Menopause

Clinic

• Also known as the climacteric, is the time in women's lives when menstrual periods stop permanently
• The age of menopause varies but it usually occurs between 45 and 55. Medical professionals often define menopause as having occurred when a woman has not had any menstrual bleeding for a year. It may also be defined by a decrease in hormone production by the ovaries. In those who have had surgery to remove their uterus but still have functioning ovaries, menopause is not considered to have yet occurred. Following the removal of the uterus, symptoms of menopause typically occur earlier.

In the years before menopause, a woman's periods typically become irregular, which means that periods may be longer or shorter in duration or be lighter or heavier in the amount of flow. During this time, women often experience hot flashes; these typically last from 30 seconds to ten minutes and may be associated with shivering, sweating, and reddening of the skin. Hot flashes can recur from four to five years. Other symptoms may include vaginal dryness, trouble sleeping, and mood changes. The severity of symptoms varies between women. Menopause before the age of 45 years is considered to be "early menopause" and when ovarian failure/surgical removal of the ovaries occurs before the age of 40 years this is termed "premature ovarian insufficiency".

In addition to symptoms (hot flushes/flashes, night sweats, mood changes, arthralgia and vaginal dryness), the physical consequences of menopause include bone loss, increased central abdominal fat, and adverse changes in a woman's cholesterol profile and vascular function. These changes predispose postmenopausal women to increased risks of osteoporosis and bone fracture, and of cardio-metabolic disease (diabetes and cardiovascular disease).

Menopause is usually a natural change. It can occur earlier in those who smoke tobacco. Other causes include surgery that removes both ovaries or some types of chemotherapy. At the physiological level, menopause happens because of a decrease in the ovaries' production of the hormones estrogen and progesterone. While typically not needed, a diagnosis of menopause can be confirmed by measuring hormone levels in the blood or urine. Menopause is the opposite of menarche, the time when a girl's periods start.

The primary indications for treatment of menopause are symptoms and prevention of bone loss. Mild symptoms may be improved with treatment. With respect to hot flashes, avoiding smoking, caffeine, and alcohol is often recommended; sleeping naked in a cool room and using a fan may help. The most effective treatment for menopausal symptoms is menopausal hormone therapy (MHT). Non hormonal therapies for hot flashes include clonidine, gabapentin, or selective serotonin reuptake inhibitors. These will not improve symptoms such as joint pain or vaginal dryness which affect over 55% of women. Exercise may help with sleeping problems. Many of the concerns about the use of MHT raised by older studies are no longer considered barriers to MHT in healthy women. High-quality evidence for the effectiveness of alternative medicine has not been found. There is tentative evidence for the use of phytoestrogens for symptomatic treatment.

Signs and symptoms

• During early menopause transition, the menstrual cycles remain regular but the interval between cycles begins to lengthen. Hormone levels begin to fluctuate. Ovulation may not occur with each cycle.

• Menopause refers to a point in time that follows one year after the last menstruation. During the menopausal transition and after menopause, women can experience a wide range of symptoms. However, for women who enter the menopause transition without having regular menstrual cycles (due to prior surgery, other medical conditions or ongoing hormonal contraception) the menopause cannot be identified by bleeding patterns and is defined as the permanent loss of ovarian function.

Vagina and uterus

• Vaginal atrophy
• During the transition to menopause, menstrual patterns can show shorter cycling (by 2–7 days); longer cycles remain possible.
• There may be irregular bleeding (lighter, heavier, spotting).
• Dysfunctional uterine bleeding is often experienced by women approaching menopause due to the hormonal changes that accompany the menopause transition.
• Spotting or bleeding may simply be related to vaginal atrophy, a benign sore (polyp or lesion), or may be a functional endometrial response.

Urogenital symptoms

• painful intercourse
• vaginal dryness
• Atrophic vaginitis
• Urinary urgency and burning
• Urinary incontinence
• Urinary urgency

Other physical effects

• Bone mineral density decreases
• Lack of energy, joint soreness, stiffness, back pain, breast enlargement, breast pain, heart palpitations, headache, dizziness, dry, itchy skin, thinning, tingling skin, rosacea, weight gain, interrupted sleeping patterns, heavy night sweats, and hot flashes.

• Mood and memory effects: Anxiety, poor memory, inability to concentrate, depressive mood, irritability, mood swings, and less interest in sexual activity.
• Cognitive impairment can be confused with the mild cognitive impairment that precedes dementia. Tentative evidence has found that forgetfulness affects about half of menopausal women and is probably caused by the effects of declining estrogen levels on the brain, or perhaps by reduced blood flow to the brain during hot flashes.

Long-term effects

• Cardiovascular health: Exposure to endogenous estrogen during reproductive years provides women with protection against cardiovascular disease, which is lost around 10 years after the onset of menopause. The menopausal transition is associated with an increase in fat mass (predominantly in visceral fat), an increase in insulin resistance, dyslipidaemia, and endothelial dysfunction. Women with vasomotor symptoms during menopause seem to have an especially unfavorable cardiometabolic profile, as well as women with premature onset of menopause (before 45 years of age). These risks can be reduced by managing risk factors, such as tobacco smoking, hypertension, increased blood lipids and body weight.

• Bone health: The annual rates of bone mineral density loss are highest starting one year before the final menstrual period and continuing through the two years after it. Thus, post menopausal women are at increased risk of osteopenia, osteoporosis and fractures.

Causes

• Premature ovarian insufficiency
• Menopause can be induced or occur naturally.
• Induced menopause occurs as a result of medical treatment such as chemotherapy, radiotherapy, oophorectomy, or complications of tubal ligation, hysterectomy, unilateral or bilateral salpingo-oophorectomy or leuprorelin usage.

Age

Menopause typically occurs at some point between 47 and 54 years of age. According to various data, more than 85% of women have their last period between the ages of 47–54 (median 49–50). 2% of women under the age of 40, 5% between the ages of 40–45 and the same number between the ages of 55–58 have their last bleeding. The average age of the last period in the United States is 51 years, in Russia is 50 years, in Greece is 49 years, in Turkey is 47 years, in Egypt is 47 years and in India is 46 years. The menopausal transition or perimenopause leading up to menopause usually lasts 3–4 years (sometimes as long as 5–14 years).

In rare cases, a woman's ovaries stop working at a very early age, ranging anywhere from the age of puberty to age 40. This is known as premature ovarian failure and affects 1 to 2% of women by age 40.

Undiagnosed and untreated coeliac disease is a risk factor for early menopause. Coeliac disease can present with several non-gastrointestinal symptoms, in the absence of gastrointestinal symptoms, and most cases escape timely recognition and go undiagnosed, leading to a risk of long-term complications. A strict gluten-free diet reduces the risk. Women with early diagnosis and treatment of coeliac disease present a normal duration of fertile life span.

Women who have undergone hysterectomy with ovary conservation go through menopause on average 1.5 years earlier than the expected age. Another factor that can promote an earlier onset of menopause (usually 1 to 3 years early) is smoking cigarettes.

Surgical menopause[edit]

Menopause can be surgically induced by bilateral oophorectomy (removal of ovaries), which is often, but not always, done in conjunction with removal of the Fallopian tubes (salpingo-oophorectomy) and uterus (hysterectomy). Cessation of menses as a result of removal of the ovaries is called "surgical menopause". Surgical treatments, such as the removal of ovaries, might cause periods to stop altogether. The sudden and complete drop in hormone levels may produce extreme withdrawal symptoms such as hot flashes, etc. The symptoms of early menopause may be more severe.

Removal of the uterus without removal of the ovaries does not directly cause menopause, although pelvic surgery of this type can often precipitate a somewhat earlier menopause, perhaps because of a compromised blood supply to the ovaries.^{[medical citation needed]} The time between surgery and possible early menopause is due to the fact that ovaries are still producing hormones.

Mechanism[edit]

Bone loss due to menopause occurs due to changes in a woman's hormone levels. The menopausal transition, and postmenopause itself, is a natural change, not usually a disease state or a disorder. The main cause of this transition is the natural depletion and aging of the finite amount of oocytes (ovarian reserve). This process is sometimes accelerated by other conditions and is known to occur earlier after a wide range of gynecologic procedures such as hysterectomy (with and without ovariectomy), endometrial ablation and uterine artery embolisation. The depletion of the ovarian reserve causes an increase in circulating follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels because there are fewer oocytes and follicles responding to these hormones and producing estrogen.

The transition has a variable degree of effects.

The stages of the menopause transition have been classified according to a woman's reported bleeding pattern, supported by changes in the pituitary follicle-stimulating hormone (FSH) levels.

In younger women, during a normal menstrual cycle the ovaries produce estradiol, testosterone and progesterone in a cyclical pattern under the control of FSH and luteinizing hormone (LH), which are both produced by the pituitary gland. During perimenopause (approaching menopause), estradiol levels and patterns of production remain relatively unchanged or may increase compared to young women, but the cycles become frequently shorter or irregular. The often observed increase in estrogen is presumed to be in response to elevated FSH levels that, in turn, is hypothesized to be caused by decreased feedback by inhibin. Similarly, decreased inhibin feedback after hysterectomy is hypothesized to contribute to increased ovarian stimulation and earlier menopause.

The menopausal transition is characterized by marked, and often dramatic, variations in FSH and estradiol levels. Because of this, measurements of these hormones are not considered to be reliable guides to a woman's exact menopausal status.

Menopause occurs because of the sharp decrease of estradiol and progesterone production by the ovaries. After menopause, estrogen continues to be produced mostly by aromatase in fat tissues and is produced in small amounts in many other tissues such as ovaries, bone, blood vessels, and the brain where it acts locally. The substantial fall in circulating estradiol levels at menopause impacts many tissues, from brain to skin.

In contrast to the sudden fall in estradiol during menopause, the levels of total and free testosterone, as well as dehydroepiandrosterone sulfate (DHEAS) and androstenedione appear to decline more or less steadily with age. An effect of natural menopause on circulating androgen levels has not been observed. Thus specific tissue effects of natural menopause cannot be attributed to loss of androgenic hormone production.

Hot flashes and other vasomotor and body symptoms accompanying the menopausal transition are associated with estrogen insufficiency and changes that occur in the brain, primarily the hypothalamus and involve complex interplay between the neurotransmitters kisspeptin, neurokinin B, and dynorphin, which are found in ‘KNDy’ neurons in the infundibular nucleus.

Long-term effects of menopause may include osteoporosis, vaginal atrophy as well as changed metabolic profile resulting in increased cardiac and metabolic disease (diabetes) risks.^{[citation needed]}

Ovarian aging[edit]

Decreased inhibin feedback after hysterectomy is hypothesized to contribute to increased ovarian stimulation and earlier menopause. Hastened ovarian aging has been observed after endometrial ablation. While it is difficult to prove that these surgeries are causative, it has been hypothesized that the endometrium may be producing endocrine factors contributing to the endocrine feedback and regulation of the ovarian stimulation. Elimination of these factors contributes to faster depletion of the ovarian reserve. Reduced blood supply to the ovaries that may occur as a consequence of hysterectomy and uterine artery embolisation has been hypothesized to contribute to this effect.

Impaired DNA repair mechanisms may contribute to earlier depletion of the ovarian reserve during aging. As women age, double-strand breaks accumulate in the DNA of their primordial follicles. Primordial follicles are immature primary oocytes surrounded by a single layer of granulosa cells. An enzyme system is present in oocytes that ordinarily accurately repairs DNA double-strand breaks. This repair system is called "homologous recombinational repair", and it is especially effective during meiosis. Meiosis is the general process by which germ cells are formed in all sexual eukaryotes; it appears to be an adaptation for efficiently removing damages in germ line DNA.

Human primary oocytes are present at an intermediate stage of meiosis, termed prophase I (see Oogenesis). Expression of four key DNA repair genes that are necessary for homologous recombinational repair during meiosis (BRCA1, MRE11, Rad51, and ATM) decline with age in oocytes. This age-related decline in ability to repair DNA double-strand damages can account for the accumulation of these damages, that then likely contributes to the depletion of the ovarian reserve.