PHARMACOTHERAPY II PHCY 410 University of Nizwa College of Pharmacy and Nursing School of Pharmacy PHARMACOTHERAPY II PHCY 410 Lecture 5 Endocrine and Metabolic Disorders Menopause & Hormone Replacement Therapy Dr. Sabin Thomas, M. Pharm. Ph. D. Assistant Professor in Pharmacy Practice School of Pharmacy University of Nizwa

Course Outcomes Upon completion of this lecture the students will be able to Describe concepts of hormone replacement therapy in post menopausal women. Develop skills for monitoring and patient education in patients on hormonal replacement therapy. Explain drug related problems in patients on hormonal replacement therapy.

Menopause is defined as natural cessation of menses (for one year duration) due to lack of estrogen production by the ovary. The average age of menopause is 50. Menopause may also be induced by medical or surgical intervention such as radiation or chemotherapy treatment or hysterectomy. Perimenopause The perimenopause is the period immediately prior to the menopause and the first year after menopause. (menopausal transition) is the time that begins (approximately 4 years prior to menopause) with an alteration in menstrual cycle length and ends with the final menstrual period.

Pathophysiologic changes associated with menopause are caused by loss of ovarian follicular activity. The postmenopausal ovary is no longer the primary site of estradiol or progesterone synthesis. As women age, circulating FSH progressively rises and ovarian inhibin declines. When ovarian function has ceased, serum FSH concentrations are greater than 40 international units/L. Menopause is characterized by a 10- to 15-fold increase in circulating FSH concentrations compared with concentrations of FSH in the follicular phase, a four- to fivefold increase in luteinizing hormone, and a greater than 90% decrease in circulating estradiol concentrations.

CLINICAL PRESENTATION Vasomotor symptoms (e.g., hot flushes and night sweats) are common short-term symptoms of estrogen withdrawal, which usually disappear within 1 to 2 years but sometimes persist for 20 years. Other symptoms include vaginal dryness, dyspareunia, urogenital atrophy, sleep disturbances, sexual dysfunction, and impaired concentration and memory. Other symptoms, including mood swings, depression, insomnia, migraine, formication, arthralgia, myalgia, and urinary frequency. Long-term morbidity associated with menopause includes accelerated bone loss and osteoporosis.

Treatment of Menopausal Symptoms Nonpharmacologic Choices Lifestyle modification may positively impact hot flushes: 1- Avoid passive smoke exposure 2- Maintaining body mass index < 27 kg/m2. 3- Stretching in overweight postmenopausal women. 4- Lowering the ambient temperature. 5- Reducing core body temperature, e.g., dressing in layers. Pharmacologic Choices The treatment would include vasomotor symptoms, vaginal symptoms and mood changes associated with menopause.

A) Vasomotor Symptoms 1- Hormone Therapy In women with an intact uterus, hormone therapy consists of an estrogen plus a progestogen. In women who have undergone hysterectomy, estrogen therapy is given unopposed by a progestogen. Estrogen is indicated for the short-term relief of vasomotor symptoms to decrease the frequency and severity of hot flashes. Use estrogen at the lowest effective dose that can control menopausal symptoms for the shortest possible time. Example: begin with a dose of 0.3 mg of conjugated estrogen (or equivalent), and then increase the dose after three weeks if no improvement in menopausal symptoms is noted.

Estrogen preparations: orally, transdermally, vaginally or parenterally. Estradiol is the predominant and most active form of endogenous estrogens. The effect of estrogen therapy on vasomotor symptoms is dose related. Standard doses (estradiol 1 mg or equivalent):substantial relief occurs within 4 weeks Common adverse effects of estrogen include nausea, headache, breast tenderness, and heavy bleeding. More serious adverse effects include increased risk for coronary heart disease, stroke, venous thromboembolism, breast cancer, and gallbladder disease. Low doses (conjugated estrogens 0.3 mg or equivalent): substantial relief occurs within 8 to 12 weeks. Lower doses of estrogen are associated with decreased incidence of irregular bleeding or breast tenderness compared to standard doses.

Ethinyl estradiol is a semisynthetic estrogen. New evidence indicates that lower doses of estrogens are effective in controlling postmenopausal symptoms and reducing bone loss. Contraindications to Estrogen - Undiagnosed vaginal bleeding - Active liver disease - Active thromboembolic disease Progestin is indicated in women using systemic estrogen who have an intact uterus, to oppose the effect of estrogen on the uterus (endometrial hyperplasia and cancer). The most commonly used oral progestogens are medroxyprogesterone acetate, micronized progesterone, and norethisterone acetate.

Regimens: 1- Cyclic regimens: estrogen is taken continuously and progestin is taken from day 15 to 28, and so a woman can expect a withdrawal bleed when the progestin is stopped. 2- Continuous combined therapy with estrogen and progestin taken daily without a break is the most commonly prescribed. Continuous regimen reduces the risk of bleeding and endometrial carcinoma. During first year of use, unexpected spotting or light bleeding may occur. Avoid abrupt discontinuation of therapy by gradually reducing the dose and frequency. If patient becomes symptomatic with lower doses, continue that dose until the vasomotor symptoms decrease.

Risks Associated with Estrogen Therapy The use of estrogen with or without progestin for treatment of menopausal symptoms should be reviewed each year to determine if continued use is expected to result in more benefit (reduced fractures) than risk (breast cancer, MI, stroke and VTE). Relative contraindications: Uterine cancer, migraine headache and seizure disorders. 2- Nonhormonal Therapies The frequency and severity of menopausal hot flashes could be managed with paroxetine, venlafaxine, clonidine and gabapentin in highly symptomatic women, but their use may be limited by side effects. A combination of phenobarbital, ergotamine and belladonna, are also indicated for the relief of hot flashes but are associated with side effects.

SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs) Tamoxifen, is the first generation SERM bind to the estrogen receptors and act as estrogen agonists in some tissues, such as bone, and as estrogen antagonists in other tissues, such as breast. The ideal SERM would protect against osteoporosis and decrease the incidence of breast, endometrial, and colorectal cancer and coronary heart disease. The second generation of SERMs, most notably raloxifene is used for prevention of osteoporosis and decreases the risk of vertebral fracture by 30% to 50%.