Primary Amenorrhea

Overview

Definition

Primary amenorrhea is defined as:

• No menses by age 13 in absence of secondary sex characteristics 
• No menses by age 15 regardless of secondary sex characteristics
• Secondary sex characteristics include: 
  • Breast development 
  • Axillary hair
  • Pubic hair

Normal physiology

Hormones of the hypothalamic–pituitary–ovarian (HPO) axis and all relevant anatomy must be present and functioning in order for a girl to get her first menses. 

• Normal physiology review:
  • Hypothalamus releases gonadotropin-releasing hormone (GNRH) → stimulates the pituitary to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH) → ovary releases estrogen and progesterone
  • Estrogen and progesterone:
    • Produced by developing follicles within the ovary
    • Estrogen stimulates the endometrium to grow.
    • Progesterone matures and stabilizes the endometrium (produced only after ovulation).
    • Both ↓ at the end of the cycle → loss of “stabilizing” hormones (particularly progesterone) triggers efflux of menstrual fluid
• Structural origins:
  • Genital ridge → primordial gonads → testes or ovaries
  • Müllerian ducts (paramesonephric ducts) → Fallopian tubes, uterus, cervix, and proximal two-thirds of the vagina
  • Urogenital sinus → distal ⅓ of the vagina
  • Wolffian ducts (mesonephric ducts) → epididymis, vas deferens, and seminal vesicles
• Process of sex differentiation:
  • Presence of the sex-determining region of the Y chromosome (SRY) gene → primordial gonads into testes, which secrete:
    • Anti-Müllerian hormone (AMH), also called Müllerian-inhibiting substance → stimulates regression of Müllerian ducts
    • Testosterone → stimulates virilization of the Wolffian ducts into the epididymis, vas deferens, and seminal vesicles
  • In the absence of the SRY gene, the primordial gonads become ovaries.
    • Without testes producing high amounts of AMH, the Müllerian ducts persist → Fallopian tubes, uterus, cervix, and proximal vagina develop
    • Patients with Müllerian anomalies will usually have a normal HPO axis, normal ovaries, and normal external female genitalia

Etiology and Pathophysiology

Hypothalamic and pituitary etiologies

• Pathophysiology: 
  • If GNRH is not being released or release is dysfunctional, there is: 
    • No FSH or LH released from the pituitary
    • No ovarian stimulation
    • No estrogen production
    • No endometrial proliferation
    • This results in no menses. 
• Functional hypothalamic amenorrhea: 
  • Stress
  • Lack of nutrition: 
    • Eating disorders
    • Famine
  • Overexercise (common in female athletes)
• Idiopathic hypogonadotropic hypogonadism (IHH): 
  • A family of genetic disorders resulting in GNRH deficiency or defects
  • Kallmann syndrome: IHH with anosmia
• Constitutional delay of puberty: 
  • Overall delay of puberty
  • Uncommon in girls (diagnosis of exclusion)
  • Difficult to distinguish from IHH
• Hyperprolactinemia: 
  • ↑ Prolactin can suppress the release of GNRH.
  • Usually presents as secondary amenorrhea, but can present as primary
  • Implicated medications: 
    • Antipsychotics
    • Tricyclic antidepressants
    • Metoclopramide
  • Often caused by pituitary adenomas
  • A similar mechanism can result from primary and central hypothyroidism: ↑ thyroid-releasing hormone → ↑ prolactin release
• Systemic illness: 
  • Severe illness can ↓ GNRH.
  • Examples:
    • Type 1 diabetes mellitus
    • Celiac disease
    • Inflammatory bowel disease (IBD)
• Infiltrative diseases: 
  • Sarcoidosis
  • Hemochromatosis
• Neoplasia/sellar mass:
  • Craniopharyngioma
  • Germinoma
  • Langerhans cell histiocytosis

Ovarian/gonadal etiologies

• Pathophysiology: 
  • The ovaries, oocytes, or follicles are abnormal.
  • No healthy oocytes/follicles → no estrogen or progesterone → no endometrial stimulation → no menses
• Gonadal dysgenesis: 
  • When the gonads fail to form correctly and do not secrete sex hormones
  • Turner syndrome (45,X or mosaic forms): Ovaries are replaced with fibrotic tissue.
  • 46,XX gonadal dysgenesis: results in nonfunctional streak ovaries
  • Swyer syndrome (46,XY), failure of testicular development resulting in the absence of:
    • Testosterone → Wolffian structures do not develop.
    • AMH →  Müllerian structures persist.
• Premature ovarian insufficiency (POI): 
  • Clinical menopause at < 40 years old
  • Often presents as secondary amenorrhea, but can present as primary
  • Causes:
    • FMR1 (the gene that causes fragile X syndrome) premutation
    • Chemotherapy
    • Radiation 
    • Autoimmune oophoritis

Uterine and vaginal etiologies

• Pathophysiology: absence or obstruction of the uterus and/or vagina 
• Müllerian agenesis (Mayer–Rokitansky–Küster–Hauser syndrome): 
  • Results in complete absence of the vagina with variable uterine development
  • Uterus may be: 
    • Normal and obstructed
    • Rudimentary with some functional endometrium
  • Ovaries are typically present and functional: 
    • HPO axis is intact → estrogen is produced
    • Breasts develop at puberty.
  • External female genitalia is normal.
• Vaginal outflow obstruction: 
  • Transverse vaginal septum
  • Imperforate hymen

Other hormonal etiologies

• Pathophysiology: hormonal interference in the HPO axis
• Polycystic ovary syndrome (PCOS): 
  • Amenorrhea plus ↑ androgen levels 
  • Folliculogenesis is abnormal → oocytes are nonovulatory → progesterone is not produced → no menses
  • Usually presents as secondary amenorrhea, but rarely can present as primary
• Complete androgen insensitivity syndrome (AIS): 
  • X-linked recessive disorder seen in 46,XY individuals
  • Testes, which make Müllerian-inhibiting substance, are present → causes regression of the Fallopian tubes, uterus, and upper vagina
  • The mutation results in defective androgen receptors → patients are resistant to testosterone (which tends to be ↑↑)
  • Testosterone is unable to virilize the Wolffian structures or external genitalia → phenotypically female
  • ↑ Testosterone is converted to estrogen → breasts develop at puberty
• Congenital adrenal hyperplasia: 
  • Gene mutations lead to deficiencies in enzymes required for steroid biogenesis. 
  • Results in ↑ androgen levels → affects ovulation

Clinical Presentation and Diagnosis

Presentation

• No menses by age 13 years in the absence of secondary sex characteristics 
• No menses by age 15 years regardless of secondary sex characteristics
• Other manifestations depend on the underlying etiology.

Physical exam

• Assess signs of secondary sex characteristics: 
  • Breast development → indicates exposure to estrogen
  • Axillary hair and pubic hair (sexual hair) → indicate exposure to testosterone
  • Hirsutism → androgen excess
• Pelvic exam:
  • Look for an outflow obstruction.
  • Presence or absence of uterus and vagina
  • Ambiguous genitalia suggests a disorder of sexual differentiation.

Diagnostic considerations

• To remember the differential diagnosis for primary amenorrhea, think about:
  • What can go wrong at each level of the HPO axis 
  • What can go wrong anatomically
• Breast development and sexual hair means exposure to estrogen and testosterone, which indicates that:
  • The HPO axis is intact.
  • The gonads are functional.
• No breasts or sexual hair → indicates no exposure to sex hormones:
  • The defect is at or above the level of the ovary.
  • Exception: presence of breasts, but no sexual hair → suspect AIS

Evaluation

Start by assessing 4 things: 

1. Rule out pregnancy! (urine pregnancy test)
2. Prolactin, thyroid-stimulating hormone (TSH), and thyroxine (T₄) levels: 
   • ↑ Prolactin → hyperprolactinemia
   • ↓ or normal TSH with ↓ T₄ → central hypothyroidism
   • ↑ TSH with ↓ T₄ → primary hypothyroidism
3. Presence of a uterus and vagina:
   • Pelvic exam and ultrasonography 
   • MRI for more complex cases
   • If the vagina is abnormal → examine under anesthesia; surgical management:
     • Transverse septum
     • Imperforate hymen
   • If the uterus is absent → order karyotype and testosterone measurement to look for:
     • 46,XX: Müllerian agenesis → normal testosterone
     • 46,XY: Complete AIS → ↑ testosterone
4. FSH level (with uterus present):
   • ↑ FSH = issue is in the ovaries, which are not responding to FSH (but hypothalamus and pituitary are likely normal)
     • POI
     • Turner syndrome → confirm with karyotype
   • ↓ FSH = issue is in the brain: 
     • Functional hypothalamic amenorrhea (stress, undernutrition, overexercise)
     • Systemic illness (celiac, type 1 diabetes mellitus, IBD)
     • Kallmann syndrome
     • Congenital GNRH deficiency
     • Consider MRI to rule out sellar mass.

Management

Management is dependent on the etiology and is usually aimed at correcting the underlying hormonal or anatomic issue.

• General measures:
  • Resolve medical issues or stress.
  • Gain weight or ↓ exercise intensity (functional hypothalamic amenorrhea)
• Medical therapy:
  • Hormone replacement therapy (HRT): ensures adequate estrogen exposure to maintain cardiovascular and bone health
  • Antiandrogen therapy (spironolactone)
• Surgery:
  • Correction of congenital anatomic lesions
  • Removal of abnormal gonads: Patients are at risk for neoplasia (e.g., germ cell tumors, gonadoblastomas)
• Consider fertility implications:
  • Pulsatile GNRH
  • In vitro fertilization
• Counseling: 
  • Fertility
  • Issues with sexual differentiation
  • Eating disorders