AMENORRHEA

AMENORRHEA - Jeanne M. Cawse-Lucas, MD
BASICS
DESCRIPTION
The absence of menses.
• Primary amenorrhea: No menses by age 14, with absence of secondary sexual characteristics, or no menses by age 16 with normal secondary characteristics
• Secondary amenorrhea: The cessation of menses for 3 cycles, or 6 months of amenorrhea
• System(s) Affected: Endocrine/metabolic; Reproductive
ALERT
Pediatric Considerations
Primary amenorrhea by definition begins in this group.
Pregnancy Considerations
Pregnancy is the most common cause of secondary amenorrhea.
GENERAL PREVENTION
Maintenance of proper body mass index (BMI)
EPIDEMIOLOGY
Incidence
• Incidence of primary amenorrhea 0.3%
• Incidence of secondary amenorrhea 3.3%
Prevalence
Menarche to menopause
RISK FACTORS
• Overtraining (e.g., long-distance runner, ballet dancer) as part of the female athlete triad
• Eating disorders
• Psychosocial crisis
Genetics
No known genetic pattern
ETIOLOGY
• Primary amenorrhea
- Imperforate hymen
- Agenesis of the uterus and upper 2/3 of the vagina (Mullerian agenesis)
- Turner syndrome
- Constitutional delay
• Secondary amenorrhea
- Physiological: Pregnancy, corpus luteal cyst, breast-feeding, menopause
- Suppression of the hypothalamic-pituitary axis: Post-pill amenorrhea, stress, intercurrent illness, weight loss, and low BMI
- Pituitary disease: Ablation of the pituitary gland, Sheehan syndrome, prolactinoma
- Uncontrolled endocrinopathies: Diabetes, hypothyroidism, or hyperthyroidism
- Polycystic ovarian syndrome (PCOS), (Stein-Leventhal syndrome)
- Chemotherapy
- Pelvic irradiation
- Endometrial ablation (inducing Asherman syndrome)
- Drug therapy: Systemic steroids, danazol, GRH-RH analogs, antipsychotics, OCPs
- Premature ovarian failure
- Female athlete triad (amenorrhea, osteoporosis, and disordered eating habits)


DIAGNOSIS
SIGNS AND SYMPTOMS
History
The absence of periods
Physical Exam
• Galactorrhea
• Symptoms of hypothyroidism
• Symptoms of early pregnancy
• Signs of androgen excess
• Signs of estrogen deficiency
• Signs of congenital abnormalities such as imperforate hymen, absence of vagina or uterus
TESTS
• Progesterone challenge test: 10 mg of medroxyprogesterone acetate PO for 5 days: If withdrawal bleeding occurs, amenorrhea most likely due to chronic anovulation with estrogen (PCOS); if no bleeding, evaluate estrogen status with FSH
• FSH high: Ovarian failure
• FSH low or normal: Give cyclic estrogen and progesterone and, if menses start, diagnose chronic anovulation
• Estrogen absent (functional hypothalamic amenorrhea) or if menses doesn't start, diagnose Mullerian agenesis
• Prolactin high: Suspect prolactinoma, proceed with imaging the sella turcica
Lab
• If pregnancy test is negative
- Serum prolactin
- FSH
- TSH
- Blood sugar
ALERT
• Women 30 with ovarian failure should have karyotype analysis.
• Conditions that may alter lab results
- Pregnancy
- Menopause
- Hyperprolactinemia
- Ovarian suppression
- Endocrinopathy
Imaging
• Ultrasound may show cysts undetectable during pelvic examination, presence or absence of uterus, and endometrial thickness.
• Radiologic evaluation of the sella turcica, if prolactinoma suspected (elevated serum prolactin) or functional hypothalamic amenorrhea suspected, because adenomas can occur even with normal prolactin levels
Diagnostic Procedures/Surgery
• Laparoscopy: Diagnosis of the streak ovaries of Turner syndrome or PCOS (not often done)
• Hysterosalpingogram: To rule out Asherman syndrome, if it is the appropriate clinical situation
Pathological Findings
Due to underlying disease
DIFFERENTIAL DIAGNOSIS
• Includes all causes listed in "Etiology"
• The most common cause of secondary amenorrhea is pregnancy.
TREATMENT
STABILIZATION
Outpatient
GENERAL MEASURES
• Definitive treatment depends on determining the cause of the amenorrhea.
• May not be necessary to treat all cases, especially if just temporary amenorrhea.
Diet
Correct overweight or underweight by dietary management
Activity
No restrictions
MEDICATION (DRUGS)
First Line
• Progesterone replacement: Medroxyprogesterone (Provera) 5 mg b.i.d. for 5 days, will result in a withdrawal bleed if the hypothalamopituitary ovarian axis is intact and some endogenous estrogen production is present.
• Estrogen replacement: Conjugated estrogen, conjugated (Premarin) 0.625 mg for 25 days with progesterone added as above for the last 10 days will result in a withdrawal bleed, if the uterus and lower genital tract are normal.
• Use of hormonal therapies will not correct underlying problem. Other drugs might be required to treat specific conditions (e.g., bromocriptine for hyperprolactinemia).
• Use of hormonal replacement therapy is NOT recommended for long-term management of amenorrhea (1)[A]. It may be safe for short-term symptom management in young women (1)[C].
• Oral contraceptive pills or patches replace estrogen and prevent pregnancy and are probably the first-line drugs to use unless contraindicated. They also have a positive effect on bone mineral density in oligo/amenorrheic women (2)[B].
• Calcium supplementation 1,500 mg/d if cause is hypoestrogenism
• Because polycystic ovarian syndrome is related to insulin resistance, metformin (Glucophage) has been used (often starting at 500 mg b.i.d.) in an effort to correct metabolic abnormalities, improve ovulation (3)[A], and restore normal menstrual patterns (3)[B].
• Contraindications
- Pregnancy
- Thromboembolic disease
- Previous myocardial infarct, cerebrovascular accident
- Estrogen-dependent malignancy
- Severe hepatic impairment or disease
• Precautions
- Patients who are amenorrheic and wish to become pregnant should not be given hormone replacement therapy, but should receive treatment for infertility based on the specific cause.
- Diabetes with insulin resistance
- Seizure disorder
- Migraine headache
- Smoker >35
• Significant possible interactions
- Barbiturates
- Phenytoin
- Rifampin
- Corticosteroids
- Theophyllines
- Tricyclics
- Oral anticoagulants (anticoagulant effect may be decreased)
SURGERY
• Hymenectomy, done as a day surgery, required for those whose primary amenorrhea is due to imperforate hymen
• Lysis adhesions in Asherman syndrome
FOLLOW-UP
PROGNOSIS
• Reflects the underlying cause
• In secondary amenorrhea from hypothalamopituitary suppression, spontaneous resumption of menses with time (99% within 6 months) and correction of BMI
COMPLICATIONS
• Estrogen deficiency symptoms (e.g., hot flashes, vaginal dryness)
• Osteoporosis, in prolonged hypoestrogenic amenorrhea
• Increased risk of endometrial cancer in hyperestrogenism without progestin
PATIENT MONITORING
• Depends on the cause and treatment chosen
• If hormonal replacement is used, discontinuation after 6 months is advised to assess spontaneous resumption of menses.
REFERENCES
1. Farquhar CM, Marjoribanks J, et al. Long term hormonal therapy for perimenopausal and postmenopausal women. The Cochrane Database of Systematic Reviews, 2006.
2. Liu S, Lebrun C. Effect of oral contraceptive and hormone replacement therapy on bone mineral density in premenopausal and perimenopausal women: a systematic review. British Journal of Sports Medicine, 2006;40:11-24.
3. Andy C, Flake D. Do insulin-sensitizing drugs increase ovulation rates for women with PCOS? The Journal of Family Practice, 2005;54(2):156, 159-160.
MISCELLANEOUS
See also: Diabetes mellitus, Type 1; Diabetes mellitus, Type 2; Hyperthyroidism; Hypothyroidism, adult; Osteoporosis; Polycystic ovary syndrome