Amenorrhea, the absence of menstruation,

can be

• primary (no menstruation by age 15 or three years after thelarche) or
• secondary (absence of menses for ≥3 months in a woman with previously regular cycles or ≥6 months in any woman with at least one previous menstruation).

The evaluation involves a comprehensive history, physical examination, pregnancy test, hormone testing, and pelvic imaging

Primary:

1. Anomalies of the Outflow Tract

• Anatomical Defects:
  • Account for 20% of primary amenorrhoea cases.
  • Distal Obstruction:
    • Conditions: Imperforate hymen, transverse vaginal septum.
    • Presentation: Cyclic pelvic pain due to hematocolpos.
    • Diagnosis: Clinical examination.
    • Treatment: Surgical resection (fertility not compromised).
  • Lack of Müllerian Structures:
    • Conditions: Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome, androgen insensitivity syndrome (AIS).
    • MRKH:
      • Features: Vaginal agenesis, uterine maldevelopment, associated anomalies (skeletal, renal, auditory).
      • Diagnosis: Ultrasound or MRI.
      • Management: Psychosocial counselling, neovagina creation, removal of uterine remnants, fertility interventions (surrogacy).
    • AIS:
      • Features: End-organ insensitivity to androgens in genetic males with functioning testes.
      • Diagnosis: Karyotype.
      • Management: Psychosocial counselling, gonadectomy, fertility interventions (surrogacy plus oocyte donation).

2. Primary Ovarian Insufficiency (POI)

• Hypergonadotropic Hypogonadism:
  • Features: High FSH, low E2, abnormal pubertal development.
• Chromosomal Derangements:
  • Turner Syndrome (1:2000–1:4000 live born girls):
    • Features: Short stature, webbed neck, low hairline, shield chest.
    • Health Issues: Cardiac, kidney anomalies, autoimmune disorders, obesity, strabismus, cataract.
    • Karyotypes: Monosomy (45XO), Turner mosaics.
  • Swyer Syndrome (46XY):
    • Features: Non-functional gonads, normal female phenotype, intact Müllerian structures.
  • Fragile X Premutation:
    • Features: Higher CGG repeats on FMR1 gene, POI occurs in 15–20% of carriers after 18 years.
• Genetic Testing:
  • Chromosomal analysis recommended for non-iatrogenic POI.
  • Turner syndrome: Additional evaluations (echocardiogram, eye test, renal imaging, thyroid studies, diabetes screen).
  • FMR1 premutation testing if normal karyotype.
  • Autoimmune markers: 21OH-Ab, TPO-Ab.
• Management:
  • Puberty induction: Low-dose estrogen, cyclic progestogen.
  • Long-term estrogen-progestin replacement.
  • Gonadectomy for individuals with Y chromosome.
  • Psychosocial support, bone health monitoring, oocyte donation for fertility.

3. Central Anomalies (Hypothalamic-Pituitary)

• Functional Hypothalamic Amenorrhea:
  • Causes: Weight loss, excessive exercise, stress.
  • Management: Good nutrition, optimal body weight, stress reduction, bone density evaluation, calcium/vitamin D supplements.
  • COCP restores menses but doesn’t improve bone density without nutritional rehabilitation.
• Congenital GnRH Deficiencies:
  • Conditions: Isolated hypogonadotropic hypogonadism (IHH), Kallmann syndrome (anosmia).
  • Genes: ANOS1 (KAL1), CHD7, FGF8, FGFR1, PROK2, PROKR2.
  • Diagnosis: Clinical.
  • Management: Puberty induction, long-term estrogen-progestin replacement, ovulation induction with exogenous gonadotrophins.
• Hyperprolactinaemia:
  • Causes: Medications, pituitary adenoma, hypothyroidism, pituitary stalk compression.
  • Management: MRI of pituitary, dopamine agonists.
• Other Central Causes:
  • Tumors, empty sella syndrome, infection, trauma, autoimmune destruction of the pituitary.

4. Other Endocrine Disorders

• Polycystic Ovary Syndrome (PCOS):
  • Features: Oligo-ovulation, hyperandrogenism, polycystic ovaries on ultrasound.
  • Management: Lifestyle modifications, restoring menstrual cyclicity, managing androgen excess, psychological support, COCP, ovulation induction (clomiphene, letrozole).
• Androgen-Producing Tumors, Congenital Adrenal Hyperplasia, Cushing’s Syndrome:
  • Should be distinguished from PCOS in hyperandrogenic amenorrhea.
• Thyroid Disorders:
  • Both hypo- and hyperthyroidism can cause menstrual abnormalities.
  • Management: Endocrinologist referral, underlying endocrinopathy correction.

Physiologic and Medication-Induced Amenorrhea:

• Pregnancy: Most common cause of amenorrhea.
• Lactation: Hyperprolactinemia during breastfeeding.
• Menopause: Natural decline of ovarian function.
• Medications:
  • Chemotherapy, illicit substances, synthetic progestins causing endometrial atrophy, antipsychotics causing hyperprolactinemia.

Key Diagnostic Steps:

1. Exclude Pregnancy: Urine pregnancy test.
2. Initial Investigations:
   • FSH, TSH, prolactin, pelvic ultrasound.
3. Karyotype:
   • For individuals with absent uterus or POI.
4. MRI of Pituitary:
   • If hyperprolactinemia or pituitary disorder is suspected.
5. Additional Testing:
   • Based on clinical presentation, such as endocrine evaluations, genetic testing, or imaging studies.

Management:

• Lifestyle Modifications:
  • Nutritional rehabilitation, weight management, stress reduction.
• Hormone Therapy:
  • Estrogen-progestin replacement, dopamine agonists for hyperprolactinemia.
• Surgery:
  • Correct anatomical abnormalities, remove gonads with malignant potential.
• Mental Health Services:
  • Support for underlying stress, eating disorders, or psychological impact.

Secondary

• Absence of menses for > 3 months if previously regular, or > 6 months if previously irregular
• Causes
  • Premature menopause/premature ovarian failure
  • PCOS
  • Medications – COCP, antipsychotics, opiates, chemotherapy
  • Illicit drugs – marijuana, cocaine
  • Hypothalamic pituitary axis chanegs – mental stress, over-exercising, anorexia (usually low FSH, LH, estrogen, progesterone)
  • Pregnancy
  • Prolactinoma/ pituitary adenoma
  • Hypothyroidism, hyperthyroidism
  • Cushings/adrenal disorders
  • Asherman syndrome – adhesions within the uterus/cervix