Amenorrhea

Background

Menarche (the onset of menses) is an important milestone in female adolescent development, and is preceded by the onset of breast development (thelarche) and pubic hair (pubarche). Menses are often irregular at first, but ultimately normalize to a more regular cycle of 21-35 days, with 3 to 7 days of bleeding per cycle. This pattern continues throughout adult life until menopause.

Amenorrhea (the lack of menstruation) is a symptom, not a disease unto itself, and may be divided into primary (delayed menarche) or secondary amenorrhea (cessation of menses in someone who has previously menstruated). While some etiologies can cause both primary and secondary amenorrhea, they are distinct entities with subtly different diagnostic and etiologic frameworks.

Primary amenorrhea

The typical age of menarche varies somewhat between different countries and ethnic groups. In the United States, the typical age of menarche in healthy female adolescents is 12-13, with more than 80% achieving menarche between 11 and 14. Primary amenorrhea is traditionally defined as failure to achieve menarche by age 16. However, diagnostic evaluation is often initiated earlier, for the following indications, among others:

•  No menarche by age 15 (98% of females have undergone menarche by this age)
• No menarche by age 14 with other concerning signs/symptoms
•  No menarche within 3 years after thelarche
• No thelarche or other signs of pubertal onset by age 13
• or other signs of pubertal onset by age 13

The initial evaluation of primary amenorrhea should include:

 A detailed history including growth, development (including other pubertal signs, especially breast development), nutrition, exercise, weight and/or BMI changes, sexual history, first-degree relatives’ ages at menarche, medical conditions including chronic disease, and medications.

 Physical exam including growth curves, sexual development and Tanner staging, cranial nerve examination with visual field testing, thyroid exam, and pelvic exam with bimanual exam to evaluate anatomic factors.

Further studies should be based on the H&P, and may include: CBC, serum LH/FSH and/or T4/TSH, karyotype, pregnancy test, ultrasound of abdomen and pelvis, CT/MRI of head.

Common causes of primary amenorrhea

• Consitutional delay
• Gonadal dysgenesis (will have high FSH due to primary ovarian insufficiency)
  • ​Most commonly Turner syndrome (45,XO): short stature, “shield chest” with widely spaced nipples, webbed neck, fibrotic “streak ovaries”
• ​Central endocrine abnormalities
  • ​ Most commonly functional hypothalamic amenorrhea: conditions such as chronic illness, chronic stress, excessive exercise, or very low BMI can impair the normal pulsatile release of GnRH from the hypothalamus
• ​Congenital absence or anomalies of uterus, cervix, and/or vagina (müllerian agenesis)
•  Transverse vaginal septum or imperforate hymen (outflow obstruction)
• Pituitary disease
• Other important, but less common, causes to keep in mind:
  • Pregnancy
  • Polycystic ovary syndrome (PCOS): hyperandrogenic state inhibits normal ovulation and menstruation cycles.
  • Thyroid disease (both hyperthyroid and hypothyroid)
  • Androgen insensitivity syndrome (46,XY): Mutation in androgen receptor leads to phenotypically female appearance with female external genitalia, but lacking all müllerian structures (uterus, ovaries, upper 1/3 of vagina) due to fully functional müllerian inhibiting factor (MIF) production by the undescended testes.

Secondary Amenorrhea

Secondary amenorrhea is typically defined as the absence of menses for a consecutive period of 3 cycles or 6 months in a woman who has previously menstruated. Although irregular menstruation is quite common in the first year or two following menarche, the absence of menstruation for more than 3 consecutive cycles merits further investigation even among this group.

The diagnostic evaluation of secondary amenorrhea is very similar to that for primary amenorrhea, with enhanced focus on the sexual history including contraceptive practices and sexually transmitted infections, as well as a detailed menstrual history. Previous gynecologic surgeries or procedures are also an important consideration since endometrial scarring and intrauterine synechiae may result (Asherman syndrome).

It is critical to remember that the most common cause of secondary amenorrhea is pregnancy! A pregnancy test should always be included in the workup of secondary amenorrhea, regardless of reported history.

The most common causes of secondary amenorrhea include:

1. Pregnancy: second most common cause of secondary amenorrhea.
2. Physical or emotional stress leading to decreased GnRH secretion, thereby decreasing LH/FSH secretion.

• Anorexia nervosa/disordered eating. Amennorhea can occur when weight falls below 85% of average for age and height.
• Exercise can lead to a decrease in pulsatile LH release. Athletes’ triad: Amenorrhea, Disordered eating pattern, Osteoporosis
• Emotional stress

3. Autoimmune disease.

• Inflammatory bowel disease
• Diabetes mellitus
• Hyperthyroidism

4. Neoplasm: Pituitary adenoma or Craniopharyngioma

• Evaluate for galactorrhea
• Ovarian or adrenal tumors

5. Drugs or medication

• Chemotherapy drugs 

6. Polycystic Ovary Syndrome, or functional ovarian hyperandrogenism: elevated ovarian androgen and elevated LH/FSH contribute to chronic anovulation.

• Associated with hirsutism and hyperinsulinism - look for acanthosis nigricans

Reference    

1. AAP Committee on Adolescence. (2006). Menstruation in girls and adolescents: using the menstrual cycle as a vital sign. Pediatrics, 118(5), 2245-2250.
2. Bloomfield, D. (2006). Secondary amenorrhea. Pediatrics in Review, 27(3), 113-114.
3. Caronia, L.M. (2011). A genetic basis for functional hypothalamic amenorrhea. NEJM, 364(3), 215-225.
4. Gray, S.H. (2013). Menstrual disorders. Pediatrics in Review, 34(1), 6-18.
5. Polanesczky, M.M. and Slap, G.B. (1992). Menstrual disorders in the adolescent: primary amenorrhea. Pediatrics in Review, 13(2), 43-48.