Microphallus early management in infancy saves adulthood sensual life: A ‎‎comprehensive review

Table 1 The causes of Microphallus and Micropenis

Factor		Description
Genetics	Specific genes mutations	Genes related to testosterone production and androgen receptor function. Genes associated with the genital tubercle development
	AIS
	Genetic deficiencies in Enzymes Involved in Hormone Production e.g., 5 alpha-reductase deficiency
	Genetic abnormalities affecting hormonal signalling
	Genetic disorders affecting pituitary gland function
	Genetic causes of congenital adrenal hyperplasia (deficiency in steroidogenic acute regulatory protein (STAR gene mutation), 3 beta-hydroxysteroid dehydrogenases (salt-wasting, non-salt-wasting, and non-classic types), 17 α-hydroxylase (mutations in the CYP17A1 gene located on chromosome 10q24-q25)
	Chromosomal Abnormalities e.g., Klinefelter syndrome (XXY), Trisomy of the chromosomes 8, 13, 18 or 21
	Inherited syndromes	Bardet-Biedl syndrome, Prader-Willi syndrome and Kallman syndrome (hypogonadotropic hypogonadism, osteoporosis, hearing impairment, and anosmia). Noonan syndrome (hypertelorism, short neck, low-set ears, skeletal malformation, bleeding disorders, and pulmonary valve stenosis). Others: Charge syndrome, Silver Russel syndrome, Rud syndrome
Hormonal and endocrinal causes	Primary Hypogonadism: Either congenital or acquired ‎ e.g., Anorchia, Klinefelter and poly-X syndromes, gonadal dysgenesis (incomplete form), luteinizing hormone receptor defect (incomplete form), testosterone steroidogenesis (incomplete form), Noonan syndrome, Trisomy 21, Robinow syndrome, Bardet-Biedl syndrome, Laurence-Moon syndrome
	Secondary Hypogonadism: Secondary to pituitary gland or hypothalamus disorders, resulting in decreased ‎secretion of luteinizing hormone and follicle-stimulating hormone ‎
	AIS
	Enzyme deficiencies affect testosterone synthesis or its conversion to the more ‎potent dihydrotestosterone
	Growth hormone deficiency or abnormalities in IGF-1 ‎
	Hypothyroidism
	Adrenal gland disorders ‎ such as adrenal hyperplasia
Anatomical and structural abnormalities	Penis agenesis, cloacal dystrophy, hypospadias or chordee, Peyronie's disease, corpus cavernosa and corpus spongiosum hypoplasia, vascular abnormalities, ligaments or connective tissue abnormalities, and inadequate penile shaft length
Environmental factors	Antenatal exposure	Endocrine-disrupting chemicals, including phthalates, bisphenol A, and ‎certain pesticides
		Anti-androgenic drugs
		Maternal substance abuse, including alcohol, drugs, or tobacco
		Ionizing radiation
		Antenatal infections
		Inadequate nutrition and a poor maternal diet ‎
		Pollutant exposure such as heavy metals and dioxins.
		Antenatal exposure of antifungal
	Postnatal exposure	Improper or excessive use of antibiotics or hormonal medications
		Hormonal treatments for conditions like precocious puberty or delayed puberty‎
		Surgical interventions or treatments for disorders affecting the genitalia ‎
Idiopathic	Unknown cause

AIS: Androgen Insensitivity Syndrome; STAR: Spliced transcripts alignment to a reference; CYP17A1: Cytochrome P450 17A1; IGF-1: Insulin-like growth factor-1.

Table 2 Factors that affect the stretched penile length at birth

Factor	Description
Genetic factors	Genetic factors influence the tissue response to androgens and can contribute to variations in penile size and development
Ethnicity‎	There may be variations in penile length at birth among different ethnic groups. African and African-Caribbean ethnic backgrounds tend to have, on average, longer penile lengths compared to other ethnic groups. Individuals from Asian ethnic backgrounds tend to have slightly shorter penile lengths than African and African-Caribbean populations. Caucasian/European and Latino/Hispanic Ethnicities fall in the intermediate range in terms of penile length
Prenatal testosterone levels	Hormones, particularly testosterone, play a crucial role in developing the male reproductive system, including the penis. Testosterone influences the growth of the penis during fetal development
Gestational age	Premature babies may have a smaller penile length at birth than full-term infants. The duration of gestation can influence the development of the reproductive organs, including the penis
Birth length	This effect is observed in preterm infants
Birth weight	Babies who have a lower birth weight also tend to have shorter penises
Maternal Health and Nutrition	The health and nutrition of the mother during pregnancy can impact fetal development, including penile growth. Adequate nutrition and a healthy pregnancy can support normal development
Fetal growth and development	The fetus's growth and development rate during pregnancy can affect penile length at birth. Factors such as intrauterine growth restriction can potentially influence penile size
Certain medical conditions	Some medical conditions, such as Klinefelter syndrome and Down syndrome, can cause a decrease in SPL at birth
Health conditions during pregnancy	Certain medical conditions during pregnancy, such as hormonal imbalances or endocrine disorders in the mother, can affect fetal development, including penile length
Environmental factors	Environmental factors, including exposure to toxins, pollutants, or substances that can disrupt hormone levels, might impact penile development in utero
Maternal exposure to certain medications	Some medications, such as corticosteroids and certain anticonvulsants, have been linked to a decrease in SPL at birth

SPL: Stretched penile length.

Table 3 The factors affecting penile length from birth to adulthood

Factor	Description
Genetics	The most important factor affecting penile length is genetics. Studies have shown that up to 80% of the variation in penile length can be attributed to genetics. Therefore, penile length is a highly heritable trait that is passed down from parents to children. In addition, Certain genetic conditions can affect penile growth. For example, boys with Klinefelter syndrome tend to have smaller penises than boys without the disorder
Race and ethnicity	Studies suggest that there may be differences in penile size among different ethnic and racial groups, although these variations are generally within a normal range and not significant
Nutrition and Health	Proper nutrition and overall good health positively influence growth and development, including penile growth
Puberty	Significant penile growth during puberty due to hormonal surges, especially testosterone
Hormonal levels	Hormonal imbalances or medical conditions affecting hormone levels may influence penile growth. Testosterone, the primary male sex hormone, plays a critical role in the development and growth of the penis during puberty. Growth hormone also contributes to overall growth, including penile growth during adolescence
Environmental factors	Some environmental factors, such as exposure to certain chemicals or toxins, may also affect penile growth. For example, boys exposed to phthalates, a type of chemical found in some plastics, had smaller penises than boys not exposed to phthalates. However, more research is needed to confirm these findings
Medical conditions	Certain medical conditions or disorders, such as endocrine disorders and chronic illnesses, affecting endocrine function can influence penile length
Obesity	Excess body fat can make the visible portion of the penis appear smaller due to the fat pad in the pubic area. Maintaining a healthy weight and reducing excess fat can help perceive penile length
Circumcision	Surgical removal of the foreskin (circumcision) affects the appearance of the penis but not its actual length
Exercising and physical activity	Regular physical activity and exercises targeting the pelvic area may help maintain good blood circulation and penile health
Medical conditions and disorders	Some medical conditions or disorders can affect penile growth or cause anomalies in penile development. These can include hormonal disorders, congenital abnormalities, and certain genetic conditions. Disorders like Peyronie's disease, characterized by fibrous scar tissue in the penis, can cause curvature and shortening of the penis
Penis disorders and injuries	Trauma, surgical procedures, or diseases affecting the penis can cause changes in penile length. In some cases, surgical procedures might impact the size or appearance of the penis
Age and aging	Natural changes in penile length and appearance as men age may occur due to changes in blood flow, tissue elasticity, and overall health

Table 4 Differences between 5α-reductase type 2 deficiency and androgen insensitivity syndrome

	5αR2D	AIS
Primary genetic defect	It is due to a deficiency in the 5α-reductase type 2 enzyme that converts testosterone to DHT	Genetic mutations in the androgen receptor gene result in the inability of cells to respond to androgens (e.g., testosterone)
Inheritance	Autosomal recessive	X-linked recessive
Chromosome location	2p23	Xq11-q12
Genotype	Typically, 46, XY karyotype (male genotype)	Typically, 46, XY karyotype (male genotype)
Phenotype	Ambiguous genitalia in male infants. Varying degrees of under-virilization during puberty	Variable degrees of feminization and incomplete masculinization despite the presence of male internal and external genitalia
Hormonal profile	Reduced levels of DHT. Normal or elevated levels of testosterone, elevated LH	Elevated testosterone levels due to a lack of androgen receptor responsiveness, elevated LH, and normal MIF
Response to androgens	Reduced response to androgens due to inadequate conversion of testosterone to DHT. DHT plays a key role in the process of sexual differentiation in the external genitalia and prostate during the development of the male fetus	Lack of response to androgens despite normal or elevated testosterone levels
Internal reproductive organs	Typically have normal male internal reproductive organs (e.g., testes, vas deferens, epididymis). Testes located in the inguinal canal or ‎scrotum	Typically, they have normal male internal reproductive organs. Testes located in the abdomen or ‎inguinal canal
External genitalia	Ambiguous or underdeveloped male external genitalia	External genitalia: Neonate: Female (complete type). But may appear as normal male external genitalia but with varying degrees of feminization (partial type)
Pubertal development	Affected males still develop typical masculine features at puberty (deep voice, facial hair, muscle bulk) since most aspects of pubertal virilization are driven by testosterone, not DHT	Minimal virilization, with absent or minimal facial hair, high-pitched voice, and breast development
Fertility	Reduced fertility due to underdeveloped reproductive organs	Infertility due to absent or underdeveloped reproductive organs
Psychological Impact	Gender dysphoria may occur due to ambiguous genitalia and delayed or incomplete virilization	Gender dysphoria may occur due to female-appearing genitalia and lack of virilization
Treatment	Hormone replacement therapy may be considered to supplement DHT. Testosterone therapy may be used to ‎induce virilization	Hormone replacement therapy is not effective due to insensitivity to androgens. In complete type, the patient is treated as female, and estrogen therapy is indicated with orchidectomy. Orchidectomy aims to prevent possible malignant degeneration of the testes. Psychological support and surgical interventions may be considered

5αR2D: 5α-Reductase Type 2 Deficiency; AIS: Androgen Insensitivity Syndrome; DHT: Dihydrotestosterone; LH: Luteinizing hormone; MIF: Müllerian-inhibiting factor.

Table 5 Advantages and disadvantages of various hormonal therapies for microphallus

Hormonal therapy	Advantages	Disadvantages
Intramuscular testosterone	Promotes penile growth and development by addressing testosterone deficiencies. Enhances the development of secondary sexual characteristics. Improves muscle mass, bone density, and overall well-being	Potential side effects include acne, mood swings, increased aggression, and accelerated skeletal maturation. May suppress natural testosterone production if used long-term. Requires regular monitoring of hormone levels and administration through injections or topical applications
Topical	Non-invasive administration, more comfortable. Gradual absorption with more stable and consistent hormone levels. Less Pain and Discomfort. Easy Application and more convenient treatment option	Erratic absorption with hormonal fluctuations, limited efficacy, and uncertain outcomes. Risk of transfer to others, especially children and women, through close physical contact with the application site. Skin Sensitivity and allergic reactions to the topical product. Lack of Standardization
hCG	Stimulates the testes to produce testosterone, aiding in penile growth. Can be used in combination with other hormonal therapies for enhanced results. Administration via injections or subcutaneous pellets	Potential side effects may include fluid retention, breast tenderness, and mood swings. Requires careful monitoring and adjustment of dosages to avoid adverse effects
Aromatase inhibitors	Inhibit the conversion of androgens to estrogen, potentially increasing testosterone levels and aiding penile growth. May be considered for individuals with aromatase excess syndrome	Limited evidence on efficacy and safety for promoting penile growth. ‎Possible side effects include joint pain, mood swings, and bone density issues
GH therapy	Stimulates growth and may indirectly impact penile growth. Beneficial for children with growth hormone deficiencies or short stature	Limited evidence regarding the direct impact on penile growth in microphallus cases. Potential side effects include fluid retention, joint pain, and increased risk of diabetes
GH therapy	Combines multiple hormones (e.g., testosterone, hCG) to synergize and enhance penile growth potentially. May optimize hormonal treatment effectiveness for promoting penile growth	Increased complexity of treatment regimen with potential for elevated side effects due to multiple hormonal agents. Requires vigilant monitoring and management of potential adverse effects

hCG: Human chorionic gonadotropin; GH: Growth hormone.

Table 6 Follow-up care for various life stages of patients with micropenis

Life stages	Follow-up protocols
Infants (0-2 yr)	Regular Pediatric Check-ups: Schedule routine pediatric visits to monitor growth and development. Hormone Assessment: If micropenis is identified in infancy, consult a pediatric endocrinologist to evaluate hormone levels and rule out any underlying medical conditions. Parental Education: Inform parents about micropenis and any potential treatment options
Children (3-12 yr)	Annual Check-ups: Continue with regular pediatric check-ups, focusing on growth and development. Psychological Support: Provide psychological counseling for both child and parents and encourage open communication to address self-esteem or body image issues. Education and Awareness: Ensure the child has accurate information about their condition and promote a positive body image. Bullying Awareness: Discuss bullying prevention strategies and provide resources if needed
Adolescents (13-18 yr)	Annual Check-ups: Transition to annual check-ups focusing on overall health. Psychological Support: Continue to offer psychological support, especially given the increased self-awareness and potential body image concerns during adolescence. Sex Education: Provide age-appropriate sex education, discussing relationships, consent, and safe sexual practices. Peer and Social Support: Encourage the adolescent to seek out supportive friends and support groups. Consultation with Specialists: It is recommended to consult with a pediatric endocrinologist or urologist to evaluate the need for potential treatments like hormone therapy or surgery. The adolescent should be fully informed and involved in decision-making
Long-term follow-up (throughout adolescence and beyond)	Mental Health Support: It's important to provide mental health support to individuals who may be struggling with body image or self-esteem issues. Regular Health Check-ups: It's also important to encourage regular health check-ups to monitor overall health and well-being. Reassessment of Treatment Options: Periodically reassessing the need for medical interventions in consultation with healthcare specialists is also recommended. Supportive Family Environment: Maintaining a supportive and open family environment where individuals feel comfortable discussing their concerns and seeking help if needed is crucial