Rowa Al- Ramahi 1

 Menopause is the permanent cessation of menses following the loss of ovarian follicular activity.  Perimenopause is the period immediately prior to the menopause and the first year after menopause. 2

 The hypothalamic–pituitary–ovarian axis controls reproductive physiology through the reproductive years. Follicle-stimulating hormone (FSH) and luteinizing hormone, 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 and the adrenal gland. 3

 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. 4

 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. 5

 Other symptoms, including anxiety, mood swings, depression, insomnia, migraine, arthralgia, and urinary frequency, are attributed to menopause, but the relationship between these symptoms and estrogen deficiency is controversial.  Long-term morbidity associated with menopause includes accelerated bone loss and osteoporosis.  Dysfunctional uterine bleeding may occur during perimenopause. 6

 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 international units/L suggests presence of perimenopause.  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 international units/L. Altered thyroid function and pregnancy must be excluded. 7

 Mild menopausal symptoms can often be alleviated by lifestyle modification, weight control, 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.  Little evidence supports the use of nonprescription herbal remedies or soy based supplements. 8

 Hormone therapy is contraindicated in women with endometrial cancer, breast cancer, undiagnosed vaginal bleeding, coronary heart disease, thromboembolism, stroke or transient ischemic attack, and active liver disease.  Relative contraindications are uterine leiomyoma, migraine headaches and seizure disorder. 9

 For women with hypertriglyceridemia, liver disease, or gallbladder disease, transdermal estrogen can be used, but oral estrogen should be avoided.  When hormone therapy is used, it should be used at the lowest effective dose and for the shortest duration needed for control. 10

 Approved indications for hormone therapy are vasomotor symptoms, urogenital atrophy, and prevention of osteoporosis. For the latter, raloxifene and bisphosphonates are considered first.  As new data are continuously published, the most current guidelines should always be consulted. 11

 Hormone therapy is the most effective treatment option for vasomotor and vaginal symptoms. 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.  The continuous combined oral estrogen– progestogen arm of the Women’s Health Initiative (WHI) study was terminated prematurely after a mean of 5.2-year follow-up because of the occurrence of a prespecified level of invasive breast cancer. The study also found increased coronary disease events, stroke, and pulmonary embolism. Beneficial effects included decreases in hip fracture and colorectal cancer. 12

 The oral estrogen-alone arm was stopped early after a mean of 7 years of follow-up. Estrogen- only therapy had no effect on coronary heart disease risk and caused no increase in breast cancer risk but the risk of stroke & hip fracture was increased.  A subsequent large epidemiologic study found a greater risk for breast cancer with combined estrogen–progestogen use, as well as increased risk for estrogen-only therapy but selection bias was found in the study population. 13

 The oral and transdermal routes are used most frequently. There is no evidence that one estrogen compound is more effective than another in relieving menopausal symptoms or preventing osteoporosis.  conjugated equine estrogens are composed of estrone sulfate (50% to 60%) and other estrogens such as equilin and17 α -dihydroequilin.  Estradiol is the predominant and most active form of endogenous estrogens. Given orally, it is metabolized by intestinal mucosa and liver (10% reaches the circulation as free estradiol), and resultant estrone concentrations are three to six times those of estradiol. 14

 Ethinyl estradiol  is a semisynthetic estrogen that has similar activity following administration by the oral and parenteral routes.  Parenteral estrogens, including transdermal, intranasal, and vaginal, avoid first-pass metabolism and result in a more physiologic estradiol-to-estrone ratio (i.e., estradiol concentrations greater than estrone concentrations). These routes also are less likely to affect sex hormone-binding globulin, circulating lipids, coagulation parameters, or C- reactive protein levels.  Variability in absorption is common with the percutaneous preparations (gels, creams, and emulsions). 15

 Estradiol pellets (implants) contain pure crystalline 17 β –estradiol and are placed subcutaneously into the anterior abdominal wall or buttock. They are difficult to remove.  Intranasal 17 β –estradiol spray is given once or twice daily, and is clinically equivalent to oral or transdermal estradiol, but causes less mastalgia.  Vaginal creams, tablets, and rings are used for treatment of urogenital atrophy. Systemic estrogen absorption is lower with the vaginal tablets and rings, compared to the vaginal creams. 16

 New evidence indicates that lower doses of estrogens are effective in controlling postmenopausal symptoms and reducing bone loss. Even ultralow doses of 17 β-estradiol delivered by vaginal ring improved serum lipid profiles and prevented bone loss in elderly women.  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. Transdermal estrogen is less likely than oral estrogen to cause nausea, headache, breast tenderness, gallbladder disease, and deep vein thrombosis. 17

 In women who have not undergone hysterectomy, a progestogen should be added because estrogen monotherapy is associated with endometrial hyperplasia and cancer.  The most commonly used oral progestogens are medroxyprogesterone acetate, micronized progesterone, and norethisterone acetate 18

 Continuous-cyclic (sequential)—results in scheduled vaginal withdrawal bleeding in approximately 90% of women, but it may be scant or absent in older women.  Continuous-combined—prevents monthly bleeding. It may initially cause unpredictable spotting or bleeding; thus, it is best reserved for women who are at least 2 years postmenopause. 19

 Continuous long-cycle (cyclic withdrawal)— reduces monthly bleeding. Estrogen is given daily, and progestogen is given six times yearly (every other month) for 12 to 14 days, resulting in six periods/year.  Intermittent-combined (continuous-pulsed)— prevents monthly bleeding. It consists of 3 days of estrogen therapy alone, followed by 3 days of combined estrogen and progestogen, which is then repeated without interruption. It causes fewer side effects than regimens with higher progestogen doses. 20

 Adverse effects of progestogens are irritability, depression, headache, mood swings, fluid retention, and sleep disturbance.  Low-dose hormone therapy (conjugated equine estrogen 0.45 mg and medroxyprogesterone acetate 1.5 mg/day) has demonstrated equivalent symptom relief and bone density preservation without an increase in endometrial hyperplasia. Whether such lower doses will be safer (cause less venous thromboembolism and breast cancer) remains to be seen. 21

 Alternatives to Estrogen for Treatment of Hot Flashes  For women with contraindications to hormone therapy, selective serotonin reuptake inhibitors may be used, but the lack of long-term efficacy or drug interactions may be a problem. 22

 The therapeutic use of testosterone in women, although controversial, is becoming more widespread even in the absence of an androgen deficiency.  Evidence from several studies shows that testosterone, with or without estrogen, improves the quality of the sexual experience in postmenopausal women 23

 Absolute contraindications to androgen therapy include pregnancy or lactation and known or suspected androgen-dependent neoplasia. Relative contraindications are concurrent use of conjugated equine estrogens (for parenteral testosterone therapy), low sex hormone binding globulin level, moderate to severe acne, clinical hirsutism, and androgenic alopecia.  Adverse effects from excessive dosage include virilization, fluid retention, and potentially adverse lipoprotein lipid effects, which are more likely with oral administration.  Further study is required to determine the long- term safety of testosterone in women. 24

 These are nonsteroidal compounds that act as estrogen agonists in some tissues such as bone and as estrogen antagonists other tissues such as breast through high-affinity binding to the estrogen receptor.  Tamoxifen is an antagonist in breast tissue and an agonist on bone and endometrium.  Raloxifene is approved for prevention of osteoporosis and reduction of risk of invasive breast cancer in postmenopausal women with osteoporosis. The dose is 60 mg once daily. It may worsen vasomotor symptoms, and it increases the risk of venous thromboembolism and fatal stroke. 25

 Tibolone has combined estrogenic, progestogenic, and androgenic activity. Its effects depend on metabolism and activation in peripheral tissues. Tibolone has beneficial effects on mood and libido and improves menopausal symptoms and vaginal atrophy. It protects against bone loss and reduces the risk of vertebral fractures. It reduces total cholesterol, triglyceride, lipoprotein (a), and, unfortunately, high-density lipoprotein concentrations. It may increase stroke risk and endometrial cancer risk. It may decrease the risk of breast and colon cancer in women ages years.  Major adverse effects include weight gain and bloating. It may increase the risk of stroke in elderly women. 26

 Most women with vasomotor symptoms need hormone treatment for less than 5 years. Without treatment, hot flushes usually disappear within 1 to 2 years. Hormone therapy can usually be tapered and stopped after about 2 or 3 years.  Estrogen is more effective than any other therapy in relieving vasomotor symptoms, and all types and routes of systemic administration are equally effective in a dose-dependent fashion. If treatment can be tapered and stopped within 5 years, no evidence of increased risk of breast cancer is seen. 27

 Most women with significant vaginal dryness because of vaginal atrophy require local or systemic estrogen therapy. It can be treated with topical estrogen cream, tablets, or vaginal ring. Vaginal estrogen may be better than systemic estrogen for these symptoms and avoids high levels of circulating estrogen.  Concomitant progestogen therapy generally is unnecessary with low-dose micronized 17 β- estradiol, but regular use of conjugated equine estrogen creams and other products that may promote endometrial proliferation in women with an intact uterus requires intermittent progestogen challenges (i.e., for 10 days every 12 weeks). 28

 Hormone therapy should be considered for osteoporosis prevention only in women at significant risk for osteoporosis who cannot take nonestrogen regimens such as bisphosphonats.  The WHI study was the first randomized, controlled trial to confirm that hormone therapy reduces colon cancer risk. 29

 The American Heart Association recommends against postmenopausal hormone therapy for reducing the risk of coronary heart disease.  The WHI trial showed an overall increase in the risk of coronary heart disease in healthy postmenopausal women aged 50 to 79 years taking estrogen–progestogen therapy compared with those taking placebo. The estrogen-alone arm of the WHI showed no effect (either increase or decrease) in the risk of coronary heart disease. Recent analysis showed that women who started hormone therapy 10 years or more after time of menopause tended to have increased coronary heart disease risk compared with women who started therapy within 10 years of menopause. 30

 In the estrogen plus progestogen arm, the increased risk for ischemic stroke and venous thromboembolism continued throughout the 5 years of therapy. In the estrogen-alone arm, there was a similar increase in risk for stroke.  In the WHI study, estrogen plus progestogen therapy had an increased risk for invasive breast cancer, which did not appear until after 3 years of study participation. The estrogen-only arm of the WHI showed no increase in risk for breast cancer during the 7-year follow-up. 31

 The Million Women Study reported that current use of hormone therapy increased breast cancer risk and breast cancer mortality. Increased incidence was observed for estrogen only, estrogen plus progestogen, and for tibolone.  In a reanalysis of 51 studies, less than 5 years of therapy with combined estrogen and progestogen was associated with a 15% increase in risk for breast cancer, and the risk increased with greater duration of treatment. Five years after discontinuation of hormone replacement therapy, the risk of breast cancer was no longer increased. 32

 Addition of progestogen to estrogen may increase breast cancer risk beyond that observed with estrogen alone.  Estrogen alone given to women with an intact uterus increases uterine cancer risk, and this increased risk begins within 2 years of treatment and persists for many years after estrogen is discontinued. The sequential addition of progestin to estrogen for at least 10 days of the cycle or continuous combined estrogen– progestogen does not increase the risk of endometrial cancer. A 4-year trial of raloxifene in women with osteoporosis showed no increased risk of endometrial cancer. 33

 Combined hormone therapy and estrogen monotherapy may increase the risk of ovarian cancer.  Women taking combined hormone therapy have a twofold increase in risk for thromboembolic events, with the highest risk occurring in the first year of use. The increased risk is dose dependent. Oral administration inceases the risk compared with transdermal administration.  Women taking estrogen or estrogen– progestogen combined therapy are at increased risk for cholecystitis, cholelithiasis, and cholecystectomy. Transdermal estrogen is an alternative to oral therapy for women at high risk for cholelithiasis. 34

 Women with vasomotor symptoms taking hormone therapy have better mental health and less depressive symptoms compared to those taking placebo, but hormone therapy may worsen quality of life in women without vasomotor symptoms.  The WHI study found that postmenopausal women 65 years or older taking estrogen plus progestogen therapy had twice the rate of dementia, including Alzheimer’s disease. Combined therapy also did not prevent mild cognitive impairment. 35

 After initiating hormone therapy, follow-up at 6 weeks is advisable to assess for efficacy, side effects, and patterns of withdrawal bleeding.  With estrogen-based therapy, there should be yearly breast exams, monthly breast self- examinations, and periodic mammograms. Women on hormonal therapy should undergo annual monitoring, including pelvic examination, blood pressure checks, and routine endometrial cancer surveillance.  Bone mineral density should be measured in women older than 65 years and in women younger than 65 years with risk factors for osteoporosis. Repeat testing should be done as clinically indicated. 36