Female reproductive physiology
Female reproductive physiology: menstrual cycle, ovulation, puberty and menopause
How GnRH, FSH, LH, oestradiol, progesterone and inhibin drive the ovarian and endometrial cycles and how to time ovulation, for FCPS Part 1. Covers puberty, menopause, PCOS, AMH, progestogen challenge, contraception and postmenopausal bone loss.
Hormonal control
- The hypothalamus releases GnRH in pulses; the pituitary releases FSH and LH. Puberty begins when pulsatile GnRH release increases (first at night).
- Two-cell, two-gonadotrophin model: LH stimulates theca cells to make androgens (androstenedione); FSH stimulates granulosa cells to convert them to oestradiol using aromatase.
- Oestradiol is the most potent natural oestrogen (reproductive years); oestrone dominates after menopause; oestriol is the main oestrogen of pregnancy (placenta) and is used in antenatal screening.
- Inhibin B from granulosa cells of small follicles selectively suppresses FSH in the follicular phase; inhibin A comes from the corpus luteum.
- Oestrogen and progesterone act on intracellular (nuclear) receptors.
Ovarian cycle
| Phase | Timing | Events |
|---|---|---|
| Follicular | Day 1 to ovulation (variable) | FSH recruits a cohort of follicles; one becomes dominant and makes rising oestradiol; the rest undergo atresia |
| Ovulation | About day 14 of a 28-day cycle | Oestradiol above about 200 pg/mL for about 36–48 hours switches to positive feedback; LH rises about tenfold (LH surge); ovulation follows 24–36 hours after the surge begins |
| Luteal | Fixed about 14 days | Corpus luteum secretes mainly progesterone, plus oestradiol and inhibin A; LH maintains it; without hCG it regresses |
- Timing ovulation: because the luteal phase is fixed, ovulation occurs about 14 days before the next period (day = cycle length minus 14). A 24-day cycle ovulates about day 10; a 32-day cycle about day 18; a 21–23-day cycle about day 7–9.
- Confirming ovulation: measure mid-luteal progesterone 7 days before the expected period: day 21 of a 28-day cycle, day 25 of a 32-day cycle. Progesterone above about 30 nmol/L confirms ovulation.
- A woman with peak oestradiol and no progesterone for 3 days is about to have her LH surge and ovulate.
- The released ovum is a secondary oocyte arrested in metaphase II; meiosis II completes only at fertilisation. Of the many follicles recruited each cycle, usually only one ovulates; the rest become atretic.
- If pregnancy occurs, hCG from the trophoblast rescues the corpus luteum, which supports pregnancy until the placenta takes over at 8–10 weeks.
Endometrial cycle
| Phase | Hormone | Changes |
|---|---|---|
| Menstrual (days 1–5) | Withdrawal of progesterone | Spiral artery constriction, ischaemia and shedding of the functional layer |
| Proliferative (to ovulation) | Oestrogen | Regrowth of glands and stroma; straight tubular glands with mitoses |
| Secretory (after ovulation) | Progesterone | Coiled glands with glycogen-filled subnuclear vacuoles (early secretory, about day 17), then secretion, stromal oedema and decidual change |
- Dysmenorrhoea: endometrial prostaglandins (PGF2α) released at menstruation cause strong uterine contractions and ischaemic pain; NSAIDs such as mefenamic acid help when started at the onset of bleeding.
- Menstrual blood normally does not clot because of fibrinolysis; small clots with heavy flow are common and harmless.
Other effects of oestrogen and progesterone
| Target | Oestrogen | Progesterone |
|---|---|---|
| Cervical mucus | Clear, thin, stretchy (spinnbarkeit, ferning): sperm-friendly | Thick, scanty: sperm-hostile |
| Breast | Duct growth | Lobuloalveolar development |
| Body temperature | No effect | Raises basal temperature 0.3–0.5 °C |
| Vagina | Glycogen-rich epithelium; lactobacilli make lactic acid (pH about 4) | |
| Bone | Restrains osteoclasts; closes epiphyses | |
| Uterine muscle | Increases excitability | Relaxes (quiescence) |
| Respiration | Stimulates breathing (lower PaCO₂ in luteal phase and pregnancy) |
Puberty and precocious puberty
- Sequence: thelarche (about 10–11 years), pubarche, growth spurt, menarche (about 12–13 years). Early cycles are often anovulatory.
- Central (GnRH-dependent) precocious puberty: early activation of pulsatile GnRH; raised LH and FSH that rise further after GnRH stimulation. Peripheral precocious puberty (ovarian or adrenal tumour, exogenous hormones) has suppressed gonadotrophins.
Menopause and ovarian reserve
- Average age about 51. As follicles run out, inhibin B falls first, so early follicular FSH rises selectively in the late 40s while cycles continue and LH and oestradiol are normal. Later oestradiol falls and FSH and LH are both high. A single raised FSH in a woman still cycling does not prove menopause.
- Anti-Müllerian hormone (AMH) from granulosa cells of small growing follicles reflects ovarian reserve and can be measured on any day. Fertility falls with age because oocyte number and quality decline.
- Postmenopausal oestrogen is mainly oestrone made by aromatase in adipose tissue from adrenal androstenedione; obese women therefore have more unopposed oestrogen and higher risk of endometrial hyperplasia and cancer.
- Osteoporosis: oestrogen loss increases RANKL and osteoclast activity, so resorption outpaces formation. Calcium, phosphate and ALP are usually normal.
- Premature ovarian insufficiency: before 40 (Turner syndrome, autoimmune, chemotherapy, surgery).
Amenorrhoea and PCOS
- Progestogen challenge: a withdrawal bleed after a short course of medroxyprogesterone shows an oestrogen-primed endometrium and a patent outflow tract; the problem is anovulation (as in PCOS). No bleed suggests low oestrogen or outflow obstruction. Exclude pregnancy first.
- Polycystic ovary syndrome: high LH:FSH ratio, hyperandrogenism, anovulation, many peripheral follicles, insulin resistance. Insulin suppresses hepatic SHBG, so free testosterone rises; weight loss and metformin lower insulin, SHBG rises and free testosterone falls even when total testosterone barely changes.
- Letrozole (aromatase inhibitor) given for a few days early in the cycle lowers oestrogen, releasing negative feedback so FSH rises and a follicle matures. Clomifene blocks hypothalamic oestrogen receptors with the same result.
- Hypothalamic amenorrhoea (low weight, heavy exercise, stress): low GnRH, low FSH and LH. Hyperprolactinaemia suppresses GnRH.
Contraception
- Combined pill: suppresses FSH and LH, so no ovulation; thickens mucus.
- Progestogens: thicken mucus; desogestrel and injectable medroxyprogesterone also suppress ovulation. Progestogens can also delay a period.
- Levonorgestrel IUS thins the endometrium; copper IUD is toxic to sperm and blocks implantation and is the most effective emergency method.
Remember Ovulation is 14 days before the next period; check progesterone 7 days before it.
Exam trap Do not use day 21 progesterone for every woman: adjust to her cycle length.
Exam trap The luteal phase is fixed; cycle length varies because of the follicular phase.
How FCPS asks about this
- Ovulation day in a 24- or 32-day cycle: cycle length minus 14 (day 10, day 18).
- Progesterone to confirm ovulation in a 32-day cycle: day 25.
- Trigger for the LH surge: sustained high oestradiol switching to positive feedback.
- Selective early FSH rise in the late 40s: falling inhibin B; AMH measures reserve on any day.
- Breast development: oestrogen for ducts, progesterone for lobules.
- Postmenopausal oestrogen source in obesity: oestrone from aromatase in fat.
- Fall in free testosterone with weight loss in PCOS: lower insulin lets the liver make more SHBG.
Test yourself on this topic
5 of the 94 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
A 58-year-old woman, postmenopausal for 8 years and never on hormone therapy, has a hip fracture after a minor fall. Bone density is low. Which of the following is the main mechanism of bone loss after menopause?
Answer: Oestrogen loss increases osteoclast activity
Oestrogen normally restrains bone resorption: it reduces RANKL and increases osteoprotegerin from osteoblasts, and it shortens the life of osteoclasts. After menopause, oestrogen loss increases osteoclast numbers and activity, so resorption outpaces formation and bone remodelling speeds up. Trabecular bone, as in vertebrae, distal radius and femoral neck, is lost fastest. Bisphosphonates and denosumab work by blocking this osteoclast activity.
Postmenopausal osteoporosis
- Low oestrogen: more RANKL, less OPG
- Osteoclasts live longer
- Trabecular bone lost first
- Fractures: hip, wrist, spine
Remember Menopause takes the brake off osteoclasts.
Exam trap Serum calcium, phosphate and ALP are usually normal in osteoporosis.
Why the other options are wrong
- Progesterone loss stops osteoblast formation Progesterone is not the main regulator of bone mass.
- Raised FSH directly dissolves bone mineral FSH is a marker of menopause, not the main cause of bone loss.
- Oestrogen loss blocks calcium absorption alone Calcium absorption falls slightly but is not the main problem.
- Falling inhibin reduces vitamin D activation Inhibin does not activate vitamin D.
A woman with polycystic ovary syndrome is given letrozole on days 3–7 of her cycle to induce ovulation. How does it work?
Answer: Lower oestrogen lifts feedback, raising FSH
Letrozole inhibits aromatase, the granulosa cell enzyme that converts theca cell androgens to oestrogens. The fall in oestradiol reduces negative feedback on the hypothalamus and pituitary, so FSH rises and drives a follicle to mature. Because peripheral oestrogen receptors are not blocked, the endometrium and cervical mucus are less affected than with clomiphene. It is now widely preferred as first-line ovulation induction in PCOS.
Letrozole
- Aromatase inhibitor
- Less oestradiol, less feedback
- FSH rises, follicle grows
- No peripheral anti-oestrogen effect
Remember Cut oestrogen, release FSH.
Exam trap Letrozole is also a breast cancer drug; in fertility it is used only for a few days per cycle.
Why the other options are wrong
- It blocks hypothalamic oestrogen receptors This is how clomiphene works.
- It directly stimulates FSH receptors It has no direct action on FSH receptors.
- It suppresses the mid-cycle LH surge It does not block the LH surge; ovulation follows.
- It acts as an LH analogue on theca cells hCG, not letrozole, acts on the LH receptor.
A 29-year-old woman with regular 32-day cycles is being investigated for subfertility. A serum progesterone is planned to confirm that she ovulates. On which day of her cycle should it be taken?
Answer: Day 25
The luteal phase is fairly constant at about 14 days, because the corpus luteum has a fixed lifespan unless rescued by hCG. Variation in cycle length comes from the follicular phase. In a 32-day cycle ovulation is around day 18, and progesterone peaks about 7 days later, so the test is done on day 25, 7 days before the expected period. The familiar 'day 21' test applies only to a 28-day cycle.
Mid-luteal progesterone
- Luteal phase about 14 days
- Follicular phase varies
- Test 7 days before the period
- 28-day cycle: day 21
Remember Count back 7 days from the next period.
Exam trap Do not use day 21 for every woman; adjust for her cycle length.
Why the other options are wrong
- Day 21 Right only for a 28-day cycle.
- Day 18 This is about the day of ovulation, before progesterone peaks.
- Day 14 Ovulation day in a 28-day cycle; progesterone is still low.
- Day 30 Too late; the corpus luteum is already regressing.
Why does basal body temperature rise by about 0.3–0.5 °C after ovulation?
Answer: Luteal progesterone
Progesterone, secreted by the corpus luteum after ovulation, has a thermogenic effect on the hypothalamic set point, raising basal body temperature by about 0.3–0.5 °C during the luteal phase; it falls again with menstruation. Charting basal temperature can retrospectively confirm ovulation. Normal body temperature also shows a circadian rhythm, lowest in the early morning and highest in the late afternoon or evening.
Temperature rhythms
- Progesterone raises BBT ~0.3–0.5 °C (luteal phase)
- Charting BBT confirms ovulation (retrospectively)
- Circadian: lowest early morning, highest evening
Remember Progesterone warms the second half of the cycle.
Why the other options are wrong
- Post-ovulation oestrogen peak Oestrogen peaks before ovulation.
- LH raising metabolic rate Not the mechanism.
- Prolactin vasoconstriction Not the mechanism.
- Mild infection at ovulation Not the cause.
A 52-year-old woman has 12 months of amenorrhoea, hot flushes and vaginal dryness. Which hormonal pattern and long-term risk are expected?
Answer: High FSH/LH; bone and CVD risk
Menopause results from depletion of ovarian follicles. Falling inhibin and oestradiol remove negative feedback, so FSH (and LH) rise markedly. It is diagnosed clinically after 12 months of amenorrhoea at the expected age (average about 50); FSH testing is mainly used in women under 45. Oestrogen deficiency causes vasomotor symptoms (hot flushes, night sweats from hypothalamic thermoregulatory instability), genitourinary syndrome (vaginal dryness, dyspareunia, urinary symptoms), mood and sleep disturbance, accelerated bone loss (osteoporosis) and an adverse lipid profile with rising cardiovascular risk. Hormone replacement therapy relieves symptoms and protects bone; women with a uterus need progestogen to protect the endometrium.
Menopause
- Follicle depletion → oestradiol↓, inhibin↓ → FSH↑↑, LH↑
- Diagnosis: 12 months amenorrhoea (FSH if <45)
- Symptoms: hot flushes, vaginal dryness, mood
- Risks: osteoporosis, cardiovascular disease
- HRT: add progestogen if uterus present
Remember No follicles, no feedback, FSH soars.
Why the other options are wrong
- Low FSH/LH; high oestradiol Opposite of menopause.
- High prolactin; low TSH Not menopausal pattern.
- Low FSH; high inhibin Inhibin falls.
- Normal hormones; no risk Risks rise.
Where this sits in the CPSP syllabus
- Paper 1: Reproduction, Female reproductive physiology: menstrual cycle, ovulation, menopause
- Surgery & Allied, Paper 2: Reproduction, Female reproductive physiology: menstrual cycle, ovulation, menopause
- Medicine & Allied, Paper 2: Reproduction, Female reproductive physiology: menstrual cycle, ovulation, menopause
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