What are the treatment options for amenorrhea (absence of menstruation)?

Treatment of Amenorrhea

The treatment of amenorrhea depends entirely on the underlying cause, which must be systematically identified through pregnancy testing, hormonal evaluation, and assessment of the clinical context before initiating any therapy.

Initial Diagnostic Approach

Rule Out Pregnancy First

• Pregnancy must be excluded in all cases of amenorrhea before proceeding with any evaluation or treatment 1, 2, 3
• This is the single most common cause of amenorrhea in reproductive-age women 4, 3

Essential Laboratory Evaluation

After excluding pregnancy, obtain the following baseline tests:

• Serum follicle-stimulating hormone (FSH) 1, 2, 3
• Serum luteinizing hormone (LH) 1, 2, 3
• Serum prolactin 1, 2, 3
• Thyroid-stimulating hormone (TSH) 1, 2, 3

Treatment Based on Specific Etiologies

Contraceptive-Induced Amenorrhea (DMPA/Implants)

Amenorrhea from hormonal contraceptives requires no medical treatment—only reassurance 5, 6

• Amenorrhea occurs in approximately 22% of etonogestrel implant users and is common after ≥1 year of DMPA use 5, 6
• These bleeding changes are generally not harmful and do not require intervention 5
• If the woman's regular bleeding pattern changes abruptly to amenorrhea, rule out pregnancy 5, 6
• If amenorrhea persists and the woman finds it unacceptable, counsel on alternative contraceptive methods 5

Important caveat: One small study found that COCs could alleviate amenorrhea in DMPA users who had experienced amenorrhea for 2 months, though this does not address the underlying physiology 5

Hyperprolactinemic Amenorrhea

When prolactin is elevated:

• Obtain pituitary imaging to rule out prolactinoma 4, 3
• Prolactin-lowering drugs (dopamine agonists) are first-line treatment 4
• Cyclic progestogen or hormone replacement therapy can manage cycle disturbances 4
• For patients desiring pregnancy, prolactin-lowering drugs induce fertility 4
• Oral contraceptives can be used if contraception is needed 4

Hypogonadotropic (Hypothalamic) Amenorrhea

Characterized by low or normal FSH/LH with low estrogen:

• Address underlying causes first: stress, nutritional deficiency, excessive exercise, eating disorders 5, 4, 2, 3
• Optimize energy availability (EA) as first-line treatment—this is the underlying cause, not exercise volume or body composition 5
• Energy availability below 30 kcal/kg fat-free mass/day in women suppresses bone formation 5
• It may take more than 6 months for favorable menstrual changes after correcting energy availability 5

Hormonal management when lifestyle modification is insufficient:

• For bone protection: transdermal β-estradiol patch (100 μg) twice weekly plus cyclic micronized progesterone (200 mg) for 12 days each month 5
• This approach is preferred over combined oral contraceptive pills (COCPs) for bone mineral density protection 5
• Note: Transdermal hormones are not contraceptive 5
• Sequential estrogen-progestogen therapy can prevent estrogen deficiency complications 4

For fertility:

• Pulsatile GnRH for hypothalamic dysfunction 4
• Gonadotropins for pituitary failure 4

Hypergonadotropic Amenorrhea (Primary Ovarian Insufficiency)

Characterized by elevated FSH indicating ovarian failure:

• No curative therapy exists 4
• Long-term estrogen replacement is essential to prevent cardiovascular disease and osteoporosis 4
• Patients can maintain unpredictable ovarian function and should not be presumed infertile 1, 2
• Hormone replacement therapy is indicated for symptom management and bone health 4, 7
• Patients may require contraception or infertility services despite the diagnosis 2

Normogonadotropic Amenorrhea (Including PCOS)

Characterized by normal FSH/LH with adequate estrogen (positive progesterone withdrawal bleed):

• Most cases are polycystic ovary syndrome (PCOS) 1, 4
• Cyclic progestogen administration induces regular withdrawal bleeding 4
• Combined oral contraceptives are indicated for:
  • Contraception needs 4
  • Treatment of acne and hirsutism (signs of hyperandrogenism) 4
  • Endometrial protection 2
• Antiandrogens can be added to enhance treatment of hyperandrogenic symptoms 4
• Screen for metabolic complications: glucose intolerance, dyslipidemia, metabolic syndrome 1, 2

For fertility in PCOS:

• Clomiphene citrate is FDA-approved for ovulatory dysfunction in women desiring pregnancy, including PCOS, post-oral-contraceptive amenorrhea, and secondary amenorrhea of undetermined etiology 8
• Clomiphene should be started on or about day 5 of the cycle 8
• Long-term cyclic therapy is not recommended beyond approximately six cycles (including three ovulatory cycles) 8
• Alternative ovulation induction: antiestrogens, GnRH, or gonadotropin preparations (though response is less favorable than in other causes) 4

Anatomical Causes

Outflow tract obstruction or uterine abnormalities:

• Congenital causes (imperforate hymen, transverse vaginal septum, Müllerian agenesis) require surgical correction 7
• Acquired causes (Asherman syndrome) may require hysteroscopic lysis of adhesions 1
• Karyotype analysis should confirm 46,XX in cases of abnormal uterine development 7

Critical Pitfalls to Avoid

• Never use COCPs to treat functional hypothalamic amenorrhea for bone protection—they do not correct the underlying cause and do not protect against bone mineral density loss 5
• Do not assume patients with primary ovarian insufficiency are infertile—they can maintain unpredictable ovarian function 1, 2
• Do not accept amenorrhea as an inevitable consequence of athletic training—amenorrhea for more than 3 months must be investigated 5
• Oral contraceptives mask clinical signs of menstrual dysfunction and low energy availability 5
• Always perform endometrial biopsy in older patients before treatment to exclude endometriosis and endometrial carcinoma 8

Treatment Goals by Diagnosis

All patients require:

• Prevention of osteoporosis 7, 3
• Prevention of endometrial hyperplasia (in estrogen-replete states) 7
• Prevention of cardiovascular disease (in hypoestrogenic states) 4, 7
• Preservation of fertility when desired 7
• Calcium supplementation (1000-1300 mg daily depending on age) and vitamin D optimization (target >50 nmol/L in winter, >75 nmol/L in summer) 5