Primary and Secondary Amenorrhea

• Hypothalamic dysfunction and GnRH deficiency: The hypothalamus secretes gonadotropin-releasing hormone (GnRH) in a pulsatile pattern (every 60-90 minutes during the follicular phase). This GnRH drives anterior pituitary gonadotrope cells to synthesize and release follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the primary drivers of ovarian function. Disruption of GnRH pulsatility—whether from central nervous system lesions, severe stress, extreme exercise, or malnutrition—eliminates the hormonal stimulus for follicular development and estrogen synthesis. The mechanism involves altered kisspeptin-neurokinin B-dynorphin (KNDy) neuronal signaling, which modulates GnRH release. Low FSH and LH levels in the presence of low estradiol characterize central hypogonadism. This accounts for 40-50% of secondary amenorrhea cases and includes conditions like hypothalamic amenorrhea, Kallmann syndrome (congenital GnRH deficiency), and hypothyroidism (which elevates thyrotropin-releasing hormone [TRH], which stimulates prolactin and suppresses GnRH).

• Pituitary pathology and secondary gonadotropin deficiency: Pituitary tumors (especially prolactinomas), pituitary insufficiency, or compression lesions prevent normal gonadotropin synthesis and release. Prolactin antagonizes GnRH action and directly inhibits gonadotropin secretion; elevated prolactin (<200 ng/mL is typical for prolactinomas) suppresses FSH and LH secretion. Pituitary apoplexy, lymphocytic hypophysitis, or infiltrative diseases (sarcoidosis, tuberculosis) cause pan-hypopituitarism with low FSH, LH, and estradiol but distinguishable by TSH, ACTH, and growth hormone deficiencies. Sheehan syndrome (postpartum pituitary necrosis from severe hemorrhage) causes secondary amenorrhea months to years after delivery through irreversible loss of gonadotroph cells.

• Primary ovarian failure (hypergonadotropic hypogonadism): When ovaries lack primordial follicles or follicles cannot respond to gonadotropins, FSH and LH rise markedly (FSH >40 mIU/mL is diagnostic) as the pituitary attempts to drive non-responsive ovaries. This pattern characterizes premature ovarian insufficiency (POI) and premature menopause. In Turner syndrome (45,X or mosaicism), developmental streaking of the gonad leaves minimal functional ovarian tissue; gonadotropin levels are elevated from childhood. In resistant ovary syndrome, follicles are present but unresponsive to FSH due to receptor mutations, autoimmune destruction (associated with autoimmune polyendocrinopathy), or impaired signal transduction. Iatrogenic ovarian failure follows chemotherapy (alkylating agents damage primordial follicles), radiation therapy, or surgical oophorectomy. Genetic defects affecting meiosis (FMR1 premutations causing fragile X-associated POI, BMP15 mutations) impair follicular development. 17α-hydroxylase deficiency and 17,20-lyase deficiency prevent androgen synthesis, causing primary amenorrhea with elevated progesterone and absent secondary sexual characteristics; conversely, 17β-hydroxysteroid dehydrogenase deficiency permits testosterone accumulation but impaired conversion to estradiol, causing virilization.

• Estrogen receptor abnormalities and end-organ dysfunction: Rare mutations in the ESR1 gene (encoding estrogen receptor-α) cause estrogen insensitivity with normal or elevated estrogen but amenorrhea and tall stature; this contrasts with typical estrogen deficiency states. Androgen insensitivity syndrome (AIS) in 46,XY individuals with absent androgen receptor function results in a female phenotype but primary amenorrhea due to absent müllerian structures (in complete AIS) or virilization (in partial AIS); gonadotropins and testosterone are typically elevated.

• Müllerian agenesis and outflow tract obstruction: Müllerian agenesis (Mayer-Rokitansky-Küster-Hauser [MRKH] syndrome) results from failure of the paramesonephric ducts to develop in 46,XX individuals; affected women have normal ovarian function (normal FSH, LH, estradiol), secondary sexual characteristics, but primary amenorrhea because the uterus and upper two-thirds of the vagina are absent. Asherman syndrome (intrauterine adhesions from curettage, infection, or radiation) obliterates the endometrial cavity and prevents normal menstrual shedding despite intact HPO axis signaling; women have normal hormone levels but amenorrhea. Cervical agenesis obstructs menstrual outflow. These structural defects account for ~15% of primary amenorrhea and feature normal gonadotropins and estradiol but amenorrhea.

• Androgen excess and polycystic ovary syndrome (PCOS): In PCOS, excessive ovarian androgen production (from theca cells driven by elevated LH or from altered enzyme regulation) causes hyperandrogenism that disrupts folliculogenesis. The elevated androgen/estrogen ratio creates a hostile follicular environment, favoring atresia of smaller follicles while large follicles accumulate. Insulin resistance (present in 50-70% of PCOS patients) stimulates theca cell androgen synthesis via altered signaling. LH is elevated relative to FSH (typical LH:FSH ratio >3:1), perpetuating the dysphoric environment. The result is anovulation with infrequent, irregular, or absent menses. The mechanism differs from true ovarian failure in that estradiol is typically normal or elevated (from peripheral conversion of androgens to estrone) and FSH is low-normal, creating a vicious cycle of inadequate follicular development.

• Thyroid hormone abnormalities: The hypothyroid state increases TRH, which stimulates prolactin secretion; prolactin inhibits GnRH. Additionally, hypothyroidism impairs metabolic clearance of estrogen, causing relatively unopposed estrogen effect. Hyperthyroidism accelerates estrogen metabolism, increasing sex hormone-binding globulin (SHBG) and reducing bioavailable estrogen, though less commonly causes amenorrhea than hypothyroidism. Both states can cause anovulation.

• Gonadal dysgenesis and Turner syndrome: Complete or partial gonadal agenesis (45,X or mosaics like 45,X/46,XX) accounts for 15-20% of primary amenorrhea. These individuals lack adequate ovarian tissue, resulting in elevated gonadotropins, low estradiol, short stature, and distinctive physical features (short neck, broad chest, webbed neck in classic Turner). Gonadal dysgenesis with Y chromosome material carries malignancy risk (gonadectomy indicated).

• Müllerian agenesis (MRKH syndrome): Accounts for 10-15% of primary amenorrhea. Most common cause of primary amenorrhea with normal secondary sexual development and normal hormone levels. 46,XX individuals have intact ovaries but absent or rudimentary uterus and upper vagina from failed paramesonephric duct development; etiology is polygenic or associated with skeletal/renal anomalies. Normal menarche-equivalent hormonal markers occur without visible menstruation.

• Constitutional delay of puberty: Normal variation in the timing of pubertal onset, more common in males but occurs in females. Usually has positive family history; bone age is delayed; hormonal values are normal for developmental stage. Girls show Tanner staging progression but menses delayed until age 16-17; this is a diagnosis of exclusion after other etiologies ruled out.

• Hypothalamic amenorrhea and functional GnRH deficiency: Includes severe eating disorders (anorexia nervosa, bulimia), excessive exercise (female athlete triad), extreme stress, and rapid weight loss. Accounts for 35-40% of primary amenorrhea in adolescents. Pathophysiology involves metabolic insufficiency signaling via leptin and altered NPY-GABA neurons that suppress GnRH. Low FSH and LH with low estradiol are characteristic. Reversible with weight restoration or stress reduction.

• Congenital hypogonadotropic hypogonadism (Kallmann syndrome and variants): Defective GnRH neuron migration or synthesis from mutations in KAL1, FGFR1, PROKR2, or other genes. Presents with primary amenorrhea, absent or incomplete puberty, and hyposmia/anosmia (if KAL1 involved). Low gonadotropins with low estradiol. Requires GnRH replacement or gonadotropin therapy for fertility.

• Androgen insensitivity syndrome (AIS): 46,XY individuals with mutations in androgen receptor gene. Complete AIS presents with female external genitalia, blind-ending vagina, absent uterus/fallopian tubes, undescended testes. Primary amenorrhea because müllerian structures are absent (normally regressed by anti-müllerian hormone from testes). Elevated testosterone in female range, elevated LH, normal FSH. Often diagnosed during workup for primary amenorrhea with normal breast development.

• 17α-hydroxylase deficiency and 17,20-lyase deficiency: Rare autosomal recessive disorders of steroid synthesis. Patients have primary amenorrhea, absent secondary sexual characteristics (hypogonadism), hypertension, and hypokalemia from elevated deoxycorticosterone and corticosterone. FSH and LH are elevated; testosterone and estradiol are very low; 17-hydroxyprogesterone is elevated (unlike 21-hydroxylase deficiency). Requires glucocorticoid and often mineralocorticoid replacement.

• Hypothyroidism and central nervous system lesions: Primary hypothyroidism or hyperprolactinemia from pituitary adenoma or CNS pathology (craniopharyngioma, germinoma, infiltrative disease) impair GnRH or gonadotropin secretion, delaying puberty. Imaging is essential.

• Pregnancy: Most common cause worldwide; β-hCG testing is essential in initial evaluation. Must be considered in any woman of reproductive age with secondary amenorrhea.

• Hypothyroidism: Increased TRH stimulates prolactin; impaired estrogen clearance. Common cause of secondary amenorrhea. TSH elevation precedes overt clinical hypothyroidism. Reverses with levothyroxine replacement.

• Hyperprolactinemia: From prolactinoma (microadenoma <10 mm or macroadenoma ≥10 mm), medications (dopamine antagonists like antipsychotics, metoclopramide, some antidepressants), hypothyroidism (elevated TRH), chest wall irritation (shingles, post-thoracotomy), or idiopathic hyperprolactinemia. Prolactin >200 ng/mL strongly suggests prolactinoma; 25-200 ng/mL requires imaging. Dopamine agonists (bromocriptine, cabergoline) are first-line therapy.

• Polycystic ovary syndrome (PCOS): Most common cause of secondary amenorrhea in reproductive-aged women (accounts for 40-50% of cases). Presents with amenorrhea/oligomenorrhea, hirsutism, acne, obesity (50%), and insulin resistance. Elevated LH and androgens with low-normal FSH and normal or elevated estradiol. Ultrasound shows >12 follicles per ovary (PCOS phenotype), though diagnosis is clinical (Rotterdam criteria: two of three criteria—hyperandrogenism, ovulatory dysfunction, polycystic ovarian morphology—with exclusion of other causes).

• Premature ovarian insufficiency (POI) and premature menopause: Occurs in <1% of women <40 years old but accounts for 10% of secondary amenorrhea. Defined by elevated FSH (typically >40 mIU/mL on two occasions ≥1 month apart) before age 40. Etiologies include autoimmune oophoritis, iatrogenic (chemotherapy, radiation, surgery), genetic (FMR1 premutation, BMP15 mutations, galactosemia), or idiopathic. Associated with infertility and decreased life expectancy from estrogen deficiency (cardiovascular disease, osteoporosis).

• Asherman syndrome: Intrauterine adhesions from D&C (most common), uterine artery embolization, endometrial ablation, or intrauterine tuberculosis/schistosomiasis. Results in secondary amenorrhea despite normal ovarian function (normal hormones). Diagnosed by hysterosalpingography showing filling defects or by hysteroscopy. May be partial (oligomenorrhea) or complete (amenorrhea).

• Severe weight loss and eating disorders: Accounts for 20-30% of secondary amenorrhea in adolescents and young women. Body weight <85% of ideal triggers hypothalamic suppression of GnRH and elevated cortisol. Anorexia nervosa has highest psychiatric mortality of any mental illness. Reversible with nutritional rehabilitation but may take months to resume menses.

• Excessive exercise and female athlete triad: Amenorrhea occurs when energy availability is critically low (exercise energy expenditure exceeds dietary intake). Associated with relative energy deficiency in sports (RED-S), which includes amenorrhea, decreased bone mineral density, and increased fracture risk. Seen in endurance athletes (distance running, gymnastics). Reversible with reduction of exercise or increased caloric intake.

• Stress and psychological factors: Acute psychosocial stressors (combat, incarceration, severe life events) or chronic stress suppress GnRH secretion. Mechanism involves elevated CRH from the stress pathway, which inhibits GnRH. Patients have low gonadotropins and low estradiol. May persist for months.

• Medications: Dopamine antagonists (antipsychotics, metoclopramide) increase prolactin. GnRH agonists (leuprolide) cause medical castration. Progestins (medroxyprogesterone acetate, levonorgestrel) suppress ovulation. Chemotherapy agents cause ovarian damage. Levothyroxine at excessive doses (causing iatrogenic hyperthyroidism) can reduce SHBG and alter estrogen metabolism.

• Systemic diseases: Chronic renal failure (uremia impairs GnRH), hepatic cirrhosis (altered estrogen metabolism and malnutrition), severe systemic lupus erythematosus (ovarian damage or medications like cyclophosphamide), and active malignancy cause amenorrhea through multiple mechanisms (malnutrition, cytokines, direct gonadal damage).

• Pituitary pathology: Pituitary adenomas, Sheehan syndrome (postpartum pituitary necrosis), lymphocytic hypophysitis, or infiltrative disease (sarcoidosis, tuberculosis, metastases) impair gonadotropin secretion. History of recent postpartum status, severe bleeding, or systemic disease with fever and headache provides clues. Absent menses accompanied by symptoms of hypopituitarism (fatigue, cold intolerance, sexual dysfunction).

The stem's opening line usually names the phenotype

• Absent menses with normal breasts and absent uterus: the blind-ending vaginal pouch patient. In müllerian agenesis (MRKH) pubic and axillary hair is normal (46,XX ovaries make androgen); in complete androgen insensitivity pubic/axillary hair is sparse or absent because the androgen receptor is nonfunctional despite male-range testosterone.
• Absent menses with absent breast development and short stature: Turner syndrome. Streak gonads make no estradiol, so breasts never develop; webbed neck, shield chest with widely spaced nipples, low posterior hairline, cubitus valgus, and a bicuspid aortic valve or coarctation murmur (brachial–femoral delay) are the exam findings.
• Absent menses with absent breasts but normal height/tall stature and anosmia: Kallmann syndrome — failed GnRH neuron migration takes the olfactory placode with it.
• The lean adolescent athlete or dancer: low BMI, cold intolerance, bradycardia, lanugo, orthostasis, and stress fractures. Low energy availability suppresses pulsatile GnRH, so the patient is hypoestrogenic — vaginal dryness, atrophic exam.
• Galactorrhea, headache, and bitemporal hemianopsia: prolactinoma compressing the optic chiasm; prolactin both suppresses GnRH and drives milk production.
• Hirsutism, acne, obesity, and acanthosis nigricans with oligo-/amenorrhea since menarche: PCOS. Estrogen is present, so the vaginal mucosa is well estrogenized — the opposite of hypothalamic amenorrhea.
• Hot flashes, night sweats, and dyspareunia before age 40: premature ovarian insufficiency — estrogen withdrawal drives vasomotor instability.
• Failure to lactate after a delivery complicated by hemorrhage, then fatigue and cold intolerance: Sheehan syndrome.
• Amenorrhea after a D&C or uterine infection, often with cyclic pelvic pain: Asherman syndrome.
• Hypertension with hypokalemia plus sexual infantilism: 17α-hydroxylase deficiency, from accumulated deoxycorticosterone.
• Cyclic pelvic pain with a bulging bluish membrane at the introitus: imperforate hymen with hematocolpos.

Step 1 — always

• Urine or serum β-hCG: pregnancy is the single most common cause of secondary amenorrhea and must be excluded before any hormonal testing or imaging, per the ASRM Practice Committee.

Step 2 — the initial hormonal panel (ASRM)

• TSH, prolactin, and FSH drawn together. TSH screens for hypothyroidism (elevated TRH raises prolactin); prolactin should be repeated fasting and without recent nipple stimulation before workup, and macroprolactin considered if the patient is asymptomatic.
• Estradiol clarifies whether low gonadotropins are truly hypogonadotropic.

Step 3 — sort by the FSH result

• High FSH (repeatedly in the menopausal range) = hypergonadotropic hypogonadism → karyotype in every patient under 30 and in all primary amenorrhea, plus FMR1 premutation testing and adrenal/thyroid autoantibodies for autoimmune oophoritis. POI requires two elevated values drawn weeks apart.
• Low or inappropriately normal FSH = central → pituitary MRI with contrast for any hyperprolactinemia not explained by drugs or hypothyroidism, for visual field loss, or for unexplained hypogonadotropic hypogonadism.
• Normal FSH with hyperandrogenism → total testosterone, DHEAS, early-morning 17-hydroxyprogesterone (nonclassic CAH), and 24-hour urinary free cortisol or dexamethasone suppression if Cushing features. PCOS is diagnosed by the Rotterdam criteria — two of three (hyperandrogenism, ovulatory dysfunction, polycystic ovarian morphology) after exclusion of mimics — as endorsed by the 2023 International Evidence-Based PCOS Guideline; ovarian ultrasound should not be used for diagnosis within roughly the first 8 years after menarche.

Step 4 — anatomy

• Pelvic ultrasound is the first imaging study in primary amenorrhea; absent uterus prompts karyotype and testosterone to separate MRKH (46,XX, female testosterone) from complete androgen insensitivity (46,XY, male-range testosterone). MRKH warrants renal imaging and spine evaluation.
• Hysteroscopy is the gold standard for Asherman syndrome; hysterosalpingography shows irregular filling defects.
• The progestin withdrawal challenge is an older bedside test of estrogenization and outflow patency; ASRM notes it is unreliable and does not replace measured hormones.
• DXA is indicated when hypoestrogenism has been prolonged.

Stabilize first when the stem demands it

• Severe anorexia nervosa with bradycardia, hypotension, hypothermia, or electrolyte derangement requires inpatient medical admission and cautious refeeding with phosphate monitoring.
• Pituitary apoplexy (thunderclap headache, ophthalmoplegia, visual loss) requires stress-dose glucocorticoids and urgent neurosurgical evaluation.

Then treat the level of the axis

• Functional hypothalamic amenorrhea: the Endocrine Society's 2017 guideline makes restoration of energy balance — increased caloric intake, reduced exercise, cognitive behavioral therapy — the first-line intervention. If hypoestrogenism persists despite nutritional rehabilitation, transdermal estradiol with cyclic oral progestin is preferred; combined oral contraceptives are explicitly not recommended solely to protect bone, since they suppress IGF-1 and mask return of menses.
• Hyperprolactinemia: dopamine agonists — cabergoline preferred over bromocriptine for efficacy and tolerability (Endocrine Society) — shrink prolactinomas and restore ovulation. Stop the offending dopamine antagonist when the cause is drug-induced. Transsphenoidal surgery is reserved for agonist-resistant or intolerant macroadenomas with mass effect.
• PCOS: lifestyle modification plus a combined hormonal contraceptive for cycle control and hyperandrogenism; metformin as adjunct for metabolic features; letrozole is first-line for ovulation induction per the 2023 International PCOS Guideline. Any patient with chronic anovulation and a uterus needs periodic progestin to prevent endometrial hyperplasia.
• Premature ovarian insufficiency and Turner syndrome: systemic estrogen replacement with a progestin (uterus present) continued to the average age of natural menopause, per ACOG; doses exceed standard menopausal hormone therapy. Turner syndrome additionally requires growth hormone in childhood and lifelong aortic imaging.
• Outflow tract disease: MRKH is managed with vaginal dilator therapy first-line (ACOG), surgical neovagina if dilation fails; imperforate hymen or transverse septum requires surgical incision; Asherman syndrome requires hysteroscopic adhesiolysis.
• Gonadectomy is indicated for any dysgenetic gonad containing Y-chromosome material; in complete androgen insensitivity it is typically deferred until after spontaneous pubertal feminization.

From chronic hypoestrogenism

• Osteoporosis and fragility fracture: estrogen restrains osteoclastogenesis through RANKL; its loss accelerates resorption. Peak bone mass is never attained if amenorrhea begins in adolescence. Signaled by stress fractures in athletes and a low DXA Z-score.
• Accelerated cardiovascular risk in POI and Turner syndrome: loss of estrogen's favorable lipid and endothelial effects; presents years later as premature coronary disease.
• Genitourinary atrophy and dyspareunia, and infertility at every level of the axis.

From unopposed estrogen (PCOS, chronic anovulation)

• Endometrial hyperplasia progressing to endometrial carcinoma: no progestin-driven shedding means continuous proliferative stimulus. Signaled by abnormal uterine bleeding after a long amenorrheic interval — biopsy, do not simply prescribe a contraceptive.

Emergencies to recognize

• Aortic dissection in Turner syndrome, especially during pregnancy — tearing chest/back pain with a dilated aortic root; this is why pregnancy is high-risk and requires pre-conception aortic imaging.
• Pituitary apoplexy in a macroprolactinoma: sudden headache, ophthalmoplegia, hypotension from secondary adrenal insufficiency.
• Adrenal crisis in unrecognized or under-replaced 17α-hydroxylase deficiency.
• Refeeding syndrome during nutritional rehabilitation of anorexia: insulin-driven intracellular phosphate shift causing hypophosphatemia, arrhythmia, and heart failure.
• Ovarian hyperstimulation syndrome after gonadotropin ovulation induction: VEGF-mediated capillary leak with ascites, hemoconcentration, and thrombosis.
• Hematocolpos/hematometra with obstructive anomalies can seed retrograde menstruation and endometriosis, and rarely causes urinary retention.

Malignancy and treatment complications

• Gonadoblastoma and dysgerminoma in dysgenetic gonads containing Y-chromosome material — the reason karyotype drives management.
• Venous thromboembolism with estrogen therapy, higher with oral than transdermal routes.
• Impulse-control disorders and valvular changes with dopamine agonists; lactic acidosis with metformin in renal failure; recurrent adhesions after hysteroscopic adhesiolysis.

• The single best next step in any amenorrhea vignette is a pregnancy test — before ultrasound, before hormones, before imaging. Missing this is the most commonly tested error.
• Breasts present + uterus absent = MRKH or complete androgen insensitivity. Separate them with karyotype and testosterone, not with FSH. Normal pubic hair favors MRKH; scant pubic hair with a blind vaginal pouch favors CAIS. MRKH also demands renal imaging.
• Short stature + no breast development + elevated FSH = Turner syndrome. The association examiners love is bicuspid aortic valve and coarctation, and the lifelong risk of aortic dissection. Streak gonads mean gonadotropins are high from childhood.
• Anosmia with absent puberty and low LH/FSH = Kallmann syndrome — failed GnRH neuron migration along the olfactory tract.
• Amenorrhea plus galactorrhea plus bitemporal hemianopsia = prolactinoma; the answer is a dopamine agonist (cabergoline), not surgery, even for macroadenomas. Check TSH first — hypothyroidism raises TRH and mimics it.
• Amenorrhea after postpartum hemorrhage with failure to lactate = Sheehan syndrome; amenorrhea after a D&C = Asherman syndrome. Asherman has entirely normal hormones — the lesion is the endometrium, confirmed by hysteroscopy.
• The lean runner or dancer has functional hypothalamic amenorrhea; the Endocrine Society answer is restoring energy availability, and combined oral contraceptives are the classic distractor because they induce withdrawal bleeding while masking recovery and failing to protect bone.
• Any dysgenetic gonad with Y-chromosome material must come out because of gonadoblastoma risk — the exception being timing in complete androgen insensitivity, where gonadectomy is usually deferred until after puberty.
• Distractor to avoid: an adolescent with a normal exam who simply has not menstruated by 15 still needs the full workup; constitutional delay is a diagnosis of exclusion, never a first answer.