Amenorrhea, Ovarian Insufficiency & Hyperandrogenism

Defining and localizing amenorrhea

Definitions. Primary amenorrhea is no menarche by age 15, or by 13 when there is no breast development. Secondary amenorrhea is absence of menses for ≥3 months in a woman with previously regular cycles, or ≥6 months if cycles were irregular. Pregnancy is the most common cause of secondary amenorrhea, so β-hCG always comes first.

Localize the level. Menses need GnRH pulses, LH and FSH, responsive follicles, an endometrium and an open outflow tract; after pregnancy is excluded, FSH, prolactin and TSH sort most cases. In primary amenorrhea, breasts present means estrogen has been made (think outflow defect or androgen insensitivity); breasts absent means the ovaries are not making estrogen, and FSH separates gonadal failure from central causes.

Challenge-test logic. A progestin is given (for example, medroxyprogesterone for 7–10 days) and then stopped.

Hypothalamic and pituitary causes

Functional hypothalamic amenorrhea. Restrictive eating, heavy training or psychological stress lowers leptin and raises CRH and cortisol, slowing GnRH pulses. LH and FSH are low or low-normal, estradiol is low and the endometrium is thin, so there is no progestin withdrawal bleed. Loss of estrogen's restraint on osteoclasts causes low bone density and stress fractures. Low energy availability, menstrual dysfunction and low bone density make up the female athlete triad (also described as relative energy deficiency in sport); restoring energy intake is the core treatment.

Hyperprolactinemia. Prolactin suppresses GnRH pulsatility, giving low LH and FSH, anovulation and galactorrhea. Causes include prolactinoma, dopamine D2-blocking drugs (risperidone, haloperidol, metoclopramide), primary hypothyroidism (TRH stimulates lactotrophs), pregnancy and chronic kidney disease. Dopamine agonists such as cabergoline and bromocriptine lower prolactin and restore ovulation; check TSH before imaging the pituitary.

Sheehan syndrome. The pituitary enlarges during pregnancy through lactotroph hyperplasia without a matching increase in blood supply. Severe postpartum hemorrhage with hypotension causes ischemic necrosis: failure to lactate is often the first sign, followed by amenorrhea, loss of pubic and axillary hair, fatigue and cold intolerance from TSH loss, and hypotension, hyponatremia or hypoglycemia from ACTH loss.

In panhypopituitarism, replace glucocorticoid before thyroid hormone; levothyroxine alone can precipitate adrenal crisis.

Ovarian insufficiency and outflow-tract causes

Primary ovarian insufficiency (POI). Loss of follicular function before age 40: oligo- or amenorrhea with FSH in the menopausal range on two samples at least 4 weeks apart, low estradiol and low anti-Müllerian hormone. Hot flashes, vaginal dryness, infertility and bone loss follow. Unlike menopause, ovarian function can fluctuate, so occasional ovulation and pregnancy occur. Hormone replacement is generally continued until the usual age of menopause to protect bone and cardiovascular health.

Causes of POI. Turner syndrome (45,X or mosaic) accelerates follicle atresia, leaving streak ovaries. An FMR1 premutation (55–200 CGG repeats) causes POI in about 20% of female carriers and late-onset fragile X–associated tremor/ataxia syndrome, whereas a full mutation (>200 repeats) causes fragile X syndrome. Autoimmune oophoritis accompanies Addison disease, autoimmune thyroiditis and type 1 diabetes. Alkylating agents such as cyclophosphamide are cell-cycle–nonspecific and destroy resting primordial follicles; pelvic radiation is also toxic. Classic galactosemia is a rarer cause, and most cases remain idiopathic. The work-up includes a karyotype, FMR1 testing and 21-hydroxylase (adrenal) antibodies.

Asherman syndrome. Intrauterine adhesions form after vigorous curettage (especially postpartum or post-abortion D&C), endometritis (including genital tuberculosis) or uterine surgery. Patients have secondary amenorrhea or scant menses, infertility and recurrent pregnancy loss. LH, FSH, estradiol and ovulation are normal, but neither progestin nor estrogen–progestin produces a bleed. Hysteroscopy diagnoses and treats the adhesions.

Outflow obstruction in primary amenorrhea. Müllerian agenesis (Mayer–Rokitansky–Küster–Hauser syndrome) and imperforate hymen both occur in 46,XX girls with normal ovaries, estrogen, breasts and pubic hair. Müllerian agenesis leaves a short, blind vaginal pouch without a uterus and often coexists with renal anomalies. An imperforate hymen traps menstrual blood (hematocolpos), producing cyclic pelvic pain and a bulging bluish membrane that is treated by hymenotomy. Complete androgen insensitivity also gives a blind vagina but is 46,XY with testes, scant pubic and axillary hair and male-range testosterone.

Hyperandrogenism

Hirsutism vs virilization. Hirsutism is male-pattern terminal hair (upper lip, chin, chest, linea alba, back), scored with the modified Ferriman–Gallwey scale, from androgen excess or heightened follicle sensitivity. Virilization adds clitoromegaly, voice deepening, temporal balding, increased muscle mass and breast atrophy; rapid onset over months demands exclusion of an androgen-secreting tumor. Hypertrichosis is different: diffuse, non-androgen-dependent hair from drugs (minoxidil, phenytoin, cyclosporine) or anorexia.

Polycystic ovary syndrome. The most common cause of hirsutism and anovulatory infertility. Rapid GnRH pulses favor LH over FSH, so theca cells overproduce androgens while relative FSH deficiency stalls follicle maturation. Insulin resistance, often signaled by acanthosis nigricans, further stimulates theca androgen synthesis and lowers hepatic SHBG, raising free testosterone. Rotterdam criteria require two of three (after excluding mimics): oligo- or anovulation, clinical or biochemical hyperandrogenism, and polycystic ovaries on ultrasound. Chronic anovulation leaves estrogen unopposed by progesterone, raising the risk of endometrial hyperplasia and carcinoma.

Ovarian tumors and hyperthecosis. Stromal hyperthecosis is nests of luteinized theca cells scattered through the ovarian stroma; it progresses slowly but can virilize. A Sertoli–Leydig cell tumor is a unilateral sex cord–stromal tumor causing rapid virilization with amenorrhea and breast atrophy.

Adrenal sources. Nonclassic 21-hydroxylase (CYP21A2) deficiency presents after childhood with hirsutism, acne and oligomenorrhea but no salt wasting; an early-morning, follicular-phase 17-hydroxyprogesterone is high, and an exaggerated rise after cosyntropin (ACTH) confirms it. It is more common in Ashkenazi Jewish, Hispanic and Mediterranean populations. By contrast, 11β-hydroxylase deficiency raises 11-deoxycortisol and causes hypertension. Androgen-secreting adrenocortical carcinoma produces very high DHEA-S, sometimes with Cushing features.

Exogenous and idiopathic causes. Exogenous androgens suppress gonadotropins. Idiopathic hirsutism, with regular ovulatory cycles and normal androgens, is attributed to increased 5α-reductase activity in hair follicles. Consider Cushing syndrome or hyperprolactinemia when other endocrine clues coexist.