Amenorrhea

Clinical description

• Primary amenorrhea:

- No menses by age 14 years in absence of growth/development of secondary sexual characteristics - No menarche by age 16 years old with normal growth and secondary sexual characteristics.

• Secondary amenorrhea:

- Cessation of menses for 6 months after menarche if regular periods - Cessation of menses for 3 cycles if irregular periods

Signs and symptoms

• Primary amenorrhea

History Ask about pubertal development, family history (including mental retardation), neonatal/child health (for congenital adrenal hyperplasia),galactorrhea, headaches, visual field defects, polyuria/polydipsia stress/weight change/exercise, sexual activity, and current medications, including contraceptive method Exam Check height/weight/BMI, look for signs of androgen excess(clitoral enlargement, hirsutism, acne, deepening voice), Tanner staging of breasts and pubic hair growth, presence of galactorrhea, neck webbing suggestive of Turner’s syndrome, bimanual exam to evaluate for presence of uterus, speculum examto evaluate for cervicovaginal anomalies.

Investigations:Pelvic ultrasound to determine if uterus is present or absent and to evaluate ovaries.

A. If Uterus Absent:

• Evaluate breast/pubic hair growth and check serum testosterone level +/- karyotype if available

a. If elevated female testosterone level, look for signs of virilisation:

i. If signs of virilisation absent, patient likely has Complete Androgen Insensitivity (46, XY) and usually has breast development, sparse/absent pubic and axillary hair, and a blind vaginal pouch.

ii. If signs of virilisation present, patient likely has 5α-reductase deficiency or Partial Androgen Insensitivity (both are 46, XY) and usually does not have breast development, but may have a blind vaginal pouch.

b. If normal female testosterone level, patient likely has Uterine Agenesis (46, XX) and will have normal breast and pubic hair development and a blind vaginal pouch.

B. If Uterus Present:

• Check UPT to rule out Pregnancy
• Check for signs of androgen excess:

a. If signs of androgen excess present, patient likely has Polycystic Ovarian Syndrome (PCOS),Late-Onset Congenital Adrenal Hyperplasia (CAH), or an Androgen-Producing Tumour (ovarian or adrenal tumours).

i. Evaluate ovaries for presence of >25 follicles on each ovary to support diagnosis of PCOS ii. Perform CT scan to evaluate for adrenal tumour.

iii. Check serum testosterone if available to evaluate for PCOS or tumours.

iv. Check morning 17OH-progesterone level if available to evaluate for CAH.

b. If signs of androgen excess absent, do progesterone withdrawal test* (see below) and check FSH, TSH, and Prolactin if available:

i. If no withdrawal flow to progesterone, patient may have Gonadal Dysgenesis, Hypothalamic Amenorrhea, Pituitary Lesion, Chronic Disease, or CNS Tumour.

a. Do trial of combined hormonal contraceptive pill for 1-3 months to evaluate for withdrawal flow with hypothalamic amenorrhea, anorexia nervosa, and chronic disease.

Clinical description

b. Neurologic assessment (including evaluation of sense of smell) +/- CT scan or MRI brain (if available) to evaluate for CNS or pituitary tumour.

c. TSH and PRL to evaluate for hypothyroidism and hyperprolactinemia.

i. Elevated TSH: Hypothyroidism ii. Elevated PRL: Pregnancy/Postpartum/Postabortion, Drugs**, Hypothyroidism, Chest Wall Stimulation,Prolactinoma, CNS Tumours, Bronchogenic/Renal Carcinoma -> do fasting PRL and consider MRI brain (if available) d. FSH if available i. If FSH elevated, likely gonadal dysgenesis, primary ovarian insufficiency, or autoimmune oophoritis -> can check karyotype or for autoimmune antibodies (anti-ovarian, anti- adrenal, anti-thyroid) if available.

ii. If FSH normal, likely PCOS or sometimes hypothalamic amenorrhea or chronic disease.

iii. If FSH low, likely hypothalamic amenorrhea, anorexia, or chronic disease.

ii. If has withdrawal flow to progesterone, likely hypothalamic amenorrhea, chronic disease, or PCOS.

*Progesterone withdrawal test: give Medroxyprogesterone or Norethindrone10mg orally once a day for 5 or 10 days. If the patient has an estrogen-primed endometrium and is not pregnant, she will have a period 3 to 10 days after the last progesterone tablet if her estradiol level was > 50 pg/ml.

**Drugs which cause hyperprolactinemia: Benzodiazapines, Haldol, Risperdone, Metoclopramide, Amitryptyline, Phenothiazines, Reserpine, Methyldopa, Prostaglandins, Cimetidine, Cocaine.

• Secondary amenorrhea: evaluation is the same as women with Primary Amenorrhea with a Uterus Present.

However, also consider Asherman’s Syndrome or Pituitary Insufficiency due to Sheehan’s Syndrome if patient has had prior uterine surgery or delivery. Patients with either condition will no withdrawal flow to progesterone, but patients with Asherman’s Syndrome will have normal FSH, whereas patients with Pituitary Insufficiency will have low FSH. Hysteroscopy can also be done to evaluate for Asherman’s Syndrome.

Treatment

Treatment is dependent on the aetiology of amenorrhea. Overall goals include correcting the underlying pathology, helping to achieve fertility if desired, and preventing complication of the disease.

5α-Reductase Deficiency:Refer to a Specialist. Treatment will depend on whether patient prefers to have a female or male social role.

Androgen Insensitivity (Complete or Partial):Gonads should be prophylactically removed after patient has attained full height and breast development because they have a high rate of malignant degeneration with formation of dysgerminoma. Until then, serial pelvic ultrasounds can be performed to assess for development of a pelvic mass.

After gonadectomy, patients should receive estrogen replacement.

Androgen-ProducingTumours: Ovarian tumours should be removed via salpingo-oophorectomy and sent to Pathology for histologic evaluation. Adrenal tumours should be referred to Surgery for management.

Asherman’s Syndrome: hysteroscopic lysis of adhesions, followed by estrogen treatment to stimulate regrowth of endometrial tissue.

Cervicovaginal Anomalies: Diagnoses include imperforate hymen, transverse vaginal septum, agenesis of the cervix or vagina. Women often present with cyclic abdominal pain and hematocolpos or hematometra on ultrasound.

Treatment is with surgery +/- postoperative use of dilators to prevent scarring.

Clinical description

Congenital Adrenal Hyperplasia: refer to Pediatrics/Endocrinology.

CNS Tumours: refer to Surgery/Neurosurgery.

Hypothalamic Amenorrhea: Is usually associated with anorexia, poor nutritional status or excessive stress or exercise, so lifestyle changes and counseling to correct these causes should be performed. Counseling on bone density risks should also be discussed.

Hypothyroidism: start on Levothyroxine1.6 mcg/kg/day. Recheck TSH in 6 weeks and titrate dose by 12-25 mcg/day as needed, rechecking TSH every 6 weeks until normal TSH level.

Gonadal Dysgenesis (Turner’s Syndrome or 45, X0):These women may have short stature, “shield” chest, webbed neck, low hairline, short 4th or 5th metacarpals, ptosis, low-set ears, narrow high-arched palate, micrognathia, lymphedema, or multiple pigmented nevi. They are at higher risk for hearing impairment, hypertension, diabetes, Hashimoto’s thyroiditis, celiac disease, cardiac anomalies (bicuspid aortic valve, coarctation of the aorta, mitral valve prolapse, dissecting aneurysms), and renal anomalies (horseshoe kidneys, unilateral pelvic kidney, hydronephrosis, etc.).Renal ultrasound and echocardiogram are often done at time of diagnosis. If diagnosed prior to age 15 years, they should be started on synthetic growth hormone if available. Otherwise, they should be started on estradiol 5 ug/kg per day for bone protection, which can be given via the combined hormonal contraceptive pill if estrogen alone is not available. Rarely, these women may achieve pregnancy.

Pituitary Insufficiency: Refer to Medicine/Endocrinology.

Pituitary Lesion (Prolactinoma, Craniopharyngioma, etc.): Refer to Surgery/Neurosurgery. If not requiring surgery, can treat with bromocriptine or cabergoline.

Polycystic Ovarian Syndrome:perform fasting blood sugar to evaluate for diabetes mellitus, encourage weight loss if overweight or obese as it will reduce their risks for diabetes, infertility, and endometrial cancer. Treat with combined hormonal contraceptive pills for management of oligomenorrhea, acne, and prevention of endometrial hyperplasia. Can consider spironolactone 50 mg BD for treatment of hirsutism if available. May experience infertility or sub-infertility.

Primary ovarian insufficiency (premature ovarian failure): Begin on estrogen therapy to prevent bone loss. Oral contraceptive pill, or replacement estrogen and progestin are options.

Uterine Agenesis: Renal ultrasound to evaluate for renal anomalies. Can consider use of vaginal dilators to create vaginal pouch when she is an adolescent. Dilators should be applied the same time every day for at least 2 months.