peds.2019-3994] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Many cancers presenting in children and adolescents are curable with surgery, chemotherapy, and/or radiotherapy. Potential adverse consequences of treatment include sterility, infertility, or subfertility as a result of gonad removal, damage to germ cells as a result of adjuvant therapy, or damage to the pituitary and hypothalamus or uterus as a result of irradiation. In recent years, treatment of solid tumors and hematologic malignancies has been modified in an attempt to reduce damage to the gonadal axis. Simultaneously, advances in assisted reproductive technology have led to new possibilities for the prevention and treatment of infertility. This clinical report reviews the medical aspects and ethical considerations that arise when considering fertility preservation in pediatric and adolescent patients with cancer.
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Affiliation(s)
- Sigal Klipstein
- Department of Obstetrics and Gynecology, Pritzker School of Medicine, University of Chicago, Chicago, Illinois; .,InVia Fertility Specialists, Chicago, Illinois
| | - Mary E Fallat
- Division of Pediatric Surgery, Hiram C. Polk Jr MD Department of Surgery, University of Louisville, Louisville, Kentucky; and
| | - Stephanie Savelli
- Division of Pediatric Hematology/Oncology, Akron Children's Hospital, Akron, Ohio
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Durrani S, Heena H. Controversies Regarding Ovarian Suppression and Infertility in Early Stage Breast Cancer. Cancer Manag Res 2020; 12:813-817. [PMID: 32104064 PMCID: PMC7008199 DOI: 10.2147/cmar.s231524] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Accepted: 01/15/2020] [Indexed: 01/24/2023] Open
Abstract
A common side effect of chemotherapy in breast cancer is early menopause in premenopausal patients, which is mainly a result of an indirect form of ovarian ablation, and is associated with substantial impairment of quality of life. Suppressing the production of ovarian estrogen has been shown to reduce the recurrence of hormone receptor-positive early breast cancer in premenopausal women, but whether it has an added advantage over tamoxifen is being discussed. Types of permanent ablation of the ovarian function include surgical oophorectomy and radiation-induced ovarian failure. Both are associated with similar response rates in hormone receptor-positive metastatic breast cancer. Medical castration with luteinizing hormone-releasing hormone analogs (LHRHa) has the benefit of being a reversible approach. Another advantage that premenopausal patients who wish to reduce the risk of developing premature ovarian insufficiency induced by chemotherapy may be offered LHRHa irrespective of whether they desire pregnancy and their age at diagnosis. This also helps reduce the risk of menopausal signs and symptoms as well as the loss of bone density in the long-term, which are primary concerns for women. This is of utmost importance to premenopausal women who do not want to conceive after treatment or are not candidates for fertility preservation strategies because of age. It should be emphasized that for women who are interested in fertility preservation, gamete cryopreservation remains the first option, and LHRHa is not an alternative. During chemotherapy, however, temporary ovarian suppression with LHRHa may be given to women who either have no access to a fertility clinic or who have declined chemotherapy or have contraindications.
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Affiliation(s)
- Sajid Durrani
- Comprehensive Cancer Center, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Humariya Heena
- Research Center, King Fahad Medical City, Riyadh, Saudi Arabia
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Nusbaum JS, Mirza I, Shum J, Freilich RW, Cohen RE, Pillinger MH, Izmirly PM, Buyon JP. Sex Differences in Systemic Lupus Erythematosus: Epidemiology, Clinical Considerations, and Disease Pathogenesis. Mayo Clin Proc 2020; 95:384-394. [PMID: 32029091 DOI: 10.1016/j.mayocp.2019.09.012] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 08/17/2019] [Accepted: 09/20/2019] [Indexed: 12/12/2022]
Abstract
Systemic lupus erythematosus (SLE) is a chronic, multiorgan, systemic autoimmune disease that is more common in women than men and is typically diagnosed during reproductive age, necessitating sex-specific considerations in care. In women there is no substantive evidence to suggest that SLE reduces fertility, but subfertility may occur as a result of active disease, immunosuppressive drugs, and age-related declines in fertility related to delays in childbearing. Although pregnancy outcomes have improved, SLE still poses risks in pregnancy that contribute to poorer maternal and fetal outcomes. Cyclophosphamide, an important agent for the treatment of severe or life-threatening lupus, may adversely affect fertility, particularly with increases in dose and patient age. Fertility preservation techniques are therefore an important consideration for women and men before cytotoxic treatment. There is mixed evidence as to whether exogenous estrogen in the form of oral contraceptive pills or hormone replacement therapy may increase the risk for the development of SLE, but among women with SLE already diagnosed, combined oral contraceptive pills and hormone replacement therapy do not confer risk for severe flare and remain important in reproductive care. The higher incidence of SLE in women may nonetheless be attributable to effects of endogenous estrogen, as well as failures in X chromosome inactivation, increased Toll-like receptor gene products, and changes in microRNA function. A greater appreciation of the biological underpinnings and consequences of sex differences in SLE may lead to more targeted treatments and improved outcomes for patients with SLE.
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Affiliation(s)
- Julie S Nusbaum
- Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York.
| | - Ibraheem Mirza
- Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York
| | - Justine Shum
- Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York
| | - Robert W Freilich
- Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York
| | - Rebecca E Cohen
- Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York
| | - Michael H Pillinger
- Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York
| | - Peter M Izmirly
- Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York
| | - Jill P Buyon
- Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York
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47
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Mauri D, Gazouli I, Zarkavelis G, Papadaki A, Mavroeidis L, Gkoura S, Ntellas P, Amylidi AL, Tsali L, Kampletsas E. Chemotherapy Associated Ovarian Failure. Front Endocrinol (Lausanne) 2020; 11:572388. [PMID: 33363515 PMCID: PMC7753213 DOI: 10.3389/fendo.2020.572388] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Accepted: 11/02/2020] [Indexed: 12/16/2022] Open
Abstract
As the incidence of malignancies in young adults is increasing, fertility preservation in cancer survivors arises as a major concern. Especially among female cancer patients, pregnancy rates are estimated to be 40% lower compared to women of the same age. Nowadays oncologists are to be preoccupied not only with their patients' successful treatment, but also with the maintenance of the potential of the latter to conceive and obtain children. Chemotherapy associated ovarian failure (COF), refers to disruption of ovarian function both as an endocrine gland and as a reproductive organ, due to previous exposure to chemotherapy agents. Although the underlying mechanism is not fully understood, it is supposed that chemotherapy agents may induce either DNA damage of premature ovarian follicle or early activation and apoptosis of them, resulting into early exhaustion of available follicle deposit. Various chemotherapy agents have been associated with COF with the highest incidence being reported for patients undergoing combination regimens. Although a variety of alternatives in order to maintain ovarian function and fertility in female cancer survivors are available, adequately established practices to do so are lacking. Thus, it is of major importance to investigate further and collect sufficient evidence, aiming to guide patients and physicians in everyday clinical practice.
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Affiliation(s)
- Davide Mauri
- Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
- Department of Medical, Oncology, Greece Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), University Hospital of Ioannina, Ioannina, Greece
- *Correspondence: Davide Mauri,
| | - Ioanna Gazouli
- Department of Medical, Oncology, Greece Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), University Hospital of Ioannina, Ioannina, Greece
| | - Georgios Zarkavelis
- Department of Medical, Oncology, Greece Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), University Hospital of Ioannina, Ioannina, Greece
| | - Alexandra Papadaki
- Department of Medical, Oncology, Greece Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), University Hospital of Ioannina, Ioannina, Greece
| | - Leonidas Mavroeidis
- Department of Medical, Oncology, Greece Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), University Hospital of Ioannina, Ioannina, Greece
| | - Stefania Gkoura
- Department of Medical, Oncology, Greece Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), University Hospital of Ioannina, Ioannina, Greece
| | - Panagiotis Ntellas
- Department of Medical, Oncology, Greece Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), University Hospital of Ioannina, Ioannina, Greece
| | - Anna-Lea Amylidi
- Department of Medical, Oncology, Greece Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), University Hospital of Ioannina, Ioannina, Greece
| | | | - Eleftherios Kampletsas
- Department of Medical, Oncology, Greece Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), University Hospital of Ioannina, Ioannina, Greece
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Close AG, Jones KA, Landowski A, Switzer GE, Kazmerski TM, Miller E, Friehling E. Current practices in menstrual management in adolescents with cancer: A national survey of pediatric oncology providers. Pediatr Blood Cancer 2019; 66:e27961. [PMID: 31441217 DOI: 10.1002/pbc.27961] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 06/23/2019] [Accepted: 07/14/2019] [Indexed: 02/04/2023]
Abstract
BACKGROUND Adolescents and young adult (AYA) women with cancer are at risk of heavy menstrual bleeding (HMB) due to thrombocytopenia, coagulopathy, and/or disruption of the hypothalamic-pituitary-gonadal axis. Currently, little is known about current practices to help prevent and treat HMB in AYA women with cancer. METHODS We surveyed providers from 100 pediatric oncology centers. Face and content validity were assessed prior to distribution. Descriptive statistics, Chi-squared and Fisher exact tests were used for analysis. RESULTS Ninety-four percent of respondents have recommended preventative menstrual suppression. More than half of respondents agreed that patients with the following types of cancers should receive preventative menstrual suppression: sarcomas, acute leukemias, lymphomas, and germ cell tumors. The most preferred form of menstrual suppression was GnRH agonists. Almost 95% of respondents felt that it is important to consider menstrual suppression and that a formal guideline about initiation of menstrual suppression would be helpful. Only 46% felt comfortable personally managing menstrual suppression. CONCLUSIONS The vast majority of pediatric oncologists who responded to this national survey have used preventative menstrual suppression and feel that it is important to consider in many types of AYA cancers. Although pediatric oncologists are most often managing menstrual suppression, they do not feel comfortable doing so and desire guidelines to help with management. Future studies to assess which patients require menstrual suppression and which menstrual suppression is best tolerated and efficacious is needed.
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Affiliation(s)
- Allison G Close
- Department of Pediatrics, Division of Hematology/Oncology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
| | - Kelley A Jones
- Department of Pediatrics, Division of Adolescent and Young Adult Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
| | - Allison Landowski
- Department of Pediatrics, Division of Adolescent and Young Adult Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
| | - Galen E Switzer
- Departments of Medicine, Psychiatry, Clinical and Translational Science, University of Pittsburgh, Pittsburgh, Pennsylvania
- Center for Health Equity Research and Promotion, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania
| | - Traci M Kazmerski
- Department of Pediatrics, Division of Adolescent and Young Adult Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
- Center for Women's Health Research and Innovation (CWHRI), University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Elizabeth Miller
- Department of Pediatrics, Division of Adolescent and Young Adult Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
- Center for Women's Health Research and Innovation (CWHRI), University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Erika Friehling
- Department of Pediatrics, Division of Hematology/Oncology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
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Ter Welle-Butalid MEE, Vriens IJHI, Derhaag JGJ, Leter EME, de Die-Smulders CEC, Smidt MM, van Golde RJTR, Tjan-Heijnen VCGV. Counseling young women with early breast cancer on fertility preservation. J Assist Reprod Genet 2019; 36:2593-2604. [PMID: 31760547 PMCID: PMC6910894 DOI: 10.1007/s10815-019-01615-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 10/18/2019] [Indexed: 02/07/2023] Open
Abstract
PURPOSE Women with early-stage breast cancer may still have a future child wish, while chemotherapy may impair fertility. To pursue on fertility preservation shortly after breast cancer diagnosis is complex. This review holds a critical reflection on all topics that need to be counseled to give them the opportunity to make a well-informed decision before starting any oncological treatment. METHODS A comprehensive literature review was performed on papers published in English language on breast cancer in young women, risk of chemotherapy-induced infertility, fertility preservation techniques, impact of possible mutation carriership, and future pregnancy outcome. RESULTS Below 40 years of age, the risk of permanent chemotherapy-induced ovarian function failure is approximately 20%, where taxanes do not significantly add to this risk. Overall, 23% of reported women who performed fertility preservation by cryopreserving oocytes or embryos returned for embryo transfer. Of these, 40% gave live birth. Both fertility preservation in women diagnosed with breast cancer and pregnancy after treatment seem safe with respect to breast cancer survival. Women who have a genetic predisposition for breast cancer like BRCA gene mutation should also be informed about the possibility of pre-implantation genetic diagnosis. CONCLUSIONS Women with an early stage of breast cancer and a possible future child wish should be referred to an expertise center in breast cancer, fertility preservation, and genetics in this complex decision-making process, shortly after diagnosis.
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Affiliation(s)
- M E Elena Ter Welle-Butalid
- Department of Obstetrics and Gynaecology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands
- GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands
| | - I J H Ingeborg Vriens
- GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands
- Department of Internal Medicine, division of Medical Oncology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands
| | - J G Josien Derhaag
- Department of Obstetrics and Gynaecology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands
- GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands
| | - E M Edward Leter
- GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands
- Department of Clinical Genetics, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, the Netherlands
| | - C E Christine de Die-Smulders
- GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands
- Department of Clinical Genetics, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, the Netherlands
| | - M Marjolein Smidt
- GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands
- Department of Surgery, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, the Netherlands
| | - R J T Ron van Golde
- Department of Obstetrics and Gynaecology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands
- GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands
| | - V C G Vivianne Tjan-Heijnen
- GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands.
- Department of Internal Medicine, division of Medical Oncology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands.
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50
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Scaruffi P, Stigliani S, Cardinali B, Massarotti C, Lambertini M, Sozzi F, Dellepiane C, Merlo DF, Anserini P, Del Mastro L. Gonadotropin Releasing Hormone Agonists Have an Anti-apoptotic Effect on Cumulus Cells. Int J Mol Sci 2019; 20:ijms20236045. [PMID: 31801245 PMCID: PMC6928931 DOI: 10.3390/ijms20236045] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 11/22/2019] [Accepted: 11/25/2019] [Indexed: 01/26/2023] Open
Abstract
Background: Ovaries are sensitive to chemotherapy, which may lead to early depletion of primordial follicle reserve. One strategy for gonadal function preservation is temporary ovarian suppression with Gonadotropin Releasing Hormone agonists (GnRHa) during chemotherapy. To date, GnRHa protective mechanism of action remains not fully elucidated. Methods: We collected 260 immature cumulus cell-oocyte complexes (COC) from 111 women < 38 years old, with a normal ovarian reserve. The COC were randomly assigned to the following groups: (a) control; culture with the addition of (b) GnRHa; (c) cyclophosphamide; (d) cyclophosphamide plus GnRHa. After in vitro treatments, RNA and proteins were extracted from oocytes and cumulus cells (CC), separately. Potential effects of drugs were evaluated on GnRH receptors, apoptosis pathways, ceramide pathway, and glutathione synthesis by quantitative PCR and, whenever possible, by Western blot. Results: Cyclophosphamide triggered activation of the extrinsic pathway of apoptosis mediated by BAX in CC. The co-administration of GnRHa inhibited the apoptosis pathway in CC. According to our model, the GnRHa does not directly act on oocytes, which do not express GnRH receptors. Moreover, glutathione synthesis was decreased after GnRHa treatment both in CC and oocytes. Conclusion: Our data suggest that the protective mechanisms induced by GnRHa is mediated by an anti-apoptotic effect on CC.
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Affiliation(s)
- Paola Scaruffi
- UOS Physiopathology of Human Reproduction, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (P.S.); (S.S.); (F.S.); (P.A.)
| | - Sara Stigliani
- UOS Physiopathology of Human Reproduction, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (P.S.); (S.S.); (F.S.); (P.A.)
| | - Barbara Cardinali
- Breast Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (B.C.); (C.D.); (L.D.M.)
| | - Claudia Massarotti
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132 Genoa, Italy;
| | - Matteo Lambertini
- Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy
- U.O.C. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
- Correspondence: ; Tel.: +39-010-555-4254
| | - Fausta Sozzi
- UOS Physiopathology of Human Reproduction, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (P.S.); (S.S.); (F.S.); (P.A.)
| | - Chiara Dellepiane
- Breast Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (B.C.); (C.D.); (L.D.M.)
| | - Domenico Franco Merlo
- Infrastruttura Ricerca e Statistica, Azienda Unità Sanitaria Locale—IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
| | - Paola Anserini
- UOS Physiopathology of Human Reproduction, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (P.S.); (S.S.); (F.S.); (P.A.)
| | - Lucia Del Mastro
- Breast Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (B.C.); (C.D.); (L.D.M.)
- Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy
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