🧠 The Gonadal axis - Part 2 : Male physiology

 In males, the HPG axis governs testicular development, spermatogenesis, and testosterone production. These processes begin in foetal life, pause in childhood, and reactivate at puberty — shaping not only fertility, but muscle mass, libido, voice, and bone health. 

Understanding normal male physiology is essential before exploring disorders like hypogonadism, delayed puberty, or infertility.

 🧠 Hormonal Cascade — From Brain to Testes

GnRH from the hypothalamus → stimulates pituitary release of LH and FSH

• LH → stimulates Leydig cells in the testes → produce testosterone
• FSH → stimulates Sertoli cells → support spermatogenesis and secrete inhibin B

Testosterone and inhibin B → provide negative feedback to hypothalamus and pituitary

💡 Testosterone is essential but not sufficient for sperm production — FSH and Sertoli cell function are also required.

🧠 Testicular Anatomy — Structure Supports Function

The testes are paired organs housed in the scrotum, responsible for sperm production and testosterone synthesis. Their internal architecture is highly specialised to support these dual roles.

🧬 Key Structural Components

• Tunica albuginea: Dense fibrous capsule surrounding each testis; sends septa inward to divide the testis into lobules
• Lobules: Each contains 1–4 seminiferous tubules, where spermatogenesis occurs
• Seminiferous tubules:
• Lined by Sertoli cells (support and nourish developing sperm)
• Interspersed with spermatogenic cells at various stages
•  Interstitial (Leydig) cells: Located between tubules; produce testosterone in response to LH
• Rete testis: Network of tubules collecting sperm from seminiferous tubules
• Efferent ductules: Transport sperm to the epididymis, where maturation occurs

💡 Clinical relevance: Testicular volume and architecture are key indicators of spermatogenic activity. Atrophy or fibrosis suggests impaired fertility.

💪 Systemic Effects of Testosterone

Testosterone is the principal androgen in males, produced primarily by Leydig cells in the testes under LH stimulation. While its role in spermatogenesis is critical, testosterone also exerts widespread effects across multiple organ systems. These effects are mediated via androgen receptors, which are expressed in tissues ranging from muscle and bone to brain and skin.

🧠 Neurological and Psychological Effects

• Libido and sexual function: Testosterone enhances sexual desire and erectile capacity.
• Mood and energy: Adequate levels support motivation, confidence, and mental clarity.
• Cognition: May influence spatial ability, memory, and executive function.
• Aggression and risk-taking: Elevated levels can amplify assertiveness and impulsivity 

💡 Low testosterone may present as fatigue, low mood, or reduced libido, often misattributed to depression or aging.

💪 Musculoskeletal Effects

• Muscle mass and strength: Promotes protein synthesis and lean body mass.
• Bone density: Stimulates osteoblast activity and inhibits bone resorption — critical for preventing osteoporosis.
• Epiphyseal closure: In adolescence, testosterone (via aromatisation to oestrogen) leads to fusion of growth plates.

💡 Delayed puberty or hypogonadism may show reduced muscle bulk, long limbs (due to delayed epiphyseal closure), and increased fracture risk.

🩸 Haematologic Effects

• Erythropoiesis: Testosterone stimulates red blood cell production via increased erythropoietin sensitivity.
• Haematocrit: Levels rise with testosterone, useful in assessing androgen status, but excessive levels may increase thrombotic risk.

💡 Elevated haematocrit in men on testosterone therapy may signal overtreatment.

🧬 Dermatologic and Hair Effects

• Facial and body hair: Androgens drive terminal hair growth in androgen-sensitive areas (face, chest, pubic region).
• Scalp hair loss: Testosterone (via DHT) contributes to male-pattern baldness in genetically predisposed individuals.
• Acne and sebaceous activity: Increased sebum production can lead to acne, especially during puberty.

💡 Excessive androgen activity may present with acne, hirsutism (in females), or early baldness.

🗣️ Voice and Laryngeal Effects

• Laryngeal growth: Testosterone enlarges the vocal cords and larynx, deepening the voice during puberty.
• Permanent change: Once established, voice changes do not reverse even if testosterone levels fall.

💡 Voice deepening is a reliable marker of androgen exposure in adolescence.

🧠 Spermatogenesis — From Stem Cell to Sperm

Spermatogenesis is the process by which diploid spermatogonia become haploid spermatozoa. It occurs in the seminiferous tubules and takes ~64–72 days.

1. Spermatogonial phase (mitosis)

• Spermatogonia (stem cells) divide to maintain the pool and produce primary spermatocytes

2. Meiotic phase

• Primary spermatocytes undergo meiosis I → secondary spermatocytes
• Secondary spermatocytes undergo meiosis II → spermatids

3. Spermiogenesis (maturation)

• Spermatids transform into spermatozoa
• Develop acrosome, flagellum, and condensed nucleus
• Shed excess cytoplasm

4. Spermiation

• Mature sperm released into the lumen of the seminiferous tubule

💡 Sertoli cells form the blood–testis barrier, secrete ABP (androgen-binding protein), and respond to FSH. They are essential for structural support and hormonal regulation.

🧠 Hormonal Regulation

• FSH → stimulates Sertoli cells → promotes spermatogenesis
•  LH → stimulates Leydig cells → testosterone production
• Testosterone → acts locally (paracrine) to support sperm development
• Inhibin B → secreted by Sertoli cells → negative feedback on FSH

💡 Intratesticular testosterone must be much higher than serum levels to support spermatogenesis — systemic hypogonadism may not reflect local failure.

🔁 Inhibin B selectively inhibits FSH secretion, while testosterone suppresses both LH and GnRH release.

🧬 Developmental Timeline — Male Gonadal Function Across Life

👶 Fetal Life

• Testosterone surge (via hCG stimulation of Leydig cells) → drives male genital differentiation
• AMH from Sertoli cells → causes regression of Müllerian ducts
• Cryptorchidism may result if testosterone or INSL3 is deficient

👶 Mini-Puberty (0–6 months)

• Transient activation of HPG axis
• LH/FSH rise → testosterone surge → penile and testicular growth
• Important for testicular descent and early Sertoli cell proliferation
• This transient activation “primes” Sertoli and Leydig cell populations and may influence future fertility — failure of mini-puberty is associated with cryptorchidism and micropenis.

🧒 Childhood

• Axis becomes quiescent
• LH, FSH, and testosterone remain low
• Testes are small; no spermatogenesis

🧑 Puberty

• GnRH pulsatility resumes → LH and FSH rise
• Testicular enlargement is the first sign (FSH → Sertoli cells)
• Testosterone rises → voice deepens, muscle mass increases, libido develops
• Spermatogenesis begins → requires both FSH and intratesticular testosterone
• Growth spurt occurs later than in females; epiphyseal closure delayed

🧔 Reproductive Years

• Axis remains active
• Testosterone levels stable; spermatogenesis continuous
• Feedback loops maintain hormonal balance

👴 Andropause

• Gradual decline in testosterone from ~40s onward
• LH/FSH may rise slightly, but axis remains functional
• Symptoms vary: reduced libido, fatigue, muscle loss, mood changes
• Not universal — some men maintain normal levels into old age
• 💡 Unlike menopause, andropause is a gradual, incomplete decline — most men retain reproductive capacity.

🧠 Reasoning Tip — Interpreting Male Gonadal Function

When evaluating male reproductive physiology, ask:

• Are testes enlarged appropriately for age?
• Is testosterone concordant with LH/FSH levels?
•  Is there evidence of spermatogenesis — fertility, semen analysis?
• Are there signs of androgen action — voice, hair, libido, muscle mass?

💡 Low testosterone with high LH/FSH → primary testicular failure

💡 Low testosterone with low LH/FSH → central hypogonadism

 

 

🧩 Summary — The Male Gonadal Axis

• LH → Leydig cells → Testosterone
• FSH → Sertoli cells → Spermatogenesis + Inhibin B
• Testosterone and Inhibin B → Negative feedback
• Intratesticular testosterone is essential for sperm maturation
• Axis active in fetal life, quiescent in childhood, reactivated at puberty