General Endocrinology of the Gonads

The gonads (testes and ovaries) combine endocrine function, producing sex steroids and peptide hormones, with gametogenesis. Their function is governed by the hypothalamic-pituitary-gonadal axis.

Axis regulation

• Hypothalamic kisspeptin neurons drive pulsatile release of gonadotropin-releasing hormone (GnRH) into the portal circulation. Pulse frequency selects the gonadotropin: fast pulses (every 60 minutes) favour LH, and slow pulses favour FSH. Continuous GnRH exposure desensitises gonadotropes, which is exploited by GnRH agonist therapy.
• Anterior pituitary LH and FSH act on gonadal cells. Sex steroids and inhibin exert negative feedback. In women, sustained high oestradiol produces positive feedback and the LH surge.
• Prolactin inhibits GnRH pulsatility, so hyperprolactinaemia causes hypogonadism.

Testis

• Leydig cells (LH-responsive) convert cholesterol to testosterone (about 5 to 7 mg/day, 95% of circulating testosterone). Sertoli cells (FSH-responsive) support spermatogenesis, secrete inhibin B, anti-Müllerian hormone and androgen-binding protein.
• Testosterone circulates bound to SHBG (about 45 to 65%) and albumin (about 35 to 55%), with 1 to 3% free. Bioavailable testosterone includes the albumin-bound fraction.
• Peripheral conversion: 5-alpha reductase (types 1 and 2) forms dihydrotestosterone (DHT), which drives prostate, external genital and hair development. Aromatase converts testosterone to oestradiol (bone and fat function).
• Spermatogenesis takes about 74 days plus transit of 10 to 14 days. It needs intratesticular testosterone levels about 100-fold higher than serum.
• Normal adult male total testosterone is about 300 to 1000 ng/dL (10 to 35 nmol/L), with morning peaks and a decline of about 1% yearly after 40.

Ovary

• Theca cells (LH-responsive) make androgens (androstenedione). Granulosa cells (FSH-responsive) aromatise androgens to oestradiol and secrete inhibin A and B, AMH, and, after ovulation, progesterone from the corpus luteum.
• Follicular phase (days 1 to 14): FSH recruits follicles, dominant follicle selection and rising oestradiol. Ovulation follows the LH surge by 34 to 36 hours. Luteal phase (about 14 days): progesterone rise supports the endometrium. Without pregnancy, luteolysis occurs and menses follow.
• Reproductive life: about 1 to 2 million oocytes at birth, 300,000 to 400,000 at menarche, and menopause at a median of 51 years when the pool is nearly exhausted. AMH reflects the follicle pool.

Developmental physiology

• Sex determination: SRY on the Y chromosome triggers testis development at 6 to 7 weeks. Fetal Leydig cells produce testosterone, and Sertoli cells produce AMH, causing Wolffian duct retention and Müllerian regression. DHT is needed for male external genitalia. In the absence of these, female differentiation follows.
• Mini-puberty in infancy (first 6 months) is a transient gonadotropin and sex steroid surge.
• Puberty begins with reactivation of the GnRH pulse generator (adrenarche is separate).

Clinical disorders arise at each level: hypothalamic (Kallmann syndrome, functional), pituitary (hyperprolactinaemia, hypopituitarism), gonadal (Klinefelter, Turner, PCOS, premature ovarian insufficiency), and peripheral (androgen insensitivity, 5-alpha reductase deficiency).

Gonadal deficiency

• Male: reduced libido, erectile dysfunction, loss of morning erections, infertility, small soft testes, reduced body hair, gynaecomastia, decreased muscle and bone mass, fatigue, hot flushes (rare), anaemia, and low mood. Prepubertal onset gives eunuchoid proportions, high-pitched voice and absent pubertal changes.
• Female: oligomenorrhoea or amenorrhoea, infertility, vasomotor symptoms, vaginal dryness, dyspareunia, reduced libido, mood change, and bone loss. Prepubertal onset gives absent breast development and primary amenorrhoea.

Gonadal excess or hyperandrogenism

• Female: hirsutism (Ferriman-Gallwey score of 8 or more), acne, androgenic alopecia, oligo-ovulation, and in severe cases virilisation (clitoromegaly, deepening voice, temporal balding, increased muscle bulk) implying an androgen-secreting tumour or congenital adrenal hyperplasia.
• Male: precocious puberty in children, and in adults, polycythaemia, acne and oligospermia with exogenous androgen or anabolic steroid use.

Oestrogen excess in men: gynaecomastia, from drugs (spironolactone, ketoconazole, cimetidine, antiandrogens, GnRH analogues, cannabis), liver disease, hyperthyroidism, hCG-secreting or Leydig cell tumours, or obesity (aromatisation).

Puberty disorders: see puberty, precocious puberty and delayed puberty articles.

Red flags: rapid virilisation, very high testosterone (above 200 ng/dL in women), unilateral testicular mass, visual field defect, galactorrhoea, headaches (pituitary lesion), anosmia (Kallmann syndrome), and primary amenorrhoea with no breast development.

Approach: define the level (hypothalamic-pituitary versus gonadal), then the cause.

Hormone assays

• Total testosterone: morning fasting sample (8 to 10 am), repeated on a separate day if low. Use a reliable assay (LC-MS/MS is the reference). Total testosterone below 8 nmol/L (230 ng/dL) is low. Free testosterone by equilibrium dialysis or calculated from total testosterone, SHBG and albumin when SHBG is abnormal (obesity, diabetes, ageing, liver disease, hyperthyroidism, drugs).
• LH and FSH: high in primary gonadal failure, low or inappropriately normal in secondary (central) failure. FSH in men reflects spermatogenic function.
• Prolactin, TSH, ferritin and iron saturation (haemochromatosis), glucose and HbA1c.
• Oestradiol (menstrual cycle phase must be considered), progesterone (mid-luteal day 21 to confirm ovulation: above 30 nmol/L (about 10 ng/mL) indicates ovulation), AMH (ovarian reserve), inhibin B, androgens in women (total and free testosterone, androstenedione, DHEAS, 17-hydroxyprogesterone in the early follicular phase).
• Dynamic testing: GnRH stimulation tests no longer routine. hCG stimulation tests Leydig reserve. Clomiphene or letrozole challenge in selected research. Progestogen withdrawal bleeding test in amenorrhoea.

Further evaluation

• Semen analysis (at least two samples, 2 to 7 days abstinence) in male infertility.
• Karyotype (Klinefelter 47,XXY, Turner 45,X), FMR1 premutation testing in premature ovarian insufficiency, Y chromosome microdeletions in azoospermia, CFTR testing in congenital absence of vas deferens, and gene panels for Kallmann syndrome and congenital hypogonadotropic hypogonadism (ANOS1, FGFR1, CHD7, PROKR2).
• Pituitary MRI for central hypogonadism, hyperprolactinaemia or visual symptoms, and full pituitary profile.
• Testicular and pelvic ultrasound for testicular tumours, volume, ovarian morphology, and endometrial thickness.
• Bone density (DEXA) in prolonged hypogonadism, and adrenal imaging for androgen excess.

Management depends on the diagnosis and on fertility goals.

Male hypogonadism (summary)

• Testosterone replacement for symptomatic men with confirmed deficiency who do not desire fertility: gel 1.62% 40.5 mg daily, undecanoate 1000 mg IM every 10 to 14 weeks, enanthate or cypionate 100 to 200 mg every 2 weeks, or transdermal patch. Monitor haematocrit (stop above 54%), PSA, symptoms and lipids. Contraindicated in prostate or breast cancer, haematocrit above 54%, untreated sleep apnoea, and severe heart failure.
• Fertility: central hypogonadism responds to hCG 1500 to 5000 units SC 2 to 3 times weekly, with FSH (recombinant FSH 75 to 150 units 3 times weekly, or hMG) added after 3 to 6 months, or pulsatile GnRH pumps. Do not use testosterone as it suppresses spermatogenesis. Clomiphene 25 mg daily or enclomiphene, anastrozole, or letrozole are used off-label to raise endogenous testosterone while preserving fertility.
• Treat reversible causes: weight loss, opioid discontinuation, hyperprolactinaemia (cabergoline 0.25 to 0.5 mg twice weekly), thyroid disease, and drug review.

Female hypogonadism and amenorrhoea

• Hormone replacement for primary ovarian insufficiency, Turner syndrome and hypothalamic hypogonadism: oestradiol (transdermal patch 50 to 100 micrograms twice weekly or oral estradiol 1 to 2 mg daily) with a progestogen (micronised progesterone 200 mg nightly for 12 to 14 days a month, or dydrogesterone 10 mg) if the uterus is intact, until about age 50. Dose escalation in puberty induction over 2 to 3 years.
• Functional hypothalamic amenorrhoea: nutritional rehabilitation, reduced exercise, psychological therapy, and transdermal oestrogen for bone protection.
• Ovulation induction in anovulation: letrozole 2.5 to 7.5 mg days 3 to 7 (first line in PCOS), clomiphene 50 to 150 mg days 3 to 7, gonadotropins, and pulsatile GnRH for hypothalamic amenorrhoea.
• Hyperprolactinaemia: cabergoline 0.25 to 0.5 mg twice weekly titrated to normalise prolactin.

Hyperandrogenism

• PCOS: lifestyle, combined oral contraceptive, metformin 500 to 1000 mg twice daily, spironolactone 50 to 200 mg daily, finasteride 5 mg, eflornithine cream, laser hair removal.
• Virilising tumours: surgery. Congenital adrenal hyperplasia: hydrocortisone replacement.
• Androgen excess in men: stop anabolic agents, and treat precocious puberty with GnRH analogues.

Pubertal disorders

• Constitutional delay: observation, or short-course testosterone enanthate 50 to 100 mg IM monthly for 3 to 6 months (boys) or low-dose oestradiol (girls). Permanent hypogonadism: puberty induction. Precocious puberty: GnRH analogue.

Menopause and andropause

• Menopausal hormone therapy for vasomotor symptoms in women under 60 or within 10 years of menopause: oestradiol 1 to 2 mg daily (or 25 to 50 micrograms patch) with a progestogen if the uterus is present; vaginal oestrogen for genitourinary symptoms. Non-hormonal options: fezolinetant 45 mg daily, venlafaxine 37.5 to 75 mg daily, gabapentin, and paroxetine 7.5 mg daily.
• Age-related testosterone decline: treat only with documented symptomatic deficiency and unequivocally low testosterone, not for ageing alone.

Bone, cardiovascular and metabolic care

• Calcium 1000 to 1200 mg and vitamin D 800 to 2000 IU daily, weight-bearing exercise, DEXA monitoring, and bisphosphonates (alendronate 70 mg weekly) for osteoporosis.
• Screen and treat cardiovascular risk, diabetes and obesity.

Contraception and gonadal protection

• Combined hormonal contraceptives suppress ovarian function. Oncofertility: sperm banking, oocyte or embryo cryopreservation before gonadotoxic therapy. GnRH agonists (goserelin 3.6 mg monthly) may reduce ovarian failure during chemotherapy.

Follow-up

• Reassess hormone levels, symptoms and adverse effects at 3 to 6 months after starting therapy, then annually. Genetic counselling for inherited disorders.