G4. Primary Amenorrhea

I. Definition and First Approach

Definition

• Primary amenorrhea: absence of menarche by age 15 years, or within 3 years after thelarche.
• Also evaluate if no breast development / no puberty by age 13 years.
• Secondary amenorrhea: absence of menses for > 3 previous cycle intervals or > 6 months in a previously menstruating patient.

First Questions

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

Initial Investigations

• Pregnancy test: exclude pregnancy even before first recognized menses if ovulation may have occurred.
• 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 when needed: total testosterone, DHEA-S, 17-OH-progesterone.
• Karyotype / genetic testing: suspected Turner syndrome, androgen insensitivity, gonadal dysgenesis, DSD.
• MRI: pituitary symptoms, high prolactin, neurologic signs, suspected hypothalamic-pituitary lesion; pelvic MRI if anatomy unclear.

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, normal testosterone.
   • Complete androgen insensitivity syndrome: 46,XY, testes, high male-range 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 before menarche: 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

• Definition: congenital GnRH deficiency + anosmia/hyposmia.
• Pathomechanism: failed migration of GnRH neurons and olfactory neurons → low GnRH → low FSH/LH → low estrogen.
• Clinical features: absent puberty, no/poor breast development, primary amenorrhea, infertility, anosmia/hyposmia.
• Anatomy: uterus, tubes and upper vagina are present because Mullerian development is normal.
• Karyotype: usually normal 46,XX in female patients.
• Labs: low FSH/LH, low estradiol.
• MRI: may show absent/hypoplastic olfactory bulbs; exclude hypothalamic-pituitary mass.
• Treatment: estrogen induction of puberty → cyclic estrogen + progestin for uterine protection.
• Fertility: pulsatile GnRH or gonadotropins → ovulation induction.

Turner Syndrome

• Definition: complete/partial X chromosome monosomy, classically 45,X.
• Pathomechanism: ovarian dysgenesis / streak gonads → low estrogen → no negative feedback → high FSH/LH.
• Clinical features: primary amenorrhea, absent/delayed puberty, infertility, short stature.
• Typical signs: webbed neck, shield chest with widely spaced nipples, cubitus valgus, neonatal lymphedema.
• Associated disease: bicuspid aortic valve, coarctation of aorta, hypertension, horseshoe kidney, metabolic risk.
• Anatomy: uterus present but often small/hypoplastic without estrogen exposure.
• Diagnosis: karyotype, high FSH/LH, low estradiol, pelvic US, echocardiography, 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 before pregnancy.
• Gonadectomy: indicated if Y-chromosome material is present because of gonadoblastoma risk; not routine for classic 45,X without Y material.

Mullerian Agenesis / MRKH Syndrome

• Definition: congenital absence/hypoplasia of uterus, cervix and upper vagina.
• Pathomechanism: failure of Mullerian duct development → no functional uterus → no menstruation.
• Ovaries: normal because ovaries do not develop from Mullerian ducts.
• Clinical features: primary amenorrhea, normal breast development, normal pubic hair, normal female external genitalia, short/blind vagina.
• Karyotype: 46,XX.
• Labs: normal FSH/LH, normal estradiol, normal female-range testosterone.
• Diagnosis: pelvic US/MRI → absent uterus/cervix/upper vagina, normal ovaries.
• Associated anomalies: renal and skeletal anomalies may occur → renal imaging is useful.
• Treatment: counseling; progressive vaginal dilatation first-line for functional vagina; surgery if dilatation fails or is not acceptable.
• Fertility: genetic offspring possible with IVF + gestational carrier where legally available; uterus absent.

Complete Androgen Insensitivity Syndrome

• Definition: 46,XY DSD due to androgen receptor defect.
• Inheritance: X-linked recessive.
• Pathomechanism: testes produce testosterone + AMH, but tissues cannot respond to androgens.
• Result: AMH → Mullerian regression → no uterus/fallopian tubes; testosterone aromatized to estrogen → breast development.
• Clinical features: female phenotype, normal breast development, scant/absent pubic and axillary hair, short/blind vagina, primary amenorrhea.
• Gonads: testes may be intra-abdominal, inguinal, or in labia majora.
• Karyotype: 46,XY.
• Labs: testosterone in male range; LH often high/normal; FSH usually normal.
• Diagnosis: absent uterus on US/MRI + testes + 46,XY karyotype.
• Treatment: gonadectomy usually after puberty → allows spontaneous breast development first and reduces malignancy risk later.
• After gonadectomy: estrogen replacement therapy; vaginal dilatation/surgery if needed for sexual function.

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.
• Pituitary adenoma / craniopharyngioma: endocrine workup, MRI, dopamine agonist for prolactinoma or neurosurgical/endocrine management as indicated.
• PCOS / thyroid / prolactin / functional hypothalamic causes: manage as secondary amenorrhea causes if uterus and estrogenization are present.

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.