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. ovarian aging 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. diagnosis ways of assessing the impact on women of some of these menopause effects, include the greene climacteric scale questionnaire, the cervantes scale and the menopause rating scale. premenopause premenopause is a term used to mean the years leading up to the last period, when the levels of reproductive hormones are becoming more variable and lower, and the effects of hormone withdrawal are present. premenopause starts some time before the monthly cycles become noticeably irregular in timing. perimenopause the term "perimenopause", which literally means "around the menopause", refers to the menopause transition years before the date of the final episode of flow. according to the north american menopause society, this transition can last for four to eight years. the centre for menstrual cycle and ovulation research describes it as a six- to ten-year phase ending 12 months after the last menstrual period. during perimenopause, estrogen levels average about 20–30% higher than during premenopause, often with wide fluctuations. these fluctuations cause many of the physical changes during perimenopause as well as menopause, especially during the last 1–2 years of perimenopause (before menopause). some of these changes are hot flashes, night sweats, difficulty sleeping, mood swings, vaginal dryness or atrophy, incontinence, osteoporosis, and heart disease. perimenopause is also associated with a higher likelihood of depression (affecting from 45 percent to 68 percent of perimenopausal women), which is twice as likely to affect those with a history of depression. during this period, fertility diminishes but is not considered to reach zero until the official date of menopause. the official date is determined retroactively, once 12 months have passed after the last appearance of menstrual blood. the menopause transition typically begins between 40 and 50 years of age (average 47.5). the duration of perimenopause may be for up to eight years. women will often, but not always, start these transitions (perimenopause and menopause) about the same time as their mother did. in some women, menopause may bring about a sense of loss related to the end of fertility. in addition, this change often occurs when other stressors may be present in a woman's life: caring for, and/or the death of, elderly parents empty nest syndrome when children leave home the birth of grandchildren, which places people of "middle age" into a new category of "older people" (especially in cultures where being older is a state that is looked down on) some research appears to show that melatonin supplementation in perimenopausal women can improve thyroid function and gonadotropin levels, as well as restoring fertility and menstruation and preventing depression associated with menopause. postmenopause the term "postmenopausal" describes women who have not experienced any menstrual flow for a minimum of 12 months, assuming that they have a uterus and are not pregnant or lactating. in women without a uterus, menopause or postmenopause can be identified by a blood test showing a very high fsh level. thus postmenopause is the time in a woman's life that takes place after her last period or, more accurately, after the point when her ovaries become inactive. the reason for this delay in declaring postmenopause is that periods are usually erratic at this time of life. therefore, a reasonably long stretch of time is necessary to be sure that the cycling has ceased. at this point a woman is considered infertile; however, the possibility of becoming pregnant has usually been very low (but not quite zero) for a number of years before this point is reached. a woman's reproductive hormone levels continue to drop and fluctuate for some time into post-menopause, so hormone withdrawal effects such as hot flashes may take several years to disappear. a period-like flow during postmenopause, even spotting, may be a sign of endometrial cancer. management perimenopause is a natural stage of life. it is not a disease or a disorder. therefore, it does not automatically require any kind of medical treatment. however, in those cases where the physical, mental, and emotional effects of perimenopause are strong enough that they significantly disrupt the life of the woman experiencing them, palliative medical therapy may sometimes be appropriate. menopausal hormone therapy main article: hormone replacement therapy in the context of the menopause, menopausal hormone therapy (mht) is the use of estrogen in women without a uterus and estrogen plus progestogen in women who have an intact uterus. mht may be reasonable for the treatment of menopausal symptoms, such as hot flashes. it is the most effective treatment option, especially when delivered as a skin patch. its use, however, appears to increase the risk of strokes and blood clots. when used for menopausal symptoms the global recommendation is mht should be prescribed for a long as there are defined treatment effects and goals for the individual woman. mht is also effective for preventing bone loss and osteoporotic fracture, but it is generally recommended only for women at significant risk for whom other therapies are unsuitable. mht may be unsuitable for some women, including those at increased risk of cardiovascular disease, increased risk of thromboembolic disease (such as those with obesity or a history of venous thrombosis) or increased risk of some types of cancer. there is some concern that this treatment increases the risk of breast cancer. women at increased risk of cardiometabolic disease and vte may be able to use transdermal estradiol which does not appear to increase risks in low to moderate doses. adding testosterone to hormone therapy has a positive effect on sexual function in postmenopausal women, although it may be accompanied by hair growth, acne if used in excess. transdermal testosterone therapy in appropriate dosing is generally safe selective estrogen receptor modulators serms are a category of drugs, either synthetically produced or derived from a botanical source, that act selectively as agonists or antagonists on the estrogen receptors throughout the body. the most commonly prescribed serms are raloxifene and tamoxifen. raloxifene exhibits oestrogen agonist activity on bone and lipids, and antagonist activity on breast and the endometrium. tamoxifen is in widespread use for treatment of hormone sensitive breast cancer. raloxifene prevents vertebral fractures in postmenopausal, osteoporotic women and reduces the risk of invasive breast cancer. other medications some of the ssris and snris appear to provide some relief from vasomotor symptoms. low dose paroxetine is the only non-hormonal medication that was fda-approved to treat moderate-to-severe vasomotor symptoms associated with menopause as of 2016. they may, however, be associated with appetite and sleeping problems, constipation and nausea. gabapentin or clonidine may help but do not work as well as hormone therapy. gabapentin can decrease the amount of hot flashes. side effects associated with its use include drowsiness and headaches. clonidine is used to improve vasomotor symptoms and may be associated with constipation, dizziness, nausea and sleeping problems. therapy one review found mindfulness and cognitive behavioural therapy decreases the amount women are affected by hot flashes. another review found not enough evidence to make a conclusion. a 2018 study found that 85% of study participants reported reduced hot flashes and night sweats when using a climate control system in their beds. exercise exercise has been thought to reduce postmenopausal symptoms through the increase of endorphin levels, which decrease as estrogen production decreases. additionally, high bmi is a risk factor for vasomotor symptoms in particular. however, there is insufficient evidence to support the benefits of weight loss for symptom management. there are mixed perspectives on the benefits of physical exercise. while one review found that there was a lack of quality evidence supporting a benefit of exercise, another review recommended regular healthy exercise to reduce comorbidities, improve mood and anxiety symptoms, enhance cognition, and decrease the risk of fractures. yoga may help with postmenopausal symptoms similar to other exercise. there is insufficient evidence to suggest that relaxation techniques reduce menopausal symptoms. alternative medicine there is no evidence of consistent benefit of alternative therapies for menopausal symptoms despite their popularity. the effect of soy isoflavones on menopausal symptoms is promising for reduction of hot flashes and vaginal dryness. evidence does not support a benefit from phytoestrogens such as coumestrol, femarelle, or the non-phytoestrogen black cohosh. as of 2011 there is no support for herbal or dietary supplements in the prevention or treatment of the mental changes that occur around menopause. hypnosis may reduce the severity of hot flashes. in addition, relaxation training with at-home relaxation audiotapes such as deep breathing, paced respiration, and guided imagery may have positive effects on relaxing muscles and reducing stress. there is no evidence to support the efficacy of acupuncture as a management for menopausal symptoms. a 2016 cochrane review found not enough evidence to show a difference between chinese herbal medicine and placebo for the vasomotor symptoms. other efforts lack of lubrication is a common problem during and after perimenopause. vaginal moisturizers can help women with overall dryness, and lubricants can help with lubrication difficulties that may be present during intercourse. it is worth pointing out that moisturizers and lubricants are different products for different issues: some women complain that their genitalia are uncomfortably dry all the time, and they may do better with moisturizers. those who need only lubricants do well using them only during intercourse. low-dose prescription vaginal estrogen products such as estrogen creams are generally a safe way to use estrogen topically, to help vaginal thinning