|
1
|
Miner M, Wang C, Kaminetsky J, Khera M, Goldstein I, Carson C, Chidambaram N, King S, Dobs A. Safety, efficacy, and pharmacokinetics of oral testosterone undecanoate in males with hypogonadism. Andrology 2025; 13:882-893. [PMID: 39252657 PMCID: PMC12006877 DOI: 10.1111/andr.13747] [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: 10/25/2023] [Revised: 07/25/2024] [Accepted: 08/14/2024] [Indexed: 09/11/2024]
Abstract
BACKGROUND Testosterone deficiency results from insufficient testosterone production. Testosterone therapy may require dose titration to reach eugonadal serum testosterone concentrations. OBJECTIVE The primary objective was the efficacy of oral testosterone undecanoate (TLANDO; Antares Pharma Inc.) in male patients with documented hypogonadism. Secondary objectives included a comparison of oral testosterone undecanoate safety and quality-of-life assessments to 1.62% topical testosterone gel (AndroGel 1.62%; AbbVie). MATERIALS AND METHODS In this phase 3 study, 315 patients were randomized 2:1 to oral testosterone undecanoate or 1.62% topical testosterone gel (NCT02081300). Patients received 225 mg oral testosterone undecanoate twice daily, and doses were adjusted by 75 mg/dose at weeks 4 and 8 based on average serum total testosterone concentration and maximum observed serum concentration. The primary endpoint was the proportion of patients receiving oral testosterone undecanoate with serum total testosterone concentration within the eugonadal reference range (300-1140 ng/dL). Secondary endpoints included the proportion of patients with maximum serum total testosterone concentrations within predetermined limits, safety parameters, and quality-of-life endpoints including the Short Form-36v2 Health Survey, Psychosexual Daily Questionnaire, and International Prostate Symptom Score. RESULTS Overall mean ± SD baseline testosterone was 205.7 ± 71.6 ng/dL. For patients receiving oral testosterone undecanoate, 87.4% demonstrated a 24-h average serum total testosterone concentration within the reference range following titration. Oral testosterone undecanoate demonstrated a nominal statistically significantly greater mean change from baseline than 1.62% topical testosterone gel for Short Form-36v2 Health Survey measures of mental health (2.91 vs. -0.10; p = 0.035), and mental component summary (3.82 vs. 0.55; p = 0.009); and Psychosexual Daily Questionnaire measure of weekly negative mood (-0.57 vs. -0.20; p = 0.021). Safety endpoints were comparable between therapies. No deaths or treatment-related serious adverse events were reported. DISCUSSION AND CONCLUSION Male patients with hypogonadism receiving oral testosterone undecanoate 225 mg twice daily demonstrated improvements in libido and sexual frequency. Serum testosterone concentrations were within the reference range in 87% of patients without dose titration.
Collapse
Affiliation(s)
- Martin Miner
- Men's Health CenterMiriam HospitalProvidenceRhode IslandUSA
| | - Christina Wang
- Clinical and Translational Science InstituteThe Lundquist Institute at Harbor‐UCLA Medical CenterTorranceCaliforniaUSA
| | | | | | | | - Culley Carson
- University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | | | | | - Adrian Dobs
- Johns Hopkins University School of MedicineBaltimoreMarylandUSA
| |
Collapse
|
|
2
|
Morgentaler A. O' testosterone, where is thy sting? A Urologist's reflection on testosterone and prostate cancer. EClinicalMedicine 2025; 80:103061. [PMID: 39867966 PMCID: PMC11764238 DOI: 10.1016/j.eclinm.2024.103061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 12/26/2024] [Accepted: 12/27/2024] [Indexed: 01/28/2025] Open
Affiliation(s)
- Abraham Morgentaler
- Blavatnik Faculty Fellow in Health and Longevity, Beth Israel Deaconess Medical Center, Harvard Medical School, USA
| |
Collapse
|
|
3
|
Goldstein I, Chidambaram N, Dobs A, King S, Miner M, Ramasamy R, Yafi FA, Khera M. Newer formulations of oral testosterone undecanoate: development and liver side effects. Sex Med Rev 2025; 13:33-40. [PMID: 39291780 DOI: 10.1093/sxmrev/qeae062] [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: 12/01/2023] [Revised: 06/27/2024] [Indexed: 09/19/2024]
Abstract
INTRODUCTION Testosterone deficiency is a clinical disorder due to either failure of the testes to produce testosterone or failure of the hypothalamus or pituitary to produce sufficient gonadotropins. Previous formulations of oral testosterone therapy, particularly methyltestosterone, have been associated with adverse liver effects. Many different routes of testosterone delivery have been developed, each with their own administrative benefits and challenges. Newer formulations of oral testosterone undecanoate (TU) provide a convenient administration option, although their use has been limited by hepatotoxicity concerns based on older methyltestosterone data, and prescribing physicians may still be concerned about adverse liver effects. OBJECTIVES In this review, we discuss the history of oral testosterone development, clarify the mechanism of action of oral TU, and describe the relevant liver safety findings. METHODS Relevant literature was allocated to present a review on the history of oral TU development and the mechanism of action of oral TU. We pooled data from individual studies of oral TU products to present a safety summary. RESULTS Overall, safety results from studies of the newer formulations of oral TU showed that increased liver function test values are not generally associated with oral TU formulations and that no clinically significant liver toxicities were noted in clinical trials of oral TU. CONCLUSION Continued research into the safety of oral TU will contribute to a better understanding of the potential risks in patients receiving this therapy, an outcome that highlights the importance of providing patient education and reassurance regarding oral TU safety.
Collapse
Affiliation(s)
- Irwin Goldstein
- University of California at San Diego, San Diego, CA 92120, United States
| | | | - Adrian Dobs
- The Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
| | - Shelby King
- Halozyme, San Diego, CA 92130, United States
| | - Martin Miner
- Men's Health Center, Miriam Hospital, Providence, RI 02906, United States
| | - Ranjith Ramasamy
- Desai Sethi Urology Institute, University of Miami Miller School of Medicine, Miami, FL 33136, United States
- Jumeirah American Clinic, Dubai, UAE
| | | | - Mohit Khera
- Department of Urology, University of California Irvine, Irvine, CA 92660, United States
| |
Collapse
|
|
4
|
Janssen DF. Comment on: "History of testosterone therapy through the ages". Int J Impot Res 2024; 36:899-901. [PMID: 37957397 DOI: 10.1038/s41443-023-00791-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 10/16/2023] [Accepted: 11/01/2023] [Indexed: 11/15/2023]
Affiliation(s)
- Diederik F Janssen
- Maastricht University, Graduate School of Arts and Social Sciences, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
| |
Collapse
|
|
5
|
Liu X, Guo X, Zhang T, Duan J, Zhang L, Wang M, Li Y, Shen Z, Mao J. Testosterone maintains male longevity and female reproduction in Chrysopa pallens. Heliyon 2024; 10:e32478. [PMID: 38933978 PMCID: PMC11201114 DOI: 10.1016/j.heliyon.2024.e32478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 05/26/2024] [Accepted: 06/04/2024] [Indexed: 06/28/2024] Open
Abstract
Vertebrate testosterone, an androgen present in the testes, is essential for male fertility. Vertebrate-type steroid hormones have been identified in insects, but their function remains unknown. Insect vitellogenin (Vg) is usually a female-specific protein involved in reproductive processes. However, males of some species, such as the green lacewing Chrysopa pallens, have Vg. Here, we demonstrated that the knockdown of C. pallens male Vg by RNAi significantly shortened the lifespan of males, suppressed the reproduction of post-mating females, and strikingly reduced the abundance of several immune-related compounds, including testosterone. LC-MS/MS revealed that C. pallens male testosterone had the same structure and molecular mass as vertebrate testosterone. Topical testosterone application partially restored the lifespan of Vg-deficient males and the reproduction of post-mating females. These results suggest that vertebrate-type testosterone maintains male longevity and female reproduction under the control of the male Vg in C. pallens.
Collapse
Affiliation(s)
- Xiaoping Liu
- Key Laboratory of Natural Enemy Insects, Ministry of Agriculture and Rural Affairs, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, PR China
| | - Xingkai Guo
- Key Laboratory of Natural Enemy Insects, Ministry of Agriculture and Rural Affairs, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, PR China
| | - Tingting Zhang
- School of Advanced Manufacturing, Fuzhou University, Jinjiang, 362251, PR China
| | - Jiaqi Duan
- Key Laboratory of Natural Enemy Insects, Ministry of Agriculture and Rural Affairs, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, PR China
| | - Lisheng Zhang
- Key Laboratory of Natural Enemy Insects, Ministry of Agriculture and Rural Affairs, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, PR China
| | - Mengqing Wang
- Key Laboratory of Natural Enemy Insects, Ministry of Agriculture and Rural Affairs, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, PR China
| | - Yuyan Li
- Key Laboratory of Natural Enemy Insects, Ministry of Agriculture and Rural Affairs, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, PR China
| | - Zhongjian Shen
- Key Laboratory of Natural Enemy Insects, Ministry of Agriculture and Rural Affairs, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, PR China
| | - Jianjun Mao
- Key Laboratory of Natural Enemy Insects, Ministry of Agriculture and Rural Affairs, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, PR China
| |
Collapse
|
|
6
|
Wang TT, Zhu HL, Ouyang KW, Wang H, Luo YX, Zheng XM, Ling Q, Wang KW, Zhang J, Chang W, Lu Q, Zhang YF, Yuan Z, Li H, Xiong YW, Wei T, Wang H. Environmental cadmium inhibits testicular testosterone synthesis via Parkin-dependent MFN1 degradation. JOURNAL OF HAZARDOUS MATERIALS 2024; 470:134142. [PMID: 38555669 DOI: 10.1016/j.jhazmat.2024.134142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 03/12/2024] [Accepted: 03/25/2024] [Indexed: 04/02/2024]
Abstract
Low testosterone (T) levels are associated with many common diseases, such as obesity, male infertility, depression, and cardiovascular disease. It is well known that environmental cadmium (Cd) exposure can induce T decline, but the exact mechanism remains unclear. We established a murine model in which Cd exposure induced testicular T decline. Based on the model, we found Cd caused mitochondrial fusion disorder and Parkin mitochondrial translocation in mouse testes. MFN1 overexpression confirmed that MFN1-dependent mitochondrial fusion disorder mediated the Cd-induced T synthesis suppression in Leydig cells. Further data confirmed Cd induced the decrease of MFN1 protein by increasing ubiquitin degradation. Testicular specific Parkin knockdown confirmed Cd induced the ubiquitin-dependent degradation of MFN1 protein through promoting Parkin mitochondrial translocation in mouse testes. Expectedly, testicular specific Parkin knockdown also mitigated testicular T decline. Mito-TEMPO, a targeted inhibitor for mitochondrial reactive oxygen species (mtROS), alleviated Cd-caused Parkin mitochondrial translocation and mitochondrial fusion disorder. As above, Parkin mitochondrial translocation induced mitochondrial fusion disorder and the following T synthesis repression in Cd-exposed Leydig cells. Collectively, our study elucidates a novel mechanism through which Cd induces T decline and provides a new treatment strategy for patients with androgen disorders.
Collapse
Affiliation(s)
- Tian-Tian Wang
- Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China
| | - Hua-Long Zhu
- Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No 81 Meishan Road, Hefei 230032, Anhui, China
| | - Kong-Wen Ouyang
- Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China
| | - Hua Wang
- Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China; Department of Respiratory Medicine, Anhui Provincial Children's Hospital, Hefei, Anhui 230000, China
| | - Ye-Xin Luo
- Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China
| | - Xin-Mei Zheng
- Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China
| | - Qing Ling
- Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China
| | - Kai-Wen Wang
- Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China
| | - Jin Zhang
- Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China
| | - Wei Chang
- Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China
| | - Qi Lu
- Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China
| | - Yu-Feng Zhang
- Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China
| | - Zhi Yuan
- Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China
| | - Hao Li
- Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China
| | - Yong-Wei Xiong
- Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No 81 Meishan Road, Hefei 230032, Anhui, China
| | - Tian Wei
- Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No 81 Meishan Road, Hefei 230032, Anhui, China
| | - Hua Wang
- Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No 81 Meishan Road, Hefei 230032, Anhui, China.
| |
Collapse
|
|
7
|
Horn J. The dichotomy between health and drug abuse in bodybuilding. NORDIC STUDIES ON ALCOHOL AND DRUGS 2024; 41:212-225. [PMID: 38645972 PMCID: PMC11027851 DOI: 10.1177/14550725231206011] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 09/21/2023] [Indexed: 04/23/2024] Open
Abstract
Aim: The aim of the present study was to investigate the expansion and prevalence of anabolic steroid use by examining the divergent effects between health and drug abuse and to create more awareness around the harmful consequences of these drugs when administered at abusive levels. Methods: A focused and concise literature search was conducted, and 101 high-quality articles were included in the review. Results: The findings underscore the adverse health risks of steroid abuse, emphasizing the stark contrast between health and drug abuse. Conclusions: While steroids and other performance-enhancing drugs can yield muscle growth, strength and even fat loss, abusing these substances can lead to adverse health outcomes. Furthermore, within the fitness subculture, particularly in the realm of bodybuilding, steroid abuse fosters an atmosphere of cheating and deception, frequently downplaying or ignoring the negative and sometimes deadly consequences it brings.
Collapse
|
|
8
|
Morgentaler A, Hanafy HM. The testis, eunuchs, and testosterone: a historical review over the ages and around the world. Sex Med Rev 2024; 12:199-209. [PMID: 38146670 DOI: 10.1093/sxmrev/qead051] [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: 09/26/2023] [Revised: 10/23/2023] [Accepted: 10/30/2023] [Indexed: 12/27/2023]
Abstract
INTRODUCTION Testosterone therapy for men with testosterone deficiency is widely used, yet remains controversial. The rich and fascinating history of the testicles, including human castration, provides a valuable perspective on this important topic. OBJECTIVES This study reviewed the history of testosterone from antiquity to the modern day. METHODS Primary sources consisted of books and relevant articles, augmented by a MEDLINE search using the key words "testis," "testicles," "castration," "eunuchs," "testosterone," and "testicular function." RESULTS An early scientific observation was that castration reduced sexual development and activity, originating with domestication of animals approximately 10 000 years ago. Human castration appears in ancient Egyptian mythology more than 4000 years ago, in Greek mythology from 8th century BCE, and in the Bible. The history of eunuchs in China spanned 2000 years, beginning with the Hsia dynasty (2205-1766 BCE). The concept that the testicles produced some factor responsible for male sexual development and behavior was thus known throughout the world since the beginning of recorded history. Testosterone was isolated and synthesized in 1935 and was soon available as a treatment. Multiple benefits of testosterone therapy were apparent by 1940. Recent large, controlled testosterone studies have conclusively demonstrated sexual and general health benefits, with a strong safety profile. CONCLUSION Testosterone has been a known substance for <1% of the historical timeline, yet knowledge that the testes were responsible for male sexual development and behavior has been known since the beginning of recorded history. Today, modern evidence has demonstrated the importance of normal levels of testosterone for general health as well as sexual function and desire. Yet, testosterone therapy remains controversial. We believe this historical review provides a helpful perspective on this age-old issue.
Collapse
Affiliation(s)
- Abraham Morgentaler
- Division of Urology, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | | |
Collapse
|
|
9
|
Traore K, Zirkin B. Use of in vitro methodology to investigate phthalate effects on the differentiation of seminiferous tubule-associated stem cells to form Leydig cells and on the Leydig cells derived from the stem cells. FRONTIERS IN TOXICOLOGY 2024; 6:1352294. [PMID: 38362108 PMCID: PMC10867263 DOI: 10.3389/ftox.2024.1352294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 01/15/2024] [Indexed: 02/17/2024] Open
Abstract
Introduction: Leydig cells isolated from the testis are able to sustain high levels of testosterone production in vitro, but only for up to 3 days. Such cells are valuable for addressing the acute effects of chemicals on steroidogenic function, but not for repeated or chronic effects. Methodology is now available by which adult Leydig cells can be derived in vitro from seminiferous tubule-associated stem cells. In contrast to isolated Leydig cells, the Leydig cells derived in this way can synthesize and secrete high levels of testosterone for months. Herein, we asked whether this system might be used to address the effect of mono-(2-ethylhexyl) phthalate (MEHP) exposure on the formation of Leydig cells from tubule-associated stem cells, and on the Leydig cells after their formation. Methods: Adult Brown Norway rats received an intraperitoneal injection of ethane dimethanesulfonate (EDS) to eliminate the existing Leydig cells. Seminiferous tubules then were isolated and cultured in medium containing Insulin-Transferrin- Selenium (ITS), Smoothened Agonist (SAG), and luteinizing hormone (LH). Results: Culture of the tubules for 8 weeks resulted in the formation of cells on the surfaces of the tubules that stained for CYP11A1 and STAR and produced high levels of testosterone. When the tubules were cultured in medium containing increasing concentrations of MEHP, concentration-dependent effects on Leydig cell formation occurred. To determine the effect of MEHP on newly produced Leydig cells, tubules were cultured for 8 weeks in the absence of MEHP, resulting in the formation of adult Leydig cells, and then in medium containing increasing concentrations of MEHP. Concentration-dependent decreases in testosterone production by the adult Leydig cells were seen, and these decreases proved to be reversible. Discussion: The use of this new system should make it possible to determine the mechanisms by which acute, repeated, or chronic exposures to increasing concentrations of MEHP and/or exposure to other chemicals affect the formation of Leydig cells from stem cells, as well as the steroidogenic function of adult Leydig cells.
Collapse
Affiliation(s)
- Kassim Traore
- Jerry M. Wallace School of Osteopathic Medicine, Campbell University, Lillington, NC, United States
- Duquesne University College of Osteopathic Medicine, Pittsburgh, PA, United States
| | - Barry Zirkin
- Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
| |
Collapse
|
|
10
|
Reiss AB, Gulkarov S, Pinkhasov A, Sheehan KM, Srivastava A, De Leon J, Katz AE. Androgen Deprivation Therapy for Prostate Cancer: Focus on Cognitive Function and Mood. MEDICINA (KAUNAS, LITHUANIA) 2023; 60:77. [PMID: 38256338 PMCID: PMC10819522 DOI: 10.3390/medicina60010077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 12/26/2023] [Accepted: 12/28/2023] [Indexed: 01/24/2024]
Abstract
Prostate cancer is the second leading cause of cancer death in men in the United States. Androgen deprivation therapy (ADT) is currently the primary treatment for metastatic prostate cancer, and some studies have shown that the use of anti-androgen drugs is related to a reduction in cognitive function, mood changes, diminished quality of life, dementia, and possibly Alzheimer's disease. ADT has potential physiological effects such as a reduction in white matter integrity and a negative impact on hypothalamic functions due to the lowering of testosterone levels or the blockade of downstream androgen receptor signaling by first- and second-generation anti-androgen drugs. A comparative analysis of prostate cancer patients undergoing ADT and Alzheimer patients identified over 30 shared genes, illustrating common ground for the mechanistic underpinning of the symptomatology. The purpose of this review was to investigate the effects of ADT on cognitive function, mood, and quality of life, as well as to analyze the relationship between ADT and Alzheimer's disease. The evaluation of prostate cancer patient cognitive ability via neurocognitive testing is described. Future studies should further explore the connection among cognitive deficits, mood disturbances, and the physiological changes that occur when hormonal balance is altered.
Collapse
Affiliation(s)
- Allison B. Reiss
- Department of Medicine and Biomedical Research Institute, NYU Grossman Long Island School of Medicine, Mineola, NY 11501, USA; (S.G.); (K.M.S.); (A.S.); (J.D.L.)
| | - Shelly Gulkarov
- Department of Medicine and Biomedical Research Institute, NYU Grossman Long Island School of Medicine, Mineola, NY 11501, USA; (S.G.); (K.M.S.); (A.S.); (J.D.L.)
| | - Aaron Pinkhasov
- Department of Psychiatry, NYU Grossman Long Island School of Medicine, Mineola, NY 11501, USA;
| | - Katie M. Sheehan
- Department of Medicine and Biomedical Research Institute, NYU Grossman Long Island School of Medicine, Mineola, NY 11501, USA; (S.G.); (K.M.S.); (A.S.); (J.D.L.)
| | - Ankita Srivastava
- Department of Medicine and Biomedical Research Institute, NYU Grossman Long Island School of Medicine, Mineola, NY 11501, USA; (S.G.); (K.M.S.); (A.S.); (J.D.L.)
| | - Joshua De Leon
- Department of Medicine and Biomedical Research Institute, NYU Grossman Long Island School of Medicine, Mineola, NY 11501, USA; (S.G.); (K.M.S.); (A.S.); (J.D.L.)
| | - Aaron E. Katz
- Department of Urology, NYU Grossman Long Island School of Medicine, Mineola, NY 11501, USA;
| |
Collapse
|
|
11
|
Santos RB, Lemos C, Saraiva M. Gender-affirming hormone therapy in Portugal: knowledge, safety and adherence. INTERNATIONAL JOURNAL OF TRANSGENDER HEALTH 2023; 26:105-118. [PMID: 39981279 PMCID: PMC11837941 DOI: 10.1080/26895269.2023.2296542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/22/2025]
Abstract
Background: More research is needed to understand the knowledge, experiences, safety, and adherence of individuals on gender-affirming hormone therapy (GAHT) for gender dysphoria treatment. Aim: To assess the knowledge of the Portuguese transgender population on GAHT about the therapy, examine the experiences of those who initiated it through the Portuguese National Health System, and evaluate the safety, monitoring and adherence to hormonal therapy. Methods: Cross-sectional study with Portuguese transgender adults who had hormonal therapy. Participants completed an original questionnaire that utilized an ordinal Likert-style scale that ranged from 0 (worst result) to 6 (best result) for most items. Descriptive statistics and non-parametric tests were used to analyze both categorical and continuous variables. The level of statistical significance was set at 0.05. Results: Participants' knowledge on GAHT was rated with a median of 5 points, relying mostly on the internet for information. 14.1% felt insufficiently informed. 71.2% faced obstacles obtaining GAHT, with long waiting times being the most common. Feminizing therapy was significantly more expensive. Initial consultation was often with psychologists/sexologists, with endocrinologists commonly being the first providers of GAHT. 43.3% didn't undergo informed consent and 11.3% had no pretreatment blood tests. Only 53.2% discussed fertility with medical professionals, and of those, only 8.0% opted for it. 79.6% regularly underwent routine analyses and 87.3% were followed up in medical appointments, mainly with an endocrinologist. 6.3% of participants discontinued therapy, mostly due to adverse effects and difficulty obtaining prescriptions. Discussion: Internet sources dominated as the main information channel for GAHT, emphasizing the importance of healthcare professionals guiding patients to reliable sources. Limited healthcare provider knowledge and access barriers were identified. Primary care physicians had limited involvement, raising safety concerns. Inadequate fertility counseling and follow-up in family medicine were found. Discontinuation of therapy and nonadherence highlighted the need for comprehensive care and monitoring.
Collapse
Affiliation(s)
| | - Carolina Lemos
- Population Studies, Instituto de Ciências Biomédicas de Abel Salazar, Porto, Portugal
| | - Miguel Saraiva
- Endocrinology Department, Centro Hospitalar Universitário de Santo António, Porto, Portugal
| |
Collapse
|
|
12
|
Munari EV, Amer M, Amodeo A, Bollino R, Federici S, Goggi G, Giovanelli L, Persani L, Cangiano B, Bonomi M. The complications of male hypogonadism: is it just a matter of low testosterone? Front Endocrinol (Lausanne) 2023; 14:1201313. [PMID: 37455904 PMCID: PMC10338218 DOI: 10.3389/fendo.2023.1201313] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 06/01/2023] [Indexed: 07/18/2023] Open
Abstract
The history of diagnosing hypogonadism and hypotestosteronemia shows us the many steps that were necessary to achieve our current knowledge and the ability to improve these patients' well-being. Moreover, so far, criteria for diagnosing hypotestosteronemia varies according to the underlying condition, and according to the consensus or guideline adopted. Furthermore, besides the many signs and symptoms, there are several complications associated with low testosterone levels such as osteoporosis, metabolic alterations, as well as cardiovascular disorders. However, data are often conflicting regarding the severity, timing or even the real clinical relevance of these complications, although these studies often lack essential information such as gonadotropin levels or the underlying cause of hypogonadism. The present review focus on the complications of male hypogonadism according to the cause of testosterone deficiency, highlighting the lack of information found in many studies investigating its effects. We thereby stress the necessity to always perform a complete evaluation of the type of hypogonadism (including at least gonadotropins and secondary causes) when investigating the effects of low testosterone levels.
Collapse
Affiliation(s)
| | - Myriam Amer
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Alessandro Amodeo
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Ruggiero Bollino
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Silvia Federici
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Giovanni Goggi
- Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy
| | - Luca Giovanelli
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Luca Persani
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
- Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy
| | - Biagio Cangiano
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
- Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy
| | - Marco Bonomi
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
- Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy
| |
Collapse
|
|
13
|
Varanoske AN, Harris MN, Hebert C, Johannsen NM, Heymsfield SB, Greenway FL, Ferrando AA, Rood JC, Pasiakos SM. Bioelectrical impedance phase angle is associated with physical performance before but not after simulated multi-stressor military operations. Physiol Rep 2023; 11:e15649. [PMID: 36949577 PMCID: PMC10033850 DOI: 10.14814/phy2.15649] [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: 02/02/2023] [Revised: 02/28/2023] [Accepted: 03/01/2023] [Indexed: 03/24/2023] Open
Abstract
Physical performance decrements observed during multi-stressor military operations may be attributed, in part, to cellular membrane dysfunction, which is quantifiable using phase angle (PhA) derived from bioelectrical impedance analysis (BIA). Positive relationships between PhA and performance have been previously reported in cross-sectional studies and following longitudinal exercise training programs, but whether changes in PhA are indicative of acute decrements in performance during military operations is unknown. Data from the Optimizing Performance for Soldiers II study, a clinical trial examining the effects of exogenous testosterone administration on body composition and performance during military stress, was used to evaluate changes in PhA and their associations with physical performance. Recreationally active, healthy males (n = 34; 26.6 ± 4.3 years; 77.9 ± 12.4 kg) were randomized to receive testosterone undecanoate or placebo before a 20-day simulated military operation, which was followed by a 23-day recovery period. PhA of the whole-body (Whole) and legs (Legs) and physical performance were measured before (PRE) and after (POST) the simulated military operation as well as in recovery (REC). Independent of treatment, PhAWhole and PhALegs decreased from PRE to POST (p < 0.001), and PhALegs , but not PhAWhole , remained lower at REC than PRE. PhAWhole at PRE and REC were associated with vertical jump height and Wingate peak power (p < 0.001-0.050), and PhAWhole at PRE was also associated with 3-RM deadlift mass (p = 0.006). However, PhA at POST and changes in PhA from PRE to POST were not correlated with any performance measure (p > 0.05). Additionally, PhA was not associated with aerobic performance at any timepoint. In conclusion, reduced PhA from PRE to POST provides indirect evidence of cellular membrane disruption. Associations between PhA and strength and power were only evident at PRE and REC, suggesting PhA may be a useful indicator of strength and power, but not aerobic capacity, in non-stressed conditions, and not a reliable indicator of physical performance during severe physiological stress.
Collapse
Affiliation(s)
- Alyssa N. Varanoske
- Military Performance Division, U.S. Army Research Institute of Environmental MedicineNatickMassachusettsUSA
- Oak Ridge Institute for Science and EducationOak RidgeTennesseeUSA
| | - Melissa N. Harris
- Pennington Biomedical Research CenterLouisiana State UniversityBaton RougeLouisianaUSA
| | - Callie Hebert
- Pennington Biomedical Research CenterLouisiana State UniversityBaton RougeLouisianaUSA
| | - Neil M. Johannsen
- Pennington Biomedical Research CenterLouisiana State UniversityBaton RougeLouisianaUSA
| | - Steven B. Heymsfield
- Pennington Biomedical Research CenterLouisiana State UniversityBaton RougeLouisianaUSA
| | - Frank L. Greenway
- Pennington Biomedical Research CenterLouisiana State UniversityBaton RougeLouisianaUSA
| | - Arny A. Ferrando
- Department of Geriatrics, Donald W. Reynolds Institute on Aging, Center for Translational Research in Aging & LongevityUniversity of Arkansas for Medical SciencesLittle RockArkansasUSA
| | - Jennifer C. Rood
- Pennington Biomedical Research CenterLouisiana State UniversityBaton RougeLouisianaUSA
| | - Stefan M. Pasiakos
- Military Performance Division, U.S. Army Research Institute of Environmental MedicineNatickMassachusettsUSA
| |
Collapse
|
|
14
|
Miller JA, Nguyen TT, Loeb C, Khera M, Yafi FA. Oral testosterone therapy: past, present, and future. Sex Med Rev 2023; 11:124-138. [PMID: 36779549 DOI: 10.1093/sxmrev/qead003] [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: 07/26/2022] [Revised: 12/17/2022] [Accepted: 12/27/2022] [Indexed: 02/14/2023]
Abstract
INTRODUCTION Testosterone replacement therapy (TRT) remains a commonly utilized treatment for men with testosterone deficiency (TD). Despite the recent FDA approval of new oral TRT medications, concerns remain regarding their efficacy and safety, and prescription rates for these medications have decreased compared to those for TD medications with other routes of administration. OBJECTIVE In this study we sought to investigate the efficacy and safety of oral testosterone undecanoate (oTU), a new oral TRT medication. METHODS A comprehensive review of the literature was performed using the Medline, EMBASE, and Cochrane Library databases; 1269 articles were identified, with 44 articles included in the final review and 12 used to perform meta-analyses to investigate the change in serum total testosterone (TT) and risk of adverse effects following oral testosterone undecanoate (oTU) use. Articles were also reviewed to investigate the reported effects of oTU on body composition, liver function, hematologic assays, lipid profiles, hormone assays, prostate growth, hypertension, and symptoms of TD. RESULTS Across placebo-controlled randomized trials, there was no significant increase in TT for those receiving oTU vs placebo (mean difference, -0.26 [95% CI, -1.26 to 0.73]). On subanalysis, when eugonadal participants received oTU, a significant decrease in TT was demonstrated (mean difference -0.86 [95% CI, -1.28 to 0.43]). When participants who were hypogonadal at baseline received oTU, a significant increase in TT compared to placebo was seen (mean difference 1.25 [95% CI, 0.22-2.29]). There was no significant risk of adverse effects (RR, -0.03 [95% CI, -0.08 to 0.03]) or serious adverse effects (RR, 0.15 [95% CI, -0.66 to 0.96]) in the oTU groups compared to placebo. CONCLUSION oTU was found to be well tolerated in hypogonadal patients, resulting in improved testosterone levels, height velocity, and sexual symptoms, without significant hepatotoxicity, prostatic enlargement, or worsening hypertension. There was no consensus regarding the effect of oTU on lean and fat mass percentages, hematologic assays, lipid profiles, mood, and general well-being.
Collapse
Affiliation(s)
- Jake A Miller
- Department of Urology, University of California, Irvine, CA, United States
| | - Tuan T Nguyen
- Department of Urology, University of California, Irvine, CA, United States
| | - Charles Loeb
- Department of Urology, University of California, Irvine, CA, United States
| | - Mohit Khera
- Scott Department of Urology, Baylor College of Medicine, Houston, TX, United States
| | - Faysal A Yafi
- Department of Urology, University of California, Irvine, CA, United States
| |
Collapse
|
|
15
|
Raičević V, Radnović ND, Rodić MV, Radulović NS. The crystal structure of 3-hydroxy-2-nitroestra-1,3,5(10)-trien-17-one, C 18H 21NO 4. Z KRIST-NEW CRYST ST 2023. [DOI: 10.1515/ncrs-2022-0602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Abstract
C18H21NO4, orthorhombic, C2221 (no. 20), a = 10.6891(2) Å, b = 11.8375(2) Å, c = 25.4410(4) Å, V = 3219.11(10) Å3, Z = 8, R
gt(F) = 0.0483, wR
ref(F
2) = 0.1449, T = 295 K.
Collapse
Affiliation(s)
- Vidak Raičević
- Faculty of Sciences, University of Novi Sad , Trg Dositeja Obradovića 3, 21000 Novi Sad , Serbia
| | - Nikola D. Radnović
- Faculty of Sciences, University of Novi Sad , Trg Dositeja Obradovića 3, 21000 Novi Sad , Serbia
| | - Marko V. Rodić
- Faculty of Sciences, University of Novi Sad , Trg Dositeja Obradovića 3, 21000 Novi Sad , Serbia
| | - Niko S. Radulović
- Faculty of Sciences and Mathematics, University of Niš , Višegradska 33, 18000 Niš , Serbia
| |
Collapse
|
|
16
|
Miller WL, White PC. History of Adrenal Research: From Ancient Anatomy to Contemporary Molecular Biology. Endocr Rev 2023; 44:70-116. [PMID: 35947694 PMCID: PMC9835964 DOI: 10.1210/endrev/bnac019] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Indexed: 01/20/2023]
Abstract
The adrenal is a small, anatomically unimposing structure that escaped scientific notice until 1564 and whose existence was doubted by many until the 18th century. Adrenal functions were inferred from the adrenal insufficiency syndrome described by Addison and from the obesity and virilization that accompanied many adrenal malignancies, but early physiologists sometimes confused the roles of the cortex and medulla. Medullary epinephrine was the first hormone to be isolated (in 1901), and numerous cortical steroids were isolated between 1930 and 1949. The treatment of arthritis, Addison's disease, and congenital adrenal hyperplasia (CAH) with cortisone in the 1950s revolutionized clinical endocrinology and steroid research. Cases of CAH had been reported in the 19th century, but a defect in 21-hydroxylation in CAH was not identified until 1957. Other forms of CAH, including deficiencies of 3β-hydroxysteroid dehydrogenase, 11β-hydroxylase, and 17α-hydroxylase were defined hormonally in the 1960s. Cytochrome P450 enzymes were described in 1962-1964, and steroid 21-hydroxylation was the first biosynthetic activity associated with a P450. Understanding of the genetic and biochemical bases of these disorders advanced rapidly from 1984 to 2004. The cloning of genes for steroidogenic enzymes and related factors revealed many mutations causing known diseases and facilitated the discovery of new disorders. Genetics and cell biology have replaced steroid chemistry as the key disciplines for understanding and teaching steroidogenesis and its disorders.
Collapse
Affiliation(s)
- Walter L Miller
- Department of Pediatrics, Center for Reproductive Sciences, and Institute for Human Genetics, University of California, San Francisco, CA, USA
| | - Perrin C White
- Division of Pediatric Endocrinology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| |
Collapse
|
|
17
|
Rouver WDN, Delgado NTB, Gonçalves LT, Giesen JAS, Santos da Costa C, Merlo E, Damasceno Costa E, Lemos VS, Bernardes Graceli J, Santos RLD. Sex hormones and vascular reactivity: a temporal evaluation in resistance arteries of male rats. J Mol Endocrinol 2023; 70:e220147. [PMID: 36476761 DOI: 10.1530/jme-22-0147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 10/18/2022] [Indexed: 11/09/2022]
Abstract
The role of androgens in vascular reactivity is controversial, particularly regarding their age-related actions. The objective of this study was to conduct a temporal evaluation of the vascular reactivity of resistance arteries of young male rats, as well as to understand how male sex hormones can influence the vascular function of these animals. Endothelium-mediated relaxation was characterized in third-order mesenteric arteries of 10-, 12-, 16-, and 18w (week-old) male rats. Concentration-response curves to acetylcholine (ACh, 0.1 nmol/L-10 µmol/L) were constructed in arteries previously contracted with phenylephrine (PE, 3 µmol/L), before and after the use of nitric oxide synthase or cyclooxygenase inhibitors. PE concentration-response curves (1 nmol/L-100 μmol/L) were also built. The levels of vascular nitric oxide, superoxide anion, and hydrogen peroxide were assessed and histomorphometry analysis was performed. The 18w group had impaired endothelium-dependent relaxation. All groups showed prostanoid-independent and nitric oxide-dependent vasodilatory response, although this dependence seems to be smaller in the 18w group. The 18w group had the lowest nitric oxide and hydrogen peroxide production, in addition to the highest superoxide anion levels. Besides functional impairment, 18w animals showed morphological differences in third-order mesenteric arteries compared with the other groups. Our data show that time-dependent exposure to male sex hormones appears to play an important role in the development of vascular changes that can lead to impaired vascular reactivity in mesenteric arteries, which could be related to the onset of age-related cardiovascular changes in males.
Collapse
Affiliation(s)
- Wender do Nascimento Rouver
- Department of Physiological Sciences, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil
| | | | - Leticia Tinoco Gonçalves
- Department of Physiological Sciences, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil
| | | | - Charles Santos da Costa
- Department of Morphology, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil
| | - Eduardo Merlo
- Department of Morphology, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil
| | - Eduardo Damasceno Costa
- Department of Physiology and Biophysics, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Virginia Soares Lemos
- Department of Physiology and Biophysics, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Jones Bernardes Graceli
- Department of Morphology, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil
| | - Roger Lyrio Dos Santos
- Department of Physiological Sciences, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil
| |
Collapse
|
|
18
|
Keuroghlian AS, Keatley J, Shaikh S, Radix AE. The context, science and practice of gender-affirming care. Nat Med 2022; 28:2464-2467. [PMID: 36522607 DOI: 10.1038/s41591-022-02082-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Alex S Keuroghlian
- The Fenway Institute, Fenway Health, Boston, MA, USA.
- Massachusetts General Hospital, Boston, MA, USA.
- Harvard Medical School, Boston, MA, USA.
| | - JoAnne Keatley
- Innovative Response Globally for Transgender Women and HIV, Oakland, CA, USA
| | - Simran Shaikh
- Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Asa E Radix
- Callen-Lorde Community Health Center, New York, NY, USA
| |
Collapse
|
|
19
|
Honig S, Gittelman M, Kaminetsky J, Wang C, Amory JK, Rohowsky N, Dudley RE, Woun Seo B, Newmark J, Swerdloff R. Two-Year Analysis of a New Oral Testosterone Undecanoate (TU) Formulation in Hypogonadal Men: Efficacy, Impact on Psychosexual Function, and Safety. J Sex Med 2022; 19:1750-1758. [PMID: 36272969 DOI: 10.1016/j.jsxm.2022.09.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 09/02/2022] [Accepted: 09/05/2022] [Indexed: 11/18/2022]
Abstract
BACKGROUND Long-term data evaluating the efficacy and safety of oral testosterone undecanoate (oral TU; JATENZO) in adult hypogonadal men provides important information for healthcare professionals who prescribe testosterone replacement therapy (TRT). AIM To determine the efficacy and safety of long-term oral TU therapy, including its impact on total testosterone (T) levels and psychosexual functioning. METHODS Hypogonadal men, between 18 and 75 years old, (mean age 56.2; 87.2% white) who completed a 12-month, open-label, multicenter, randomized, active-controlled trial were given the opportunity to enroll in a 12-month extension study. Among the 129 eligible TU-treated subjects, 86 chose this option, and 69 completed 24 months of uninterrupted oral TU therapy. OUTCOMES The efficacy of oral TU was documented by measuring total serum T concentrations; sexual function was measured using the Psychosexual Daily Questionnaire (PDQ). For safety, liver function tests, cardiovascular endpoints, and prostate health were measured. RESULTS Over 2 years, total serum T concentrations for patients treated with oral TU were in the eugonadal range (300-1,000 ng/dL [10-35 nmol/L]; mean ± SD: 617 ± 427 ng/dL [21 ± 15 nmol/L]) and increased significantly from baseline (P < .0001). For sexual function, mean score changes versus baseline for all PDQ domains at all time points were significantly improved (P < .0011 for all). For the sexual activity and sexual desire components, patient scores were consistently greater than validated thresholds for clinically meaningful change. Typical T-induced safety changes were observed, including a 3-6 mm Hg increase in systolic blood pressure (P < .05); a slight increase in hematocrit (P < .0001) that stayed <48% throughout the study; no clinically significant changes in prostate-specific antigen levels; and decreased high-density lipoprotein cholesterol (-9.8 ± 0.9 mg/dL from baseline; P < .0001). There were no clinically significant changes from baseline in liver function tests. CLINICAL IMPLICATIONS Over 2 years of treatment, this novel oral TU formulation maintained total T concentrations in mideugonadal ranges, with improvements in sexual function and no clinically significant changes in liver function or other safety concerns previously associated with oral TRT. STRENGTHS & LIMITATIONS These are the first long-term data to evaluate the efficacy and safety of a novel formulation of oral TU; the comparative long-term safety of oral TU would be strengthened by confirmatory studies versus other TRT formulations. CONCLUSION Oral TU offers a safe and effective long-term treatment option for men with hypogonadism. Honig S, Gittelman M, Kaminetsky J, et al. Two-Year Analysis of a New Oral Testosterone Undecanoate (TU) Formulation in Hypogonadal Men: Efficacy, Impact on Psychosexual Function, and Safety. J Sex Med 2022;19:1750-1758.
Collapse
Affiliation(s)
- Stanton Honig
- Department of Urology, Yale School of Medicine, New Haven, CT, USA.
| | - Marc Gittelman
- UroMedix and South Florida Medical Research, Aventura, FL, USA
| | - Jed Kaminetsky
- Department of Urology, New York University School of Medicine, New York, NY, USA
| | - Christina Wang
- The Lundquist Institute at Harbor-UCLA, Torrance, CA, USA
| | - John K Amory
- Divison of Endocrinology, University of Washington School of Medicine, Seattle, WA, USA
| | - Nestor Rohowsky
- Integrated Data Consultation Services, Inc., La Grange, IL, USA
| | | | - B Woun Seo
- Clarus Therapeutics, Northbrook, IL, USA
| | | | | |
Collapse
|
|
20
|
Dahiya V, Bagchi G. Non-canonical androgen signaling pathways and implications in prostate cancer. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2022; 1869:119357. [PMID: 36100060 DOI: 10.1016/j.bbamcr.2022.119357] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 08/11/2022] [Accepted: 09/01/2022] [Indexed: 06/15/2023]
Abstract
Androgen signaling is a critical determinant of timely and proper development of all male organs including the prostate. Maturation of prostate and its neoplastic transformation is intricately associated with accurate androgen signaling. Ablation of androgen has therefore been the primary treatment mechanism of Prostate cancer (PCa) patients for several decades. Upon removal, the tumor recedes for a while, yet it reappears soon, in an androgen independent state, untreatable by current therapeutic regimens. Studies reveal that apart from the classical androgen signaling pathway known and targeted for almost a century, there exist several non-canonical pathways, with marked impact on classical androgen signaling and PCa growth. These include non-genomic signaling by androgens via alternate membrane GPCRs, signaling by non-androgens that ultimately impact the androgen signaling pathway, or an integration of non-genomic and genomic response as seen in case of protein kinase A activation. Accurate understanding of these various non-canonical androgen signaling pathways and their influence on the typical androgen signaling pathway can help design important interventions for PCa patients. This review analyses in detail the various non-classical androgen signaling pathways and their impact, if any, on classical mode of androgen action and PCa.
Collapse
Affiliation(s)
- Versha Dahiya
- Amity Institute of Biotechnology, Amity University Haryana, India, 122413
| | - Gargi Bagchi
- Amity Institute of Biotechnology, Amity University Haryana, India, 122413.
| |
Collapse
|
|
21
|
Doping and sports endocrinology: anabolic-androgenic steroids. Rev Clin Esp 2022; 222:612-620. [PMID: 36400345 DOI: 10.1016/j.rceng.2022.09.003] [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: 06/25/2022] [Accepted: 09/16/2022] [Indexed: 11/17/2022]
Abstract
The use of anabolic steroids affects not only professional athletes but also the general population (bodybuilders, gym clients, and adolescents). In the first case, its use is prohibited and sanctioned by the World Anti-Doping Agency and Olympic committees. For the other users, it is difficult to establish its prevalence since many obtain the products via the internet. The reasons for its use are varied and different forms of use and other types of users have been described. Among the side effects of steroid use, hypogonadism is the most frequent cause for endocrinological consultation. After a general introduction to doping, this review describes the historical background of anabolic-androgenic steroids, their classification, forms of use, physiological effects, adverse effects on different organs and systems, treatment of hypogonadism, as well as detection methods.
Collapse
|
|
22
|
Bhat SZ, Dobs AS. Testosterone Replacement Therapy: A Narrative Review with a Focus on New Oral Formulations. TOUCHREVIEWS IN ENDOCRINOLOGY 2022; 18:133-140. [PMID: 36694887 PMCID: PMC9835814 DOI: 10.17925/ee.2022.18.2.133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 05/12/2022] [Indexed: 12/13/2022]
Abstract
Male hypogonadism affects 10-30% of the male population and is often under-recognized and under-treated. Different replacement formulations exist, each with specific benefits and limitations. These replacements include gels, patches and short- and long-acting injectables. JATENZO® (oral testosterone undecanoate; Clarus Therapeutics Inc., Northbrook, IL, US) is the first oral formulation of testosterone approved by the US Food and Drug Administration. TLANDO® (oral testosterone undecanoate; Lipocine Inc., Salt Lake City, UT, US), another oral testosterone formulation, has also recently been approved by the US Food and Drug Administration. Based on unique chemistry using a self-emulsifying drug delivery system and lymphatic absorption, JATENZO and TLANDO address some of the limitations of other dosing routes while providing a safe option without evidence of liver dysfunction. This review discusses various testosterone treatment options, focusing on the role and pharmacokinetics of the new oral formulations.
Collapse
Affiliation(s)
- Salman Z Bhat
- Department of Endocrinology, Diabetes and Metabolism, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Adrian S Dobs
- Department of Endocrinology, Diabetes and Metabolism, Johns Hopkins Hospital, Baltimore, MD, USA
| | | | | |
Collapse
|
|
23
|
Thirumalai A, Anawalt BD. Androgenic Steroids Use and Abuse. Urol Clin North Am 2022; 49:645-663. [DOI: 10.1016/j.ucl.2022.07.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
|
|
24
|
Rostom M, Ramasamy R, Kohn TP. History of testosterone therapy through the ages. Int J Impot Res 2022; 34:623-625. [PMID: 35075296 DOI: 10.1038/s41443-021-00493-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 10/17/2021] [Accepted: 10/28/2021] [Indexed: 11/08/2022]
Abstract
The symptoms of testosterone deficiency have been known throughout history with evidence dating back to the twenty-first century BCE when men were castrated to be docile and obedient servants. Experimentation ingesting mammalian testicles began during the reign of the Roman empire and continued through the nineteenth century with claims that the substance found within these testicles could improve energy, erectile function, and urination. In the twentieth century, studies transplanting animal testes onto other castrated animals suggested that a substance produced in the testicle was responsible for systemic effects. Then in 1929, Adolf Butendant was the first to isolate testosterone and shortly after synthetic formulations of testosterone were created. While testosterone therapy is an important treatment for testosterone deficiency, the history of testosterone therapy has not been without abuse from doping scandals in the twentieth century and the use of testosterone therapy for conversion therapy and treatment of psychiatric disease. Today, there are clear and appropriate clinical uses of testosterone set by the American Urological Association to treat clinically significant testosterone deficiency. Still, even with such guidelines, the potential for misuse and abuse remains high in physicians and athletes. There is a long history that has led to the development of testosterone therapy and when used appropriately can significantly improve the quality of life for men with testosterone deficiency.
Collapse
Affiliation(s)
- Mary Rostom
- The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ranjith Ramasamy
- Department of Urology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Taylor P Kohn
- The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| |
Collapse
|
|
25
|
Alemany M. The Roles of Androgens in Humans: Biology, Metabolic Regulation and Health. Int J Mol Sci 2022; 23:11952. [PMID: 36233256 PMCID: PMC9569951 DOI: 10.3390/ijms231911952] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 09/26/2022] [Accepted: 09/27/2022] [Indexed: 11/17/2022] Open
Abstract
Androgens are an important and diverse group of steroid hormone molecular species. They play varied functional roles, such as the control of metabolic energy fate and partition, the maintenance of skeletal and body protein and integrity and the development of brain capabilities and behavioral setup (including those factors defining maleness). In addition, androgens are the precursors of estrogens, with which they share an extensive control of the reproductive mechanisms (in both sexes). In this review, the types of androgens, their functions and signaling are tabulated and described, including some less-known functions. The close interrelationship between corticosteroids and androgens is also analyzed, centered in the adrenal cortex, together with the main feedback control systems of the hypothalamic-hypophysis-gonads axis, and its modulation by the metabolic environment, sex, age and health. Testosterone (T) is singled out because of its high synthesis rate and turnover, but also because age-related hypogonadism is a key signal for the biologically planned early obsolescence of men, and the delayed onset of a faster rate of functional losses in women after menopause. The close collaboration of T with estradiol (E2) active in the maintenance of body metabolic systems is also presented Their parallel insufficiency has been directly related to the ravages of senescence and the metabolic syndrome constellation of disorders. The clinical use of T to correct hypoandrogenism helps maintain the functionality of core metabolism, limiting excess fat deposition, sarcopenia and cognoscitive frailty (part of these effects are due to the E2 generated from T). The effectiveness of using lipophilic T esters for T replacement treatments is analyzed in depth, and the main problems derived from their application are discussed.
Collapse
Affiliation(s)
- Marià Alemany
- Facultat de Biologia, Universitat de Barcelona, Av. Diagonal, 635, 08028 Barcelona, Catalonia, Spain;
- Institut de Biomedicina, Universitat de Barcelona, 08028 Barcelona, Catalonia, Spain
| |
Collapse
|
|
26
|
Abstract
The androgen receptor (AR) plays a key role in the maintenance of muscle and bone and the support of male sexual-related functions, as well as in the progression of prostate cancer. Accordingly, AR-targeted therapies have been developed for the treatment of related human diseases and conditions. AR agonists are an important class of drugs in the treatment of bone loss and muscle atrophy. AR antagonists have also been developed for the treatment of prostate cancer, including metastatic castration-resistant prostate cancer (mCRPC). Additionally, selective AR degraders (SARDs) have been reported. More recently, heterobifunctional degrader molecules of AR have been developed, and four such compounds are now in clinical development for the treatment of human prostate cancer. This review attempts to summarize the different types of compounds designed to target AR and the current frontiers of research on this important therapeutic target.
Collapse
Affiliation(s)
- Weiguo Xiang
- Departments of Internal Medicine, Pharmacology and Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Shaomeng Wang
- Departments of Internal Medicine, Pharmacology and Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States
| |
Collapse
|
|
27
|
Liu B, Zheng S, Tang H, Liu Q, Li H, Gao B, Zhao X, Sun F. Highly sensitive detection of free testosterone assisted by magnetic nanobeads and gap-enhanced SERS nanotags. Colloids Surf B Biointerfaces 2022; 214:112460. [PMID: 35298951 DOI: 10.1016/j.colsurfb.2022.112460] [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: 09/27/2021] [Revised: 03/07/2022] [Accepted: 03/10/2022] [Indexed: 01/03/2023]
Abstract
The quantitative determination of trace free testosterone (FT) is of great significance for the diagnosis of androgen-related endocrine diseases. Herein, a fascinating detection protocol was developed for highly sensitive FT analysis through a competitive immunoassay mechanism, which was composed of magnetic nanobeads (MNBs) and gap-enhanced surface enhanced Raman scattering (SERS) nanotags. With the MNBs as detection carriers, trace FT could be enriched by simple magnetic separation. The SERS nanotag constructed with silver-gold core-shell nanoparticle was acted as quantitative label, and Raman indicators were located at the interface between silver core and gold shell. It is demonstrated that the as-proposed protocol achieves high detection sensitivity for FT of 12.11 fg mL-1, and wider linear dynamic detection range (LDR) in the concentration of 100 fg mL-1 to 100 ng mL-1 with R2 value of 0.979, which is due to the enhanced Raman signal of the gap-enhanced SERS nanotag and the high surface-to-volume ratio of the MNB, respectively. Taking advantages of such sensitivity and accuracy approach, the as-developed powerful strategy presents potential applications for rapid disease diagnosis through analyzing trace levels of FT, and can also provide guidance for the exploitation of analysis project of other analytes.
Collapse
Affiliation(s)
- Bing Liu
- Medical School, Institute of Reproductive Medicine, Nantong University, Nantong 226001, China.
| | - Shiya Zheng
- Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Hanyu Tang
- Medical School, Institute of Reproductive Medicine, Nantong University, Nantong 226001, China
| | - Qian Liu
- Medical School, Institute of Reproductive Medicine, Nantong University, Nantong 226001, China
| | - Haitao Li
- Medical School, Institute of Reproductive Medicine, Nantong University, Nantong 226001, China
| | - Bingbing Gao
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, China
| | - Xiangwei Zhao
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China; Southeast University Shenzhen Research Institute, Shenzhen 518000, China.
| | - Fei Sun
- Medical School, Institute of Reproductive Medicine, Nantong University, Nantong 226001, China.
| |
Collapse
|
|
28
|
Comparative application of testosterone undecanoate and/or testosterone propionate in induction of benign prostatic hyperplasia in Wistar rats. PLoS One 2022; 17:e0268695. [PMID: 35584179 PMCID: PMC9116659 DOI: 10.1371/journal.pone.0268695] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Accepted: 05/04/2022] [Indexed: 11/19/2022] Open
Abstract
Testosterone undecanoate is a hormone agent with long-acting potential and is used for testosterone replacement therapy for hypogonadism. This study was designed to investigate application of testosterone undecanoate in maintaining high androgen levels for inducing benign prostatic hyperplasia more conveniently than that for testosterone propionate. We conducted two-part studies to determine the optimal dosage and dosing cycle for efficient and stable induction of benign prostatic hyperplasia using testosterone undecanoate. In the injection dosage substudy, single testosterone undecanoate dose (125, 250, 500, 750, or 1000 mg/kg body weight) was administered, and the optimal concentration was determined for 8weeks by measuring changes in testosterone, dihydrotestosterone, and 5-alpha reductase levels. And then, testosterone undecanoate was administered at the optimal dose at intervals of 1, 2, 3, or 4 weeks for 12weeks to induce benign prostatic hyperplasia. The injection dosage substudy showed dose-dependently higher and more stable levels of testosterone in groups administrated testosterone undecanoate than in groups administered testosterone propionate. In the injection cycle substudy, testosterone undecanoate-administered group stably maintained high levels of testosterone, dihydrotestosterone, and 5-alpha reductase compared with testosterone propionate-administered group for the same injection cycle; moreover, the prostate measurements, an important sign of benign prostatic hyperplasia, were significantly increased. Based on these two substudies, we determined the optimal conditions for inducing benign prostatic hyperplasia stably and more conveniently than that for testosterone propionate. This study suggests an extended application of testosterone undecanoate for inducing benign prostatic hyperplasia that can improve research reliability considering the half-life of testosterone as well as injection dosage and concentration.
Collapse
|
|
29
|
Abstract
ABSTRACT Hypogonadism is a clinical syndrome of testosterone deficiency that presents with nonspecific symptoms of sexual dysfunction, fatigue, and decreased strength or muscle mass. Men with obesity, diabetes, and other comorbidities are at higher risk for hypogonadism. Patients presenting with symptoms should be tested for low testosterone and treated with testosterone replacement. Testosterone therapy carries risks and must be closely monitored. Patients treated for hypogonadism may experience improvement of symptoms and quality of life.
Collapse
Affiliation(s)
- Gina Ugo-Neff
- Gina Ugo-Neff practices at Uropartners at Rush University in Chicago, Ill. Denise Rizzolo is an assistant clinical professor in the Pace Completion Program in the Department of Physician Assistant Studies in New York City and an assessment specialist at the Physician Assistant Education Association. The authors have disclosed no potential conflicts of interest, financial or otherwise
| | | |
Collapse
|
|
30
|
Sansone A, Jannini TB, Dolci S, Jannini EA. Castration and emasculation in the middle age. The andrological conundrum of Peter Abelard. Andrology 2022; 10:825-836. [PMID: 35355434 DOI: 10.1111/andr.13180] [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: 03/01/2022] [Revised: 03/23/2022] [Accepted: 03/24/2022] [Indexed: 11/30/2022]
Abstract
: Peter Abelard (1079 - 1142) is still considered one of the giants of philosophy, theology, and psychology, and the unsurpassed master of dialectical debate. Born in Le Pallet, near Nantes, Abelard became an academic and wandering cleric of great fame, founder of several schools that attracted students from all countries, arousing the admiration of his contemporaries and the profound envy of his colleagues. Around 1115, Abelard became master of the school of the Cathedral of Notre-Dame. Shortly after, the canon Fulbert asked him to take his niece, the equally famous and highly cultured Héloïse d'Argenteuil (1092 ? - 1164), as a pupil. Thus a relationship began, celebrated for centuries to come, characterized by burning sexual and intellectual passion, famous correspondence which will be the archetype of sentimental education and the template of romantic love letters, the birth of a son and consequent marriage, and the cowardly revenge of Fulbert, who, together with a band of servants, mutilated<<those parts of my body with which I had done what was the cause of their pain>>, as Abelard wrote. While this unclear self-description has suggested to contemporaries and to posterity that Abelard was castrated, we aim to question this belief by analyzing in-depth this historical-andrological clinical case to understand if there is any evidence that could suggest that Abelard was instead the victim of an even more brutal punishment: penectomy. Signs and symptoms gleaned from the personal writings and historical perspectives of Abelard and his time are used here to provide a possible answer to a thousand-year-old question: what makes a man … a man? This article is protected by copyright. All rights reserved.
Collapse
Affiliation(s)
- Andrea Sansone
- Chair of Endocrinology and Medical Sexology (ENDOSEX), Department of Systems Medicine, University of Rome Tor Vergata, Italy
| | - Tommaso B Jannini
- School of Psychiatry, Department of Systems Medicine, University of Rome Tor Vergata, Italy
| | - Susanna Dolci
- Chair of Anatomy, Department of Biomedicine and Prevention, University of Rome Tor Vergata
| | - Emmanuele A Jannini
- Chair of Endocrinology and Medical Sexology (ENDOSEX), Department of Systems Medicine, University of Rome Tor Vergata, Italy
| |
Collapse
|
|
31
|
Fodor I, Pirger Z. From Dark to Light - An Overview of Over 70 Years of Endocrine Disruption Research on Marine Mollusks. Front Endocrinol (Lausanne) 2022; 13:903575. [PMID: 35872980 PMCID: PMC9301197 DOI: 10.3389/fendo.2022.903575] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 06/13/2022] [Indexed: 11/13/2022] Open
|
|
32
|
Oral Testosterone. CURRENT SEXUAL HEALTH REPORTS 2021. [DOI: 10.1007/s11930-021-00319-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
|
|
33
|
Elz AS, Trevaskis NL, Porter CJH, Bowen JM, Prestidge CA. Smart design approaches for orally administered lipophilic prodrugs to promote lymphatic transport. J Control Release 2021; 341:676-701. [PMID: 34896450 DOI: 10.1016/j.jconrel.2021.12.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 12/03/2021] [Accepted: 12/04/2021] [Indexed: 12/22/2022]
Abstract
Challenges to effective delivery of drugs following oral administration has attracted growing interest over recent decades. Small molecule drugs (<1000 Da) are generally absorbed across the gastrointestinal tract into the portal blood and further transported to the systemic circulation via the liver. This can result in a significant reduction to the oral bioavailability of drugs that are metabolically labile and ultimately lead to ineffective exposure and treatment. Targeting drug delivery to the intestinal lymphatics is attracting increased attention as an alternative route of drug transportation providing multiple benefits. These include bypassing hepatic first-pass metabolism and selectively targeting disease reservoirs residing within the lymphatic system. The particular physicochemical requirements for drugs to be able to access the lymphatics after oral delivery include high lipophilicity (logP>5) and high long-chain triglyceride solubility (> 50 mg/g), properties required to enable drug association with the lipoprotein transport pathway. The majority of small molecule drugs, however, are not this lipophilic and therefore not substantially transported via the intestinal lymph. This has contributed to a growing body of investigation into prodrug approaches to deliver drugs to the lymphatic system by chemical manipulation. Optimised lipophilic prodrugs have the potential to increase lymphatic transport thereby improving oral pharmacokinetics via a reduction in first pass metabolism and may also target of disease-specific reservoirs within the lymphatics. This may provide advantages for current pharmacotherapy approaches for a wide array of pathological conditions, e.g. immune disease, cancer and metabolic disease, and also presents a promising approach for advanced vaccination strategies. In this review, specific emphasis is placed on medicinal chemistry strategies that have been successfully employed to design lipophilic prodrugs to deliberately enable lymphatic transport. Recent progress and opportunities in medicinal chemistry and drug delivery that enable new platforms for efficacious and safe delivery of drugs are critically evaluated.
Collapse
Affiliation(s)
- Aurelia S Elz
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia.
| | - Natalie L Trevaskis
- Department of Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC 3052, Australia.
| | - Christopher J H Porter
- Department of Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC 3052, Australia.
| | - Joanne M Bowen
- School of Biomedicine, The University of Adelaide, Adelaide, SA 5005, Australia.
| | - Clive A Prestidge
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia.
| |
Collapse
|
|
34
|
Kean AC, Saroufim R, Meininger E, Fuqua JS, Fortenberry JD. Cardiovascular Health of Youth During Gender-Affirming Testosterone Treatment: A Review. J Adolesc Health 2021; 69:896-904. [PMID: 34627656 DOI: 10.1016/j.jadohealth.2021.08.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 07/21/2021] [Accepted: 08/05/2021] [Indexed: 01/13/2023]
Abstract
PURPOSE Many birth-assigned female/transgender male and nonbinary people (identified as masculine spectrum here) begin gender-affirming testosterone therapy by the age of 24 years. Few data inform assessment of cardiovascular health of masculine spectrum youth as a specific subgroup of the 1.5 million transgender people in the United States. The purpose of this review is to help youth-serving practitioners consider, understand, and evaluate cardiovascular health in adolescent and young adult masculine spectrum patients receiving gender-affirming testosterone treatment. METHODS This is a narrative review intended to synthesize a broad body of clinical and research literature. RESULTS Common cardiovascular health changes associated with testosterone include increased red blood cell mass and likely insignificant changes in high-density lipoprotein and low-density lipoprotein levels. Changes in heart mass, heart electrophysiology, and endothelial reactivity are likely, based on extrapolation of data from adults. Testosterone may have indirect effects on cardiovascular health through influences on depression, anxiety, stress, and anorexia nervosa as well as on behaviors such as tobacco use. CONCLUSIONS Testosterone contributes importantly to the cardiovascular health and well-being of masculine spectrum gender-diverse youth. We need to do a better job of supporting these young people with data on cardiovascular health over the life span.
Collapse
Affiliation(s)
- Adam C Kean
- Division of Pediatric Cardiology, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
| | - Rita Saroufim
- Division of Pediatric Endocrinology, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
| | - Eric Meininger
- Division of Adolescent Medicine, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
| | - John S Fuqua
- Division of Pediatric Endocrinology, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
| | - J Dennis Fortenberry
- Division of Adolescent Medicine, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.
| |
Collapse
|
|
35
|
Fessner ND, Grimm C, Srdič M, Weber H, Kroutil W, Schwaneberg U, Glieder A. Natural Product Diversification by One‐Step Biocatalysis using Human P450 3A4. ChemCatChem 2021. [DOI: 10.1002/cctc.202101564] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Nico D. Fessner
- Institute of Molecular Biotechnology NAWI Graz Graz University of Technology Petersgasse 14 8010 Graz Austria
| | - Christopher Grimm
- Institute of Chemistry NAWI Graz University of Graz Heinrichstraße 28 8010 Graz Austria
| | - Matic Srdič
- SeSaM-Biotech GmbH Forckenbeckstraße 50 52074 Aachen Germany
- Bisy GmbH Wuenschendorf 292 Hofstätten an der Raab 8200 Hofstaetten Austria
| | - Hansjörg Weber
- Institute of Organic Chemistry NAWI Graz Graz University of Technology Stremayrgasse 9 8010 Graz Austria
| | - Wolfgang Kroutil
- Institute of Chemistry NAWI Graz University of Graz Heinrichstraße 28 8010 Graz Austria
| | - Ulrich Schwaneberg
- Institute of Biotechnology RWTH Aachen University Worringerweg 3 52074 Aachen Germany
| | - Anton Glieder
- Institute of Molecular Biotechnology NAWI Graz Graz University of Technology Petersgasse 14 8010 Graz Austria
| |
Collapse
|
|
36
|
Tijerina AN, Srivastava AV, Patel VR, Osterberg EC. Current use of testosterone therapy in LGBTQ populations. Int J Impot Res 2021; 34:642-648. [PMID: 34815551 DOI: 10.1038/s41443-021-00490-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 10/14/2021] [Accepted: 10/25/2021] [Indexed: 01/23/2023]
Abstract
Testosterone therapy (TT) is a type of gender-affirming hormone therapy (GAHT) in lesbian, gay, bisexual, transgender, and genderqueer (LGBTQ) populations for gender dysphoria (GD), body uneasiness, and sexual dysfunction. The physical and physiological effects of TT vary widely depending on the dosing regimen and duration of treatment. An individualized approach prioritizing patient-specific desired effects in the context of pre-existing characteristics and health history is strongly recommended. Although TT is an effective treatment for many patients, there has been an increase in the illegitimate acquisition of TT in recent years. Non-judicious prescribing and lack of physician surveillance increases the risk of unintended side effects and potential serious health consequences.
Collapse
Affiliation(s)
- A N Tijerina
- University of Texas Dell Medical School, Austin, TX, 78712, USA.
| | - A V Srivastava
- University of Texas Dell Medical School, Austin, TX, 78712, USA
| | - V R Patel
- University of Texas Dell Medical School, Austin, TX, 78712, USA
| | - E C Osterberg
- University of Texas Dell Medical School, Austin, TX, 78712, USA.,Dell Medical School Department of Surgery and Perioperative Care and Ascension Seton Hospital Network, Austin, TX, 78712, USA
| |
Collapse
|
|
37
|
Alemany M. Estrogens and the regulation of glucose metabolism. World J Diabetes 2021; 12:1622-1654. [PMID: 34754368 PMCID: PMC8554369 DOI: 10.4239/wjd.v12.i10.1622] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/10/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
The main estrogens: estradiol, estrone, and their acyl-esters have been studied essentially related to their classical estrogenic and pharmacologic functions. However, their main effect in the body is probably the sustained control of core energy metabolism. Estrogen nuclear and membrane receptors show an extraordinary flexibility in the modulation of metabolic responses, and largely explain gender and age differences in energy metabolism: part of these mechanisms is already sufficiently known to justify both. With regard to energy, the estrogen molecular species act essentially through four key functions: (1) Facilitation of insulin secretion and control of glucose availability; (2) Modulation of energy partition, favoring the use of lipid as the main energy substrate when more available than carbohydrates; (3) Functional protection through antioxidant mechanisms; and (4) Central effects (largely through neural modulation) on whole body energy management. Analyzing the different actions of estrone, estradiol and their acyl esters, a tentative classification based on structure/effects has been postulated. Either separately or as a group, estrogens provide a comprehensive explanation that not all their quite diverse actions are related solely to specific molecules. As a group, they constitute a powerful synergic action complex. In consequence, estrogens may be considered wardens of energy homeostasis.
Collapse
Affiliation(s)
- Marià Alemany
- Faculty of Biology, University of Barcelona, Barcelona 08028, Catalonia, Spain
| |
Collapse
|
|
38
|
Odland SU, Ravna AW, Smaglyukova N, Dietrichs ES, Sager G. Inhibition of ABCC5-mediated cGMP transport by progesterone, testosterone and their analogues. J Steroid Biochem Mol Biol 2021; 213:105951. [PMID: 34271023 DOI: 10.1016/j.jsbmb.2021.105951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 06/18/2021] [Accepted: 07/11/2021] [Indexed: 11/17/2022]
Abstract
The biodynamics and biokinetics of sex hormones are complex. In addition to the classical steroid receptors (nuclear receptors), these hormones act through several non-genomic mechanisms. Modulation of ABC-transporters by progesterone represents a non-genomic mechanism. In the present study, we employed inside out vesicles from human erythrocytes to characterize high affinity cGMP transport by ABCC5 (member 5 of the ATP-Binding Cassette subfamily C). Progesterone and testosterone inhibited the transport with respective Ki of 1.2 ± 0.3 and 2.0 ± 0.6 μmol/L. We used virtual ligand screening (VLS) to identify analogues to progesterone and testosterone. A large number of substances were screened in silico and the 19 most promising candidates were screened in vitro. Each substance was tested for a concentration of 10 μmol/L. The range of cGMP transport reduction was 21.5% to 86.2% for progesterone analogues and 8.6% to 93.8 % for testosterone analogues. Three of the most potent test compounds (TC) of each analogue class, in addition to progesterone and testosterone, were characterized for concentrations from 1 nanomol/L to 1 mmol/L. The progesterone analogues showed following Ki-values (μmol/L): TC-08: 0.61, TC-16: 0.66 and TC-15: 9.3. The Ki-values (μmol/L) for the testosterone analogues were: TC-18: 0.10, TC-07: 0.67 andTC-05: 2.0. The present study shows that VLS may be a versatile tool in the development of membrane transport modulating agents (MTMAs).
Collapse
Affiliation(s)
- Sondre Ulstein Odland
- Experimental and Clinical Pharmacology, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway; AJ Vaccines A/S Artillerivej 5, 2300, Copenhagen S, Denmark(1)
| | - Aina Westrheim Ravna
- Experimental and Clinical Pharmacology, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway
| | - Natalia Smaglyukova
- Experimental and Clinical Pharmacology, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway
| | - Erik Sveberg Dietrichs
- Experimental and Clinical Pharmacology, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway; Centre for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway
| | - Georg Sager
- Experimental and Clinical Pharmacology, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway.
| |
Collapse
|
|
39
|
Bhasin S, Hatfield DL, Hoffman JR, Kraemer WJ, Labotz M, Phillips SM, Ratamess NA. Anabolic-Androgenic Steroid Use in Sports, Health, and Society. Med Sci Sports Exerc 2021; 53:1778-1794. [PMID: 34261998 DOI: 10.1249/mss.0000000000002670] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
This consensus statement is an update of the 1987 American College of Sports Medicine (ACSM) position stand on the use of anabolic-androgenic steroids (AAS). Substantial data have been collected since the previous position stand, and AAS use patterns have changed significantly. The ACSM acknowledges that lawful and ethical therapeutic use of AAS is now an accepted mainstream treatment for several clinical disorders; however, there is increased recognition that AAS are commonly used illicitly to enhance performance and appearance in several segments of the population, including competitive athletes. The illicit use of AAS by competitive athletes is contrary to the rules and ethics of many sport governing bodies. Thus, the ACSM deplores the illicit use of AAS for athletic and recreational purposes. This consensus statement provides a brief history of AAS use, an update on the science of how we now understand AAS to be working metabolically/biochemically, potential side effects, the prevalence of use among athletes, and the use of AAS in clinical scenarios.
Collapse
Affiliation(s)
- Shalender Bhasin
- Department of Medicine, Brigham and Women's Hospital, Boston, MA
| | - Disa L Hatfield
- Department of Kinesiology, University of Rhode Island, Kingston, RI
| | - Jay R Hoffman
- Department of Physical Therapy, Ariel University, Ariel, Israel
| | - William J Kraemer
- Department of Human Sciences, The Ohio State University, Columbus, OH
| | | | | | - Nicholas A Ratamess
- Department of Health and Exercise Science, The College of New Jersey, Ewing, NJ
| |
Collapse
|
|
40
|
Abstract
During adolescence, androgens are responsible for the development of secondary
sexual characteristics, pubertal growth, and the anabolic effects on bone and
muscle mass. Testosterone is the most abundant testicular androgen, but some
effects are mediated by its conversion to the more potent androgen
dihydrotestosterone (DHT) or to estradiol. Androgen deficiency, requiring
replacement therapy, may occur due to a primary testicular failure or secondary
to a hypothalamic–pituitary disorder. A very frequent condition characterized by
a late activation of the gonadal axis that may also need androgen treatment is
constitutional delay of puberty. Of the several testosterone or DHT formulations
commercially available, very few are employed, and none is marketed for its use
in adolescents. The most frequently used androgen therapy is based on the
intramuscular administration of testosterone enanthate or cypionate every 3 to 4
weeks, with initially low doses. These are progressively increased during
several months or years, in order to mimic the physiology of puberty, until
adult doses are attained. Scarce experience exists with oral or transdermal
formulations. Preparations containing DHT, which are not widely available, are
preferred in specific conditions. Oxandrolone, a non-aromatizable drug with
higher anabolic than androgenic effects, has been used in adolescents with
preserved testosterone production, like Klinefelter syndrome, with positive
effects on cardiometabolic health and visual, motor, and psychosocial functions.
The usual protocols applied for androgen therapy in boys and adolescents are
discussed.
Collapse
Affiliation(s)
- Rodolfo A Rey
- Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina.,Departamento de Biología Celular, Histología, Embriología y Genética, Facultad de Medicina, Universidad de Buenos Aires, Argentina
| | - Romina P Grinspon
- Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina
| |
Collapse
|
|
41
|
El-Masry SA, Mahmoud RA, Ahmed HH, Al-Tohamy M, Abdel Latif HM, Afify MAS. Clinical significance of serum gonadotropin and androgen levels among Egyptian overweight/obese pubertal girls. JOURNAL OF COMPLEMENTARY & INTEGRATIVE MEDICINE 2021; 19:389-398. [PMID: 34109772 DOI: 10.1515/jcim-2020-0260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Accepted: 05/26/2021] [Indexed: 11/15/2022]
Abstract
OBJECTIVES Evaluate the association between overweight/obesity with serum gonadotropin and androgen levels in Egyptian pubertal girls. SUBJECTS AND METHODS A case-control study carried out in "Obesity Clinic" of "Diabetes, Endocrine and Metabolism Pediatric Unit (DEMPU)", Pediatric Hospital, Cairo University. It included 40 overweight and obese girls and 40 age-matching normal weight (control) ones, aged 12-18 years. Anthropometric assessment (weight, height and hip and waist circumferences) was done, and waist/hip and BMI were calculated. Laboratory investigations: lipid profile, serum gonadotropin (LH, FSH), androgen (free and total testosterone), estradiol, insulin, and FBG were quantified, while insulin resistance (IR) was calculated. RESULTS Hypogonadotropins (FSH and LH) and hyperandrogenaemia (total and free testosterone) were significantly prominent among obese girls. Correlation between gonadotropin, androgen and all of the studied variables, for the three studied groups (obese, overweight and control) revealed constant relations. Gonadotropin and androgens showed opposing correlations. Gonadotropin had significant negativ e correlations with the anthropometric parameters of obesity (BMI, Waist C, and W/H ratio), insulin, insulin resistance and lipid profile (triglycerides, total cholesterol and LDL), whereas androgens had significant positiv e ones. In addition, gonadotropin showed significant positiv e correlations with estradiol and HDL, while androgens showed significant negative ones. CONCLUSIONS Overweight/obesity had no effect on the correlations between gonadotropin and androgen on one side, with the anthropometric measurements and laboratory investigations on the other one. Alterations in androgen levels occur at earlier ages than gonadotropin, among both overweight and obese girls.
Collapse
Affiliation(s)
- Sahar A El-Masry
- Biological Anthropology Dept., National Research Centre, Giza, Egypt
| | - Rehab A Mahmoud
- Pediatrics Dept., Faculty of Postgraduate, Childhood Studies, Ain Shams University, Cairo, Egypt
| | - Hanaa H Ahmed
- Hormones Dept., National Research Centre, Giza, Egypt
| | | | | | - Mahmoud A S Afify
- Biological Anthropology Dept., National Research Centre, Giza, Egypt
| |
Collapse
|
|
42
|
Su Y, Tian Z, Qi X, Luo D, Liu L, Liu S, Zheng D, Wei F, He Z, Guan Q. Effects of increasing intake of soybean oil on synthesis of testosterone in Leydig cells. Nutr Metab (Lond) 2021; 18:53. [PMID: 34039393 PMCID: PMC8157704 DOI: 10.1186/s12986-021-00580-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 05/18/2021] [Indexed: 11/24/2022] Open
Abstract
Background Soybean oil is a very common edible oil in daily life. With the changes in the dietary composition, the intake of soybean oil increased. However, the effects of dietary intake of soybean oil on testosterone production are still unclear. Methods In order to study the effects of increasing intake of soybean oil on the synthesis of testosterone in Leydig cells, we fed male C57BL/6 mice on the diet which added 20% soybean salad oil (SOY group). We detected the hormone levels by enzyme-linked immunosorbent assay (ELISA) kits and serum fatty acid composition by gas chromatography, and analyzed the expression of steroidogenic enzymes by Real-Time PCR or immunoblotting analysis. Results After the 16-week feeding period, serum linoleic acid (LA) and α-linolenic acid (ALA) significantly increased and serum palmitic acid (PA) significantly decreased in SOY group mice. Compared to the normal diet (ND group), increasing intake of soybean oil raised the luteinizing hormone (LH) levels and up-regulated luteinizing hormone/chorionic gonadotropin receptor (LHCGR), steroidogenic acute regulatory protein (StAR) and cytochrome P450 family 11 subfamily A member I (CYP11A1). Testosterone levels in SOY group were higher than that in the ND group, and significantly difference showed. Conclusions Increasing intake of soybean oil could raise the serum LA and ALA levels and decrease serum PA levels. This could activate the LH/LHCGR pathway and improve the function of steroid synthesis in Leydig cells, and finally lead to the elevated testosterone levels. Supplementary Information The online version contains supplementary material available at 10.1186/s12986-021-00580-1.
Collapse
Affiliation(s)
- Yu Su
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China.,Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, 250021, Shandong, China
| | - Zhenhua Tian
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China.,Department of Endocrinology and Metabolism, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Xiangyu Qi
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China.,Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, 250021, Shandong, China
| | - Dandan Luo
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China.,Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, 250021, Shandong, China
| | - Luna Liu
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China.,Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, 250021, Shandong, China
| | - Shuang Liu
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China.,Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, 250021, Shandong, China
| | - Dongmei Zheng
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China.,Department of Endocrinology and Metabolism, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Fang Wei
- Department of Clinical Expert, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Zhao He
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China. .,Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, 250021, Shandong, China. .,Department of Endocrinology and Metabolism, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
| | - Qingbo Guan
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China. .,Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, 250021, Shandong, China. .,Department of Endocrinology and Metabolism, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
| |
Collapse
|
|
43
|
Grober ED, Krakowsky Y, Khera M, Holmes DT, Lee JC, Grantmyre JE, Patel P, Bebb RA, Fitzpatrick R, Campbell JD, Carrier S, Morgentaler A. Canadian Urological Association guideline on testosterone deficiency in men: Evidence-based Q&A. Can Urol Assoc J 2021; 15:E234-E243. [PMID: 33661092 PMCID: PMC8095276 DOI: 10.5489/cuaj.7252] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Ethan D Grober
- Division of Urology, Women's College Hospital & Sinai Health System, Department of Surgery, University of Toronto, Toronto, ON, Canada
| | - Yonah Krakowsky
- Division of Urology, Women's College Hospital & Sinai Health System, Department of Surgery, University of Toronto, Toronto, ON, Canada
| | - Mohit Khera
- Scott Department of Urology, Baylor College of Medicine, Houston, TX, United States
| | - Daniel T Holmes
- Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Jay C Lee
- Division of Urology, Department of Surgery, University of Calgary, Calgary, AB, Canada
| | - John E Grantmyre
- Department of Urology, Dalhousie University, Halifax, NS, Canada
| | - Premal Patel
- Division of Urology, Department of Surgery, University of Manitoba, Winnipeg, MB, Canada
| | - Richard A Bebb
- Division of Endocrinology & Department of Urological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Ryan Fitzpatrick
- Division of Urology, Women's College Hospital & Sinai Health System, Department of Surgery, University of Toronto, Toronto, ON, Canada
| | - Jeffrey D Campbell
- Division of Urology, Department of Surgery, University of Western Ontario, London, ON, Canada
| | - Serge Carrier
- Division of Urology, Department of Surgery, McGill University, Montreal, QC, Canada
| | | |
Collapse
|
|
44
|
Jaschke N, Wang A, Hofbauer LC, Rauner M, Rachner TD. Late-onset hypogonadism: Clinical evidence, biological aspects and evolutionary considerations. Ageing Res Rev 2021; 67:101301. [PMID: 33610812 DOI: 10.1016/j.arr.2021.101301] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 11/23/2020] [Accepted: 02/15/2021] [Indexed: 12/15/2022]
Abstract
The growing life expectancy in modern societies has raised scientific interest in identifying medical interventions to alleviate age-associated pathologies such as vascular calcification, cognitive decline, sarcopenia, osteoporosis and sexual dysfunction. Although no such single treatment has thus far been established in humans, some clinicians and patients have set their hopes on testosterone replacement therapy (TRT) as a potential "fountain of youth" for aging men. While TRT has proven effective in ameliorating distinct symptoms of late-onset hypogonadism (LOH), its safety remains to be demonstrated. Besides humans, multiple other species exhibit age-related reductions in circulating testosterone levels, raising the question whether such changes are an inherent, pathological feature of growing organismal age or rather reflect an adaptive response. In this manuscript, we apply key principles of evolutionary medicine to testosterone biology and LOH to provide a novel perspective on these two fields. Additionally, we discuss insightful data derived from the animal kingdom to illustrate the plasticity of individual testosterone trajectories across the lifespan, outline cost-benefit-considerations of TRT in LOH and highlight potential caveats of such therapies.
Collapse
Affiliation(s)
- Nikolai Jaschke
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany.
| | - Andrew Wang
- Department of Medicine (Rheumatology, Allergy & Immunology), Yale University School of Medicine, New Haven, CT, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
| | - Lorenz C Hofbauer
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Martina Rauner
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Tilman D Rachner
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| |
Collapse
|
|
45
|
Takeuchi Y, Otsuka R, Kojima H, Fetters MD. Comparison of self-report and objective measures of male sexual dysfunction in a Japanese primary care setting: a cross-sectional, self-administered mixed methods survey. Fam Med Community Health 2021; 9:e000403. [PMID: 33483417 PMCID: PMC7831740 DOI: 10.1136/fmch-2020-000403] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
OBJECTIVES Erectile dysfunction (ED) is a common problem among middle-aged males and men often do not talk about sexual problems with their primary care physicians (PCPs). We hypothesised that many Japanese men who meet the criteria for ED would not recognise their condition based on responses to an internationally validated scale. Our secondary aims were to examine potential barriers to seeking treatment for ED by their PCPs. We sought to elucidate their perspectives about male sexual dysfunction qualitatively. Through merging of the quantitative and qualitative findings, we sought an enhanced understanding of the factors affecting sexual dysfunction treatment. DESIGN A cross-sectional, self-administered mixed methods survey was distributed at a suburban family medicine clinic in Sapporo, Japan. Eligible participants were 40 to 69-year-old men who came for routine scheduled visits from 5 November to 21 December 2018. During the office visit, participants completed a confidential 11-item survey addressing sexual dysfunction including the 5-item version of the International Index of Erectile Function scale and open-ended questioning. SETTING Teine Family Medicine Clinic, a suburban family medicine clinic in Sapporo, Japan. PARTICIPANTS We enroled 66 male patients aged 40-69 years who presented for routine outpatient care in the Teine Family Medicine Clinic. RESULTS Of surveyed participants, 39% (26/66) reported having sexual dysfunction, but 92% (61/66) met ED criteria. Of respondents, 48% (16/33) had desire for treatment, but only one man had discussed sexual dysfunction with his PCP. Among the 12 desiring treatment from PCPs, the main barriers to discussing were shame (n=7) and lack of awareness that PCPs can treat ED (n=5). These men's perspectives about sexual dysfunction included viewing sexual dysfunction as normal ageing, attributing sexual dysfunction to decreased libido, considering sexual activity for a healthy life, having good rapport with PCPs, having incomplete knowledge about treatment and lacking an intimate relationship. Through a resulting model, the merged mixed methods findings illustrate how patient perceptions can reinforce or attenuate issues of awareness, desire for treatment and barriers to access. CONCLUSIONS In a Japanese primary care setting, the majority of participating male patients met ED criteria on an internationally validated measure, namely, the five-item version of the International Index of Erectile Function, but many were not aware of their ED. Misperceptions, lack of knowledge and personal factors are barriers to treatment. The mixed methods findings suggest misperceptions and personal attributes reinforce or attenuate awareness, preference for treatment and barriers to access. We conclude PCPs should routinely inquire about sexual dysfunction of men at risk and offer treatment to men who would benefit.
Collapse
Affiliation(s)
- Yuki Takeuchi
- Teine Family Medicine Clinic, Teine Keijinkai Hospital, Sapporo, Hokkaido, Japan
| | - Ryohei Otsuka
- Teine Family Medicine Clinic, Teine Keijinkai Hospital, Sapporo, Hokkaido, Japan
| | - Hajime Kojima
- Teine Family Medicine Clinic, Teine Keijinkai Hospital, Sapporo, Hokkaido, Japan
| | - Michael D Fetters
- Mixed Methods Program, Department of Family Medicine, University of Michigan, Ann Arbor, Michigan, USA
| |
Collapse
|
|
46
|
Beecken WD, Kersting M, Kunert W, Blume G, Bacharidis N, Cohen DS, Shabeeh H, Allen MS. Thinking About Pathomechanisms and Current Treatment of Erectile Dysfunction-"The Stanley Beamish Problem." Review, Recommendations, and Proposals. Sex Med Rev 2020; 9:445-463. [PMID: 33358577 DOI: 10.1016/j.sxmr.2020.11.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 11/12/2020] [Accepted: 11/18/2020] [Indexed: 11/17/2022]
Abstract
INTRODUCTION Up to 50% of all men over 50 years of age suffer from erectile dysfunction. Since the late 1990s erectile dysfunction has been treated mostly with phosphodiesterase 5 inhibitors (PDE5I). Over the past 20 years, numerous scientific findings on the development of erectile dysfunction have been collected, which have so far received little attention in the treatment of erectile dysfunction. OBJECTIVES The objectives of this study were to review the existing medical literature on erectile dysfunction regarding physiology, pathophysiology, and especially therapeutic options beyond treatment with PDE5I and to enable a more effective and especially sustainable treatment for erectile dysfunction. METHODS A literature review was performed by using PubMed from 1985 to 2020 regarding the physiology, pathophysiology, and treatment of erectile dysfunction. RESULTS Since the end of the 1990s an enormous amount of knowledge has been gained about the physiology/pathophysiology of erection/erectile dysfunction. Based on these findings, numerous physical, drug, and holistic therapeutic options (beyond the application of PDE5I) have been developed for the treatment of erectile dysfunction. However, these are still relatively rarely used in the therapeutic concept of erectile dysfunction today. CONCLUSION Based on scientific findings of the last 20 years, there are numerous therapeutic approaches, including lifestyle modification, specific pelvic floor exercises, shock wave treatment, and the application of different supplements. The long-term treatment of erectile dysfunction should now go beyond the purely symptomatic use of PDE5I. W-D Beecken, M Kersting, W Kunert, et al. Thinking About Pathomechanisms and Current Treatment of Erectile Dysfunction-"The Stanley Beamish Problem." Review, Recommendations, and Proposals. Sex Med Rev 2021;9:445-463.
Collapse
Affiliation(s)
- Wolf-D Beecken
- UroGate, Practice for Urology, Frankfurt, Germany; Regimen/with O Inc, San Jose, CA, USA.
| | | | | | | | | | - Deborah S Cohen
- Regimen/with O Inc, San Jose, CA, USA; Fundamental Physical Therapy & Pelvic Wellness, Poway, CA, USA
| | - Husain Shabeeh
- Regimen/with O Inc, San Jose, CA, USA; Department of Cardiology, Croydon University Hospital, London, UK
| | - Mark S Allen
- Regimen/with O Inc, San Jose, CA, USA; Faculty of Social Sciences, University of Wollongong, Wollongong, Australia
| |
Collapse
|
|
47
|
Swerdloff RS, Wang C, White WB, Kaminetsky J, Gittelman MC, Longstreth JA, Dudley RE, Danoff TM. A New Oral Testosterone Undecanoate Formulation Restores Testosterone to Normal Concentrations in Hypogonadal Men. J Clin Endocrinol Metab 2020; 105:5834353. [PMID: 32382745 PMCID: PMC7282712 DOI: 10.1210/clinem/dgaa238] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 05/22/2020] [Indexed: 12/20/2022]
Abstract
CONTEXT A novel formulation of oral testosterone (T) undecanoate (TU) was evaluated in a phase 3 clinical trial. OBJECTIVE Determine efficacy, short-term safety, and alignment of new oral TU formulation with current US approval standards for T replacement therapy. DESIGN Randomized, active-controlled, open-label study. SETTING AND PATIENTS Academic and private clinical practice sites; enrolled patients were clinically hypogonadal men 18 to 65 years old. METHODS Patients were randomized 3:1 to oral TU, as prescribed (JATENZO®; n = 166) or a topical T product once daily (Axiron®; n = 56) for 3 to 4 months. Dose titration was based on average T levels (Cavg) calculated from serial pharmacokinetic (PK) samples. T was assayed by liquid chromatography-mass spectrometry/mass spectrometry. Patients had 2 dose adjustment opportunities prior to final PK visit. Safety was assessed by standard clinical measures, including ambulatory blood pressure (BP). RESULTS 87% of patients in both groups achieved mean T Cavg in the eugonadal range. Sodium fluoride-ethylenediamine tetra-acetate plasma T Cavg (mean ± standard deviation) for the oral TU group was 403 ± 128 ng/dL (~14 ± 4 nmol/L); serum T equivalent, ~489 ± 155 ng/dL (17 ± 5 nmol/L); and topical T, 391 ± 140 ng/dL (~14 ± 5 nmol/L). Modeling/simulation of T PK data demonstrated that dose titration based on a single blood sample 4 to 6 h after oral TU dose yielded efficacy (93%) equivalent to Cavg-based titration (87%). Safety profiles were similar in both groups, but oral TU was associated with a mean increase in systolic BP of 3 to 5 mm Hg. CONCLUSION A new oral TU formulation effectively restored T to mid-eugonadal levels in hypogonadal patients.
Collapse
Affiliation(s)
- Ronald S Swerdloff
- The Lundquist Institute and Harbor-UCLA Medical Center, Torrance, CA, US
- Correspondence and Reprint Requests: Ronald S. Swerdloff, MD, The Lundquist Institute at Harbor-UCLA Medical Center, 1124 W. Carson Street, Torrance, CA 90502. E-mail:
| | - Christina Wang
- The Lundquist Institute and Harbor-UCLA Medical Center, Torrance, CA, US
| | - William B White
- University of Connecticut School of Medicine, Farmington, CT, US
| | | | | | | | | | | |
Collapse
|
|
48
|
Swerdloff RS, Dudley RE. A new oral testosterone undecanoate therapy comes of age for the treatment of hypogonadal men. Ther Adv Urol 2020; 12:1756287220937232. [PMID: 32655691 PMCID: PMC7328356 DOI: 10.1177/1756287220937232] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 06/01/2020] [Indexed: 12/15/2022] Open
Abstract
Background: A novel formulation of oral testosterone undecanoate (TU) was studied in a
long- and short-term phase III trial to evaluate safety and efficacy. Methods: Hypogonadal men (age 18–65 years; two morning serum testosterone
(T) <300 ng/dl with signs/symptoms) were recruited into a 365 day (trial
I) or 105 day (trial II), randomized, multicenter trial. Patients were
randomized 1:1 to oral TU (n = 161) or T-gel
(n = 160) in trial I, and 3:1 to oral TU, twice daily
(BID) JATENZO® (n = 166) or a topical T product [Axiron®
(n = 56)] in trial II. Dose adjustments were based on
average T concentrations (Cavg). Efficacy was assessed
based on T levels, body composition and bone density. Safety was assessed by
standard clinical measures. Results: Oral TU efficacy (% of patients with eugonadal T Cavg) was
84% (serum Cavg = 628 ± 343 ng/dl) and 87% (serum T
equivalent Cavg ≈ 489 ± 155 ng/dl) in trials I and II,
respectively. Oral TU significantly (p <0.0001) improved
all Psychosexual Daily Questionnaire parameters in trials I and II. In trial
I, lean mass increased 3.2 ± 2.7 kg and fat decreased by 2.4 ± 3.6 kg (both
p <0.0001) and bone density improved in hip
(+0.012 ± 0.0225 g/cm2) and spine
(+0.018 ± 0.0422 g/cm2) after 365 days (both
p <0.0001). Oral TU-associated adverse effects were
consistent with other T-replacement therapies but oral TU patients
experienced a greater number of mild gastrointestinal adverse effects. Oral
TU subjects in both studies exhibited an increase in mean systolic blood
pressure of about 3–5 mmHg. Oral TU was not associated with liver toxicity
nor did it cause an elevation in high-sensitivity C-reactive protein or
lipoprotein-associated phospholipase A2 (cardiovascular safety
biomarkers) after 365 days of therapy. Conclusion: A new oral TU formulation was safe and effective and represents a significant
therapeutic advance for the treatment of appropriate hypogonadal men.
Collapse
Affiliation(s)
- Ronald S Swerdloff
- David Geffen School of Medicine at UCLA, Division of Endocrinology, Harbor-UCLA Medical Center, The Lundquist Institute at Harbor-UCLA Medical Center, 1124 W. Carson Street, Torrance, CA 90502, USA
| | | |
Collapse
|
|
49
|
No evidence found for an association between trial characteristics and treatment effects in randomized trials of testosterone therapy in men: a meta-epidemiological study. J Clin Epidemiol 2020; 122:12-19. [PMID: 32105799 DOI: 10.1016/j.jclinepi.2020.02.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 12/19/2019] [Accepted: 02/19/2020] [Indexed: 11/24/2022]
Abstract
OBJECTIVE The objective of this study was to identify potential trial characteristics associated with reported treatment effect estimates in randomized trials of testosterone therapy in adult men. STUDY DESIGN AND SETTING This is a meta-epidemiological study. MEDLINE was searched for meta-analyses of randomized trials of testosterone therapy in men published between 2008 and 2018. Data on trial characteristics were extracted independently by two reviewers. The impact of trial characteristics on reported treatment effects was investigated using a two-step meta-analytic approach. RESULTS We identified 132 randomized trials, included in 19 meta-analyses, comprising data from 10,725 participants. None of the investigated design characteristics, including year of publication, sample size, trial registration status, center status, regionality, funding source, and conflict of interest were statistically significantly associated with reported treatment effects of testosterone therapy in men. Although trials rated at high risk of bias overall reported treatment effects that were 21% larger compared with trials rated at low risk of bias overall, the 95% confidence interval included the null (ratio of odds ratio: 0.79, 95% confidence interval: 0.60 to 1.03). CONCLUSION The present study found no clear evidence that trial characteristics are associated with treatment effects in randomized trials of testosterone therapy in men. To establish stronger evidence about the treatment effects of testosterone therapy in men, future randomized trials should not only be adequately designed but also transparently reported. STUDY REGISTRATION osf.io/x9g6m.
Collapse
|
|
50
|
Nieschlag E. Late-onset hypogonadism: a concept comes of age. Andrology 2019; 8:1506-1511. [PMID: 31639279 DOI: 10.1111/andr.12719] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 09/17/2019] [Accepted: 10/21/2019] [Indexed: 01/20/2023]
Abstract
The term Late-onset hypogonadism (LOH) was coined in 2002 and defined as a disease entity in the ISA, ISSAM, EAU, EAA and ASA endorsed Recommendations for Investigation, Treatment and Monitoring of LOH (2005 and 2008) as 'a clinical and biochemical syndrome associated with advancing age, characterized by symptoms and a deficiency in serum testosterone (T)'. LOH was classified as a combined primary and secondary hypogonadism since the endocrine capacity of the testes and the pituitary are impaired. Symptoms of LOH include loss of libido, erectile dysfunction, loss of muscle mass, increased body fat, anemia, osteoporosis, depressed mood, decreased vitality, sweating, and hot flushes. Since these symptoms may also have origins other than LOH, exclusion of other disease entities and subnormal serum T levels are considered prerequisites for the diagnosis and possible treatment of LOH. However, during following years these guidelines were often neglected and, especially in the USA, indiscriminate prescribing of T was widely practised so that the US FDA warned against such irresponsible behavior. In Europe, T prescribing remained largely restricted to LOH as defined above. Nevertheless, a discussion started whether LOH really exists or is only a consequence of age-related comorbidities. Numerous studies have helped to clarify the situation, in particular, the European Male Aging Study (EMAS) and the US-initiated 7 T trials. Consequently, the newest US Endocrine Society Practice Guideline on T treatment (2018) includes advanced age as a cause of organic hypogonadism and recommends that 'in men >65 years who have symptoms or conditions suggestive of T deficiency … and consistently and unequivocally low morning T concentrations we suggest that clinicians offer T therapy on an individualised basis after explicit discussion of the potential risks and benefits'. Thus, the concept of LOH as conceived two decades ago has weathered criticism and survived the times.
Collapse
Affiliation(s)
- E Nieschlag
- Center for Reproductive Medicine and Andrology, University of Münster, Münster, Germany
| |
Collapse
|