Hayley A. Crossman MD, Maria D. Fan MD

Amy (Meg) Autry MD, Sandra Oza MD MA

BOTTOM LINE ✔ Rule out pregnancy first! ✔ Amenorrhea can be due tochromosomal abnormalities,hypothalamic dysfunction,structural issues, pituitarydisease, hyperandrogenism

Definition:

• Primary amenorrhea: absence of menarche by age 15 with normal growth & secondary sex characteristics, OR by age 13 with complete absence of secondary sexual characteristics
• Secondary amenorrhea: new-onset absence of menses for three months in those with regular cycles or six months in those with irregular cycles

Etiology:

Primary Amenorrhea

Etiology is usually genetic or anatomic abnormality:

• 43% Gonadal dysgenesis (Turner’s, etc.)
• 15% Mullerian anomaly(absence of uterus and upper vagina (Mullerian agenesis), vaginal septum, imperforate hymen)
• 14% Physiological delay of puberty (constitutional delay, chronic illness)
• 7% PCOS
• Other causes: endocrine – hypothalamic, hypothalamic, androgen insensitivity

Secondary Amenorrhea

• 40% ovary: PCOS, gonadal failure
• 35% hypothalamus: low or normal FSH due to various causes
• 17% pituitary: tumor, empty sella, high prolactin
• 7% uterus: asherman syndrome
• 1% other

Evaluation:

Structure your approach to etiology of amenorrhea by thinking about the level of control of the menstrual cycle: hypothalamus, pituitary, ovary, uterus

• History: LMP, evaluate for recent stress, change in weight, diet/eating disorders, amount of exercise, systemic illness, medications, symptoms of hyper-androgenism (hirsutism, acne), galactorrhea, headaches, visual field defects, peri-menopausal symptoms, history of uterine instrumentation.
• Physical: Tanner staging. Note BMI. Examine for hirsutism, acne, striae, acanthosis nigricans, vitiligo, galactorrhea; palpate thyroid. Pelvic exam to verify normal anatomy.
• Labs/tests: First pass tests include urine hCG, prolactin, and TSH. See below for more specific testing based on primary or secondary amenorrhea. 

Management:

Variable given etiology

• Primary amenorrhea due to gonadal failure & hypergonadotropic hypogonadism require cyclic estrogen & progestin to initiate, mature, and maintain secondary sex characteristics. Estrogen therapy also helps prevent osteoporosis, in addition to Ca and Vit D supplementation.
• PCOS: OCPs or cyclic progestin or progestin intrauterine device to avoid endometrial hyperplasia or cancer from the unopposed estrogen. If desires pregnancy may need ovulation induction w clomiphene citrate
• Hyperprolactinoma: brain MRI and referral to endocrine possible neurosurgery
• Lifestyle factors: regulation of nutrition in eating disorders, decreased exercise may all be appropriate management of hypothalamic amenorrhea.
• If no underlying cause is found, consider starting cyclic estrogen-progestin or OCPs to prevent osteoporosis
• Referral to OBGYN and/or endocrine is often appropriate

Primary Amenorrhea, detailed approach

• Rule out pregnancy first with urine pregnancy test.
• Primary amenorrhea approach: eval for secondary sex characteristics- breast development (marker of estrogen action & ovarian function), presence of uterus with exam and/or pelvic ultrasound, FSH, estradiol, prolactin, TSH.

• No breast development: obtain FSH. If elevated FSH, obtain karyotype. DDX includes primary ovarian insufficiency, Turner syndrome, partial deletion of X chromosome, mosaicism, gonadal dysgenesis
  • If Y chromosome present, need to remove gonads after puberty to prevent gonadoblastoma/dysgerminoma
  • If karyotype normal, consider 17α-hydroxylase deficiency (serum progesterone high, 17α-hydroxyprogesterone low, deoxycorticosterone high). Confirm with ACTH stimulation test.
• Absent uterus & normal FSH: Mullerian agenesis or androgen insensitivity syndrome (testosterone resistance due to defect in androgen receptor, leading to lack of male sexual characteristics). Testosterone in female range if mullerian agenesis, male range if androgen insensitivity syndrome and Y chromosome in karyotype. Gonads need to be removed for AIS after puberty for increased risk of malignancy.
• Low FSH: hypogonadotropic hypogonadism (constitutional delay, anorexia)
• FSH normal, exam consistent with septum or imperforate hymen or blood in uterus on US: obstructed outflow tract (these patients usually have cyclical pain c/w obstructed outflow)
• FSH normal, breast & uterus present: anovulation, check height/weight, prolactin, TSH, progesterone withdrawal test

Secondary Amenorrhea, detailed approach

• Rule out pregnancy first with urine pregnancy test
• Obtain prolactin, TSH. If normal, most likely diagnosis is anovulation or polycystic ovarian syndrome (defined by two of the following: anovulation, clinical or laboratory evidence of hyperandrogenism, or polycystic ovaries on ultrasound). If no clinical evidence of hyperandrogenism, obtain free testosterone, DHEAS, and pelvic ultrasound

A. Ovarian disorders: obtain FSH, pelvic US

• Premature ovarian failure (premature if < 40 years old), can be due to Turner syndrome, fragile X pre-mutation, auto-immune destruction, radiation, or chemotherapy with alkylating agents e.g. cyclophosphamide. Obtain karyotype and if normal, check for other autoimmune disorders (diabetes, thyroid disease, and Fragile X)
• PCOS (hyperandrogenism, oligomenorrhea or amenorrhea, polycystic ovaries on ultrasound)
• Androgen producing ovarian tumors (rare)

B. Hypothalamic/pituitary/thyroid dysfunction: FSH, prolactin, TSH, pituitary MRI if elevated prolactin

• Functional: Decrease in GnRH secretion. Etiologies include stress, anorexia, nutritional deficiency (e.g. celiac), severe illness, excessive exercise (female athlete triad).
• Hypothalamic tumors/Infiltrative disease: craniopharyngiomas, lymphoma, Langerhans cell histiocytosis, sarcoidosis (rare)
• Pituitary disease: Prolactinoma, pituitary adenomas, sellar masses, Sheehan’s syndrome, radiation, infarction, hemochromatosis, lymphocytic hypophysitis.
  • Prolactinoma -> galactorrhea, elevated prolactin
• Thyroid disease: Hypothyroidism, hyperthyroidism
• Medications: Anti-psychotics, metoclopramide, tricyclic antidepressants, calcium channel blockers, methyldopa, reserpine (all through hyperprolactinemia effects), hormonal therapy (continuous OCPs, DepoProvera, levonorgestrel IUD)

C. Hyperandrogenic chronic anovulation: testosterone, DHEAS, 21-hydroxylase

• Cushing's syndrome
• Adrenal hyperplasia (21-hydroxylase deficiency)
• Adrenal insufficiency
• Androgen-producing adrenal & ovarian tumors

D. Outflow tract obstruction: pelvic exam, pelvic US

• Asherman's syndrome - endometrial scarring, usually post-curettage and associated with infection. Confirm w hysterosalpingogram
• Cervical stenosis - usually post-cone biopsy or LEEP

References

Practice Committee of the American Society of Reproductive Medicine. Current evaluation of amenorrhea. Fertil Steril 2008; 90:S219-25.

Schillings WJ and McClamrock HD. Chapter 27. In: Berek JS, ed. Berek & Novak’s Gynecology. 14^th ed. Philadelphia: Lippincott Williams & Wilkins; 2007.  

Simon A, Chang WY, and DeCherney AH. Chapter 54. In: DeCherney AH, Nathan L, eds. CURRENT Diagnosis & Treatment Obstetrics & Gynecology. 11th ed. New York: McGraw-Hill; 2013.

Welt CK, Barbieri RL. Etiology, diagnosis, and treatment of primary amenorrhea. UpToDate

Welt CK, Barbieri RL. Etiology, diagnosis, and treatment of secondary amenorrhea. UpToDate.

Reindollar RH, Byrd JR, McDonough PG. Delayed sexual development: a study of 252 patients. Am J Obstet Gynecology 1981 Jun 15;140(4):371-80.

Guidelines for Women’s Health Care: A Resource Manual, fourth edition. American College of Obstetricians and Gynecologists. Washington DC; Sept 2016, p567-572.