What are the treatment options for a woman with amenorrhea (absence of menstruation), considering various underlying causes such as Polycystic Ovary Syndrome (PCOS), hypogonadotropic hypogonadism, and lifestyle factors?

Treatment of Amenorrhea

Primary Treatment Strategy: Address the Underlying Cause

The treatment of amenorrhea must be directed at the specific underlying etiology, with functional hypothalamic amenorrhea (FHA) requiring lifestyle modification as first-line therapy, PCOS requiring metabolic management and ovulation induction when fertility is desired, and hypogonadotropic states requiring hormone replacement to prevent long-term complications. 1

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Functional Hypothalamic Amenorrhea (FHA)

First-Line Treatment: Lifestyle and Nutritional Intervention

For FHA, the primary treatment is increasing caloric intake to achieve >30 kcal/kg fat-free mass/day and reducing excessive exercise, NOT prescribing oral contraceptives. 1

• Calculate energy availability to ensure the patient consumes >30 kcal/kg fat-free mass/day 1
• Reduce exercise volume and intensity if excessive, particularly if >10 hours/week of intense training 1
• Provide nutritional counseling by a sports dietitian experienced with energy availability assessment 1
• Address psychological stressors through counseling about stress management, adequate nutrition, and appropriate activity levels 1
• Screen for eating disorders, as adolescents frequently minimize symptoms and require direct questioning about specific behaviors 1

Timeline and Expectations

• Recovery of menstrual function may take >6 months despite addressing energy deficits 1
• Monitor with mid-luteal progesterone testing to confirm ovulation if cycles resume 1

Hormone Replacement Therapy for Persistent FHA

If amenorrhea persists >6 months despite addressing stressors and energy availability, use transdermal estradiol (100 μg patch twice weekly) with cyclic micronized progesterone (200 mg for 12 days/month) for bone health, NOT oral contraceptives. 1

• Oral contraceptives do not correct the underlying cause and do not protect bone mineral density as effectively as physiologic estrogen replacement 1
• Obtain a DXA scan for bone mineral density if amenorrhea extends beyond 6 months, regardless of age 1
• Estrogen replacement therapy is necessary for patients with low estrogen levels to prevent long-term complications including osteoporosis and cardiovascular disease 1

Critical Pitfall to Avoid

• Do NOT prescribe oral contraceptives as first-line therapy, as this masks the problem without addressing the underlying energy deficit and provides false reassurance 1

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Polycystic Ovary Syndrome (PCOS)

For Menstrual Regulation (Non-Fertility Goals)

• Induce menstrual bleeding with cyclical progestogen administration or sequential use of estrogen plus progestogen 2
• Oral contraceptives are indicated for patients desiring contraception and for those with acne and hirsutism, as ovarian suppression improves hyperandrogenic signs 2
• The beneficial effect can be reinforced by simultaneous use of antiandrogens 2

For Fertility/Ovulation Induction

Clomiphene citrate is FDA-approved for ovulatory dysfunction in women desiring pregnancy, with patients having PCOS being most likely to achieve success. 3

• Clomiphene citrate should be started on or about the 5th day of the cycle once ovulation is the goal 3
• Long-term cyclic therapy is not recommended beyond a total of about six cycles (including three ovulatory cycles) 3
• Women with PCOS have a less favorable response to all forms of ovulation induction compared to other causes of anovulation 2

Metabolic Management

• Screen for glucose intolerance, dyslipidemia, and other aspects of metabolic syndrome 4
• Address weight and metabolic factors as part of comprehensive management 1

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Hypogonadotropic Hypogonadism (Low FSH/LH)

Non-Fertility Treatment

• Sequential use of estrogen and progestogen can be used to prevent estrogen deficiency or for psychological reasons 2
• If contraception is needed, oral contraception may be the choice for both cycle and fertility control 2
• Estrogen replacement therapy with cyclic progestogen is indicated to prevent bone loss and cardiovascular complications 1, 2

Fertility Treatment

For patients with hypogonadotropic hypogonadism desiring pregnancy, pulsatile GnRH therapy is the most effective treatment for hypothalamic dysfunction. 5

• Pulsatile GnRH therapy is more efficient than exogenous gonadotropins in FHA patients, including those with polycystic ovarian morphology (FHA-PCOM) 5
• Ovulation rates are similar between FHA-PCOM and FHA-non-PCOM patients (80.8% vs 77.7%) with equivalent GnRH doses 5
• Ongoing pregnancy rates are comparable (70% vs 63% per patient) between FHA-PCOM and FHA-non-PCOM groups 5
• For pituitary failure (not hypothalamic), use gonadotropins for ovulation induction 2

Clomiphene Citrate in FHA: NOT Recommended

Clomiphene citrate cannot be recommended as first-line treatment for FHA, as there are no randomized clinical trials supporting its use and success rates remain uncertain. 5

• The Endocrine Society suggests possible trial of clomiphene citrate ONLY for women with sufficient endogenous estrogen level (FHA being recovered), but the chances of success remain uncertain 5
• Many non-randomized studies do not support its use in FHA 5

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Hypergonadotropic Amenorrhea (Primary Ovarian Insufficiency)

Hormone Replacement Therapy

• There is no curative therapy for ovarian failure 2
• Long-term hypoestrogenic condition should be treated with estrogen to cure symptoms and prevent increased risk of cardiovascular disease and osteoporosis 2
• Hormonal replacement therapy is indicated to reduce risk of osteoporosis, cardiovascular diseases, and urogenital atrophy 1
• Management with a multidisciplinary team including gynecologists, endocrinologists, dietitians, and psychologists is recommended 1

Important Consideration

• Patients with primary ovarian insufficiency can maintain unpredictable ovarian function and should not be presumed infertile 4

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Secondary Amenorrhea: Specific Treatment by Cause

For Secondary Amenorrhea Due to Progesterone Deficiency

Progesterone capsules 400 mg at bedtime for 10 days is the FDA-approved treatment for secondary amenorrhea due to decreased progesterone. 6

• Progesterone capsules should be taken at bedtime as some women become very drowsy and/or dizzy 6
• In a few cases, symptoms may include blurred vision, difficulty speaking, difficulty with walking, and feeling abnormal 6

For Endometrial Protection in Postmenopausal Women on Estrogen

• A postmenopausal woman with a uterus taking estrogens should take 200 mg progesterone capsules at bedtime for 12 continuous days per 28-day cycle 6
• The addition of a progestin is generally recommended for a woman with a uterus to reduce the chance of getting cancer of the uterus 6

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Hyperprolactinemia

• Prolactin-lowering drugs are the treatment of choice for cycle disturbance 2
• Cyclical progestogen and hormone replacement therapy are alternative options 2
• A contraceptive pill can be used to ensure contraception 2
• Prolactin-lowering drugs induce fertility in patients who desire pregnancy 2
• Treatment should be performed in specialist centers with pituitary-specific multidisciplinary teams for pituitary adenomas 1

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Long-Term Monitoring and Complication Prevention

Bone Health

• DXA scan for bone mineral density assessment is recommended for patients with amenorrhea lasting >6 months 1
• 90% of peak bone mass is attained by age 18, making it critical to address amenorrhea in adolescents to prevent long-term bone loss 1
• FHA is associated with a 2-fold increased risk of fractures compared to healthy eumenorrheic women 5

Cardiovascular Health

• Low estrogen levels in secondary amenorrhea increase risk for cardiovascular disease 1, 7
• About one-third of FHA patients reveal decreased reactive hyperaemia index, consistent with endothelial dysfunction 5

Endometrial Health

• Amenorrhea with hyperandrogenism (PCOS) may cause endometrial hyperplasia and increases the risk of endometrial adenocarcinoma 7

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Critical Red Flags Requiring Urgent Evaluation

• Significant weight loss or signs of eating disorder requires multidisciplinary eating disorder team 1
• Galactorrhea suggesting hyperprolactinemia requires immediate evaluation 1, 8
• Headaches or visual changes suggesting pituitary pathology require immediate evaluation 1
• Hirsutism or acne may indicate PCOS or late-onset congenital adrenal hyperplasia 1