Sex steroid hormones
Oestrogen, progesterone and androgens: actions; male reproduction and spermatogenesis
Oestrogen, progesterone and androgens for FCPS Part 1: synthesis, actions, sources in pregnancy and the drugs that mimic or block them. Covers Leydig and Sertoli cells, spermatogenesis, sperm structure, semen and male infertility patterns.
One of the most tested topics in past papers
Synthesis
- Cholesterol enters mitochondria via StAR and is cleaved by side-chain cleavage enzyme (desmolase) to pregnenolone: the rate-limiting step.
- 17-alpha-hydroxylase leads to androgens; aromatase converts androgens to oestrogens (granulosa, placenta, fat); 5-alpha-reductase converts testosterone to dihydrotestosterone (DHT) in prostate, genital skin and hair follicles.
- Oestrogen potency: oestradiol > oestrone > oestriol. Oestradiol is the most potent and the main premenopausal oestrogen; oestrone dominates after menopause; oestriol dominates in pregnancy and is measured in the quadruple screening test.
- In women about half of testosterone comes from peripheral conversion of androstenedione. High DHEA sulphate points to the adrenal; high testosterone with normal DHEA sulphate points to the ovary.
- SHBG is raised by oestrogen and thyroid hormone and lowered by androgens, insulin and obesity.
- All sex steroids act through intracellular (nuclear) receptors that alter gene transcription.
Sources of oestrogen and progesterone in pregnancy
| Period | Main source |
|---|---|
| Luteal phase and first 7–10 weeks | Corpus luteum, maintained by hCG |
| After about 10 weeks to term (second and third trimesters) | Placenta (syncytiotrophoblast) |
- The placenta makes progesterone from maternal LDL cholesterol, but it lacks 17-alpha-hydroxylase, so it makes oestrogens (mainly oestriol) from fetal adrenal DHEA sulphate: the fetoplacental unit.
Oestrogen actions
| Target | Effect |
|---|---|
| Endometrium | Proliferation; induces progesterone receptors |
| Cervix, vagina | Clear, abundant mucus; thick, glycogen-rich epithelium |
| Breast | Duct growth and fat deposition |
| Bone | Preserves bone; growth spurt, then closes epiphyses (in both sexes, from aromatised androgen) |
| Liver | Raises SHBG, TBG, CBG, angiotensinogen, clotting factors (venous thrombosis); HDL up, LDL down |
| Bile | More cholesterol secreted into bile, supersaturating it: cholesterol gallstones (yellow, radiolucent); progesterone adds gallbladder stasis |
- Intrahepatic cholestasis of pregnancy: high sex steroid levels impair bile acid export by hepatocytes; itching of palms and soles without rash, high bile acids, resolving after delivery. Twins carry more placental steroid, so more risk.
- Ethinylestradiol has a 17-alpha-ethinyl group that blocks hepatic metabolism, so microgram doses work orally.
- Oestradiol peak without progesterone: in a 28-day cycle, the late follicular oestradiol peak (sustained about 36 hours) switches to positive feedback and triggers the LH surge, followed by ovulation about 36 hours after surge onset.
Progesterone actions
- Converts proliferative to secretory endometrium. The first sign, about 36–48 hours after ovulation, is glycogen-filled subnuclear vacuoles in coiled glands (early secretory phase).
- Antiproliferative: reduces endometrial oestrogen receptors and increases conversion of oestradiol to oestrone (17-beta-HSD). This is why HRT in a woman with a uterus includes a progestogen; after hysterectomy oestrogen alone is used.
- Thick cervical mucus; thermogenic; sensitises the respiratory centre to CO2, so pregnant women hyperventilate (PaCO2 about 4 kPa, 30 mmHg) and often feel physiological breathlessness.
- Smooth muscle relaxation: keeps myometrium quiet and the cervix firm (nightly vaginal progesterone for a short cervix at 22 weeks lowers preterm birth risk), relaxes the lower oesophageal sphincter, ureters and gallbladder.
- Anti-mineralocorticoid effect in pregnancy.
| Drug | Mechanism or point |
|---|---|
| Mifepristone | Progesterone receptor antagonist |
| Ulipristal | Selective progesterone receptor modulator; emergency contraception |
| Norethisterone | Taken from 3 days before the period is due, it prevents progesterone withdrawal, so the endometrium does not shed (delaying a period) |
| Depot medroxyprogesterone | Suppresses ovulation; the low oestrogen state reduces bone mineral density |
| Cyproterone acetate | Progestogen that also blocks androgen receptors and suppresses gonadotrophins: used with ethinylestradiol for hirsutism and acne |
| Raloxifene | SERM: oestrogen agonist on bone, antagonist on breast and endometrium; tamoxifen differs by stimulating the endometrium |
| Danazol | Androgenic; may permanently deepen the voice |
- Progestogens derived from 19-nortestosterone (norethisterone, levonorgestrel) are mildly androgenic and can worsen acne.
Androgens and the testis
| Cell | Stimulus | Products and roles |
|---|---|---|
| Leydig | LH (hCG in the first trimester) | Testosterone |
| Sertoli | FSH and testosterone | Androgen-binding protein, inhibin B, AMH (fetus), blood–testis barrier |
- Testosterone builds the Wolffian ducts directly; DHT forms the external genitalia and prostate. Finasteride (5-alpha-reductase inhibitor) handled by a pregnant woman can leave a male fetus with undermasculinised external genitalia, while internal ducts are spared.
- Testosterone across life: high in early fetal life, a second rise for 2–3 months after birth (mini-puberty), lowest in mid-childhood, rising at puberty and peaking in early adulthood, then declining slowly.
- Androgens drive the pubertal growth spurt only up to a limit, because aromatised oestrogen fuses the epiphyses.
- Castration in adult life: loss of libido, erectile dysfunction and hot flushes, later loss of muscle and bone. Changes fixed at puberty, such as a deep voice and laryngeal size, do not reverse.
- Exogenous testosterone suppresses LH and FSH: small testes and azoospermia.
- Obese men aromatise testosterone to oestradiol, which suppresses LH. Anastrozole removes this oestradiol feedback, so LH and testosterone rise.
- Klinefelter (47,XXY): small firm testes, high FSH and LH, gynaecomastia.
Spermatogenesis
| Cell | Division | Chromosomes |
|---|---|---|
| Spermatogonium | Mitosis | 46 |
| Primary spermatocyte | Meiosis I | 46 (duplicated) |
| Secondary spermatocyte | Meiosis II within hours | 23, two chromatids each |
| Spermatid | Spermiogenesis (no division) | 23, single chromatid |
- Takes about 64–74 days (often quoted as about 2.5 months), so semen is repeated after about 3 months. It needs a temperature 2–3 °C below core: cryptorchidism and varicocele damage germ cells.
- Sperm leave the seminiferous tubules immotile, gain partial motility in the epididymis and are stored in the tail of the epididymis and the vas. Fertilising ability (capacitation) develops in the female tract.
- Spermatogenesis continues into old age; men over 70 still make sperm, but with lower volume and reduced motility (asthenospermia).
Sperm structure
| Part | Contents | Defect |
|---|---|---|
| Head | Nucleus and acrosome (hyaluronidase, acrosin) | Failed zona penetration |
| Middle piece | Helical mitochondrial sheath around the axoneme | Disorganised sheath: poor motility with a normal count |
| Tail | Axoneme (9+2 microtubules with dynein arms) | Dynein defect (Kartagener): immotile sperm |
- Fertilin on the sperm head binds integrins on the oocyte membrane, mediating sperm–oocyte membrane binding and fusion.
Semen and male infertility
| Source | Share | Contents |
|---|---|---|
| Seminal vesicles | About 65–75% | Fructose, alkaline fluid, semenogelin (forms the coagulum) |
| Prostate | About 25–30% | Citrate, zinc, PSA (protease that liquefies the coagulum within about 20 minutes), acid phosphatase |
- A coagulum persisting for hours means a PSA (prostate) problem; semenogelin is the substrate, not the enzyme.
| Pattern | Meaning |
|---|---|
| Azoospermia, high FSH, small testes | Primary testicular failure |
| Azoospermia, normal FSH and testes, normal ejaculation | Obstruction (vas, epididymis, ejaculatory duct) |
| Low volume, acidic, no fructose | Absent seminal vesicles or ejaculatory duct obstruction |
- After vasectomy sperm already stored beyond the cut keep appearing for about 12 weeks, so contraception continues until a clear semen test.
Remember Leydig: LH and testosterone. Sertoli: FSH, inhibin and the barrier.
Exam trap The first cells with 23 single-chromatid chromosomes are spermatids, not secondary spermatocytes.
Exam trap Progestogen in HRT protects the endometrium by reducing oestrogen receptors, not by killing cells.
How FCPS asks about this
- Most potent oestrogen: oestradiol; oestriol is the pregnancy oestrogen used in screening.
- Source of oestrogen and progesterone after the first trimester: the placenta; corpus luteum before 7–10 weeks.
- Glycogen-filled subnuclear vacuoles: early secretory phase, progesterone.
- Duration of spermatogenesis: about 64–74 days.
- Where sperm are stored and become partly motile: epididymis.
- Testosterone is synthesised by: Leydig cells under LH.
- Enzyme liquefying the semen coagulum: prostate-specific antigen.
Test yourself on this topic
5 of the 90 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
A 30-year-old man has semen volume 0.6 mL, pH 6.8, no sperm and no fructose. His testes are of normal size, FSH is normal and both vasa deferentia are palpable. Transrectal ultrasound shows dilated seminal vesicles. Where is the obstruction?
Answer: Ejaculatory ducts
Seminal vesicles contribute most of the semen volume, along with fructose and an alkaline pH. Low volume, acidic semen with no fructose and no sperm means seminal vesicle fluid is not reaching the ejaculate. Dilated vesicles and palpable vasa place the block in the ejaculatory ducts, which run through the prostate to the urethra. A block in the epididymis or vas would cause azoospermia with normal volume and fructose.
Reading semen chemistry
- Seminal vesicles: volume, fructose, alkali
- Prostate: acid phosphatase, citrate, PSA
- Low volume, no fructose: vesicles blocked
- Azoospermia, normal volume: above the vesicles
Remember No fructose means no seminal vesicle fluid.
Exam trap Azoospermia alone cannot locate an obstruction; volume, pH and fructose do.
Why the other options are wrong
- Epididymis Volume and fructose would be normal.
- Vas deferens in the inguinal canal Volume and fructose would be normal.
- Rete testis Volume and fructose would be normal.
- Penile urethra Semen would still contain vesicle fluid and fructose.
A 25-year-old woman has six months of amenorrhoea, deepening voice and clitoromegaly. Testosterone is high and DHEA sulphate normal. A 7 cm solid unilateral ovarian mass shows tubules lined by Sertoli-like cells with clusters of Leydig-like cells between them. What is the diagnosis?
Answer: Sertoli–Leydig cell tumour
Sertoli–Leydig cell tumours are sex cord–stromal tumours of young women. The Leydig cell component secretes testosterone, causing defeminisation followed by virilisation. Normal DHEA sulphate excludes an adrenal source. Granulosa cell tumours and thecomas usually secrete oestrogen, and hilus cell tumours are small nodules in older women made of Leydig cells alone.
Sertoli–Leydig cell tumour
- Young woman, virilisation
- High testosterone, normal DHEAS
- Tubules plus Leydig cells
- Sex cord–stromal tumour
Remember Virilising mass in a young ovary: Sertoli–Leydig.
Exam trap Most sex cord–stromal tumours are oestrogenic; this one is the main androgenic exception.
Why the other options are wrong
- Granulosa cell tumour Usually oestrogenic, with Call–Exner bodies.
- Thecoma Usually oestrogenic, in older women.
- Dysgerminoma Germ cell tumour; not androgenic.
- Hilus cell tumour Small, postmenopausal, pure Leydig cells.
A 30-year-old man has azoospermia. His testes are 12 mL each, testosterone and LH are normal, but FSH is raised. Testicular biopsy shows seminiferous tubules lined only by Sertoli cells. What explains the selective rise in FSH?
Answer: Low inhibin B from the tubules
Inhibin B is secreted by Sertoli cells and selectively suppresses FSH at the pituitary. Its output depends on active spermatogenesis, so when germ cells are lost, inhibin B falls and FSH rises. LH is controlled mainly by testosterone feedback, and Leydig cells are intact in Sertoli-cell-only syndrome, so LH and testosterone remain normal. A raised FSH in an azoospermic man therefore points to failure of spermatogenesis rather than obstruction.
FSH and inhibin B
- Sertoli cells make inhibin B
- Inhibin B selectively suppresses FSH
- Germ cell loss: inhibin B falls
- FSH rises, LH normal
Remember High FSH with azoospermia means the factory has failed.
Exam trap Normal testosterone does not mean normal spermatogenesis; the two compartments are controlled separately.
Why the other options are wrong
- Low testosterone feedback Testosterone is normal here.
- Faster GnRH pulse frequency Faster pulses favour LH, not FSH.
- Absent androgen-binding protein Does not feed back on the pituitary.
- More activin from Leydig cells Activin comes mainly from Sertoli cells and pituitary, not this cause.
In normal pregnancy, plasma renin activity and aldosterone rise several-fold, yet women do not become hypokalaemic or hypertensive. Which hormone competes with aldosterone at the renal mineralocorticoid receptor?
Answer: Progesterone
Progesterone binds the mineralocorticoid receptor in the distal nephron and acts as an antagonist, promoting natriuresis. This natriuretic tendency, together with the fall in vascular resistance, stimulates the renin–angiotensin–aldosterone system. The high aldosterone balances progesterone's effect so that sodium is retained overall, supporting plasma volume expansion without potassium loss. Cortisol also binds the receptor but is normally inactivated in the kidney by 11β-HSD2.
RAAS in pregnancy
- Renin and aldosterone rise
- Progesterone blocks the MR
- Net sodium retention
- No hypokalaemia
Remember Progesterone is a natural anti-aldosterone.
Exam trap High aldosterone in pregnancy is physiological and does not mean primary hyperaldosteronism.
Why the other options are wrong
- Oestradiol Tends to retain sodium; not an aldosterone antagonist.
- Human placental lactogen Metabolic hormone; no mineralocorticoid action.
- Relaxin Causes vasodilatation; does not block the receptor.
- Cortisol Inactivated by renal 11β-HSD2 and an agonist if not.
A 27-year-old woman has four months of rapidly worsening hirsutism and clitoromegaly. Testosterone is moderately raised, DHEA sulphate is markedly raised and ovarian ultrasound is normal. Where is the androgen most likely coming from?
Answer: Adrenal zona reticularis
DHEA sulphate is made almost entirely by the adrenal cortex, mainly the zona reticularis, so a markedly raised level points to an adrenal source such as an adrenal tumour. Rapid virilisation suggests a tumour rather than PCOS. Ovarian androgen-secreting tumours raise testosterone strongly but leave DHEA sulphate near normal. The zona fasciculata makes mainly cortisol, and the medulla makes catecholamines.
Source of androgen excess
- High DHEA sulphate: adrenal
- High testosterone, normal DHEAS: ovary
- Rapid virilisation: think tumour
- Reticularis makes adrenal androgens
Remember DHEAS is the adrenal fingerprint.
Exam trap Testosterone can be raised from either source; DHEA sulphate separates them.
Why the other options are wrong
- Ovarian theca interna Ovarian sources raise testosterone, not DHEA sulphate.
- Ovarian hilus cells Ovarian; raises testosterone with normal DHEA sulphate.
- Adrenal zona fasciculata Makes mainly cortisol.
- Adrenal medulla Makes catecholamines, not steroids.
Where this sits in the CPSP syllabus
- Obstetrics & Gynaecology, Paper 2: Reproduction, pregnancy and labour, Oestrogen, progesterone and androgens: actions; male reproduction and spermatogenesis
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