1. Definition and epidemiology
   • Definition: absence of menses for 3 months in previously regular cycles, or 6 months in previously irregular cycles
   • Pregnancy is the first diagnosis to exclude
2. Physiology of the normal menstrual axis
   • Hypothalamic GnRH pulsatility
   • Pituitary LH/FSH secretion
   • Ovarian folliculogenesis, estradiol, progesterone
   • Endometrial response and withdrawal bleeding
3. Etiologic classification
   • Pregnancy
   • Hypothalamic causes: functional hypothalamic amenorrhea, CNS lesions
   • Pituitary causes: hyperprolactinemia, pituitary tumors, Sheehan syndrome
   • Ovarian causes: primary ovarian insufficiency, menopause, resistant ovary syndrome
   • Chronic anovulation: PCOS and other hyperandrogenic disorders
   • Thyroid and adrenal disease
   • Uterine/outflow causes: Asherman syndrome, cervical stenosis
   • Drug-related and contraceptive-related amenorrhea
4. Clinical assessment
   • Key history, focused examination, red flags
   • Pattern recognition: galactorrhea, hyperandrogenism, hypoestrogenism, virilization, eating disorder/exercise history
5. Diagnostic workup and algorithms
   • β-hCG, TSH, prolactin, FSH, LH, estradiol
   • Androgen and 17-hydroxyprogesterone testing
   • Pelvic ultrasound, pituitary MRI, progestin challenge and estrogen-progestin challenge
   • Interpretation of gonadotropin patterns
6. Detailed management by cause
   • Functional hypothalamic amenorrhea
   • Hyperprolactinemia
   • PCOS-related anovulation
   • Primary ovarian insufficiency
   • Intrauterine adhesions
   • Thyroid/adrenal disorders
7. Long-term consequences
   • Infertility
   • Endometrial hyperplasia in unopposed estrogen states
   • Bone loss and cardiovascular implications in hypoestrogenic states

Secondary Amenorrhea: Postgraduate Note

Definition

• For 3 months in a woman with previously regular cycles, or
• For 6 months in a woman with previously irregular cycles.

1. Physiology Relevant to Amenorrhea

1. Hypothalamus: pulsatile GnRH secretion
2. Pituitary: pulsatile LH and FSH release
3. Ovary: follicular development, estradiol production, ovulation, progesterone production
4. Endometrium: estrogen-induced proliferation followed by progesterone-induced secretory transformation
5. Uterus and outflow tract: a patent pathway for blood loss

Normal sequence producing menstruation

• Pulsatile hypothalamic GnRH stimulates pituitary secretion of FSH and LH.
• FSH recruits follicles; the dominant follicle produces estradiol.
• Estradiol causes endometrial proliferation.
• LH surge produces ovulation and corpus luteum formation.
• Corpus luteum secretes progesterone.
• Regression of corpus luteum causes a fall in estrogen and progesterone.
• Hormonal withdrawal produces endometrial shedding and menstruation.

• absence of estrogen,
• chronic anovulation with persistent estrogen but no progesterone withdrawal,
• lack of functional endometrium, or
• obstruction to menstrual outflow.

2. Etiological Classification

3. Differential Diagnosis by Endocrine Pattern

A. Hypergonadotropic hypogonadism

• FSH high
• LH often high
• Estradiol low

Causes

• Spontaneous/idiopathic POI
• Genetic: Turner mosaicism, X chromosome abnormalities, FMR1 premutation
• Autoimmune oophoritis
• Chemotherapy
• Pelvic irradiation
• Bilateral oophorectomy
• Severe ovarian surgery or vascular injury
• Infections, rarely
• Enzyme defects or gonadotropin receptor abnormalities, rarely

Clinical features

• Hot flushes
• Night sweats
• Vaginal dryness
• Dyspareunia
• Reduced libido
• Sleep and mood disturbance
• Infertility
• Osteopenia/osteoporosis with prolonged hypoestrogenism

B. Hypogonadotropic hypogonadism

• FSH low or inappropriately normal
• LH low or inappropriately normal
• Estradiol low

1. Functional hypothalamic amenorrhea

Causes

• Weight loss
• Low energy availability
• Restrictive eating or eating disorders
• Excessive exercise
• Psychologic stress
• Chronic illness
• Severe systemic disease

Pathophysiology

Clinical clues

• Recent weight loss
• Low body weight or low BMI, although FHA can occur at normal BMI
• High training load
• Vegetarian/restrictive dieting
• Fear of weight gain
• Stress, anxiety, depression
• History of stress fractures
• Vaginal dryness, low libido, hot flushes in more severe cases

Complications

• Infertility
• Reduced bone mineral density
• Stress fractures
• Possible adverse cardiometabolic effects
• Sexual dysfunction

2. Organic hypothalamic-pituitary disease

• Headache
• Visual field defect
• Polyuria/polydipsia
• Neurologic signs
• History of cranial irradiation, traumatic brain injury, or CNS surgery
• Postpartum hemorrhage and failure of lactation
• Multiple pituitary hormone deficiencies

• Pituitary adenoma
• Craniopharyngioma
• Infiltrative disease: sarcoidosis, tuberculosis, hemochromatosis
• Sheehan syndrome
• Lymphocytic hypophysitis
• Pituitary apoplexy
• Empty sella syndrome

C. Eugonadotropic amenorrhea or chronic anovulation

• FSH usually normal
• Estradiol often normal or mildly reduced
• Anovulation is present

Polycystic ovary syndrome

1. Hyperandrogenism, clinical and/or biochemical
2. Ovulatory dysfunction: oligomenorrhea or amenorrhea
3. Polycystic ovarian morphology on ultrasound

Clinical manifestations

• Oligomenorrhea or amenorrhea
• Hirsutism
• Acne
• Androgenic alopecia
• Obesity or central adiposity
• Acanthosis nigricans
• Subfertility
• Polycystic ovarian morphology

Important exclusions before diagnosing PCOS

• Pregnancy
• Hyperprolactinemia
• Thyroid disease
• Nonclassic congenital adrenal hyperplasia
• Cushing syndrome, if clinically suspected
• Androgen-secreting ovarian/adrenal tumor
• Severe insulin resistance syndromes, where relevant

Why amenorrhea occurs in PCOS

Long-term risks

• Endometrial hyperplasia and endometrial carcinoma due to prolonged unopposed estrogen
• Type 2 diabetes
• Dyslipidemia
• Hypertension and cardiovascular risk factors
• Obstructive sleep apnea
• Psychological morbidity

D. Hyperprolactinemic amenorrhea

Causes

• Pregnancy and lactation
• Prolactinoma
• Pituitary stalk compression
• Primary hypothyroidism
• Chronic kidney disease
• Chest-wall stimulation/injury
• Antipsychotics, especially risperidone and typical antipsychotics
• Metoclopramide/domperidone
• Antidepressants, opioids, verapamil, methyldopa
• Macroprolactinemia

Clinical clues

• Galactorrhea
• Oligomenorrhea/amenorrhea
• Infertility
• Decreased libido
• Vaginal dryness
• Headache
• Bitemporal visual disturbance in macroadenoma

E. Thyroid-related amenorrhea

Hypothyroidism

• increased TRH stimulation of prolactin,
• hyperprolactinemia,
• altered GnRH secretion,
• altered sex hormone-binding globulin and peripheral hormone metabolism.

Hyperthyroidism

F. Uterine and outflow tract causes

Asherman syndrome: intrauterine adhesions

Causes

• Curettage after miscarriage or postpartum hemorrhage
• Retained products of conception
• Postpartum infection/endometritis
• Uterine surgery: myomectomy, hysteroscopic procedures
• Genital tuberculosis, particularly in endemic settings
• Severe endometrial injury

Clues

• Amenorrhea or markedly reduced menstrual flow after uterine instrumentation
• Cyclical pelvic pain with absent bleeding
• Infertility or recurrent pregnancy loss
• Failure to bleed after estrogen-progestin challenge

Cervical stenosis

G. Drug- and contraception-related amenorrhea

• Depot medroxyprogesterone acetate
• Levonorgestrel-releasing intrauterine system
• Continuous combined hormonal contraception
• Progestin-only pills or implants
• GnRH agonists/antagonists
• Lactation
• Some gender-affirming hormone regimens

• Antipsychotics
• Metoclopramide
• Opioids
• Chemotherapy
• Pelvic irradiation
• High-dose glucocorticoids in some contexts

4. Clinical Evaluation

A. History

Menstrual and reproductive history

• Age at menarche
• Previous regularity, flow, duration, dysmenorrhea
• Date of last menstrual period
• Sudden or gradual cessation
• Previous pregnancies and pregnancy complications
• Lactation status
• Contraceptive history
• Infertility history
• Recent uterine evacuation, delivery, postpartum hemorrhage, or pelvic surgery

Symptoms suggesting pregnancy

• Nausea
• Breast tenderness
• Fatigue
• Urinary frequency

Symptoms of estrogen deficiency

• Hot flushes
• Night sweats
• Vaginal dryness
• Dyspareunia
• Reduced libido

Symptoms suggesting hyperprolactinemia/pituitary lesion

• Galactorrhea
• Headache
• Visual disturbance
• Polyuria/polydipsia

Hyperandrogenic symptoms

• Hirsutism
• Acne
• Scalp hair thinning
• Deepening of voice
• Increased muscularity
• Clitoromegaly
• Rapid onset or rapidly progressive virilization suggests an androgen-secreting tumor.

Lifestyle and systemic history

• Weight change
• Diet, caloric restriction, purging, binge eating
• Exercise intensity
• Emotional stress
• Chronic systemic illness
• Symptoms of thyroid disease
• Symptoms of Cushing syndrome
• Tuberculosis exposure
• Medication and substance history

B. Examination

• Height, weight, BMI, waist circumference
• Blood pressure
• Signs of malnutrition or eating disorder
• Thyroid enlargement, bruit, eye signs
• Breast examination and galactorrhea
• Hirsutism score, acne, androgenic alopecia
• Acanthosis nigricans
• Cushingoid features: central obesity, facial plethora, purple striae, proximal myopathy
• Virilization: clitoromegaly, temporal balding, deep voice
• Visual field assessment if pituitary disease suspected
• Abdominal and pelvic examination:
  • uterine size,
  • pelvic masses,
  • vaginal atrophy,
  • cervical stenosis,
  • genital tract abnormalities.

5. Investigations

Initial tests in essentially all cases

1. Pregnancy test
   • Urine β-hCG is usually adequate.
   • Serum β-hCG is preferred if the likelihood of pregnancy remains meaningful despite a negative urine test.
2. Serum TSH
3. Serum prolactin
4. FSH with estradiol
   • Often LH is measured concurrently.
   • Distinguishes hypergonadotropic from hypogonadotropic/eugonadotropic states.
5. Pelvic ultrasound
   • Uterus and endometrial thickness
   • Ovarian morphology and antral follicle count
   • Ovarian/adnexal mass
   • Clues to PCOS, POI, hematometra, or uterine pathology

Interpretation of FSH and estradiol

Additional targeted tests

If hyperandrogenism is present

• Total testosterone, preferably reliable high-quality assay
• SHBG and calculated free testosterone, or free testosterone by an appropriate assay
• DHEAS if adrenal source suspected
• Early-morning 17-hydroxyprogesterone for nonclassic 21-hydroxylase-deficient CAH
• Consider cortisol testing if Cushing syndrome is suspected

If POI is confirmed or likely

• Repeat FSH if needed
• Karyotype, especially in younger patients or suspected chromosomal disorder
• FMR1 premutation testing
• 21-hydroxylase/adrenal autoantibodies where appropriate
• Assessment for associated autoimmune disease
• Bone density assessment in prolonged hypoestrogenism
• Cardiometabolic risk assessment

If hyperprolactinemia is detected

• Repeat prolactin if modestly elevated and clinically discordant
• Exclude pregnancy, hypothyroidism, renal impairment, and drugs
• Consider macroprolactin
• Pituitary MRI for persistent unexplained elevation, especially substantial elevation or neurologic symptoms

If pituitary/hypothalamic disease is suspected

• Pituitary MRI with contrast
• Visual field assessment if macroadenoma near optic chiasm
• Assess other pituitary axes: free T4, morning cortisol, IGF-1, and others guided by context

If Asherman syndrome or cervical stenosis is suspected

• Saline-infusion sonography
• Hysteroscopy: diagnostic and therapeutic standard
• Hysterosalpingography may be useful in infertility workup

6. Role of Progesterone Challenge Test

Protocol

• Medroxyprogesterone acetate 5-10 mg orally daily for 5-10 days, or
• Micronized progesterone, depending on local practice.

Interpretation

Positive withdrawal bleed

• some endogenous estrogen exposure,
• a responsive endometrium,
• a patent outflow tract.

No withdrawal bleed

• hypoestrogenism with a thin, unprimed endometrium,
• endometrial damage,
• intrauterine adhesions,
• outflow obstruction.

• Bleeding after estrogen-progestin: hypoestrogenism is likely.
• No bleeding after estrogen-progestin: suspect endometrial damage or outflow obstruction.

Limitation

7. Diagnostic Algorithm

Step 1: Exclude pregnancy

• Positive: evaluate pregnancy, including ectopic pregnancy where clinically relevant.
• Negative: proceed.

Step 2: Identify obvious clinical pattern

• Lactation or hormonal contraception?
• Weight loss/excess exercise/stress?
• Hyperandrogenism?
• Galactorrhea/headache/visual symptoms?
• Hot flushes/vaginal dryness?
• Uterine instrumentation or postpartum curettage?

Step 3: Initial laboratory assessment

• TSH
• Prolactin
• FSH, LH, estradiol
• Pelvic ultrasound

Step 4: Interpret

A. FSH high, estradiol low

• Repeat FSH if necessary
• Evaluate genetic, autoimmune, and iatrogenic causes
• Address hormone replacement, bone, cardiovascular, and fertility issues.

B. FSH low/normal, estradiol low

• Assess FHA triggers.
• Check prolactin.
• If unexplained, severe, or neurologic symptoms present, obtain pituitary MRI.

C. Normal FSH with hyperandrogenism or polycystic ovaries

• Exclude thyroid disease, hyperprolactinemia, nonclassic CAH, Cushing syndrome, and tumor as appropriate.

D. Normal ovarian hormonal pattern but absent/very scant bleeding after uterine trauma

• Hysteroscopy or cavity imaging.

8. Management

1. Treat the underlying cause
2. Restore fertility if desired
3. Prevent consequences of hypoestrogenism or chronic unopposed estrogen

A. Functional hypothalamic amenorrhea

First-line treatment

• Increase caloric intake
• Reduce excessive exercise
• Restore weight where clinically indicated
• Dietitian input
• Psychological therapy, often cognitive behavioral therapy
• Assess and treat eating disorder
• Calcium and vitamin D adequacy
• Avoid smoking and excess alcohol

Bone health

• Obtain bone mineral density assessment when amenorrhea/hypoestrogenism is prolonged or there are risk factors for skeletal loss.
• Hormonal therapy can be considered for hypoestrogenism after addressing energy deficit, but it should not replace nutritional and behavioral treatment.
• Combined oral contraceptives may create withdrawal bleeding but do not prove recovery of the HPO axis and may mask persistent amenorrhea.

Fertility

• specialist reproductive endocrinology referral,
• pulsatile GnRH where available, or
• gonadotropin therapy with careful monitoring.

B. Hyperprolactinemia

Correct reversible causes

• Stop or replace offending medication if feasible, in coordination with the prescribing clinician.
• Treat hypothyroidism.
• Address renal/hepatic disease where relevant.

Prolactinoma

• Dopamine agonist therapy is generally first line:
  • Cabergoline is commonly preferred because of effectiveness and tolerability.
  • Bromocriptine remains useful, including where pregnancy experience or drug availability influences selection.
• Surgery is reserved for selected cases: intolerance/resistance to medical therapy, compression complications, or specific tumor circumstances.
• Monitor prolactin level, symptoms, pituitary size, and visual fields as appropriate.

C. PCOS-related amenorrhea

If pregnancy is not desired

• endometrial protection,
• menstrual regulation,
• treatment of hyperandrogenism,
• metabolic risk reduction.

• Combined hormonal contraception
• Cyclic progestin therapy
• Levonorgestrel intrauterine system
• Lifestyle management for metabolic health and weight-related concerns
• Metformin in selected patients, especially impaired glucose tolerance/type 2 diabetes or where hormonal contraception is unsuitable
• Antiandrogens for hirsutism only with reliable contraception because of fetal risk

If fertility is desired

• Weight and metabolic optimization where relevant
• Letrozole is generally first-line pharmacologic ovulation induction in PCOS where no contraindication exists.
• Alternatives: clomiphene citrate, metformin in selected settings, gonadotropins, ovarian drilling in selected refractory cases, IVF.

D. Primary ovarian insufficiency

Hormone therapy

• physiologic estrogen replacement, oral or transdermal,
• plus adequate progestogen if the uterus is present.

• control vasomotor and genitourinary symptoms,
• protect bone,
• support cardiovascular and urogenital health,
• improve quality of life.

Additional care

• Counsel about intermittent ovarian activity: spontaneous ovulation and pregnancy can occur, so contraception is required if pregnancy is not desired.
• Fertility counseling: donor-oocyte IVF remains the most established reproductive option for many affected patients.
• Bone density, calcium/vitamin D, exercise, and fracture-risk care.
• Screen and manage associated autoimmune/genetic conditions.
• Provide psychological support.

E. Thyroid disease

• Treat hypothyroidism with levothyroxine.
• Treat hyperthyroidism with appropriate antithyroid, radioactive iodine, or surgical strategy depending on clinical circumstances.
• Menses often resume with restoration of euthyroidism, but persistent amenorrhea requires reassessment for coexisting causes.

F. Asherman syndrome and cervical stenosis

Asherman syndrome

• Hysteroscopic adhesiolysis
• Postoperative estrogen therapy may be used to encourage endometrial recovery
• Temporary intrauterine stent/balloon or other anti-adhesion approach in selected cases
• Follow-up cavity assessment
• Fertility counseling due to risks of recurrence, miscarriage, placental abnormalities, and preterm birth

Cervical stenosis

• Cervical dilation and treatment of the underlying cause
• Assess for hematometra and recurrent obstruction

9. Complications of Untreated Secondary Amenorrhea

Hypoestrogenic states

• Osteopenia and osteoporosis
• Stress fractures
• Urogenital atrophy
• Sexual dysfunction
• Reduced fertility
• Possible adverse cardiometabolic effects

Chronic anovulation with unopposed estrogen

• Endometrial hyperplasia
• Endometrial carcinoma
• Abnormal uterine bleeding when breakthrough shedding occurs
• Infertility
• Metabolic syndrome and diabetes risk

10. Red Flags Requiring Urgent Evaluation

• Severe lower abdominal pain with amenorrhea and positive pregnancy test: exclude ectopic pregnancy
• Headache, visual loss, vomiting, altered consciousness: pituitary mass/apoplexy or other intracranial pathology
• Rapid virilization: androgen-secreting ovarian or adrenal tumor until proven otherwise
• Postpartum hemorrhage with inability to lactate and amenorrhea: consider Sheehan syndrome
• Amenorrhea after uterine curettage with cyclic pain: consider intrauterine adhesions or cervical stenosis
• Severe weight loss, bradycardia, syncope, electrolyte disturbance, or suicidal thoughts: eating disorder emergency assessment

11. High-Yield Viva Points

1. First investigation in secondary amenorrhea: pregnancy test.
2. Most common cause: pregnancy.
3. High FSH with low estradiol: primary ovarian insufficiency.
4. Low/normal FSH with low estradiol: hypothalamic-pituitary dysfunction.
5. Amenorrhea + galactorrhea: check prolactin and TSH.
6. Amenorrhea + hirsutism: consider PCOS, nonclassic CAH, Cushing syndrome, and androgen-secreting tumor.
7. Amenorrhea after curettage: suspect Asherman syndrome.
8. Amenorrhea in a highly active woman with low energy availability: functional hypothalamic amenorrhea.
9. Amenorrhea with prolonged anovulation: protect the endometrium using progestogen exposure.
10. Amenorrhea is not a diagnosis: it is a clinical manifestation of pregnancy, endocrine dysfunction, ovarian failure, chronic anovulation, uterine disease, or medication effect.

12. One-Page Exam Summary

First step

Initial evaluation

• History and examination
• β-hCG
• TSH
• Prolactin
• FSH, LH, estradiol
• Pelvic ultrasound

Core interpretation

• High FSH + low E2: POI
• Low/normal FSH + low E2: FHA or pituitary/hypothalamic cause
• Normal FSH + androgen excess/chronic anovulation: PCOS after exclusion of mimics
• No bleeding after estrogen-progestin challenge or post-instrumentation amenorrhea: Asherman syndrome/outflow obstruction

Treat

• FHA: restore energy balance and address stress/eating disorder
• PCOS: endometrial protection, metabolic management, ovulation induction if fertility desired
• Hyperprolactinemia: treat cause, dopamine agonist for prolactinoma
• POI: hormone therapy to natural menopause age and fertility/genetic/autoimmune assessment
• Asherman: hysteroscopic adhesiolysis
• Thyroid disease: restore euthyroidism