Ovary
The ovary is a gland with a countdown on it: it makes one egg and two hormones a month from a pool that only ever shrinks, and it does it by talking to the brain in pulses. Almost every disease here is that conversation breaking — too much drive, too little drive, or nothing left to answer — and almost every drug on this page acts on the brain, the liver or the fat, not on the ovary itself.
What it normally does
The hypothalamus does not release gonadotrophin-releasing hormone (GnRH) in a steady stream. It fires it in pulses, roughly one every 60-90 minutes in the follicular phase, slowing to every 3-4 hours in the luteal phase under progesterone. The pituitary reads the rhythm, not just the amount: fast pulses favour luteinising hormone (LH); slow pulses favour follicle-stimulating hormone (FSH). Give GnRH continuously instead of in pulses and the pituitary GnRH receptors downregulate and the whole axis switches off [pulsatile GnRH, hypothalamic-pituitary-ovarian axis].
Explains why starvation, over-training and stress silence the ovary from the top (functional hypothalamic amenorrhoea), and why PCOS runs with a fast pulse and a high LH. It also explains two different ways to switch the axis off, which students routinely merge: a continuous GnRH agonist (goserelin, leuprorelin) causes an initial flare then receptor downregulation, whereas the combined pill works by steady steroid negative feedback on the hypothalamus and pituitary, not by GnRH receptor downregulation.
Making oestrogen takes two cells and two hormones. LH tells the theca cell to turn cholesterol into androgens (androstenedione and testosterone) — the theca has no aromatase, so that is as far as it can go. FSH tells the neighbouring granulosa cell to switch on aromatase, which converts those androgens into oestradiol — the granulosa has essentially no 17-hydroxylase/17,20-lyase (CYP17A1), so it cannot make its own substrate. Androgen is not a contaminant of the process; it is the raw material [two-cell, two-gonadotrophin model].
Explains why anything that raises LH or insulin raises androgens (hirsutism and acne in PCOS), why blocking aromatase is a way to induce ovulation, and why fat tissue — which also expresses aromatase — keeps making oestrogen (mostly oestrone, from adrenal and ovarian androstenedione) after the ovary has stopped.
Oestradiol normally feeds back negatively. But once a dominant follicle pushes oestradiol high and holds it there — in the order of 700 pmol/L (about 200 pg/mL) for roughly two days — the feedback flips positive and the pituitary dumps LH. Ovulation follows roughly 36 hours after the surge begins (about 10-12 hours after the LH peak). The emptied follicle becomes the corpus luteum and makes progesterone, which slows GnRH pulses back down and turns proliferative endometrium into secretory endometrium. With no hCG from an implanting embryo the corpus luteum involutes on schedule at about 14 days, oestradiol and progesterone fall off a cliff, and the endometrium is shed [oestradiol positive feedback, luteal phase, hormone withdrawal bleed].
Explains why the luteal phase is a fixed length and the follicular phase is not, why a period is a withdrawal bleed rather than a hormone-driven event, and why a woman who does not ovulate gets oestrogen with no progesterone to oppose it.
The follicle pool is fixed before birth and only ever falls — about 1-2 million at birth, 300,000-400,000 at puberty, a few hundred ovulated in a lifetime, the rest lost to atresia. Granulosa cells of preantral and small antral follicles secrete anti-Mullerian hormone (AMH), which restrains recruitment of primordial follicles and blunts their FSH sensitivity, and inhibin B, which selectively suppresses pituitary FSH. As the pool empties, inhibin B falls and FSH climbs to shout at follicles that are no longer there [ovarian reserve, inhibin B and AMH feedback].
Explains why a high FSH with a low oestradiol is the biochemical signature of a failing ovary at any age, why AMH tracks the size of the pool (high in PCOS, low approaching menopause), and why the consequences of menopause are the consequences of losing oestradiol everywhere at once.
What goes wrong
- Polycystic ovary syndrome (PCOS)← from “Making oestrogen takes two cells and two hormo…”
Two drivers converge on the theca cell. GnRH pulses run fast, so LH is high relative to FSH and the theca is over-stimulated. Insulin resistance means high circulating insulin, and insulin acts as a co-gonadotrophin at the theca — it amplifies LH-driven androgen synthesis, and it suppresses hepatic sex hormone binding globulin (SHBG) so a greater fraction of that androgen circulates free. Meanwhile the ovary is crowded with small antral follicles secreting a lot of AMH, which blunts FSH sensitivity. Plenty of follicles start, none is selected, none ovulates. No ovulation means no corpus luteum, no progesterone, and no organised shedding.
PCOS is androgen excess plus anovulation, and insulin is what ties them together. Insulin raises theca androgen production and lowers SHBG, so free testosterone rises twice over. That is why weight and insulin sensitivity change the phenotype, and why metformin has anything at all to do with a gynaecological diagnosis.
You would find: Rotterdam criteria, retained by the 2023 international guideline: two of three — irregular or absent ovulation, clinical or biochemical hyperandrogenism (hirsutism, acne, raised free androgen index), and polycystic ovarian morphology (20 or more follicles of 2-9 mm in at least one ovary, or ovarian volume 10 mL or more in at least one ovary, on a modern endovaginal probe) — with other causes excluded: thyroid function, prolactin, 17-hydroxyprogesterone for non-classical congenital adrenal hyperplasia, and Cushing if the picture fits. The 2023 guideline, led from Monash, allows serum AMH as an alternative to ultrasound for polycystic ovarian morphology in adults, and says neither ultrasound nor AMH should be used for diagnosis within 8 years of menarche because multifollicular ovaries and high AMH are normal then — in that window the diagnosis rests on hyperandrogenism plus irregular cycles. An LH:FSH ratio above 2 is common but is not a diagnostic test and should not be ordered as one. Around 8-13% of women of reproductive age; reported higher in Aboriginal and Torres Strait Islander women, who also develop type 2 diabetes younger and more often, so the metabolic screening matters more, not less.
- Unopposed oestrogen: anovulatory bleeding and endometrial hyperplasia← from “Oestradiol normally feeds back negatively. But…”
No ovulation means no corpus luteum, so progesterone is never made. But oestrogen keeps coming — from the small follicles still turning over, and from aromatase in adipose tissue converting adrenal and ovarian androstenedione into oestrone. The endometrium proliferates continuously with nothing to convert it to secretory tissue and nothing to trigger an orderly withdrawal bleed. It outgrows its blood supply and sheds patchily and unpredictably. Sustained mitotic drive without differentiation is how hyperplasia, and then endometrioid carcinoma, gets started.
A period is progesterone withdrawal. If she does not ovulate she makes no progesterone, so any bleeding she has is breakthrough from an overgrown endometrium — not a period, and not reassurance.
You would find: Cycles longer than 35 days, or fewer than eight bleeds a year, then bleeding that is heavy, prolonged and unpredictable rather than absent. Thickened endometrium on ultrasound. Any postmenopausal bleeding needs urgent assessment — transvaginal ultrasound first, with endometrial (pipelle) biopsy if the endometrial thickness is above 4 mm, if bleeding recurs, or if the scan is non-diagnostic; persistent abnormal bleeding or a thickened endometrium in an anovulatory premenopausal woman is also a reason to sample. PCOS carries roughly a two to six-fold increase in endometrial cancer, and it is the one hard outcome you can prevent cheaply.
- Functional hypothalamic amenorrhoea← from “The hypothalamus does not release gonadotrophi…”
Low energy availability — restricted intake, heavy training, illness, psychological stress — drops leptin and raises cortisol and ghrelin. Kisspeptin neurons quieten, GnRH pulse frequency falls, and the pituitary stops sending enough FSH and LH to recruit a follicle. The ovary is structurally fine and full of follicles; nobody is calling it. Oestradiol stays low, so the endometrium never proliferates and bone remodelling swings towards resorption.
Low gonadotrophins with low oestradiol means the problem is above the ovary; high gonadotrophins with low oestradiol means the ovary itself has failed. One FSH separates hypothalamic amenorrhoea from premature ovarian insufficiency.
You would find: Amenorrhoea in a lean, stressed or athletic woman with low or low-normal LH and FSH and a low oestradiol — the opposite gonadotrophin pattern to ovarian failure. Negative pregnancy test, normal prolactin and thyroid function, no androgen excess. It remains a diagnosis of exclusion: image the pituitary if there are headaches, visual field loss or other pituitary hormone deficits. Look for the rest of relative energy deficiency in sport (RED-S): stress fractures, low bone density, fatigue, disordered eating. The treatment is restoring energy availability, not prescribing a bleed.
- Premature ovarian insufficiency (POI)← from “The follicle pool is fixed before birth and on…”
The follicle pool is exhausted or destroyed before 40 — most often no cause is found, but Turner syndrome and the fragile X (FMR1) premutation, autoimmune oophoritis, and chemotherapy or pelvic radiotherapy all do it. With too few granulosa cells left, inhibin B and AMH collapse and pituitary FSH rises unopposed while oestradiol falls. Unlike menopause it is not always a one-way door: follicular activity flickers back intermittently in a substantial minority, and around 5% conceive spontaneously.
POI is not early menopause and it is not contraception — intermittent ovulation happens, so she still needs contraception if she does not want to conceive. High FSH, low oestradiol, under 40 — and hormone therapy here is replacing what she should still have, continued until about the natural age of menopause, not the short-term symptom treatment used at 55.
You would find: Oligomenorrhoea or amenorrhoea for 4 months or more under the age of 40, with an FSH above 25 IU/L. The 2024 ESHRE/ASRM/IMS guideline keeps biochemical confirmation on two occasions at least 4 weeks apart, and does not recommend AMH as a diagnostic test — so a single raised FSH under 40 is a reason to repeat the test, not to make the diagnosis. Prevalence is higher than the traditional 1 in 100: current estimates are around 3.5% of women. Then look for the cause — karyotype, FMR1 premutation, adrenal (21-hydroxylase) and thyroid antibodies — and count the decades of oestrogen deficiency ahead: bone loss, cardiovascular risk and genitourinary atrophy starting 15 years early.
The pool runs out. Median age in Australia is around 51. Oestradiol falls to the low level that peripheral aromatisation can sustain — after menopause the dominant oestrogen is oestrone, made in adipose tissue from adrenal androstenedione — and FSH and LH rise because nothing is feeding back. In the hypothalamus the kisspeptin/neurokinin B/dynorphin (KNDy) neurons of the arcuate (infundibular) nucleus that ran the pulse generator hypertrophy without oestrogen restraint; their neurokinin B projections to the median preoptic nucleus, the thermoregulatory centre, narrow the thermoneutral zone, so a trivial rise in core temperature triggers a full heat-dumping response. The same missing ligand releases osteoclasts from restraint, thins vaginal and urethral epithelium, and shifts the lipid profile.
Hot flushes are a brain symptom of an ovarian failure. The KNDy neurons are hyperactive because oestradiol no longer restrains them — which is why oestrogen fixes flushes, and why a drug blocking neurokinin B at the NK3 receptor does too without touching a hormone receptor.
You would find: Hot flushes and night sweats, sleep disruption, mood change; vaginal dryness, dyspareunia and urinary urgency (genitourinary syndrome of menopause) which, unlike flushes, does not settle with time. Over 45 with typical symptoms the diagnosis is clinical — an FSH adds nothing and misleads in the perimenopause when it swings month to month. Spinal (trabecular) bone loss runs at roughly 2-3% a year in the early postmenopausal years.
What we give, and how it works
Open a drug to see what it binds, what that does to the cell, and what you then see in the patient.
- Binds
- Oestrogen and progesterone receptors in the hypothalamus and anterior pituitary; progesterone receptors in endometrium and cervix; hepatic oestrogen receptors driving protein synthesis.
- Which does
- Continuous steroid exposure flattens GnRH pulsatility and suppresses FSH, so no dominant follicle is recruited, and the progestogen blocks the mid-cycle LH surge, so nothing ovulates. The progestogen also keeps the endometrium thin and atrophic and the cervical mucus thick. Separately, ethinylestradiol passing through the liver drives SHBG synthesis up two- to four-fold, which mops up free testosterone.
- So you see
- Predictable withdrawal bleeds in the pill-free interval, less hirsutism and acne over 6-9 months as free androgen falls, and an endometrium that cannot become hyperplastic. The bleed is a manufactured withdrawal bleed — it is not evidence that her own cycle has been repaired.
- And the same mechanism causes
- The same hepatic first-pass that raises SHBG also raises factors VII and X and fibrinogen and lowers protein S and antithrombin, producing acquired activated protein C resistance. The clotting change is not a separate side effect — it is the identical mechanism acting on a different set of liver genes, which is why venous thromboembolism risk rises two- to four-fold (from roughly 2 to 5-12 per 10,000 woman-years; pregnancy and especially the puerperium are higher again). Pills containing drospirenone or cyproterone carry a higher VTE signal than levonorgestrel.
- Handling
- The contraindications follow the same logic. Category 4 (do not use) includes migraine with aura at any age, previous VTE, known thrombophilia, and smoking 15 or more cigarettes a day at age 35 or over; lighter smoking at 35 or over is category 3 (risks usually outweigh benefits). A progestogen-only option or a levonorgestrel intrauterine device protects the endometrium without the hepatic oestrogen load.
Catches people out: It controls the phenotype; it does not touch the insulin resistance underneath, and it is not a fertility treatment. It also masks the natural cycle, so it tells you nothing about whether ovulation has returned.
- Binds
- Mitochondrial complex I in hepatocytes and enterocytes; the resulting rise in AMP:ATP activates AMPK.
- Which does
- Hepatic gluconeogenesis falls, so less insulin is needed to hold glucose steady and circulating insulin drops. Less insulin at the theca cell means less amplification of LH-driven androgen synthesis; less insulin at the hepatocyte means SHBG synthesis recovers and binds more of the testosterone still being made.
- So you see
- Free androgen index falls, cycles become more regular in some women, and weight and glycaemic trajectory improve modestly. It is an adjunct — its effect on ovulation and live birth is smaller than letrozole's.
- And the same mechanism causes
- Blocking complex I forces cells towards anaerobic glycolysis, so lactate production rises — harmless while the kidneys clear metformin and the liver clears lactate, dangerous when they cannot (lactic acidosis in significant renal impairment, sepsis, hypoxia or decompensated liver disease). The same action on drug sitting unabsorbed in the gut explains the nausea, bloating and diarrhoea that dominate the first weeks, and years of use impair the calcium-dependent uptake of the intrinsic factor-B12 complex in the terminal ileum, so B12 drifts down.
- Handling
- Dose is limited by renal function because the drug is cleared unchanged by the kidney, and it is withheld around iodinated contrast where renal function is already impaired, and during acute intercurrent illness, for the same reason.
Catches people out: Metformin does not treat hirsutism to any useful degree — that needs the pill or an anti-androgen. And restoring ovulation restores fertility, which is welcome or not depending on what she wants.
- Binds
- Aromatase (CYP19A1), inhibited reversibly and non-steroidally.
- Which does
- Androgens can no longer be converted to oestradiol, so serum oestradiol falls. The hypothalamus and pituitary read that as too little oestrogen and raise FSH output. That FSH recruits a follicle, which makes its own oestradiol once the drug has cleared, and the normal positive-feedback LH surge follows.
- So you see
- Ovulation in the majority of women with PCOS, usually of a single follicle, with higher live-birth rates than clomifene in this population. Letrozole's half-life is around 2 days, so it is gone well before implantation and the endometrium and cervical mucus see a normal oestrogen environment.
- And the same mechanism causes
- An induced low-oestrogen state for a few days: hot flushes, headache, fatigue — menopausal symptoms, from the menopausal cause. Recruit more than one follicle and you get multiple pregnancy, at a few per cent. Clomifene, a selective oestrogen receptor modulator and the older comparator, shows the flip side of the same logic: acting as an oestrogen receptor antagonist with a very long half-life, it blocks receptors in endometrium and cervix as well as hypothalamus, which is why it gives a good ovulation rate but a thin endometrium, hostile mucus, and a pregnancy rate that lags behind.
- Handling
- Cycles are monitored so multi-follicular responses are picked up. Early teratogenicity concerns with letrozole were not borne out — the short half-life relative to the time to implantation was always against them.
Catches people out: It induces one ovulation. It does not treat PCOS: the anovulation returns when the drug stops, and the metabolic risk was never addressed.
- Binds
- Oestrogen receptors alpha and beta; the added progestogen acts at endometrial progesterone receptors.
- Which does
- Restoring oestradiol re-restrains the hyperactive KNDy neurons, so the thermoneutral zone widens again; in bone it restores the osteoprotegerin/RANKL balance so osteoclast recruitment and survival fall; in vaginal and urethral epithelium it restores thickness, glycogen and blood flow. The progestogen opposes endometrial proliferation, converting it to a secretory then atrophic pattern.
- So you see
- Flushes settle within weeks, sleep and genitourinary symptoms improve, and bone loss stops. In POI the target is a physiological replacement level, higher than the doses used for symptom control at 55.
- And the same mechanism causes
- Every important adverse effect is the same mechanism in another tissue. Oestrogen at the endometrial receptor without a progestogen is precisely the unopposed-oestrogen pathology above — hyperplasia and endometrial carcinoma — which is why endometrial protection is mandatory with an intact uterus. Oestrogen at breast receptors is why combined therapy raises breast cancer incidence with duration of use (of the order of one extra case per 1000 women per year of use); oestrogen-alone therapy in hysterectomised women is different but not clearly safe — the WHI randomised trial found no increase and a trend to fewer breast cancers, while the 2019 Collaborative Group meta-analysis of observational data found a small excess, so counsel it as a smaller risk than combined therapy rather than as no risk. And oral oestrogen delivered through the portal circulation drives the same hepatic clotting factor synthesis as the contraceptive pill, hence the VTE and stroke risk — transdermal oestradiol bypasses that first pass and does not carry the signal, which is why it is preferred in women with VTE risk, migraine or obesity.
- Handling
- The risk-benefit balance turns on timing: started under 60 or within 10 years of the final period, benefit generally outweighs risk; started 20 years later into an aged vasculature, it does not. That timing rule does not apply to POI, where replacement to the normal age of menopause is the default. Vaginal oestrogen for genitourinary symptoms alone is barely absorbed and needs no progestogen.
Catches people out: MHT is not contraception in the perimenopause. Where oestrogen is contraindicated, non-hormonal options act further down the same pathway — SSRIs and SNRIs and gabapentin (all off-label for this in Australia), and neurokinin B (NK3) receptor antagonists such as fezolinetant, which block the KNDy signal directly rather than replacing the hormone that used to silence it. Fezolinetant is TGA-registered for moderate to severe vasomotor symptoms but is not PBS-subsidised, so it is a private-prescription cost, and it carries a hepatotoxicity warning requiring baseline and scheduled liver function monitoring.
One FSH sorts the amenorrhoeas. Low FSH with low oestradiol: the brain has stopped calling (functional hypothalamic amenorrhoea — feed her, do not prescribe a bleed). High FSH with low oestradiol: the ovary has nothing left to answer with (POI under 40, menopause after — and the POI diagnosis needs an FSH above 25 IU/L confirmed on a second sample at least 4 weeks apart). Normal FSH with androgen excess and no ovulation: PCOS. Then remember the two consequences of not ovulating — no progesterone, so unopposed oestrogen and a hyperplasia risk that needs a progestogen or the pill; and no corpus luteum, so infertility that needs letrozole. And the liver runs through the whole page: oral ethinylestradiol raises SHBG (good for hirsutism) and clotting factors (bad) by the identical first-pass mechanism, which is why transdermal oestradiol is the safer route when you want the receptor effect and nothing else.
Now test whether it stuck
Reading this through is not the same as being able to reconstruct it. Every question in the bank is free, with a full debrief on each option.