G4. Primary Amenorrhea

I. Definition and First Approach

Definition

• Primary amenorrhea: absence of menarche by age 15 years with normal secondary sex characteristics, or by age 13 years without puberty/secondary sex characteristics.
• Also evaluate earlier if cyclic pelvic pain, virilization, severe systemic illness or suspected genital obstruction is present.

First Questions

1. Pregnancy possible? → beta-hCG first.
2. Secondary sexual characteristics present? → estrogen effect / HPO axis activity.
3. Uterus present? → normal Mullerian development; if absent think MRKH or androgen insensitivity.
4. FSH high or low? → ovarian failure vs hypothalamic-pituitary failure.
5. Androgen excess / virilization? → DSD, androgen-secreting tumor, CAH, PCOS.

Initial Investigations

• Pregnancy test: exclude pregnancy.
• Physical examination: height, weight, pubertal stage, breast development, pubic hair, external genitalia, hymen/vaginal patency.
• Pelvic ultrasound: uterus present/absent, ovaries, obstructive anomaly, pelvic mass.
• Hormones: FSH, LH, estradiol, prolactin, TSH.
• Androgens/karyotype/MRI when indicated: virilization, Turner phenotype, absent uterus with suspected DSD, high PRL or neurologic symptoms.

II. Etiologic Classification

By Secondary Sexual Characteristics and Uterus

1. Secondary sexual characteristics present + uterus absent:
   • Mullerian agenesis / Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH): 46,XX, normal ovaries.
   • Complete androgen insensitivity syndrome: 46,XY, testes, high testosterone, sparse pubic hair.
2. Secondary sexual characteristics absent + uterus present:
   • Hypogonadotropic hypogonadism: Kallmann syndrome, hypothalamic disease, pituitary tumor, chronic illness, eating disorder, excessive exercise.
   • Hypergonadotropic hypogonadism: Turner syndrome, gonadal dysgenesis, primary ovarian insufficiency.
3. Secondary sexual characteristics present + uterus present:
   • Outflow obstruction: imperforate hymen, transverse vaginal septum, cervical agenesis.
   • Anovulation/endocrine causes: PCOS, thyroid disease, hyperprolactinemia, stress/weight loss.
   • Pregnancy before first recognized period.

By Gonadotropins

• High FSH/LH + low estrogen: ovarian failure / gonadal dysgenesis → Turner syndrome, Swyer syndrome, primary ovarian insufficiency.
• Low or normal FSH/LH + low estrogen: hypothalamic-pituitary cause → Kallmann syndrome, functional hypothalamic amenorrhea, pituitary tumor.
• Normal FSH/LH + normal estrogen + no uterus: Mullerian agenesis or androgen insensitivity.

III. Main Causes

Kallmann Syndrome

• Pathomechanism: failed migration of GnRH neurons and olfactory neurons → low GnRH → low FSH/LH → low estrogen.
• Clinical features: absent puberty/no secondary sex characteristics, primary amenorrhea, infertility, anosmia/hyposmia.
• Anatomy: normal female external genitalia; uterus/tubes/upper vagina present.
• Karyotype: usually normal 46,XX in female patients.
• Labs: low GnRH, low FSH/LH, low estradiol.
• MRI: may show absent/hypoplastic olfactory bulbs; exclude hypothalamic-pituitary mass.
• Treatment: estrogen + progestin for secondary sex characteristic development; pulsatile GnRH/gonadotropins for fertility.

Turner Syndrome

• Pathomechanism: ovarian dysgenesis / streak gonads → low estrogen → no negative feedback → high FSH/LH.
• Clinical features: primary amenorrhea, absent/delayed puberty, infertility, short stature, webbed neck, shield chest with widely spaced nipples, cubitus valgus.
• Associated disease: bicuspid aortic valve, coarctation of aorta, hypertension, horseshoe kidney, metabolic risk.
• Diagnosis: 45,X karyotype; high FSH/LH, low estradiol; pelvic US = streak ovaries/small uterus; echocardiography and renal imaging.
• Treatment: growth hormone in childhood; estrogen puberty induction → later cyclic estrogen + progestin.
• Fertility: usually donor-oocyte IVF if pregnancy is safe; cardiac assessment is essential.
• Remove streak gonads if Y-chromosome material is present due to gonadoblastoma risk.

Mullerian Agenesis / MRKH Syndrome

• Pathomechanism: failure of Mullerian duct development → congenital absence of uterus, cervix and upper 2/3 of vagina.
• Ovaries are normal → normal estrogen/ovulation → normal secondary sex characteristics, but no uterus → amenorrhea.
• Clinical features: primary amenorrhea, normal breast development, normal pubic hair, normal female external genitalia, short/blind vagina.
• Diagnosis: 46,XX; normal FSH/LH/estradiol; pelvic US/MRI = absent uterus/cervix/upper vagina, normal ovaries.
• Associated renal/skeletal anomalies may occur → renal imaging is useful.
• Treatment: counseling + creation of functional vagina by progressive dilatation or surgery.

Complete Androgen Insensitivity Syndrome

• Pathomechanism: X-linked androgen receptor mutation in 46,XY patient; testes produce testosterone and AMH.
• AMH → Mullerian regression → no uterus; androgen resistance → female external genitalia; aromatized testosterone → breast development.
• Clinical features: female phenotype, normal breasts, scant/absent pubic/axillary hair, short/blind vagina, cryptorchid testes.
• Diagnosis: 46,XY; high/male-range testosterone, estrogen, LH/FSH; pelvic US/MRI = absent uterus + intra-abdominal/inguinal testes.
• Treatment: gonadectomy after puberty due to malignancy risk; estrogen replacement after gonadectomy; vaginal dilatation/surgery if needed.

IV. Treatment Principles and Exam Points

Treatment by Cause

• Hypogonadotropic hypogonadism: treat underlying cause; estrogen/progestin replacement; fertility induction with GnRH/gonadotropins.
• Hypergonadotropic hypogonadism: hormone replacement for puberty, uterus, bone and cardiovascular health; fertility counseling.
• Outflow obstruction: surgical correction if obstructed menstrual blood or pain.
• Mullerian agenesis / AIS: counseling + creation of functional vagina when desired; AIS needs gonadectomy after puberty.
• Pituitary/thyroid/prolactin/PCOS/functional hypothalamic causes: treat the underlying endocrine cause.

Exam Differentiation

• Absent uterus + normal secondary sexual characteristics:
  • MRKH: 46,XX, normal pubic hair, normal female testosterone, ovaries present.
  • AIS: 46,XY, sparse pubic hair, testes present, testosterone in male range.
• Absent secondary sexual characteristics + uterus present:
  • Low FSH/LH: hypothalamus/pituitary problem.
  • High FSH/LH: gonadal failure, especially Turner syndrome.
• Primary amenorrhea + cyclic pain + normal puberty: think outflow obstruction.
• Primary amenorrhea + anosmia: Kallmann syndrome.
• Primary amenorrhea + short stature/webbed neck: Turner syndrome.