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Amenorrhoea

Essentials

  • In primary amenorrhoea, the patient has never had a menstruation. In secondary amenorrhoea, menstruation remains absent for 6 consecutive months or, if the menstrual cycle is clearly longer than normal, three consecutive menstrual periods remain absent. In practice, the boundary between the different conditions is not always this clear-cut.

Primary amenorrhoea

  • Investigate further if
    • no signs of puberty have emerged by the age of 14 or
    • menstruation has not started by the age of 16, even though puberty has otherwise progressed normally.

Causes

  • The most common cause is irreversible ovarian failure; often no onset of puberty.
    • Usually associated with chromosomal abnormalities, e.g. Turner's syndrome
    • Other ovarian defect (dysgenesis)
    • Malignancy treated in childhood
  • Pituitary causes; often no onset of puberty
    • Pituitary tumour (most often prolactinoma)
    • Medication increasing prolactin levels
    • Hypofunction of the pituitary gland
  • Hypothalamic causes; pubertal changes often lacking
  • Structural causes; development of puberty otherwise normal
    • Imperforate hymen - blood retained in the vagina (hematocolpos) and cyclic lower abdominal pain
    • Rare: transverse vaginal septum, absent cervix or agenesis of the uterus
    • Rare: androgen insensitivity syndrome, i.e. an XY female, female external genitalia and body habitus, short vagina, absent internal genitalia
  • Systemic illnesses
    • Hypothyroidism, untreated coeliac disease, Cushing's syndrome, adrenal hyperandrogenism
    • Obesity

Diagnosis and treatment

  • Specialist referral (a referral both to a paediatrician and gynaecologist)
  • Bimanual pelvic examination should not be done!
  • The referral should include the patient's growth charts, past medical history and the history of the parents' puberty.

Secondary amenorrhoea

  • A normal functioning of both the hypothalamus-pituitary-ovary axis and endometrium are prerequisites for a regular menstrual cycle.
  • See also Abnormal menstrual bleeding Abnormal Menstrual Bleeding.

History

  • Previous menstrual history, contraception Contraception: Initiation, Choice of Method and Follow-Up Hormonal Contraception
  • Pregnancies, deliveries and associated procedures
  • Weight loss or weight gain (assess the significance of the weight change in relation to baseline weight, i.e. if BMI is 18, a weight loss of a few kg may cause amenorrhoea)
  • History of increased physical exercise, recent stress, current diseases and their medication, earlier diseases and their treatments (e.g. history of cytotoxic chemotherapy or radiotherapy), family history as regards diseases (e.g. coeliac diseases) and menstrual abnormalities
  • Any other symptoms associated with amenorrhoea (sudden sweating, vaginal dryness, increased hair growth, acne etc.)

Status

  • Height, weight, blood pressure
  • Fat distribution (truncal obesity)
  • Striae, abnormal pigmentation of external genitalia and armpits
  • Hirsutism, greasy skin, acne
  • Thyroid gland
  • Breasts, possible galactorrhoea
  • Gynaecological examination: state of the vaginal epithelium, size of the uterus and ovaries.
    • Bimanual pelvic examination should not be done if the patient is an adolescent who has not had sexual intercourses.

Diagnosis and treatment

  • Exclude pregnancy.
  • Serum prolactin
  • Serum TSH
  • Progestogen challenge test for 7-10 days (e.g. dydrogesterone 10-20 mg/day or medroxyprogesterone 10 mg/day)
    • If withdrawal bleeding occurs within 2 weeks of the last tablet, the level of oestrogen is sufficient to proliferate the endometrium. If no bleeding occurs, the level of oestrogen is low or the endometrium is nonresponsive.
  • If no withdrawal bleeding occurs, measure FSH and LH.
    1. Low FSH and LH
      • Hypothalamic/pituitary aetiology
      • Anorexia: refer to a psychiatric team
      • Excessive exercise: inform the patient about the risk of osteoporosis. The goal is to increase caloric intake.
      • If the amount of exercise and low body weight offer no explanation for the finding, refer the patient for further investigation, since the possibility of hypothalamic or pituitary tumour must be excluded.
    2. High FSH and LH, and additionally low AMH (anti-Müller-hormone, which may be determined as required)
      • Ovarian insufficiency
      • The aetiology and treatment (e.g. risk of osteoporosis) in a woman less than 40 years of age should be evaluated at an appropriate hospital.
      • Early menopause (familial tendency in 30-50% of cases; see Menopausal Symptoms and Hormone Therapy)
      • Polyendocrinopathy
      • Iatrogenic aetiology (surgery, chemotherapy)
    3. Normal FSH and LH
      • The aetiology is related to endometrial response
      • Presence of intrauterine adhesions, e.g. after curettage (Asherman's syndrome)
      • Referral to a specialist
    4. Systemic illness may cause amenorrhoea.
      • Hyperthyroidism, hypothyroidism, renal or hepatic insufficiency, severe untreated coeliac disease Coeliac Disease etc. Usually no withdrawal bleeding after progestogen challenge test.
  • If withdrawal bleeding occurs the patient is normoestrogenic and anovulatory.
    1. Ask about possible stress factors (problems with personal relationships, recent changes in employment status, death of a close family member etc.). The condition is transient.
      • Treat with cyclical progestogen (dydrogesterone 10 mg on days 15-24 of the cycle) for three months.
      • If normal menstrual cycle is not achieved without medication, refer the patient to a gynaecologist.
    2. Obvious weight gain, truncal obesity, acne, hirsutism
      • Polycystic ovary syndrome (PCOS), see Polycystic Ovary Syndrome (PCOS).
      • Ovulation disturbed by obesity alone; treated with cyclical progestogen until weight normalizes to avoid the risk of endometrial hyperplasia Benign Gynaecological Lesions and Tumours Abnormal Menstrual Bleeding
      • Rare: Cushing's syndrome Cushing's Syndrome
      • If there are clear signs of virilism (alopecia, marked hirsutism, enlargement of the clitoris, deepening of the voice) and serum testosterone level is increased, the patient must be referred to a gynaecologist. The patient may have an androgen-producing adrenal or ovarian tumor. See also Excessive Hair Growth (Hirsutism).
      • Note! If the testosterone level is very high, no withdrawal bleeding will occur after the progestogen challenge test.

    References

    • Klein DA, Paradise SL, Reeder RM. Amenorrhea: A Systematic Approach to Diagnosis and Management. Am Fam Physician 2019;100(1):39-48. [PubMed]
    • Gordon CM, Ackerman KE, Berga SL et al. Functional Hypothalamic Amenorrhea: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2017;102(5):1413-1439. [PubMed]