Primary Amenorrhea

Definition

• Absence of menses by age 13 when there is no visible development of secondary sexual characteristics, OR
• Absence of menses by age 15 in the presence of normal secondary sexual characteristics

Diagnostic Flowchart (Fig. 34-1)

Classification Framework

1. Are secondary sexual characteristics (breasts) present?
2. Is pelvic anatomy normal?

CATEGORY 1: Amenorrhea WITHOUT Secondary Sexual Characteristics

A. Hypergonadotropic Hypogonadism (High FSH/LH)

• Initially normal ovarian development in utero, then accelerated follicular atresia → streak (fibrotic) ovaries
• Stigmata: short stature, webbed neck, shield chest, cubitus valgus, low hairline, high-arched palate, multiple pigmented nevi, short 4th metacarpal
• Associated conditions: coarctation of the aorta (30%), horseshoe kidney, autoimmune thyroiditis, hearing loss, diabetes
• If Y cell line present (45,X/46,XY mosaicism): gonadectomy required due to risk of gonadoblastoma and dysgerminoma
• Pregnancy via oocyte donation is possible but carries risk of aortic dissection - requires careful cardiac evaluation beforehand

• Partial X chromosome deletions (46,XX with deletions): variable phenotype overlapping Turner syndrome
• Pure gonadal dysgenesis: 46,XX or 46,XY (Swyer syndrome) individuals with streak gonads; those with XY must undergo gonadectomy
• 17α-hydroxylase deficiency: enzyme defect prevents normal estrogen production; patients have streak gonads, absent sex characteristics, hypertension, and hypokalemia
• FSH receptor mutation: autosomal recessive single amino acid substitution (described in Finland); prevents FSH binding; variable secondary sexual development; high FSH/LH
• Gonadal damage before puberty: radiation, alkylating agents (e.g., cyclophosphamide), or combined chemo-radiation

B. Hypogonadotropic Hypogonadism (Low/Normal FSH/LH)

• GnRH pulse generator is delayed in reactivation
• FSH/LH are functionally deficient for chronologic age but normal for physiologic age
• Family history of delayed puberty common
• Management: reassurance; development will eventually occur

• Deficient pulsatile GnRH secretion due to failure of GnRH neuron migration during fetal development
• Classic association: anosmia (though the patient may not be aware of it)
• Varied modes of genetic transmission (X-linked, autosomal dominant, autosomal recessive)
• Treatment: hormone replacement therapy; pulsatile GnRH or injectable gonadotropins for ovulation induction

• Autosomal recessive; most patients are compound heterozygotes
• Mutations impair GnRH binding or second-messenger signaling → no FSH/LH stimulation
• Patients are normosomic (distinguishes from Kallmann syndrome)

• Testosterone cannot be converted to dihydrotestosterone (DHT)
• No breast development (testosterone suppresses it; DHT is required for male external genitalia)
• Normal wolffian duct derivatives (testosterone-dependent) but absent external male genitalia
• Low gonadotropins (testosterone maintains feedback)

• Rare; presents with primary amenorrhea and delayed puberty
• Distinguishing feature: decreased FSH but increased LH (opposite of hypergonadotropic pattern)
• Autosomal recessive mutations in FSHβ subunit
• Treatment: injectable gonadotropins (pregnancy reported)

• Craniopharyngioma (most common CNS tumor causing primary amenorrhea) - extracellular mass interfering with GnRH/pituitary gonadotropin secretion; virtually all have multi-hormone deficiencies
• Functional causes (malnutrition, anorexia nervosa, excessive exercise, chronic disease, marijuana use) - more commonly cause secondary amenorrhea but can occasionally present as primary amenorrhea if the problem predates puberty
• Hypothyroidism, PCOS, Cushing syndrome, hyperprolactinemia - rare causes of primary amenorrhea

CATEGORY 2: Amenorrhea WITH Secondary Sexual Characteristics + Abnormal Pelvic Anatomy

Transverse Outflow Obstruction

• Imperforate hymen
• Transverse vaginal septum
• Absence of cervix or vagina
• These cause cyclic pelvic pain without bleeding; blood accumulates causing hematocolpos, hematometra, or hemoperitoneum, and may lead to endometriosis
• Diagnosis: bulging bluish membrane at introitus (imperforate hymen); MRI for higher obstructions
• Treatment: surgical correction

Mayer-Rokitansky-Küster-Hauser (MRKH) Syndrome

• Vaginal agenesis with variable uterine development; karyotype 46,XX
• Accounts for 10-15% of all primary amenorrhea
• Two subtypes:
  • Type 1: isolated Müllerian aplasia
  • Type 2: Müllerian anomaly + renal malformations (absent/horseshoe kidney, double collecting system), skeletal abnormalities, cardiac defects, hearing impairment
• External genitalia and ovaries are normal; breasts are normal
• Distinction from androgen insensitivity: MRKH has pubic/axillary hair (androgen-sensitive)
• Treatment: vaginal dilation (Frank technique) or surgical creation of neovagina

Androgen Insensitivity Syndrome (AIS) - Complete (CAIS)

• Karyotype 46,XY with testosterone levels in the male range
• Androgen receptor is nonfunctional → tissues cannot respond to testosterone or DHT
• Phenotypically female: normal breast development (testosterone is converted to estrogen peripherally)
• Absent or sparse pubic and axillary hair (key clinical clue vs. MRKH)
• Absent uterus and upper vagina (no Müllerian structures because Müllerian inhibiting substance is produced)
• Blind-ending vaginal pouch
• Testes in abdomen or inguinal canal → risk of malignant transformation; gonadectomy recommended after puberty completes (to allow estrogen-induced breast development from gonadal aromatization)
• Treatment: estrogen replacement after gonadectomy; vaginal dilation if needed

17-20 Lyase Deficiency and 17α-Hydroxylase Deficiency (46,XY)

• Enzyme deficiencies in steroidogenesis; absent uterus; karyotype XY

CATEGORY 3: Amenorrhea WITH Secondary Sexual Characteristics + Normal Pelvic Anatomy

• PCOS - most common cause of anovulatory amenorrhea in reproductive-age women
• Hyperprolactinemia - prolactinomas (rarer in childhood)
• Thyroid disease (hypothyroidism or hyperthyroidism)
• Hypothalamic amenorrhea - functional GnRH suppression (exercise, stress, weight loss)
• Absence of functioning endometrium - Asherman syndrome (rare as a cause of primary amenorrhea; more commonly secondary)

Evaluation

Key Diagnostic Tests

1. hCG - rule out pregnancy first
2. FSH and estradiol - differentiate hypergonadotropic vs. hypogonadotropic hypogonadism
3. LH - assess LH:FSH ratio
4. Prolactin (PRL)
5. TSH
6. Anti-Müllerian hormone (AMH) - may be helpful
7. Karyotype - mandatory when gonadal failure is present (to identify Y cell line)
8. Pelvic ultrasound or MRI - assess uterus, ovaries, anatomy
9. If CNS lesion suspected: MRI brain; if craniopharyngioma suspected: CT/MRI

Evaluation When Secondary Sexual Characteristics Are Absent

• Physical examination - look for Turner stigmata; assess smell (Kallmann); visual fields/optic discs (CNS lesion); galactorrhea
• Short stature with consistent growth + family history → physiologic delay
• Headaches, visual changes, symptoms of diabetes insipidus → CNS lesion
• High FSH → karyotype (Turner, Y line, pure gonadal dysgenesis)
• Low/normal FSH + absent uterus → 5α-reductase deficiency, 17-20 lyase deficiency, 17α-hydroxylase deficiency (all associated with XY karyotype)
• Low/normal FSH + normal uterus → Kallmann syndrome, physiologic delay, disorders of low estrogen before puberty

Treatment Principles

1. Hormone Replacement Therapy (Hypogonadism without Secondary Characteristics)

• Sequential estrogen-progestogen therapy to induce and maintain secondary sexual characteristics
• Typically start with low-dose estrogen, gradually increasing over 2-3 years to mimic normal pubertal progression
• Add cyclic progestogen once breast development is established or after 2 years
• Goals: develop secondary sexual characteristics; protect bone density; provide symptomatic relief of estrogen deficiency

2. Bone Protection

• Calcium and vitamin D supplementation in addition to hormone therapy for women with low circulating estrogen

3. Physiologic Delay

• Reassurance only; development will occur eventually

4. Kallmann Syndrome and Other Hypothalamic Causes

• Hormone replacement therapy
• For fertility: pulsatile GnRH infusion or injectable gonadotropins (clomiphene is ineffective in deeply hypoestrogenic patients)

5. Gonadectomy Indications

• Any patient with a Y cell line in the karyotype (gonadoblastoma risk)
• Turner syndrome 45,X/46,XY mosaicism
• Pure gonadal dysgenesis 46,XY
• Complete AIS (CAIS): typically deferred until after spontaneous puberty, then performed

6. Outflow Obstruction (Imperforate Hymen, Septum)

• Surgical correction (hymenectomy, septum resection)

7. MRKH Syndrome

• Vaginal dilation (progressive dilator therapy; Frank technique) is first-line
• Surgical neovagina creation (McIndoe procedure) if dilation fails
• Pregnancy: not possible without uterus; gestational surrogacy is an option

8. Fertility in Turner Syndrome

• Oocyte donation is generally successful
• However: aortic dissection during pregnancy is a serious risk - thorough cardiac assessment (echo, MRI aorta) mandatory before pursuing pregnancy with donated oocytes

Key Points Summary