Reproductive Endocrinology

Steroidogenesis Pathway

Cholesterol → Pregnenolone → (two pathways)

• Delta-4 pathway: Pregnenolone → Progesterone → 17-OH progesterone → Androstenedione → Testosterone → Oestradiol
• Delta-5 pathway: Pregnenolone → 17-OH pregnenolone → DHEA → Androstenedione

Key Enzymes

• CYP11A1 (cholesterol side-chain cleavage): cholesterol → pregnenolone (rate-limiting step, stimulated by LH/ACTH)
• 3-beta-HSD: pregnenolone → progesterone (converts delta-5 to delta-4 pathway)
• CYP17 (17-alpha-hydroxylase / 17,20-lyase): adds 17-OH group; converts to androgens
• CYP19 (aromatase): converts androgens to oestrogens (testosterone → oestradiol; androstenedione → oestrone)
• 5-alpha reductase: testosterone → DHT (dihydrotestosterone — most potent androgen; important for external male genitalia development)
• CYP21 (21-hydroxylase): 17-OH progesterone → 11-deoxycortisol (cortisol pathway) and progesterone → 11-deoxycorticosterone (aldosterone pathway)

Congenital Adrenal Hyperplasia (CAH)

21-Hydroxylase Deficiency (>90% of CAH)

• Most common cause of CAH; autosomal recessive
• Block in cortisol synthesis → ACTH increase → adrenal hyperplasia → androgen excess
• Classic salt-wasting (severe): cortisol and aldosterone deficiency + virilisation; neonatal salt-wasting crisis
• Classic simple virilising: cortisol deficiency + androgen excess; ambiguous genitalia in females at birth
• Non-classic (late-onset): mild androgen excess; presents with hirsutism, acne, oligomenorrhoea in adolescence/adulthood
• Biochemical hallmark: elevated 17-hydroxyprogesterone
• Treatment: glucocorticoid replacement (hydrocortisone) ± mineralocorticoid (fludrocortisone)

11-Beta-Hydroxylase Deficiency

• Second most common; androgen excess + hypertension (11-deoxycorticosterone has mineralocorticoid activity)
• Elevated 11-deoxycortisol

17-Alpha-Hydroxylase Deficiency

• Rare; cannot make cortisol or sex steroids; mineralocorticoid excess → hypertension, hypokalaemia
• 46,XY individuals: female phenotype (no androgens)
• 46,XX individuals: primary amenorrhoea, absent secondary sexual characteristics

Polycystic Ovary Syndrome (PCOS)

Rotterdam Criteria (need 2 of 3)

1. Oligo-ovulation or anovulation (irregular or absent periods)
2. Clinical or biochemical hyperandrogenism (hirsutism, acne, raised total/free testosterone)
3. Polycystic ovarian morphology on USS (≥12 follicles 2-9mm in at least one ovary, OR ovarian volume >10ml)

Pathophysiology

• Insulin resistance → hyperinsulinaemia → stimulates ovarian androgen production + reduces hepatic SHBG → increased free androgens
• Increased LH pulse frequency and amplitude → increased LH:FSH ratio (>2:1)
• Androgen excess disrupts normal folliculogenesis → follicular arrest → anovulation
• Chronic anovulation → unopposed oestrogen → endometrial hyperplasia risk

Clinical Features

• Oligomenorrhoea/amenorrhoea, subfertility
• Hirsutism, acne, alopecia (androgenic)
• Obesity (50-70% of PCOS patients)
• Metabolic syndrome, insulin resistance, type 2 diabetes risk
• Long-term risks: endometrial cancer (unopposed oestrogen), cardiovascular disease, obstructive sleep apnoea

Thyroid Function in Pregnancy

• TBG increases (oestrogen effect) → total T4/T3 increase, but FREE T4/T3 remain normal
• First trimester: hCG stimulates TSH receptors → transient decrease in TSH (physiological)
• Gestational thyrotoxicosis: hCG-mediated; associated with hyperemesis gravidarum; self-limiting
• Hypothyroidism: increase levothyroxine dose by 25-50% early in pregnancy; check TSH each trimester
• Subclinical hypothyroidism: treat if TSH >4.0 mU/L with positive TPO antibodies

Prolactin

• Secreted by lactotroph cells of anterior pituitary
• Under tonic inhibitory control by dopamine from hypothalamus
• Physiological elevation: pregnancy (10-fold), breastfeeding, stress, sleep
• Hyperprolactinaemia causes: pituitary adenoma (prolactinoma), drugs (antipsychotics, metoclopramide), hypothyroidism, PCOS
• Effects of excess: galactorrhoea, amenorrhoea (suppresses GnRH pulsatility → hypogonadotrophic hypogonadism)
• Treatment: dopamine agonists (cabergoline preferred over bromocriptine — fewer side effects, once-weekly dosing)

Important Facts for MRCOG

• Aromatase converts androgens → oestrogens (target of letrozole therapy)
• 21-hydroxylase deficiency: most common CAH; elevated 17-OHP; virilisation of females
• PCOS Rotterdam criteria: 2 of 3 (anovulation, hyperandrogenism, polycystic morphology)
• PCOS: insulin resistance is central to pathophysiology
• Unopposed oestrogen in PCOS → endometrial hyperplasia/cancer risk
• TBG increases in pregnancy → total T4 rises but free T4 stays normal
• Prolactin is tonically inhibited by dopamine; treated with dopamine agonists
• 5-alpha reductase: testosterone → DHT (most potent androgen)

Clinically reviewed by NHS obstetricians and gynaecologists

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