Amenorrhea - As per OBG (Berek & Novak's Gynecology, Chapter 34)

Definition

• Primary amenorrhea: Absence of menses by age 13 when there is no visible development of secondary sexual characteristics, OR by age 15 in the presence of normal secondary sexual characteristics.
• Secondary amenorrhea: Absence of menses for 3 months in a woman who previously had regular cycles, or for 6 months in a woman who had irregular cycles.
• Oligomenorrhea: Cycles occurring at intervals > 35 days (but not complete absence).

Pregnancy must always be excluded first regardless of the type of amenorrhea.

Physiology of Normal Menstruation

1. Hypothalamus secretes GnRH in a pulsatile fashion (modulated by neurotransmitters and hormones)
2. GnRH stimulates pituitary to release FSH and LH
3. FSH/LH promote ovarian follicular development and ovulation
4. Pre-ovulatory follicle secretes estrogen; post-ovulation corpus luteum secretes progesterone + estrogen
5. These hormones stimulate endometrial development
6. If no pregnancy, estrogen and progesterone fall → withdrawal bleeding

Classification

PRIMARY AMENORRHEA

A. Amenorrhea WITHOUT Secondary Sexual Characteristics

1. Hypergonadotropic Hypogonadism (High FSH)

• Gonadal dysgenesis (Turner syndrome - 45,X): Most common cause. Short stature, webbed neck, shield chest, streak gonads, horseshoe kidney, cardiac defects (coarctation of aorta). Mosaic forms (45X/46XX) may have some development.
• Pure gonadal dysgenesis (Swyer syndrome - 46,XY): Normal female phenotype with streak gonads. Y chromosome material warrants gonadectomy due to ~25-30% risk of gonadoblastoma/dysgerminoma.
• Other causes of primary ovarian failure: Autoimmune, galactosemia, FSH receptor mutations.

When gonadal failure occurs with primary amenorrhea, there is a high incidence of abnormal karyotype.

2. Hypogonadotropic Hypogonadism (Low FSH/LH)

• Kallmann syndrome: GnRH deficiency + anosmia/hyposmia (failure of GnRH neurons to migrate from olfactory placode). X-linked (KAL1 gene) or autosomal. Characterized by absent/diminished sense of smell.
• Idiopathic hypogonadotropic hypogonadism: Low GnRH without anosmia. Various gene mutations (GNRH1, KISS1, etc.)
• GnRH receptor mutations: G-protein coupled receptor mutations → decreased GnRH binding → no FSH/LH stimulation. Patients are normosomic.
• FSH β-subunit deficiency: Low FSH, elevated LH (paradoxically), low androgens. Rare autosomal recessive.

3. Androgen Insensitivity Syndrome (AIS) - 46,XY

• Complete AIS: XY karyotype with female phenotype. Testes present (undescended), functioning AMH (no mullerian structures), absent pubic/axillary hair (hallmark), blind vaginal pouch, breast development at puberty (due to testosterone aromatization to estrogen).
• Testes must be removed after puberty due to malignancy risk.

4. 5α-Reductase Deficiency - 46,XY

• Testosterone cannot be converted to dihydrotestosterone (DHT) → ambiguous external genitalia at birth. Virilization occurs at puberty. No breast development (testosterone intact, suppresses breast development). Distinguishes from AIS. Normal AMH → no mullerian structures.

B. Amenorrhea WITH Secondary Sexual Characteristics (Normal Pubertal Development but No Menses)

Anatomic / Outflow Tract Causes

Anatomic causes are relatively few and can be diagnosed by history, physical examination, and imaging.

SECONDARY AMENORRHEA

1. Hypothalamic Causes - Functional Hypothalamic Amenorrhea (FHA)

• Weight loss / anorexia nervosa / malnutrition: Energy deficit suppresses GnRH. Low BMI is a red flag.
• Excessive exercise: Common in female athletes (part of the "female athlete triad": amenorrhea + low energy availability + low bone density).
• Psychosocial stress: Corticotropin-releasing hormone (CRH) and opioids suppress GnRH.
• Obesity: Adipose tissue produces leptin and estrone; can disrupt HPO axis.

2. Pituitary Causes

• Hyperprolactinemia: Elevated prolactin → abnormal GnRH secretion → anovulation and amenorrhea.
  • Causes: Prolactinoma (most common pituitary tumor), CNS lesions disrupting dopamine transport down the pituitary stalk, drugs (antidepressants, antipsychotics - especially risperidone, metoclopramide, antihypertensives, opiates, H2 blockers).
  • Galactorrhea may or may not be present.
  • Hypothyroidism elevates TRH, which stimulates prolactin → treat hypothyroidism first.
• Sheehan syndrome: Post-partum pituitary necrosis due to obstetric hemorrhage and hypovolemia. Presents with failure to lactate, inability to regrow shaved pubic hair, and secondary amenorrhea.
• Empty sella syndrome: CSF herniation into the sella; pituitary function usually preserved.

3. Ovarian Causes

• Primary Ovarian Insufficiency (POI) (formerly premature ovarian failure/premature menopause):
  • Defined as amenorrhea for ≥4 months + two FSH levels in the menopausal range (>40 IU/L), measured ≥1 month apart, before age 40.
  • Causes: Autoimmune (most common identifiable cause - associated with thyroid disease, Addison's disease), chromosomal (Turner mosaic, fragile X premutation), iatrogenic (chemotherapy, radiation), idiopathic (~90%).
  • Unlike menopause, POI is not always permanent - spontaneous ovulation and even pregnancy can occasionally occur.
  • Health consequences: Osteoporosis, cardiovascular disease, sexual dysfunction, psychological impact.
  • Management: Hormone therapy (estrogen + progestogen) until age ~51.

4. Uterine / Outflow Tract Causes

• Asherman syndrome (intrauterine adhesions / synechiae):
  • Most common cause: Vigorous curettage (especially post-abortion or post-partum with infection).
  • Presents as hypomenorrhea or amenorrhea after a D&C.
  • Diagnosis: Hysteroscopy (gold standard), sonohysterography.
  • Treatment: Hysteroscopic adhesiolysis + post-operative estrogen therapy to promote endometrial regeneration.

5. Other Endocrine Causes

• Hypothyroidism: Elevated TRH → elevated prolactin → amenorrhea. Also direct effect on menstrual cycle.
• Hyperthyroidism: Can also disrupt cycle; usually oligomenorrhea.
• PCOS (Polycystic Ovary Syndrome):
  • Prevalence 6-10%; most common endocrine disorder in women of reproductive age.
  • Rotterdam criteria (2003): Diagnosis requires 2 of 3: (1) hyperandrogenism (clinical or biochemical), (2) oligomenorrhea or amenorrhea, (3) polycystic ovaries on ultrasound.
  • Although PCOS more commonly causes irregular bleeding, it is one of the most common causes of amenorrhea.
  • Associated with insulin resistance, obesity, endometrial hyperplasia/cancer risk, diabetes, and cardiovascular disease.
  • Not all hirsute amenorrheic women have PCOS - consider androgen-secreting tumors (rapid-onset hirsutism), congenital adrenal hyperplasia (non-classic).
• Cushing syndrome: Hypercortisolism suppresses GnRH.
• Congenital Adrenal Hyperplasia (non-classical): Elevated androgens disrupt HPO axis.

EVALUATION OF AMENORRHEA

History

• Age of onset, duration
• Weight changes, exercise habits, stress
• Galactorrhea, hot flushes (suggest hypoestrogenism)
• Hirsutism, acne (suggest hyperandrogenism)
• Headaches, visual field defects (suggest pituitary mass)
• Cyclic pelvic pain (suggest outflow obstruction)
• Prior uterine procedures, obstetric history
• Medications

Physical Examination

• BMI, height, weight
• Secondary sexual characteristics (Tanner staging)
• Signs of Turner syndrome, androgen excess, Cushing features
• Pelvic exam: vaginal patency, uterine presence, cervical abnormalities

Investigations (Step-wise)

• Prolactin - if elevated, MRI pituitary
• TSH - if elevated, treat hypothyroidism
• FSH + Estradiol:
  • High FSH + low estradiol → hypergonadotropic hypogonadism (ovarian failure)
  • Low/normal FSH + low estradiol → hypogonadotropic hypogonadism (hypothalamic/pituitary)
  • Normal FSH + normal/slightly low estradiol with anatomic uterus → consider outflow/uterine cause
• AMH (anti-Müllerian hormone): Can be helpful to assess ovarian reserve

• Karyotype: If primary amenorrhea with absent secondary sexual characteristics, or POI <30 years
• Pelvic ultrasound: Ovarian morphology (PCOS, POI), uterine anatomy, hematocolpos
• MRI brain/pituitary: If elevated prolactin, visual symptoms, hypogonadotropic hypogonadism
• Hysteroscopy/sonohysterography: If Asherman syndrome suspected
• Testosterone, DHEA-S: If hyperandrogenism present
• 17-OHP: To rule out CAH

Progestogen Challenge Test (historical)

TREATMENT

Bone Health

• Hormone therapy (estrogen)
• Adequate calcium (1000-1300 mg/day) and Vitamin D
• Weight-bearing exercise (once energy balance is restored)

Ovulation Induction (for women desiring pregnancy)

• Hypothalamic cause: Pulsatile GnRH therapy or FSH injections
• PCOS: Letrozole (first-line) or clomiphene citrate; +/- metformin
• POI: Oocyte donation (spontaneous pregnancy is rare but possible)

KEY POINTS SUMMARY (Berek & Novak)

1. Primary amenorrhea = no menses by age 13 (no secondary sex characteristics) or age 15 (with secondary sex characteristics).
2. Absent/irregular menses may indicate an underlying medical condition affecting overall health - always pursue an etiology.
3. Gonadal failure with primary amenorrhea has a high incidence of abnormal karyotype.
4. Most important diagnostic steps: β-hCG, prolactin, TSH, FSH + estradiol, physical exam for secondary sexual characteristics and anatomy. AMH may also be helpful.
5. Management includes: treating the primary cause, hormone therapy (for hypoestrogenism, bone protection, symptom relief), and ovulation induction for women desiring pregnancy.
6. Anatomic causes are relatively few and can be diagnosed by history, physical exam, and imaging.

Clinical Interpretation: Complete Androgen Insensitivity Syndrome (CAIS)

Diagnosis: Complete Androgen Insensitivity Syndrome (CAIS)

Clinching the Diagnosis - The Key Triad

Pathophysiology

46,XY Genotype
     ↓
Functioning testes → produce testosterone (male range) + AMH (Müllerian-Inhibiting Substance)
     ↓
AMH → Regression of Müllerian structures (no uterus, no fallopian tubes, upper 1/3 vagina absent)
     ↓
Testosterone → Cannot act (androgen receptor non-functional)
     ↓
NO external virilization → Female external phenotype
NO androgen-dependent hair growth → Absent pubic/axillary hair (androgen-dependent, not estrogen)
     ↓
Testosterone aromatized peripherally → ESTROGEN
     ↓
Breast development at puberty (estrogenic effect)
     ↓
No endometrium → No menses → PRIMARY AMENORRHEA

"Phenotypic females with complete congenital androgen insensitivity have breast development, little or no axillary and pubic hair, and primary amenorrhea. Genotypically they are male (XY) but have a defect that prevents normal androgen receptor function, leading to the development of the female external phenotype." - Berek & Novak's Gynecology, Chapter 34

Differentiating CAIS from Similar Conditions

Expected Physical Examination Findings

• Female external phenotype - normal labia, clitoris
• Blind vaginal pouch - short, blind-ending vagina (upper 1/3 absent - no cervix, no uterus)
• Absent uterus on pelvic examination / ultrasound
• Scant or absent axillary and pubic hair
• Breast development (but pale areolae, immature nipples - estrogen-driven, not progesterone-matured)
• Testes - may be palpable in inguinal canals or labia majora (often as "inguinal hernias" - ~50% of CAIS patients have an inguinal hernia)
• Tall stature with eunuchoid tendency - long arms, big hands and feet (absence of androgen effect on growth plate closure)

Investigations to Order

Confirmatory workup:

"The diagnosis of this disorder is based on physical examination, serum testosterone concentration, and karyotype." - Berek & Novak's Gynecology

Management

1. Gonadectomy (Orchidectomy)

• The retained testes carry a 2-5% risk of malignancy (gonadoblastoma, dysgerminoma, seminoma)
• Traditionally performed after puberty (so that puberty completes naturally using endogenous testosterone-derived estrogen for breast development - which has already occurred in this 16-year-old)
• Recent data suggests gonadectomy may be deferred until adulthood given the low absolute malignancy risk before age 25-30 and benefits of endogenous hormones
• In this patient (16 years, puberty complete): Gonadectomy is appropriate to plan

2. Hormone Replacement Therapy (HRT) - Post-gonadectomy

• After gonadectomy, exogenous estrogen is required to:
  • Maintain secondary sexual characteristics
  • Protect bone health (prevent osteoporosis)
  • Maintain general wellbeing
• Regimen: Conjugated estrogen 0.3-0.625 mg/day OR estradiol 0.5-1 mg/day
• No progestogen needed - no uterus, no risk of endometrial hyperplasia

3. Vaginal Dilation / Vaginoplasty (if needed)

• The blind vaginal pouch may be short
• Progressive vaginal dilation (Frank's method) can gradually lengthen the vagina
• Surgical vaginoplasty (McIndoe procedure) if dilation insufficient
• Goal: Functional vaginal length for sexual intercourse

4. Psychological Counseling

• Critically important - disclosure of karyotype and the underlying biology requires sensitive communication
• The patient identifies as female; her gender identity is female and must be affirmed
• Counseling regarding infertility (no uterus, no ovaries - cannot carry a pregnancy)
• Support for self-image, relationships, and sexuality
• Genetic counseling for family members (X-linked recessive - mother may be a carrier)

5. Long-term Monitoring

• Bone density (DXA scan) - ongoing on HRT
• Annual follow-up
• If gonads retained (deferred gonadectomy): regular surveillance imaging

Summary Box