Menopausal, Perimenopausal and Postmenopausal Hormone Therapy

Introduction

Menopause is the permanent cessation of menses following the loss of ovarian follicular activity.

• Perimenopause begins with the onset of menstrual irregularity and ends 12 months after the last menstrual period.
• The hypothalamic-pituitary-ovarian axis controls reproductive physiology.
• Follicle stimulating hormone (FSH) and luteinizing hormone (LH), produced by the pituitary in response to gonadotropin-releasing hormone from the hypothalamus, regulate ovarian function.
• Gonadotropins are also influenced by negative feedback from the sex steroids estradiol (produced by the dominant follicle) and progesterone (produced by the corpus luteum).
• Other sex steroids are androgens, primarily testosterone and androstenedione, secreted by the ovarian stroma.
• Physiologic changes of menopause result from loss of ovarian follicular activity.
• As women age, circulating FSH progressively rises and ovarian inhibin-B and antiMullerian hormone declines. In menopause there is a 10- to 15-fold increase in circulating FSH, a four- to fivefold increase in LH, and a greater than 90% decrease in circulating estradiol concentrations.

CLINICAL PRESENTATION

• Symptoms of perimenopause and menopause include vasomotor symptoms (hot flushes and night sweats), sleep disturbances, depression, anxiety, poor concentration and memory, vaginal dryness and dyspareunia, headache, sexual dysfunction, and arthralgia.
• Signs include urogenital atrophy in menopause and dysfunctional uterine bleeding in perimenopause. Other potential causes of dysfunctional uterine bleeding should be ruled out.
• Additionally, loss of estrogen production results in metabolic changes; increase in central abdominal fat; and effects on lipids, vascular function, and bone metabolism.

DIAGNOSIS

• Menopause is determined retrospectively after 12 consecutive months of amenorrhea. FSH on day 2 or 3 of the menstrual cycle greater than 10 to 12 IU/L indicates diminished ovarian reserve.
• The diagnosis of menopause should include a comprehensive medical history and physical examination, complete blood count, and measurement of serum FSH. When ovarian function has ceased, serum FSH concentrations exceed 40 IU/L. Altered thyroid function and pregnancy must be excluded.

TREATMENT

• Goals of Treatment: The goals are to relieve symptoms, improve quality of life, and minimize medication adverse effects.
• Mild vasomotor and/or vaginal symptoms can often be alleviated by lowering the room temperature; decreasing intake of caffeine, spicy foods, and hot beverages; smoking cessation; exercise; and a healthy diet.
• Mild vaginal dryness can sometimes be relieved by nonestrogenic vaginal creams, but significant vaginal dryness often requires local or systemic estrogen therapy.

FDA Indications and Contraindications for Menopausal Hormone Therapy with Estrogens and Progestins

Indications:

For systemic use: Treatment of moderate to severe vasomotor symptoms (i.e., moderate to severe hot flushes)

For intravaginal use (low systemic exposure): Treatment of moderate to severe symptoms of vulvar and vaginal atrophy (i.e., moderate to severe vaginal dryness, dyspareunia, and atrophic vaginitis)

Contraindications:

Absolute contraindications: Undiagnosed abnormal genital bleeding Known, suspected, or history of cancer of the breast Known or suspected estrogen- or progesterone-dependent neoplasia, Active deep vein thrombosis, pulmonary embolism, or a history of these conditions, Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction), Liver dysfunction or disease

Relative contraindications:

Elevated blood pressure, Hypertriglyceridemia, Impaired liver function and past history of cholestatic jaundice, Hypothyroidism, Fluid retention, Severe hypocalcemia, Ovarian cancer, Exacerbation of endometriosis, Exacerbation of asthma, diabetes mellitus, migraine, systemic lupus erythematosus, epilepsy, porphyria, and hepatic hemangioma.

Evidence-Based Hormone Therapy Guidelines for Menopausal Symptom Management

• In the absence of contraindications, estrogen-based postmenopausal hormone therapy should be used for treatment of moderate to severe vasomotor symptoms, recommended grade is A1
• Systemic or vaginal estrogen therapy should be used for treatment of urogenital symptoms and vaginal atrophy A1
• Postmenopausal women taking estrogen-based therapy should be followed up every year, taking into account findings from new clinical trials A1
• Postmenopausal women taking estrogen-based therapy should be informed about potential risks A1
• Safety and tolerability may vary substantially with the type and regimen of hormone therapy B2
• Breast cancer risk increases after use of continuous combined hormone therapy for longer than 5 years A1
• Breast cancer risk does not increase after long-term estrogen-only therapy (6.8 years) in postmenopausal women with hysterectomy
• A1 Hormone therapy should not be used for primary or secondary prevention of coronary heart disease A1
• Oral hormone therapy increases risk of venous thromboembolism A1
• Nonoral hormone therapy may be safer for postmenopausal women at risk for venous thromboembolism who choose to take hormone therapy B2
• Oral hormone therapy increases risk of ischemic stroke A1
• Although hormone therapy decreases risk of osteoporotic fractures, it cannot be recommended as a first-line therapy for the treatment of osteoporosis A1
• Potential harm (cardiovascular disease, breast cancer, and thromboembolism) from long-term hormone therapy (use greater than 5 years) outweighs potential benefits A1
• Young women with primary ovarian insufficiency have severe menopausal symptoms and increased risk for osteoporosis and cardiovascular disease. Decisions on whether and how these young women must be treated should not be based on studies of hormone therapy in women older than 50 years B3.