Menopause overview
Rahmah Al-Edresi, M.D.

# Overview
Menopause is the permanent cessation of the menstrual cycle in women without any pathological causes because of physiological deficiency of estrogen hormone production in women. Menopause happens in women between 49 to 52 of age at the average. A woman is considered in menopause after amenorrhea for 12 months and she becomes suffering from the menopausal symptoms. Menopause is passes gradually through 3 stages until it reaches the permanent cessation of the menstrual cycle. These stages include premenopause, Perimenopause, and postmenopause. Premenopause is a word used to describe the years leading up to the last period even when the levels of reproductive hormones are already becoming lower and more erratic, and symptoms of hormone withdrawal may be present. Perimenopause or "menopause transition" means the menopause transition years, the years before and after the last period ever, when the majority of women find that they undergo at least some symptoms of hormonal change and fluctuation. Postmenopause, a woman has considered in post-menopause after amenorrhea more than 12 months. Several risk factors accelerate early menopause such as family history and cigarette smoking has been found to decrease the age at menopause by as much as one year and women who smoke have early menopause before non-smoking women. Menopause should be differentiated from other diseases presenting with menstrual irregularities (oligomenorrhea/amenorrhea). The prevalence of menopause is estimated to be about 50 million cases worldwide annually. The common symptoms of menopause include hot flashes, night sweats, headach, palpitation, dyspareunia, stress incontinence, urgency, frequency, dysuria, anxiety, sleep disturbance, depression. Left untreated women, increased the risk of  hypertension, atherosclerosis, and hyperlipidemia. Common complications of menopause include cardiovascular disease, stroke, osteoporosis. Generally, the prognosis of menopause is good with treatment and a healthy lifestyle include stop smoking, a healthy diet, and exercise.   An elevated serum of Follicle Stimulating Hormone (FSH) greater than 40 mIU/mL is diagnostic of menopause.  Medical treatments of severe menopausal symptoms include Hormone therapy(HT), non-hormonal therapy, and complementary or alternative therapies. Hormonal therapy (HT) provides the best relief, but it increases the relative risks of uterine cancer, ovarian cancer, breast cancer, thromboembolism, and coronary heart disease, especially in women who start HT after menopause. A woman and her doctor should carefully review her symptoms and relative risk before determining whether the benefits of HT or other therapies outweigh the risks.

# Historical Perspective
In 1821, a French physician named the cessation of the menstrual cycle as a term of menopause.The medical interest in menopause started in the mid-19th century, and was treated by estrogen replacement therapy in the 1970s. The Grandmother hypothesis considers that the menopause may have been selected for in human evolution. Unlike humans, other mammals rarely experience menopause, but some of the other few mammal species that experience menstrual cycles, such as rhesus monkeys and some cetaceans.

# Classification
Menopause is classified according to causes into three types including natural menopause, premature menopause/early menopause, and induced menopause. Natural    menopause, does not happen suddenly, but it passes through 3 stages include perimenopause, premenopause, and postmenopause. Premature menopause because of premature ovarian failure and several medical diseases. Induced menopause because of bilateral oophorectomy, salpingo-oophorectomy, and hysterectomy. In addition to complication of chemotherapy and radiotherapy.

# Pathophysiology
Menopause is natural amenorrhea that is happened without any pathological causes, but premature menopause/early menopause is caused by  pathological diseases in ovaries and other organs such as premature ovarian failure (Primary ovarian insufficiency, POI),  Adrenal insufficiency, type1 diabetes mellitus, autoimmune thyroid disease, Fanconis anemia,  and Congenital adrenal hyperplasia. Cardiovascular disease and osteoporosis are most important conditions associated with menopause. Women who had genetic disorders ( Fragile X syndrome, Turners syndrome)  more prone able to early menopause. The histopathological analysis include ovaries's cortex becomes thinner and it has fewer follicles and the medulla develops  fibrosis and scars. Decrease of ciliated cells of  Fallopian tubes and Uterus. And atrophy of  vaginal mucosal layer.

# Causes
menopause is caused by the increased age of women. But the common causes of  premature menopause include Premature ovarian failure, chemotherapy, and radiotherapy and bilateral oophorectomy, salpingo-oophorectomy, and hysterectomy. Less common causes include Autoimmune diseases, diabetes mellitus, Thyroid disease. chronic fatigue syndrome.  Genetic causes include Fragile X Syndrome and Turners syndrome.

# Differential Diagnosis
Menopause should be differentiated from other diseases presenting with menstrual irregularities (oligomenorrhea/amenorrhea) that are include Sheehan's syndrome, Lymphocytic hypophysitis, Pituitary apoplexy, Empty sella syndrome, Pituitary cachexia, Hypothyroidism, Hypogonadotropic hypogonadism, Hypoprolactinemia, Primary adrenal insufficiency/Addison's disease.

# Epidemiology and Demographics
The prevalence of menopause is estimated to be about 50 million cases annually. Menopause naturally occurs in women between 49 to 52 of age the average. The fatality cases were 345 cases per 3191 women aged between 50-86 years in the United States. There is no racial predilection to Menopause,  but   African American women had experienced the largest number of menopausal symptoms compared with other ethnic groups.

# Risk Factors
There are several risk factors that accelerate menopause onset. Common risk factors include women's age, age at menarche, age at first gestation, number of pregnancies, oral contraceptives, irregular menses, unilateral oophorectomy, body mass index, smoking, tobacco, and alcohol, high physical activity, high serum lead level, high intake of fat.

# Natural History, Complications and Prognosis
If left untreated, women with menopause  may progress to develop hypertension, hyperlipidemia, and  atherosclerosis. Common complications of menopause  includecardiovascular disease, osteoporosis, Stroke. The complication that is happened with  hormonal replacement therapy includes ovarian cancer, breast cancer, and endometrial cancer. Generally, the prognosis of menopause is good with treatment and a healthy lifestyle. In the late postmenopause stage, most menopausal symptoms relieved in most women. but untreated menopausal symptoms are poor prognosis in women who have high-risk factors to develop complications of menopause.

# Diagnosis

## History and Symptoms
The hallmark of menopause is amenorrhea. The most common symptoms of menopause include hot flashes, night sweats, headach, palpitations, dyspareunia, stress incontinence, urgency, frequency, dysuria, anxiety, sleep disturbance, depression. Less common symptoms of menopause include loss of concentration, and loss of self confidence.

## Physical Examination
Women with menopause are usually well-appearing. Common physical examination of women with menopause include elevated blood pressure, hot flushes, weight gain, change of breast size, vaginal atrophy, external genital organs become thinner. In premature menopause, Signs of Turner syndrome, and Signs of Fragil X syndrome.

## Laboratory Findings
Laboratory findings consistent with the diagnosis of menopause include an elevated Follicle Stimulating Hormone > 40 mIU/mL, decreased  estradiol level <20 pg/ml, and decreased serum of the Anti-Mullerian Hormone level below 0.20 ng/ml. In addition to other blood tests that are related to premature menopause such as positive karyotype test of FMR1 in  Fragile X syndrome and decrease of Thyroid-stimulating hormone.

## Ultrasonography
On pelvic ultrasound, menopause is characterized by small uterus and an endometrial thickness between 5-8 mm. Small ovaries with either a few follicles or no, and normal or non-visible adnexa. Transvaginal ultrasound is helpful for intitial evaluation of postmenopausal bleeding women, if endometrial thickness is 4mm or less, women more prone able for endometrial cancer. Endometrial biopsy is indicated in recurrent postmenopausal bleeding cases.

# Treatment

## Medical Therapy
While perimenopause is a natural stage of life when the symptoms are severe, this may be alleviated through medical treatments that include Hormone therapy(HT), non-hormonal therapy, and complementary or alternative therapies.Hormonal therapy (HT) provides the best relief, but hormone therapy should only be used for a short duration  and the lowest effective dose, as it increases the relative risk of uterine cancer, ovarian cancer, breast cancer, thromboembolism, and coronary heart disease, especially in women who start HT after menopause. Some other drugs afford limited relief from hot flashes. A woman and her doctor should carefully review her symptoms and relative risk before determining whether the benefits of HT or other therapies outweigh the risks.

## Prevention
Menopause is not preventable. Early menopause are preventable with the following strategie such as stop smoking, healthy food, regular exercies. Secondary prevention of menopause include HRT, followup of associated medical diseases and postmenopausal bleeding. Early determination of these conditions is very important in terms of morbidity/mortality and cost of the treatment.

## Coast-Effectiveness of Therapy
Given the morbidity associated with menopause, and the high cost of  HRT and non- hormonal therapy, current pharmacotherapy to treat menopause are cost-effective.