It also fails to explain the detrimental effects of losing ovarian follicular activity. While continued post-menopausal synthesis of estrogen occurs in peripheral tissues through the adrenal pathways, [ 34 ]  these women undoubtedly face an increased risk of conditions associated with lower levels of estrogen:  osteoporosis ,  osteoarthritis ,  Alzheimer's disease  and  coronary artery disease . [ 35 ]


However, cross-cultural studies of menopause have found that menopausal symptoms are quite variable among different populations, and that some populations of females do not recognize, and may not even experience, these "symptoms". [ 36 ]  This high level of variability in menopausal symptoms across populations brings into question the plausibility of menopause as a sort of " culling  agent" to eliminate non-reproductive females from competition with younger, fertile members of the species. This also faces the task of explaining the paradox between the typical age for menopause onset and the life expectancy of female humans.


The  Greene Menopause Index , also known as the  Greene Climacteric Scale , is a  questionnaire  a tool used by  researchers  to study the  symptoms  of  menopause . It is a standard list of 21 questions, divided into three categories (psychological, somatic, and vasomotor), which women use to rate how much they are bothered by menopause symptoms such as  hot flashes ,  night sweats ,  rapid heartbeat , and  difficulty sleeping . [ 1 ]


Henopause , a  portmanteau  of " hen " and " menopause ", is sometimes used to refer to the point at which  hens  stop laying  eggs .


Although daily egg production starts to tail off after one year old, it may continue until 5–7 years old. Older hens gradually produce fewer eggs, and the eggs are usually larger. [ 1 ]  Since the average lifespan of a pet layer hen is 8–15 years, [ 2 ]  henopause has received attention as a potential problem for backyard or  urban chicken farmers  who are eventually faced with the decision to either slaughter older layers or  keep them as non-producing pets . In the UK, the  British Hen Welfare Trust  charity rescues commercial hens who would otherwise be sent to slaughter when they become no longer commercially viable. [ 3 ]


As many breeds of hen have been selectively bred for maximum egg production (300+ per year versus an ancestral 12 per year), many hens continue to lay for long periods, but may start to experience health complications such as egg yolk peritonitis (where the egg does not exit the body and thus causes fatal infections). Increasingly, those caring for chickens as pets may not have the expectation of eggs; some may even feed their hens' eggs back to them or even hormonally implant their hens to prevent egg-laying, which is purported to offer welfare benefits for the hens. [ 3 ]


In commercial farming, a layer hen is considered no longer commercially viable at around thirteen months and is called a "spent hen". [ 4 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ]


This  poultry  article is a  stub . You can help Wikipedia by  expanding it .


Hormone replacement therapy  ( HRT ), also known as  menopausal hormone therapy  or  postmenopausal hormone therapy , is a form of  hormone therapy  used to treat  symptoms  associated with female  menopause . [ 1 ] [ 2 ]  Effects of menopause can include symptoms such as  hot flashes , accelerated skin aging,  vaginal dryness , decreased  muscle mass , and complications such as  osteoporosis  (bone loss),  sexual dysfunction , and  vaginal atrophy . They are mostly caused by low levels of female  sex hormones  (e.g.  estrogens ) that occur during menopause. [ 1 ] [ 2 ]


Estrogens  and  progestogens  are the main hormone drugs used in HRT.  Progesterone  is the main female sex hormone that occurs naturally and is also  manufactured  into a drug that is used in menopausal hormone therapy. [ 1 ]  Although both classes of hormones can have symptomatic benefit, progestogen is specifically added to estrogen regimens, unless the  uterus  has been removed, to avoid the increased risk of endometrial cancer. Unopposed estrogen therapy promotes  endometrial hyperplasia  and increases the risk of  cancer , while progestogen reduces this risk. [ 3 ] [ 4 ]   Androgens  like  testosterone  are sometimes used as well. [ 5 ]  HRT is available through a variety of different  routes . [ 1 ] [ 2 ]


The long-term effects of HRT on most organ systems vary by age and time since the last  physiological  exposure to hormones, and there can be large differences in individual regimens, factors which have made analyzing effects difficult. [ 6 ]  The  Women's Health Initiative  (WHI) is an ongoing study of over 27,000 women that began in 1991, with the most recent analyses suggesting that, when initiated within 10 years of menopause, HRT reduces all-cause  mortality  and risks of coronary disease, osteoporosis, and dementia; after 10 years the beneficial effects on mortality and coronary heart disease are no longer apparent, though there are decreased risks of hip and vertebral fractures and an increased risk of  venous thromboembolism  when taken orally. [ 7 ] [ 8 ]


"Bioidentical" hormone replacement is a development in the 21st century and uses manufactured compounds with "exactly the same chemical and molecular structure as hormones that are produced in the human body." [ 9 ]  These are mainly manufactured from  plant steroids [ 10 ]  and can be a component of either registered  pharmaceutical  or custom-made  compounded  preparations, with the latter generally not recommended by regulatory bodies due to their lack of standardization and formal oversight. [ 11 ]  Bioidentical hormone replacement has inadequate  clinical research  to determine its safety and efficacy as of 2017. [ 12 ]


The current indications for use from the United States  Food and Drug Administration  (FDA) include short-term treatment of  menopausal symptoms , such as  vasomotor   hot flashes  or  vaginal atrophy , and prevention of  osteoporosis . [ 13 ]


Approved uses of HRT in the United States include short-term treatment of menopausal symptoms such as hot flashes and vaginal atrophy, and prevention of osteoporosis. [ 13 ]  The  American College of Obstetrics and Gynecology  (ACOG) approves of HRT for symptomatic relief of menopausal symptoms, [ 14 ]  and advocates its use beyond the age of 65 in appropriate scenarios. [ 15 ]  The  North American Menopause Society  (NAMS) 2016 annual meeting mentioned that HRT may have more benefits than risks in women before the age of 60. [ 16 ]


A consensus expert opinion published by  The Endocrine Society  stated that when taken during perimenopause or the initial years of menopause, HRT carries fewer risks than previously published, and reduces all cause mortality in most scenarios. [ 17 ]  The  American Association of Clinical Endocrinologists  (AACE) has also released position statements approving of HRT when appropriate. [ 12 ]


Women receiving this treatment are usually  post- ,  peri- , or  surgically induced menopausal . Menopause is the permanent cessation of  menstruation  resulting from loss of ovarian follicular activity, defined as beginning twelve months after the final natural menstrual cycle. This twelve month time point divides menopause into early and late transition periods known as 'perimenopause' and 'postmenopause'. [ 4 ]  Premature menopause can occur if the ovaries are  surgically removed , as can be done to treat  ovarian  or  uterine cancer .


Demographically, the vast majority of data available is in postmenopausal American women with concurrent pre-existing conditions and an average age of over 60 years. [ 18 ]


HRT is often given as a short-term relief from menopausal symptoms during  perimenopause . [ 19 ]  Potential menopausal symptoms include: [ 1 ] [ 2 ]


The most common of these are  loss of sexual drive  and  vaginal dryness . [ 4 ] [ 22 ]


The use of hormone therapy for heart health among menopausal women has declined significantly over the past few decades. [ 23 ]  In 1999, nearly 27% of menopausal women in the U.S. used estrogen, but by 2020, that figure had dropped to less than 5%. [ 24 ] [ 25 ]   Recent evidence in 2024 suggests  evidence supporting the cardiovascular benefits of hormone therapy, including improvements in insulin resistance and other heart-related markers. [ 26 ]  This adds to a growing body of research highlighting hormone therapy’s effectiveness, not only for heart health but also for managing menopausal symptoms like hot flashes, disrupted sleep, vaginal dryness, and painful intercourse. [ 27 ]  Despite its proven benefits, many menopausal women avoid hormone therapy, often due to lingering misconceptions about its risks and societal discomfort with openly discussing menopause. [ 28 ]


HRT can help with the lack of sexual desire and sexual dysfunction that can occur with menopause. Epidemiological surveys of women between 40 and 69 years suggest that 75% of women remain sexually active after menopause. [ 4 ]  With increasing life spans, women today are living one third or more of their lives in a postmenopausal state, a period during which healthy sexuality can be integral to their  quality of life . [ 29 ]


Decreased libido and sexual dysfunction are common issues in postmenopausal women, an entity referred to  hypoactive sexual desire disorder  (HSDD); its signs and symptoms can both be improved by HRT. [ 5 ] [ 30 ]  Several hormonal changes take place during this period, including a decrease in estrogen and an increase in  follicle-stimulating hormone . For most women, the majority of change occurs during the late perimenopausal and postmenopausal stages. [ 4 ]  Decreases in  sex hormone-binding globulin  (SHBG) and  inhibin  (A and B) also occur. Testosterone is present in women at a lower level than men, peaking at age 30 and declining gradually with age; there is less variation during the menopausal transition relative to estrogen and progesterone. [ 4 ]


A global consensus position statement has advised that postmenopausal testosterone replacement to premenopausal levels can be effective for HSDD. Safety information for testosterone treatment is not available beyond two years of continuous therapy however and dosing above physiologic levels is not advised. [ 31 ]  Testosterone patches have been found to restore sexual desire in post menopausal women. [ 32 ]  There is insufficient data to evaluate the impact of testosterone replacement on heart disease, breast cancer, with most trials having included women taking concomitant estrogen and progesterone and with testosterone therapy itself being relatively short in duration. In the setting of this limited data, testosterone therapy has not been associated with adverse events. [ 31 ]


Not all women are responsive, especially those with preexisting sexual difficulties. [ 22 ]  Estrogen replacement can restore vaginal cells,  pH  levels, and blood flow to the vagina, all of which tend to deteriorate at the onset of menopause.  Pain or discomfort with sex  appears to be the most responsive component to estrogen. [ 22 ]  It also has been shown to have positive effects on the urinary tract. [ 22 ]  Estrogen can also reduce vaginal atrophy and increase  sexual arousal , frequency and  orgasm . [ 22 ]


The effectiveness of hormone replacement can decline in some women after long-term use. [ 22 ]  A number of studies have also found that the combined effects of estrogen/androgen replacement therapy can increase libido and arousal over estrogen alone. [ 22 ]   Tibolone , a synthetic steroid with estrogenic, androgenic, and progestogenic properties that is available in Europe, has the ability to improve mood, libido, and physical symptomatology. In various placebo-controlled studies, improvements in vasomotor symptoms, emotional response, sleep disturbances, physical symptoms, and sexual desire have been seen, though it also carries a similar risk profile to conventional HRT. [ 5 ]


There is a significant decrease in  hip fracture  risk during treatment that to a lesser degree persists after HRT is stopped. [ 33 ] [ 34 ]  It also helps  collagen  formation, which in turn improves  intervertebral disc  and bone strength. [ 35 ]


Hormone replacement therapy in the form of estrogen and androgen can be effective at reversing the effects of aging on muscle. [ 36 ]  Lower testosterone is associated with lower bone density and higher free testosterone is associated with lower hip fracture rates in older women. [ 37 ]  Testosterone therapy, which can be used for decreased sexual function, can also increase bone mineral density and muscle mass. [ 31 ]


Side effects  in HRT occur with varying frequency and include: [ 38 ]


The effect of HRT in menopause appears to be divergent, with lower risk of heart disease when started within five years, but no impact after ten. [ 40 ] [ 41 ] [ 42 ]   For women who are in early menopause and have no issues with their cardiovascular health, HRT comes with a low risk of adverse cardiovascular events. [ 43 ]  There may be an increase in heart disease if HRT is given twenty years post-menopause. [ 44 ]  This variability has led some reviews to suggest an absence of significant effect on  morbidity . [ 45 ]  Importantly, there is no difference in long-term mortality from HRT, regardless of age. [ 46 ]


A  Cochrane review  suggested that women starting HRT less than 10 years after menopause had lower mortality and  coronary heart disease , without any strong effect on the risk of stroke and  pulmonary embolism . [ 40 ]  Those starting therapy more than 10 years after menopause showed little effect on mortality and coronary heart disease, but an increased risk of stroke. Both therapies had an association with  venous clots  and pulmonary embolism. [ 40 ]


HRT with estrogen and progesterone also improves  cholesterol levels . With menopause,  HDL  decreases, while  LDL ,  triglycerides  and  lipoprotein a  increase, patterns that reverse with estrogen. Beyond this, HRT improves  heart contraction ,  coronary  blood flow,  sugar   metabolism , and decreases  platelet  aggregation and  plaque formation . HRT may promote  reverse cholesterol transport  through induction of  cholesterol   ABC transporters . [ 47 ]  Atherosclerosis imaging trials show that HRT decreases the formation of new vascular lesions, but does not reverse the progression of existing lesions. [ 48 ]   HRT also results in a large reduction in the pro-thrombotic  lipoprotein a . [ 49 ]


Studies on cardiovascular disease with testosterone therapy have been mixed, with some suggesting no effect or a mild negative effect, though others have shown an improvement in surrogate markers such as cholesterol, triglycerides and weight. [ 50 ] [ 51 ]  Testosterone has a positive effect on vascular endothelial function and tone with observational studies suggesting that women with lower testosterone may be at greater risk for heart disease. Available studies are limited by small sample size and study design. Low  sex hormone-binding globulin , which occurs with menopause, is associated with increased body mass index and risk for type 2 diabetes. [ 52 ]


Effects of hormone replacement therapy on  venous blood clot  formation and potential for  pulmonary embolism  may vary with different estrogen and progestogen therapies, and with different doses or method of use. [ 18 ]  Comparisons between routes of administration suggest that when estrogens are applied to the skin or vagina, there is a lower risk of blood clots, [ 18 ] [ 53 ]  whereas when used orally, the risk of blood clots and pulmonary embolism is increased. [ 54 ]  Skin and vaginal routes of hormone therapy are not subject to  first pass metabolism , and so lack the  anabolic  effects that oral therapy has on liver synthesis of  vitamin K -dependent  clotting factors , possibly explaining why oral therapy may increase blood clot formation. [ 55 ]


While a 2018 review found that taking progesterone and estrogen together can decrease this risk, [ 53 ]  other reviews reported an increased risk of blood clots and pulmonary embolism when estrogen and progestogen were combined, particularly when treatment was started 10 years or more after menopause and when the women were older than 60 years. [ 18 ] [ 54 ]


The risk of venous thromboembolism may be reduced with bioidentical preparations, though research on this is only preliminary. [ 56 ]


Multiple studies suggest that the possibility of HRT related stroke is absent if therapy is started within five years of menopause, [ 57 ]  and that the association is absent or even preventive when given by non-oral routes. [ 8 ]   Ischemic stroke  risk was increased during the time of intervention in the WHI, with no significant effect after the cessation of therapy [ 33 ]  and no difference in mortality at long term follow up. [ 6 ]  When oral synthetic estrogen or combined estrogen-progestogen treatment is delayed until five years from menopause,  cohort studies  in Swedish women have suggested an association with  hemorrhagic  and ischemic stroke. [ 57 ]  Another large cohort of Danish women suggested that the specific route of administration was important, finding that although oral estrogen increased risk of stroke, absorption through the skin had no impact, and vaginal estrogen actually had a decreased risk. [ 8 ]


In postmenopausal women, continuous combined estrogen plus progestin decreases  endometrial cancer  incidence. [ 58 ]  The duration of progestogen therapy should be at least 14 days per cycle to prevent endometrial disease. [ 59 ]


Endometrial cancer has been grouped into two forms in the context of hormone replacement. Type 1 is the most common, can be associated with estrogen therapy, and is usually low grade. Type 2 is not related to estrogen stimulation and usually higher grade and poorer in prognosis. [ 60 ]  The  endometrial hyperplasia  that leads to  endometrial cancer  with estrogen therapy can be prevented by concomitant administration of  progestogen . [ 60 ]  The extensive use of high-dose estrogens for  birth control  in the 1970s is thought to have resulted in a significant increase in the incidence of type 1 endometrial cancer. [ 61 ]


Paradoxically, progestogens do promote the growth of  uterine fibroids , and a  pelvic ultrasound  can be performed before beginning HRT to make sure there are no underlying uterine or endometrial lesions. [ 60 ]


Androgens do not stimulate endometrial proliferation in post menopausal women, and appear to inhibit the proliferation induced by estrogen to a certain extent. [ 62 ]


There is insufficient high‐quality evidence to inform women considering hormone replacement therapy after treatment for endometrial cancer. [ 63 ]


In general, hormone replacement therapy to treat  menopause  is associated with only a small increased risk of  breast cancer . [ 64 ] [ 65 ] [ 66 ]  The level of risk also depends on the type of HRT, the duration of the treatment and the age of the person.  [ 67 ] [ 68 ]   Oestrogen -only HRT, taken by people who had a  hysterectomy , comes with an extremely low level of breast cancer risk. The most commonly taken combined HRT (oestrogen and  progestogen ) is linked to a small risk of breast cancer. This risk is lower for women in their 50s and higher for older women. The risk increases with the duration of HRT. When HRT is taken for a year or less, there is no increased risk of breast cancer. HRT taken for more than 5 years comes with an increased risk but the risk reduces after the therapy is stopped. [ 65 ] [ 66 ]


There is a  non-statistically significant  increased rate of breast cancer for hormone replacement therapy with synthetic  progestogens . [ 6 ]  The risk may be reduced with  bioidentical  progesterone, [ 69 ]  though the only prospective study that suggested this was  underpowered  due to the rarity of breast cancer in the  control population . There have been no  randomized controlled trials  as of 2018. [ 70 ]  The relative risk of breast cancer also varies depending on the interval between menopause and HRT and route of synthetic progestin administration. [ 71 ] [ 72 ]


The most recent follow up of the Women's Health Initiative participants demonstrated a lower incidence of breast cancer in post-hysterectomy participants taking equine estrogen alone, though the relative risk was increased if estrogen was taken with medroxyprogesterone. [ 73 ]  Estrogen is usually only given alone in the setting of a hysterectomy due to the increased risk of vaginal bleeding and uterine cancer with unopposed estrogen. [ 74 ] [ 75 ]


HRT has been more strongly associated with risk of breast cancer in women with lower  body mass indices  (BMIs). No breast cancer association has been found with BMIs of over 25. [ 76 ]  It has been suggested by some that the absence of significant effect in some of these studies could be due to selective prescription to overweight women who have higher baseline  estrone , or to the very low progesterone serum levels after oral administration leading to a high tumor inactivation rate. [ 77 ]


Evaluating the response of breast tissue density to HRT using mammography appears to help assessing the degree of breast cancer risk associated with therapy; women with dense or mixed- dense breast tissue  have a higher risk of developing breast cancer than those with low density tissue. [ 78 ]


Micronized  progesterone does not appear to be associated with breast cancer risk when used for less than five years with limited data suggesting an increased risk when used for longer duration. [ 79 ]


For women who previously have had breast cancer, it is recommended to first consider other options for menopausal effects, such as  bisphosphonates  or  selective estrogen receptor modulators  (SERMs) for osteoporosis,  cholesterol-lowering agents  and  aspirin  for cardiovascular disease, and  vaginal estrogen  for local symptoms. Observational studies of systemic HRT after breast cancer are generally reassuring. If HRT is necessary after breast cancer, estrogen-only therapy or estrogen therapy with a progestogen may be safer options than combined systemic therapy. [ 80 ]  In women who are  BRCA1  or  BRCA2  mutation carriers, HRT does not appear to impact breast cancer risk. [ 81 ]  The relative number of women using HRT who also obtain regular screening mammograms is higher than that in women who do not use HRT, a factor which has been suggested as contributing to different breast cancer detection rates in the two groups. [ 82 ]


With androgen therapy, pre-clinical studies have suggested an inhibitory effect on breast tissue though the majority of epidemiological studies suggest a positive association. [ 83 ]


HRT is associated with an increased risk of  ovarian cancer , with women using HRT having about one additional case of ovarian cancer per 1,000 users. [ 84 ]  This risk is decreased when progestogen therapy is given concomitantly, as opposed to estrogen alone, and also decreases with increasing time since stopping HRT. [ 85 ]  Regarding the specific  subtype , there may be a higher risk of  serous cancer , but no association with  clear cell ,  endometrioid , or  mucinous ovarian cancer . [ 85 ]  Hormonal therapy in ovarian cancer survivors after surgical removal of the ovaries is generally thought to improval survival rates. [ 86 ]


In the WHI, women who took combined estrogen-progesterone therapy had a lower risk of getting  colorectal cancer . However, the cancers they did have were more likely to have spread to  lymph nodes  or distant sites than colorectal cancer in women not taking hormones. [ 87 ]  In colorectal cancer survivors, usage of HRT is thought to lead to lower recurrence risk and overall mortality. [ 88 ]


There appears to be a significantly decreased risk of cervical squamous cell cancer in post menopausal women treated with HRT and a weak increase in adenocarcinoma. No studies have reported an increased risk of recurrence when HRT is used with cervical cancer survivors. [ 89 ]


For prevention, the WHI suggested that HRT may increase risk of dementia if initiated after 65 years of age, but have a neutral outcome or be neuroprotective for those between 50 and 55 years. [ 33 ]  Other studies in perimenopause have shown HRT to be consistently associated with a lower risk of Alzheimer's. [ 90 ] [ 91 ]  With Parkinson's the majority of clinical and epidemiological studies show have demonstrated either no association [ 92 ] [ 93 ]  or inconclusive results. [ 90 ] [ 94 ]  A Danish study suggested an increased risk of Parkinson's with HRT in cyclical dosing schedules. [ 95 ]


With regards to treatment, randomized trials have shown that HRT improves executive and attention processes outside of the context of dementia in postmenopausal women, both in those that are asymptomatic and those with mild cognitive impairment. [ 96 ] [ 97 ] [ 98 ]  Estrogen replacement appears to improve motor symptoms and activities of daily living in post menopausal women with Parkinson's, with significant improvement of  UPDRS scores . [ 99 ]  Clinical trials have also shown testosterone replacement to be associated with small statistically significant improvements in verbal learning and memory in postmenopausal women. [ 100 ]  DHEA has not been found to improve cognitive performance after menopause. [ 37 ]  Pre-clinical studies indicate that endogenous estrogen and testosterone are neuroprotective and can prevent brain amyloid deposition. [ 101 ] [ 102 ]


The following are absolute and relative  contraindications  to HRT: [ 103 ]


The extraction of CEEs from the urine of pregnant  mares  led to the marketing in 1942 of  Premarin , one of the earlier forms of estrogen to be introduced. [ 104 ] [ 105 ]  From that time until the mid-1970s, estrogen was administered without a supplemental progestogen. Beginning in 1975, studies began to show that without a progestogen, unopposed estrogen therapy with Premarin resulted in an eight-fold increased risk of  endometrial cancer , eventually causing sales of Premarin to plummet. [ 104 ]  It was recognized in the early 1980s that the addition of a progestogen to estrogen reduced this risk to the endometrium. [ 104 ]  This led to the development of combined estrogen–progestogen therapy, most commonly with a combination of conjugated equine estrogen (Premarin) and medroxyprogesterone (Provera). [ 104 ]


The Women's Health Initiative trials were conducted between 1991 and 2006 and were the first large,  double-blind , placebo-controlled clinical trials of HRT in healthy women. [ 104 ]  Their results were both positive and negative, suggesting that during the time of hormone therapy itself, there are increases in invasive breast cancer, stroke and  lung clots . Other risks include increased  endometrial cancer ,  gallbladder  disease, and  urinary incontinence , while benefits include decreased  hip fractures , decreased incidence of  diabetes , and improvement of  vasomotor  symptoms. There is also an increased risk of  dementia  with HRT in women over 65, though at younger ages it appears to be neuroprotective. After the cessation of HRT, the WHI continued to observe its participants, and found that most of these risks and benefits dissipated, though some elevation in breast cancer risk did persist. [ 33 ]  Other studies have also suggested an increased risk of  ovarian cancer . [ 85 ]


The arm of the WHI receiving combined estrogen and progestin therapy was closed prematurely in 2002 by its  Data Monitoring Committee  (DMC) due to perceived health risks, though this occurred a full year after the data suggesting increased risk became manifest. In 2004, the arm of the WHI in which post-hysterectomy patients were being treated with estrogen alone was also closed by the DMC. Clinical medical practice changed based upon two parallel  Women's Health Initiative  (WHI) studies of HRT. Prior studies were smaller, and many were of women who electively took hormonal therapy. One portion of the parallel studies followed over 16,000 women for an average of 5.2 years, half of whom took  placebo , while the other half took a combination of CEEs and MPA (Prempro). This WHI estrogen-plus-progestin trial was stopped prematurely in 2002 because preliminary results suggested risks of combined CEEs and progestins exceeded their benefits. The first report on the halted WHI estrogen-plus-progestin study came out in July 2002. [ 106 ]


Initial data from the WHI in 2002 suggested mortality to be lower when HRT was begun earlier, between age 50 to 59, but higher when begun after age 60. In older patients, there was an apparent increased incidence of breast cancer, heart attacks,  venous thrombosis , and stroke, although a reduced incidence of  colorectal cancer  and  bone fracture . At the time, The WHI recommended that women with non-surgical menopause take the lowest feasible dose of HRT for the shortest possible time to minimize associated risks. [ 106 ]  Some of the WHI findings were again found in a larger national study done in the United Kingdom, known as the  Million Women Study  (MWS). As a result of these findings, the number of women taking HRT dropped precipitously. [ 107 ]  In 2012, the  United States Preventive Task Force  (USPSTF) concluded that the harmful effects of combined estrogen and progestin therapy likely exceeded their chronic disease prevention benefits. [ 108 ] [ 109 ]


In 2002 when the first WHI follow up study was published, with HRT in post menopausal women, both older and younger age groups had a slightly higher incidence of breast cancer, and both heart attack and stroke were increased in older patients, although not in younger participants. Breast cancer was increased in women treated with estrogen and a progestin, but not with estrogen and progesterone or estrogen alone. Treatment with unopposed estrogen (i.e., an estrogen alone without a progestogen) is contraindicated if the uterus is still present, due to its proliferative effect on the  endometrium . The WHI also found a reduced incidence of colorectal cancer when estrogen and a progestogen were used together, and most importantly, a reduced incidence of bone fractures. Ultimately, the study found disparate results for all cause mortality with HRT, finding it to be lower when HRT was begun during ages 50–59, but higher when begun after age 60. The authors of the study recommended that women with non-surgical menopause take the lowest feasible dose of hormones for the shortest time to minimize risk. [ 106 ]


The data published by the WHI suggested supplemental estrogen increased risk of  venous thromboembolism  and breast cancer but was protective against  osteoporosis  and  colorectal cancer , while the impact on cardiovascular disease was mixed. [ 110 ]  These results were later supported in trials from the United Kingdom, but not in more recent studies from France and China. Genetic polymorphism appears to be associated with inter-individual variability in metabolic response to HRT in postmenopausal women. [ 111 ] [ 112 ]


The WHI reported  statistically significant  increases in rates of breast cancer,  coronary heart disease , strokes and  pulmonary emboli . The study also found statistically significant decreases in rates of  hip fracture  and  colorectal cancer . "A year after the study was stopped in 2002, an article was published indicating that estrogen plus progestin also increases the risks of dementia." [ 113 ]  The conclusion of the study was that the HRT combination presented risks that outweighed its measured benefits. The results were almost universally reported as risks and problems associated with HRT in general, rather than with Prempro, the specific proprietary combination of CEEs and MPA studied. [ citation needed ]


After the increased clotting found in the first WHI results was reported in 2002, the number of Prempro prescriptions filled reduced by almost half. Following the WHI results, a large percentage of HRT users opted out of them, which was quickly followed by a sharp drop in breast cancer rates. The decrease in breast cancer rates has continued in subsequent years. [ 114 ]  An unknown number of women started taking alternatives to Prempro, such as compounded bioidentical hormones, though researchers have asserted that compounded hormones are not significantly different from conventional hormone therapy. [ 115 ]


The other portion of the parallel studies featured women who were post  hysterectomy  and so received either placebo progestogen or CEEs alone. This group did not show the risks demonstrated in the combination hormone study, and the estrogen-only study was not halted in 2002. However, in February 2004 it, too, was halted. While there was a 23% decreased incidence of breast cancer in the estrogen-only study participants, risks of stroke and pulmonary embolism were increased slightly, predominantly in patients who began HRT over the age of 60. [ 116 ]


Several other large studies and meta-analyses have reported reduced mortality for HRT in women younger than age 60 or within 10 years of menopause, and a debatable or absent effect on mortality in women over 60. [ 117 ] [ 118 ] [ 119 ] [ 120 ] [ 17 ] [ 121 ]


Though research thus far has been substantial, further investigation is needed to fully understand differences in effect for different types of HRT and lengths of time since menopause. [ 122 ] [ 123 ] [ 35 ]   As of 2023 [update] , for example, no trial has studied women who begin taking HRT around age 50 and continue taking it for longer than 10 years. [ 124 ]


There are five major human steroid hormones: estrogens, progestogens,  androgens ,  mineralocorticoids , and  glucocorticoids . Estrogens and progestogens are the two most often used in menopause. They are available in a wide variety of FDA approved and non–FDA-approved formulations. [ 9 ]


In women with intact  uteruses , estrogens are almost always given in combination with progestogens, as long-term unopposed estrogen therapy is associated with a markedly increased risk of  endometrial hyperplasia  and  endometrial cancer . [ 1 ] [ 2 ]  Conversely, in women who have undergone a  hysterectomy  or do not have a uterus, a progestogen is not required, and estrogen can be used alone. There are many  combined formulations  which include both estrogen and progestogen. [ citation needed ]


Specific types of hormone replacement include: [ 1 ] [ 2 ]


Tibolone  – a synthetic medication available in Europe but not the United States– is more effective than  placebo  but less effective than combination hormone therapy in postmenopausal women. It may have a decreased risk of breast and colorectal cancer, though conversely it can be associated with vaginal bleeding, endometrial cancer, and increase the risk of stroke in women over age 60 years. [ 127 ] [ 128 ]


Vaginal estrogen  can improve local  atrophy  and dryness, with fewer systemic effects than estrogens delivered by other routes. [ 129 ]  Sometimes an androgen, generally testosterone, can be added to treat diminished  libido . [ 130 ] [ 131 ]


Dosage is often varied cyclically to more closely mimic the ovarian hormone cycle, with estrogens taken daily and progestogens taken for about two weeks every month or every other month, a schedule referred to as 'cyclic' or 'sequentially combined'. Alternatively, 'continuous combined' HRT can be given with a constant daily hormonal dosage. [ 132 ]  Continuous combined HRT is associated with less complex endometrial hyerplasia than cyclic. [ 133 ]  Impact on breast density appears to be similar in both regimen timings. [ 134 ]


The medications used in menopausal HRT are available in numerous different  formulations  for use by a variety of different  routes of administration : [ 1 ] [ 2 ]


More recently developed forms of drug delivery are alleged to have increased local effect lower dosing, fewer side effects, and constant rather than cyclical serum hormone levels. [ 1 ] [ 2 ]  Transdermal and vaginal estrogen, in particular, avoid  first pass metabolism  through the liver. This in turn prevents an increase in clotting factors and accumulation of anti-estrogenic metabolites, resulting in fewer adverse side effects, particularly with regard to cardiovascular disease and stroke. [ 135 ]


Injectable forms of estradiol exist and have been used occasionally in the past. [ 136 ] [ 137 ]  However, they are rarely used in menopausal hormone therapy in modern times and are no longer recommended. [ 136 ] [ 138 ]  Instead, other non-oral forms of estradiol such as transdermal estradiol are recommended and may be used. [ 136 ]  Estradiol injectables are generally well-tolerated and convenient, requiring infrequent administration. [ 136 ] [ 137 ]  However, this form of estradiol does not release estradiol at a constant rate and there are very high circulating estradiol levels soon after injection followed by a rapid decline in levels. [ 136 ]  Injections may also be painful. [ 136 ]  Examples of estradiol injectables that may be used in menopausal hormone therapy include  estradiol valerate  and  estradiol cypionate . [ 136 ] [ 137 ]  In terms of injectable progestogens, injectable progesterone is associated with pain and injection site reactions as well as a short duration of action requiring very frequent injections, and is similarly not recommended in menopausal hormone therapy. [ 139 ] [ 137 ]


Bioidentical hormone therapy  (BHT) is the usage of hormones that are chemically identical to those produced in the body. Although proponents of BHT claim advantages over non-bioidentical or conventional hormone therapy, the FDA does not recognize the term 'bioidentical hormone', stating there is no scientific evidence that these hormones are identical to their  naturally  occurring counterparts. [ 11 ] [ 140 ]  There are, however, FDA approved products containing hormones classified as 'bioidentical'. [ 12 ] [ 9 ]


Bioidentical hormones can be used in either  pharmaceutical  or  compounded  preparations, with the latter generally not recommended by regulatory bodies due to their lack of standardization and regulatory oversight. [ 11 ]  Most classifications of bioidentical hormones do not take into account manufacturing, source, or delivery method of the products, and so describe both non-FDA approved compounded products and FDA approved pharmaceuticals as 'bioidentical'. [ 9 ]  The British Menopause Society has issued a  consensus statement  endorsing the distinction between "compounded" forms (cBHRT), described as unregulated, custom made by specialty pharmacies and subject to heavy marketing and "regulated" pharmaceutical grade forms (rBHRT), which undergo formal oversight by entities such as the  FDA  and form the basis of most clinical trials. [ 141 ]  Some practitioners recommending compounded bioidentical HRT also use salivary or serum hormonal testing to monitor response to therapy, a practice not endorsed by current clinical guidelines in the United States and Europe. [ 142 ]


Bioidentical hormones in pharmaceuticals may have very limited clinical data, with no randomized controlled prospective trials to date comparing them to their animal derived counterparts. Some pre-clinical data has suggested a decreased risk of  venous thromboembolism ,  cardiovascular disease , and breast cancer. [ 11 ]  As of 2012, guidelines from the  North American Menopause Society , the  Endocrine Society , the  International Menopause Society , and the  European Menopause and Andropause Society  endorsed the reduced risk of bioidentical pharmaceuticals for those with increased clotting risk. [ 11 ] [ 143 ]


Compounding for HRT is generally discouraged by the FDA and medical industry in the United States due to a lack of regulation and standardized dosing. [ 11 ] [ 140 ]  The  U.S. Congress  did grant the FDA explicit but limited oversight of compounded drugs in a 1997 amendment to the  Federal Food, Drug, and Cosmetic Act  (FDCA), but they have encountered obstacles in this role since that time. After 64 patient deaths and 750 harmed patients from a 2012 meningitis outbreak due to contaminated steroid injections, Congress passed the 2013  Drug Quality and Security Act , authorizing creation by the FDA of a voluntary registration for facilities that manufactured compounded drugs, and reinforcing FDCA regulations for traditional compounding. [ 144 ]  The DQSA and its reinforcement of provision §503A of the FDCA solidifies FDA authority to enforce FDCA regulation of against compounders of bioidentical hormone therapy. [ 144 ]


In the United Kingdom, on the other hand, compounding is a regulated activity. The  Medicines and Healthcare products Regulatory Agency  regulates compounding performed under a Manufacturing Specials license and the  General Pharmaceutical Council  regulates compounding performed within a pharmacy. All testosterone prescribed in the United Kingdom is bioidentical, with its use supported by the  National Health Service . There is also marketing authorisation for male testosterone products.  National Institute for Health and Care Excellence  guideline 1.4.8 states: "consider testosterone supplementation for menopausal women with low sexual desire if HRT alone is not effective". The footnote adds: "at the time of publication (November 2015), testosterone did not have a United Kingdom marketing authorisation for this indication in women. Bioidentical progesterone is used in IVF treatment and for pregnant women who are at risk of premature labour." [ citation needed ]


Wyeth , now a subsidiary of  Pfizer , was a  pharmaceutical company  that marketed the HRT products Premarin (CEEs) and Prempro (CEEs + MPA). [ 145 ] [ 146 ]  In 2009,  litigation  involving Wyeth resulted in the release of 1,500 documents that revealed practices concerning its promotion of these medications. [ 145 ] [ 146 ] [ 147 ]  The documents showed that Wyeth commissioned dozens of  ghostwritten   reviews  and commentaries that were published in  medical journals  to promote unproven benefits of its HRT products, downplay their harms and risks, and cast competing therapies in a negative light. [ 145 ] [ 146 ] [ 147 ]  Starting in the mid-1990s and continuing for over a decade, Wyeth pursued an aggressive "publication plan" strategy to promote its HRT products through the use of ghostwritten publications. [ 147 ]  It worked mainly with DesignWrite, a medical writing firm. [ 147 ]  Between 1998 and 2005, Wyeth had 26 papers promoting its HRT products published in scientific journals. [ 145 ]


These favorable publications emphasized the benefits and downplayed the risks of its HRT products, especially the "misconception" of the association of its products with breast cancer. [ 147 ]  The publications defended unsupported cardiovascular "benefits" of its products, downplayed risks such as breast cancer, and promoted  off-label  and unproven uses like prevention of dementia,  Parkinson's disease ,  vision problems , and  wrinkles . [ 146 ]  In addition, Wyeth emphasized negative messages against the SERM  raloxifene  for osteoporosis, instructed writers to stress the fact that "alternative therapies have increased in usage since the WHI even though there is little evidence that they are effective or safe...", called into question the quality and therapeutic equivalence of approved generic CEE products, and made efforts to spread the notion that the unique risks of CEEs and MPA were a class effect of all forms of menopausal HRT: "Overall, these data indicate that the benefit/risk analysis that was reported in the Women's Health Initiative can be generalized to all postmenopausal hormone replacement therapy products." [ 146 ]


Following the publication of the WHI data in 2002, the stock prices for the pharmaceutical industry plummeted, and huge numbers of women stopped using HRT. [ 148 ]  The stocks of Wyeth, which supplied the Premarin and Prempro that were used in the WHI trials, decreased by more than 50%, and never fully recovered. [ 148 ]  Some of their articles in response promoted themes such as the following: "the WHI was flawed; the WHI was a controversial trial; the population studied in the WHI was inappropriate or was not representative of the general population of menopausal women; results of clinical trials should not guide treatment for individuals; observational studies are as good as or better than randomized clinical trials; animal studies can guide clinical decision-making; the risks associated with hormone therapy have been exaggerated; the benefits of hormone therapy have been or will be proven, and the recent studies are an aberration." [ 104 ]  Similar findings were observed in a 2010 analysis of 114 editorials, reviews, guidelines, and letters by five industry-paid authors. [ 104 ]  These publications promoted positive themes and challenged and criticized unfavorable trials such as the WHI and MWS. [ 104 ]  In 2009, Wyeth was acquired by Pfizer in a deal valued at US$68 billion. [ 149 ] [ 150 ]  Pfizer, a company that produces Provera and Depo-Provera (MPA) and has also engaged in medical ghostwriting, continues to market Premarin and Prempro, which remain best-selling medications. [ 104 ] [ 147 ]


According to Fugh-Berman (2010), "Today, despite definitive scientific data to the contrary, many gynecologists still believe that the benefits of [HRT] outweigh the risks in asymptomatic women. This non-evidence–based perception may be the result of decades of carefully orchestrated corporate influence on medical literature." [ 146 ]  As many as 50% of physicians have expressed skepticism about large trials like the WHI and HERS in a 2011 survey. [ 151 ]  The positive perceptions of many physicians of HRT in spite of large trials showing risks that potentially outweigh any benefits may be due to the efforts of pharmaceutical companies like Wyeth, according to May and May (2012) and Fugh-Berman (2015). [ 147 ] [ 104 ]


The 1990s showed a dramatic decline in prescription rates, though more recently they have begun to rise again. [ 135 ] [ 152 ]  Transdermal therapy, in part due to its lack of increase in venous thromboembolism, is now often the first choice for HRT in the United Kingdom. Conjugate equine estrogen, in distinction, has a potentially higher thrombosis risk and is now not commonly used in the UK, replaced by estradiol based compounds with lower thrombosis risk. Oral progestogen combinations such as medroxyprogesterone acetate have changed to dyhydrogesterone, due to a lack of association of the latter with venous clot. [ 153 ]


Hot flashes , also known as  hot flushes , are a form of  flushing , often caused by the changing  hormone  levels that are characteristic of  menopause . They are typically experienced as a feeling of intense heat with  sweating  and  rapid heartbeat , and may typically last from two to 30 minutes for each occurrence.


Hot flashes, a common symptom of  menopause  and  perimenopause , are typically experienced as a feeling of intense heat with  sweating  and rapid  heartbeat , and may typically last from two to thirty minutes for each occurrence, ending just as rapidly as they began. The sensation of heat usually begins in the face or chest, although it may appear elsewhere such as the back of the neck, and it can spread throughout the whole body. [ 1 ]  Some people feel as if they are going to faint. In addition to being an internal sensation, the surface of the skin, especially on the face, becomes hot to the touch. This is the origin of the alternative term "hot flush", since the sensation of heat is often accompanied by visible reddening of the face.


The hot-flash event may be repeated a few times each week or every few minutes throughout the day. Hot flashes may begin to appear several years before menopause starts and last for years afterwards. Some people undergoing menopause never have hot flashes. Others have mild or infrequent flashes. Those most affected experience dozens of hot flashes each day. In addition, hot flashes are often more frequent and more intense during hot weather or in an overheated room, the surrounding heat apparently making the hot flashes themselves both more likely to occur, and more severe.


Severe hot flashes can make it difficult to get a full night's sleep (often characterized as  insomnia ), which in turn can affect mood, impair concentration, and cause other physical problems. When hot flashes occur at night, they are called " night sweats ". As  estrogen  is typically lowest at night, some people get night sweats without having any hot flashes during the daytime. [ 2 ]


If hot flashes occur at other times in a young female's menstrual cycle, then it might be a symptom of a problem with the  pituitary gland ; seeing a doctor is highly recommended. In younger females who are surgically menopausal, hot flashes are generally more intense than in older females, and they may last until natural age at menopause. [ 3 ]


Hot flashes in males could have various causes. It can be a sign of low testosterone. [ 4 ] [ 5 ] [ 6 ]  Males with  prostate cancer  or  testicular cancer  can also have hot flashes, especially those who are undergoing hormone therapy with  antiandrogens , also known as androgen antagonists, which reduce testosterone to castrate levels. [ 7 ]  Males who are  castrated  can also get hot flashes. [ 8 ] [ 9 ] [ 10 ]


Some menopausal females may experience both standard hot flashes and a second type sometimes referred to as "slow hot flashes" or "ember flashes". The standard hot flash comes on rapidly, sometimes reaching maximum intensity in as little as a minute. It lasts at full intensity for only a few minutes before gradually fading.


Slow "ember" flashes appear almost as quickly but are less intense and last for around half an hour. Females who experience them may undergo them year round, rather than primarily in the summer, and ember flashes may linger for years after the more intense hot flashes have passed.


Research on hot flashes is mostly focused on treatment options.  The exact cause and  pathogenesis , or causes, of  vasomotor  symptoms (VMS)—the clinical name for hot flashes—has not yet been fully studied. [ 11 ] [ 12 ]


Hot flashes are associated with declining levels of estrogen (estrogen withdrawal) and other hormonal changes. [ 13 ]  It does not appear that low levels of estrogen are the sole cause of hot flashes, as women who experience hot flashes have around the same plasma estrogen levels as women who do not have them, and prepubertal girls do not have hot flashes despite low estrogen levels. [ 13 ]


There are indications that hot flashes may be due to a change in the  hypothalamus 's control of temperature regulation. [ 14 ]


Transgender  men also commonly report experiences of hot flashes. [ 15 ]  This is linked to hormonal changes possible from many aspects of masculinizing gender-affirming care, including the use of  gonadotropin-releasing hormone agonists  as  puberty blockers , [ 16 ]  reduction of estrogen levels after having undergone  oopherectomy , [ 17 ]  and long term testosterone use reducing production of estradiols. [ 18 ]


Hormone replacement therapy  may relieve many of the symptoms of menopause. However, oral HRT may increase the risk of breast cancer, stroke, and dementia and has other potentially serious short-term and long-term risks. [ 19 ] [ 20 ]  Since the incidence of cardiovascular disease in women has shown a rise that matches the increase in the number of post menopausal women, recent studies have examined the benefits and side effects of oral versus transdermal application of different estrogens and found that transdermal applications of estradiol may give the vascular benefits lowering the incidences of cardiovascular events with fewer adverse side effects than oral preparations. [ 21 ] [ 22 ]


Women who experience troublesome hot flashes are advised by some to try alternatives to hormonal therapies as the first line of treatment. If a woman chooses hormones, they suggest she take the lowest dose that alleviates her symptoms for as short a time as possible. [ 23 ]  The US Endocrine Society concluded that women taking hormone replacement therapy for 5 years or more experienced overall benefits in their symptoms including relief of hot flashes and symptoms of urogenital atrophy and prevention of fractures and diabetes. [ 24 ]


When estrogen as estradiol is used transdermally as a patch, gel, or pessary with micronized progesterone this may avoid the serious side effects associated with oral estradiol HRT since this avoids first pass metabolism ( Phase I drug metabolism ). [ 25 ]  Women taking bioidentical estrogen, orally or transdermally, who have a uterus must still take a progestin or micronized progesterone to lower the risk of endometrial cancer. A French study of 80,391 postmenopausal women followed for several years concluded that estrogen in combination with micronized progesterone is not associated with an increased risk of breast cancer. [ 26 ]  The natural, plant-derived progesterone creams sold over the counter contain too little progesterone to be effective.  Wild yam ( Dioscorea villosa ) extract creams are not effective since the natural progesterone present in the extract is not bioavailable. [ 27 ]


SSRIs  are a class of pharmaceuticals that are most commonly used in the treatment of  depression . They have been found efficient in alleviating hot flashes. [ 28 ]  On 28 June 2013 FDA approved Brisdelle (low-dose paroxetine mesylate) for the treatment of moderate-to-severe vasomotor symptoms (e.g. hot flashes and night sweats) associated with menopause. Paroxetine became the first and only non-hormonal therapy for menopausal hot flashes approved by FDA. [ 29 ]


Clonidine  is a blood pressure-lowering medication that can be used to relieve menopausal hot flashes when hormone replacement therapy is not needed or not desired. For hot flashes, clonidine works by helping reduce the response of the blood vessels to stimuli that cause them to narrow and widen. [ 30 ]  While not all women respond to clonidine as a hot flash medication, it can reduce hot flashes by 40% in some peri-menopausal women. [ 31 ]


Isoflavones  are commonly found in  legumes  such as soy and  red clover . The two soy isoflavones implicated in relieving menopausal symptoms are  genistein  and  daidzein , and are also known as  phytoestrogens . The half life of these molecules is about eight hours, which might explain why some studies have not consistently shown effectiveness of soy products for menopausal symptoms. [ citation needed ]   Although red clover ( Trifolium pratense ) contains isoflavones similar to soy, the effectiveness of this herb for menopausal symptoms at relatively low concentrations points to a different mechanism of action. [ 32 ]


It is believed  [ by whom? ]  that dietary changes that include a higher consumption of  phytoestrogens  from sources such as soy, red clover, ginseng, and yam may relieve hot flashes.


Acupuncture  has been suggested to reduce incidence of hot flashes in women with breast cancer and men with prostate cancer, but the quality of evidence is low. [ 38 ] [ 39 ]


It has been speculated that hot flashes are less common among  Asian women . [ 40 ] [ 41 ]


Menopausal women who have more hot flashes have a higher risk of  hypertension  and  cardiovascular disease . [ 42 ]


The  International Menopause Society  ( IMS ) is a UK based charity. The Association was created in 1978 in Jerusalem during the second Menopause Congress and currently has members in 62 countries. In addition to organizing congresses, symposia, and workshops, the IMS owns its own journal:  Climacteric , the Journal of Adult Women's Health and Medicine, published by  Taylor & Francis .


The Society's official journal,  Climacteric , the Journal of Adult Women's Health and Medicine, was founded in 1998 and is listed in Index Medicus/MEDLINE. [ 1 ]  The Editor-in-Chief is Rodney Baber Australia. It publishes international, original, peer-reviewed research on all aspects of aging in women, especially during the  menopause  and climacteric. The content of the journal covers the whole range of subject areas relevant to climacteric studies and adult women’s health and medicine, including underlying endocrinological changes, treatment of the symptoms of the menopause and other age-related changes,  hormone replacement  therapies, alternative therapies, effective life-style modifications, non-hormonal midlife changes, and the counselling and education of  perimenopausal  and  postmenopausal  patients. [ 2 ] [ 3 ]


The IMS hold a biennial World Congress in the different regions of the world, the 18th being held in Lisbon, Portugal in 2022 to be followed by Melbourne Australia 2024 [ 4 ]


Late-onset hypogonadism  ( LOH ) or  testosterone deficiency syndrome  ( TDS ) [ 1 ] [ 2 ]  is a term for a condition in older men characterized by measurably low  testosterone  levels and clinical symptoms mostly of a sexual nature, including decreased desire for mating, fewer spontaneous erections, and  erectile dysfunction . [ 3 ]  It is the result of a gradual drop in testosterone; a steady decline in testosterone levels of about 1% per year can happen and is well documented in both men and women. [ 4 ] [ 5 ]


Some men present with symptoms, but they have normal testosterone levels, while others with low testosterone levels have no symptoms. The reasons for this phenomenon are currently unknown. [ 3 ] [ 6 ]


In their late 40s and early 50s, some men may experience depression, loss of libido, erectile dysfunction, and other physical and emotional symptoms. These symptoms include irritability, loss of muscle mass and reduced ability to exercise, weight gain, lack of energy, difficulty sleeping, and poor concentration. It is important to note that many of these symptoms may arise from a  midlife crisis  or as the results of a long-term unhealthy lifestyle (smoking, excess drinking, overeating, lack of exercise) and may be best addressed by lifestyle changes, therapy, or antidepressants. [ 7 ]


Testosterone levels are well-documented to decline with aging at about 1% per year in both men and women after a certain age; the causes are not well understood. [ 3 ] [ 4 ] [ 5 ] [ 8 ] [ 9 ]


As of 2016, the International Society for the Study of the Aging Male defines late-onset hypogonadism as a series of symptoms in older adults related to testosterone deficiency that combines features of both  primary  and  secondary  hypogonadism; the European Male Aging Study (a prospective study of ~3000 men) [ 10 ]  defined the condition by the presence of at least three sexual symptoms (e.g. reduced libido, reduced spontaneous erections, and erectile dysfunction) and total testosterone concentrations less than 11 nmol/L (3.2 ng/mL) and free testosterone concentrations less than 220 pmol/L (64 pg/mL). [ 3 ]


If a person has symptoms of late-onset hypogonadism, testosterone is measured by taking blood in the morning on at least two days; while  immunoassays  are commonly used,  mass spectrometry  is more accurate and is becoming more widely available. [ 6 ]  The meaning of the measurement is different depending on many factors that affect how testosterone is made and how it is carried in the blood. Increased concentrations of proteins that bind testosterone in blood occur if the person is older, has hyperthyroidism or liver disease, or is taking  anticonvulsant  drugs (which are increasingly used for depression and various  neuropathies ), and decreased concentrations of proteins that bind testosterone occur if the person is obese, has diabetes, has hypothyroidism, has liver disease, or is taking  glucocorticoids  or  androgens , or  progestins . [ 6 ]  If levels are low, conditions that cause primary and secondary hypogonadism need to be ruled out. [ 6 ] [ 11 ] [ 12 ]


Due to difficulty and expense of testing, and the ambiguity of the results, screening is not recommended. [ 3 ] [ 6 ]  While some clinical instruments (standard surveys) had been developed as of 2016, their  specificity  was too low to be useful clinically. [ 3 ]


The significance of a decrease in testosterone levels is debated and its treatment with replacement is controversial. The  Food and Drug Administration  (FDA) stated in 2015 that neither the benefits nor the safety of  testosterone  have been established in older men with low testosterone levels. [ 13 ]
Testosterone replacement therapy should only be started if low levels have been confirmed; [ 11 ]  in the US, this confirmation is not done about 25% of the time, as of 2015. [ 12 ]  Testosterone levels should also be monitored during therapy. [ 11 ]


Adverse effects of testosterone supplementation may include increased cardiovascular (CV) events (including  strokes  and  heart attacks ) and  deaths , especially in men over 65 and men with pre-existing heart conditions. [ 3 ]  The potential for CV risks from testosterone therapy led the FDA to issue a requirement in 2015 that testosterone pharmaceutical labels include warning information about the possibility of an increased risk of heart attacks and stroke. [ 3 ] [ 13 ]  However, the data are mixed, so the European Medicines Agency, the American Association of Clinical Endocrinologists, and the American College of Endocrinology have stated that no consistent evidence shows that testosterone therapy either increases or decreases cardiovascular risk. [ 3 ]


Other significant adverse effects of testosterone supplementation include acceleration of pre-existing  prostate cancer  growth; increased  hematocrit , which can require  venipuncture  to treat; and, exacerbation of sleep  apnea . [ 3 ]


Adverse effects may also include minor side effects such as acne and oily skin, as well as significant hair loss and/or thinning of the hair, which may be prevented with  5-alpha reductase  inhibitors ordinarily used for the treatment of  benign prostatic hyperplasia , such as  finasteride  or  dutasteride . [ 14 ]


Exogenous testosterone may also cause suppression of  spermatogenesis , leading to, in some cases, infertility. [ 3 ]


As of 2015, the evidence is inconclusive as to whether testosterone replacement therapy can help with erectile dysfunction in men with late-onset hypogonadism. [ 12 ]  It appears that testosterone replacement therapy may benefit men with symptoms of  frailty  who have late-onset hypogonadism. [ 12 ]


The epidemiology is not clear; 20% of men in their 60s and 30% of men in their 70s have low testosterone; [ 4 ] [ 12 ]  around 5% of men between 70 and 79 have both low testosterone and the symptoms, so are diagnosed with late-onset hypogonadism. [ 4 ]  The UK  National Health Service  describes it as rare. [ 7 ]


The impact of low levels of  testosterone  has been previously reported. In 1944, Heller and Myers identified symptoms of what they labeled the "male  climacteric " including loss of  libido  and potency, nervousness,  depression , impaired memory, the inability to concentrate,  fatigue ,  insomnia , hot flushes, and sweating. Heller and Myers found that their subjects had lower than normal levels of testosterone, and that symptoms decreased dramatically when patients were given replacement doses of testosterone. [ 15 ] [ 16 ]


The 1997 book  Male Menopause [ 17 ] [ 18 ]  by Jed Diamond, a psychologist with a PhD in international health, [ 19 ]
fueled popular interest in the concept of "andropause". [ citation needed ]
Diamond regards andropause as a change of life in middle-aged men which has hormonal, physical, psychological, interpersonal, social, sexual, and spiritual aspects. Diamond claims that this change occurs in all men, that it may occur as early as age 45 to 50 and more dramatically after the age of 70 in some men, and that women's and men's experiences are somewhat similar phenomena. [ 20 ] [ 21 ]  The medical community has rejected the term "andropause" and its supposed parallels with menopause. [ 22 ] [ 23 ]


Thomas Perls and David J. Handelsman, in a 2015 editorial in the  Journal of the American Geriatrics Society , say that between the ill-defined nature of the diagnosis and the pressure and advertising from drug companies selling testosterone and human-growth hormone, as well as  dietary supplement  companies selling all kinds of "boosters" for aging men, the condition is  overdiagnosed  and  overtreated . [ 24 ]
Perls and Handelsman note that in the US, "sales of testosterone increased from $324 million in 2002 to $2 billion in 2012, and the number of testosterone doses prescribed climbed from 100 million in 2007 to half a billion in 2012, not including the additional contributions from compounding pharmacies, Internet, and direct-to-patient clinic sales." [ 24 ]


Late-onset hypogonadism is an  endocrine  condition as well as a result of  aging . [ 3 ]


The terms "male  menopause " and "andropause" are used in the popular media but are misleading, as they imply a sudden change in hormone levels similar to what women experience in  menopause . [ 7 ]  A decrease in libido in men as a result of age is sometimes colloquially referred to as  penopause . [ 25 ]


As of 2016, research was necessary to find better ways to measure testosterone and to be better able to understand the measurements in any given person, and to understand why some people with low testosterone do not present with symptoms and some with seemingly adequate levels do present with symptoms. [ 3 ]  Research was also necessary to better understand the cardiovascular risks of testosterone replacement therapy in older men. [ 3 ]


A relationship between late-onset hypogonadism and risk of  Alzheimer's disease  has been hypothesized, and some small clinical studies have been conducted to investigate the prevention of Alzheimer's disease in men with late-onset hypogonadism; as of 2009, results were inconclusive. [ 26 ]


Menopause in incarceration  is a social and policy campaigning issue in which people work to raise awareness of the  gender specific impact  menopause  symptoms can have on people in  prison . [ 1 ]   Although women are a minority of those incarcerated, the age of women in the prison system is increasing across the world. As this happens it becomes necessary for inmates to be assessed for menopausal symptoms and offered the gender and age-specific services and support they need. [ 2 ]  Researchers have identified this as a gap in  prison healthcare  which leaves the needs of many people unmet. [ 3 ] [ 4 ]


Menopausal women experience a range of medical and health issues whether or not they are in prison. Particular aspects of incarceration, however, may exacerbate the experience of  menopause  and these are the responsibility of organisations making health policy. [ 5 ]   In the US, a third of older women prisoners say they are concerned about it. [ 3 ]   Menopause is an inter-sectional issue in women's health as it combines gender and age. [ 6 ]  Incarceration brings a complex combination of inequality factors for women's needs in terms of  menstruation ,  pregnancy ,  contraception ,  post-natal  health, mental health and menopause. In countries where prisons are privatized, women's health needs may be seen as low priority. [ 7 ]


In prisons access to hygiene and medical supplies are restricted, [ 8 ] [ 9 ]  and it is difficult to regulate the temperature of rooms.  Peri-menopause  leads to erratic periods and many women experience frequent hot-flashes. [ 10 ]    Many facilities do not provide access to locally controlled air conditioning or fans which are needed to regulate and relieve  hot flashes , which are a common symptom of menopause. Additional layers of clothing may be needed for increased comfort during hot flashes and night sweating. [ 11 ]  The symptoms of menopause may also include mental health issues such as feelings of shame, embarrassment, short-temper, loneliness and  depression  which are challenging to manage for well-being in prison. [ 12 ] [ 13 ]  In the UK, 65% of women in prison suffer from depression. [ 14 ]  Shame and embarrassment results from physical changes but also from societal norms in which menopause continues to be a 'taboo subject'. [ 15 ]   Women inmates in prisons report that their concerns were often dismissed. [ 3 ]


There are additional physical complications as menopause often brings  osteoporosis  and in prisons the weight-bearing exercises and extra support may not be available to help in treatment. [ 11 ]  In the UK the health of older prisoners is seen to be worse than that of the wider community and many have additional  disabilities  or long-standing illness. [ 16 ]


In the USA the fastest-growing segment of the prison population is women but health systems which have been designed for men fail to meet their needs. [ 17 ]   The  National Commission on Correctional Health Care  recognize the need for standards in care in jails and prisons. [ 18 ]


The  UK Government  has set standards for care of women in prison  which includes appropriate treatment and support for transition through the menopause and  access to the similar standards of care as they would have in the community.  Women are offered access to  hormone replacement therapy  and the option to change their sheets frequently if they suffer from night sweats. [ 19 ]


In 2009 the  Kyiv  Declaration on Women's Health in Prison reviewed issues affecting women's health in the criminal justice system. [ 20 ]  The Declaration raises awareness of the differences in health needs between men and women prisoners. The  World Health Organisation  considers that prison health services contribute to the social well-being of all of society and  suggests that prisons should have written policies showing  the practices that are sensitive to women. [ 5 ]  The United Nations 2010 Rules for the Treatment of Women Prisoners and Non-custodial Measures for Women Offenders are known as ' The Bangkok Rules '. The 70 Rules give guidance to cover healthcare and humane treatment . [ 12 ] [ 21 ]


Menopause in the workplace  is a social and  human resources  campaigning issue in which people work to raise awareness of the impact  menopause  symptoms can have on attendance and performance in the  workplace .


Campaigners, journalists, personnel professionals and academics draw upon published research  [ 1 ] [ 2 ] [ 3 ]  and lobby for support for workers via industrial  trades unions  (including  ACAS , [ 4 ]   TUC , [ 5 ]   UCU , [ 6 ]   UNISON , [ 7 ]   EIS , [ 8 ]   NASUTW [ 9 ] ) and changes in legislation. [ 10 ]   In the UK under the  Equality Act 2010 , menopause discrimination is covered by three of the protected characteristics: age, sex and disability discrimination. [ 11 ]  A UK government cross-party equalities working group explored why workplaces were failing women going through the menopause  [ 12 ] [ 13 ] [ 14 ]


The average age for the menopause transition is 51. [ 2 ]  Women over the age of 50 are a growing demographic in the workforce. [ 15 ]   14 million working days are lost to menopause each year in the UK. [ 16 ]   Around 900,000 women have left jobs in the UK because of menopause symptoms making continuing work impossible. [ 12 ] [ 17 ]


A June 2023 study by the Mayo Clinic estimated an annual loss of $1.8 billion in the United States due to workdays missed as a result of menopause symptoms. [ 18 ]  This was one of the largest studies to date examining the impact of menopause symptoms on work outcomes. The research concluded there was a strong need to improve medical treatment for menopausal women and make the workplace environment more supportive to avoid such productivity losses.


Many women go through the menopause during their working lives, and workplace support is vital. [ 19 ] [ 4 ]   Menopause is considered by many to be a private matter [ 20 ]  or ‘a women's issue' or the 'last taboo' [ 21 ]  subject in workplaces. [ 22 ] [ 23 ]  The  TUC  found that many employers were unaware of the issues involved and not tackling problems in ways that helped workers. The impact of employers failing to make reasonable adjustments include loss of work days due to absence [ 24 ]  and women being disciplined on competency grounds for health issues. [ 5 ]  The number of UK employment tribunals concerning menopause is increasing. [ 25 ] [ 26 ]


A  UK government  report suggests that employers can make positive changes by "changing organisational cultures; compulsory equality and diversity training; providing specialist advice; tailored absence policies; flexible working patterns for mid-life women; and fairly low cost environmental changes" to cater for women's differing experiences. [ 2 ]  The  CIPD  have produced a range of guides for HR professionals and managers  [ 27 ]


There remains a research gap in evaluating the effectiveness of these interventions.


In the US, National Institute on Aging has conducted research exploring the impact of menopause on women's health and aging. [ 28 ]  Particular care has been taken to include in the research participants women from different racial and ethnic backgrounds, including African American, Chinese, Hispanic and Japanese. This has helped scientists identify racial and ethnic differences in women's experiences. [ 28 ]


The social acceptability of discussions of menopause vary across cultures. Menopause is an  intersectional  issue of  sex  and  age.


For many women it is experienced as a 'double or triple whammy' of home and workplace responsibilities coming as it does just at the time when their children are teenagers, their parents are elderly and they have just made it back from a career break. It may also come at the time of increased leadership and management responsibilities. [ 29 ]  When women eligible for senior management roles leave work at the peak of their careers, there are compounding effects on the  gender pay-gap  and the  gender pension gap . Three out of five (59%) working women between the ages of 45 and 55 who are experiencing menopause symptoms say it has a negative impact on them at work  [ 30 ]


Menopause support may also be linked to mental health at work. A 2018 Radio 4  Woman's Hour  poll that found that 48% of women experiencing the menopause reported that it had "a negative impact on their mental health and mood". [ 31 ]  Employers may not be aware that there are different cultural attitudes to menopause. [ 32 ]  In the workplace menopause becomes an intersectional issue of supporting workers with regard to age, sex, disability and race. [ 33 ]


As of yet, menopause is not a protected characteristic [ 3 ]  specified under the  Equality Act 2010 . The  Health and Safety at Work etc. Act 1974  provides for safe working, which extends to the working conditions when experiencing symptoms of menopause. Recently, there have been calls made for further legislation [ 7 ]  to require employers to put in place a workplace menopause policy to protect women going through the menopause against discrimination whilst at work. [ 34 ]


Some aspects of workplace environments can make menopause symptoms worse, especially hot or poorly ventilated environments. [ 35 ] [ 36 ]


Menopause also impacts  remote workers . During the  COVID-19 pandemic , many women who had previously worked in their employer's premises shifted to remote work. [ 37 ] [ 38 ]  While there are some elements of remote work which might be assumed to be better for menopausal women such as more control over the temperature and comfort of their home environments, there are multiple factors such as the responsibilities of home schooling and sharing limited space in the home which combined to shape working women's experiences of lockdown.


Caroline Nokes , Chair of the  Women and Equalities Committee , said in 2021: "Three in every five women are negatively affected at work as a result of the menopause. The repercussions of that are not merely individual. Excluding menopausal women from the workplace is detrimental to our economy, our society and our place on the world stage. Despite the fact that hundreds of thousands of women in the UK are currently going through the menopause- a process that can be both physically and mentally draining- it is ignored in legislation. It is time to uncover and address this huge issue, which has been left near-invisible for far too long." [ 14 ]


In 2022 members of the UK government considered amending the  Equality Act 2010  to include menopause as a protected characteristic. They also hoped to require employers to provide reasonable adjustments for employees experiencing menopause. [ 39 ] [ 15 ] [ 40 ]  As it stands, UK law fails to provide proper redress for women who are discriminated against in the workplace as a result of their menopausal status. There is also generally poor understanding of health and safety at work in this regard.  The authors of the report propose significant change to improve the working conditions for women and those who ultimately seek legal redress: [ 15 ]


Our recommendations for employers are designed to ensure fewer women need legal redress. However, those who do need to rely on the law need, and deserve, a better safety net. We call on the Government to commence section 14 of the Equality Act 2010 to allow dual discrimination claims based on more than one protected characteristic. We also want the Government to urgently consult on making menopause a protected characteristic under the Equality Act 2010.


The 2022 report from the UK Women and Equalities Committee stimulated discussions about the possibility of employers establishing policies and support for 'menopause leave'. [ 41 ] [ 42 ] [ 43 ]


There are a number of high-profile media professionals and journalists in the UK who have worked to raise awareness of menopause through sharing their own experiences publicly. These include  Patsy Kensit ,  Davina McCall ,  Jenni Murray , [ 44 ]   Kirsty Wark , [ 45 ]   Jennifer Saunders , [ 46 ]   Bridget Christie , [ 47 ]   Jo Whiley [ 48 ]  and  Jenny Eclair . [ 49 ]


Some higher education institutions [ 50 ]  have made changes to support their staff. These include  University of Leicester [ 51 ]  and  University College London . [ 52 ]


Academics who research in this area include:  Jo Brewis , [ 53 ] [ 54 ]  Belinda Steffan, [ 55 ] [ 56 ]   Wendy Loretto [ 57 ]  and  Myra Hunter .


Guidance for supporting teachers during menopause has been published by  EIS , [ 8 ]   NASUWT [ 9 ]  and  NEU [ 58 ]


The Police in England and Wales have published National Menopause Guidance which is designed to help support and advise individuals, line managers, senior leaders and occupational health advisors  [ 59 ]  The national lead for Gender at the National Police Chiefs' Council, said: "I genuinely believe that the launch of this guidance is a huge step forward for policing." The demographic of the police workforce across the UK is changing, with an increasing number of female colleagues, and an aging workforce in key front-line roles as well as other roles in our organisations. There are clear health and safety implications for women, their colleagues, and the general public, if we do not support, understand and deal with menopause issues properly. [ 59 ]  Support is also available for members of  Police Federation Scotland [ 60 ]   and Police Federation of Northern Ireland . [ 61 ]


The  NHS  recognise that "with our population now living longer, working longer, and with so many women working in the NHS, it's vital that staff are supported to stay well and thrive in the workplace". [ 62 ] [ 63 ]  The  BMA  argue that employers should take a pro-active approach to an inclusive workplace. [ 64 ]


British MPs have pushed for clear workplace policies to protect women going through the menopause.   Rachel Maclean  said "My central message is: menopause is the last taboo because it is still hidden and it only affects women and it only affects older women. It's ageism, it's sexism, all rolled into one." [ 65 ]  Other women who have spoken about their experiences include  Carolyn Harris , [ 66 ]   Julie Marson , [ 67 ]   Maria Caulfield , [ 67 ]  and  Caroline Nokes . [ 68 ]   Dawn Butler , in her role as Shadow Women and Equalities Secretary, announced the Labour Party's commitment to introduce a menopause workplace policy including providing and ensuring flexible working policies and absence procedures that cater for women experiencing the menopause. [ 69 ]  This menopause workplace policy was included in the  Labour Party 's 2019 Manifesto. [ 70 ]


The Law Society issued guidance for women experiencing menopause in the legal profession [ 71 ] [ 72 ]  and guidance for judges receiving evidence from women. [ 73 ]


Night sweats  or  nocturnal hyperhidrosis [ 1 ]  is the repeated occurrence of  excessive sweating  during  sleep . [ 2 ]  The person may or may not also  perspire  excessively while awake.


One of the most common causes of night sweats in women over 40 is the hormonal changes related to  menopause  and  perimenopause . [ 3 ]  This is a very common occurrence during the menopausal transition years. Over 80% of women experience  hot flashes , which may include excessive sweating, during menopause. [ 4 ]


Night sweats range from being relatively harmless to a sign of underlying  disease . Night sweats may happen because the sleep environment is too warm, either because the bedroom is unusually hot or because there are too many covers on the bed. [ 2 ]   Night sweats have been associated with a long list of clinical conditions. [ 5 ]  However, there is very little evidence that supports clinical recommendations for this condition. [ 5 ]


The condition may be a  sign  of various  disease  states, including but not exclusive to the following:


Postmenopausal confusion , also commonly referred to as  postmenopausal brain fog , is a group of symptoms of  menopause  in which women report problems with  cognition  at a higher frequency during postmenopause than before. [ 1 ] [ 2 ]


Multiple studies on  cognitive  performance following menopause have reported noticeable declines in greater than 60% of the patients. [ 3 ] [ 4 ]  The common issues presented included impairments in reaction time and attention, difficulty recalling numbers or words, and forgetting reasons for involvement in certain behaviors. Association between subjective cognitive complaints and objective measures of performance show a significant impact on health-related quality of life for postmenopausal women. [ 5 ]


Treatment primarily involves symptom management through non-pharmacological treatment strategies. This includes involvement in  physical activity  and following medically supervised diets, especially those that contain  phytoestrogens  or  resveratrol . [ 6 ] [ 7 ] [ 8 ] [ 9 ]   Pharmacological interventions in treating postmenopausal confusion are currently being researched.  Hormone replacement therapy  (HRT) is currently not indicated for the treatment of postmenopausal confusion due to inefficacy. [ 10 ] [ 11 ]  The use of HRT for approved indications has identified no significant negative effect on postmenopausal cognition. [ 10 ]


Although much of the literature references women, all people who undergo menopause, including those who do not self-identify as women, may experience symptoms of postmenopausal confusion.


Research on menopause as a whole declined with the end of the  Women's Health Initiative  (WHI) studies, but research on the treatment of symptoms associated with menopause—especially the treatment of cognitive decline—continues. The Study of Women's Health Across the Nation (SWAN), first started in 1996, continues to publish progress reports which include cognitive symptoms associated with menopausal transition, including those in postmenopause. [ 4 ]  As of 2019 [update] , SWAN indicated, "Approximately 60% of midlife women report problems with memory during the [menopause transition], yet studies of measured cognitive performance during the transition are rare." [ 4 ]


Although there are many relationships between hormone levels in postmenopause and cognitive function, the previously favored HRT therapies ( estrogen  therapies) have been shown to be ineffective in specifically treating postmenopausal confusion. [ 12 ] [ 10 ] [ 13 ]  The use of hormone replacement therapies, once considered detrimental to cognition in postmenopausal women, has now been shown to have no negative effect when used properly for approved indications. [ 10 ] [ 13 ] [ 14 ]  There are no conclusive studies to support any pharmacological agents, but several potential drug candidates are still being explored.


Menopause is a natural decline in the  ovarian  function of women who reach the age between 45 and 54 years. "About 25 million women pass through menopause worldwide each year, and it has been estimated that, by the year 2030, the world population of menopausal and postmenopausal women will be 1.2 billion, with 47 million new entrants each year." [ 15 ]


Postmenopause begins immediately following menopause (one year after the final  menstrual cycle ). [ 16 ]  Postmenopausal confusion is often manifested through the following cognitive symptoms: memory problems,  forgetfulness , and poor concentration. [ 17 ]   Confusion  which is otherwise unexplained and coincides with the onset of postmenopause may be postmenopausal confusion. [ 18 ]


A 2019 literature review identified  hypertension  and history of  pre-eclampsia  as significant risk factors for the accelerated decline of cognitive function in women during midlife. Although the mechanism remains unclear,  neuroimaging  studies included in the review found that those with hypertension have evident structural changes in their brains; specifically,  gray matter  brain volume decreased and  white matter  hyperintensity volume increased. [ 18 ]


Atherosclerosis  and comorbidities such as  hyperlipidemia  and  diabetes mellitus  have long been considered risk factors for cognitive decline because they have the propensity to cause the formation of  amyloid plaques  (aggregates of  misfolded , deleterious proteins) in the brain. [ 19 ]


Many postmenopausal women report  insomnia . Studies have shown "associations between poor sleep quality and cognitive decline" in postmenopausal women as those with insufficient sleep, or with difficulty falling or staying asleep, reported decreased cognitive performance including "verbal memory,  attention , and general cognition." [ 3 ]


There is evidence linking  depression  and cognitive decline in postmenopausal women. Research suggests that increased  cortisol  levels from depressive episodes may affect the  hippocampus , area of the brain responsible for  episodic memory . Studies have also shown a correlation between depression and decreased cognitive performance including " processing speed ,  verbal memory , and  working memory " in postmenopausal women. [ 3 ]


There are studies indicating a correlation between frequency of  hot flashes  in postmenopausal women and a deficit in verbal memory performance. It is suggested that faster blood flow in the brain or higher  cortisol  levels from hot flashes may cause changes in the brain and affect information processing and memory. [ 3 ]


A 2019 systematic review and meta-analysis identified  surgical menopause , especially when performed at or before the age of 45, as a substantial risk factor for cognitive decline and  dementia . [ 20 ]


Cardiac procedures such as  invasive cerebral and coronary angiography ,  coronary artery bypass graft surgery  (CABG), surgical  aortic valve replacement , and  transcatheter aortic valve replacement  (TAVR) have been found to increase the risk of cognitive decline in females as they been found to increase the incidence of brain  lesions . [ 19 ]


The mechanism of postmenopausal confusion is poorly understood due to simultaneous aging-related physiological changes, as well as differential diagnoses presenting with similar symptoms. [ 2 ]  Research remains ongoing.


There are pharmacological and  non-pharmacological  considerations in improving the symptoms of postmenopausal confusion. Currently, no pharmacological agents are indicated to treat postmenopausal confusion, but research remains ongoing. [ citation needed ]  Non-pharmacological strategies to manage postmenopausal confusion symptoms are utilized, with focus on diet and exercise.


Hormone therapy , also known as estrogen therapy, was previously a common treatment for postmenopausal confusion. However, more recent research indicates that  hormone therapy is not an effective treatment  for postmenopausal cognitive symptoms. [ 10 ] [ 11 ]  A 2008 Cochrane review of 16 trials concluded that there is a body of evidence that suggests that hormone replacement therapy is unable to prevent cognitive decline or maintain cognitive function in healthy postmenopausal women when given over a short or long period of time. [ 11 ]  Conversely, studies have also suggested that the use of hormone replacement therapy are unlikely to have negative cognitive effects when used for their approved indications. [ 10 ]


Previous research suggested that increases in blood flow to the hippocampus and temporal lobe occurred from hormone therapy, improving postmenopausal confusion symptoms. [ 21 ]  More recent research no longer supports this, and is inconclusive as to the true effects of estrogen on hippocampal volume as studies show results differing from improved cognition and maintained hippocampal volume when hormone therapy is administered during menopause to results showing no obvious beneficial results. [ 22 ]


Research focusing on  adiponectin  (ADPN) has yielded positive results in the development of possible treatments for postmenopausal confusion. A study has shown an association between higher levels of ADPN and increased cognitive performance in postmenopausal women. However, an ADPN receptor agonist has yet to be discovered. [ 23 ]


There is ongoing research regarding the efficacy of psychostimulant drugs such as  lisdexamphetamine  (Vyvanse) and  atomoxetine  (Strattera) in treating postmenopausal and menopausal confusion. [ 24 ] [ 25 ]


Individuals play an important role in maintaining their cognitive health. One way to achieve this is by the promotion of healthy nutrition. In particular, the  Mediterranean diet , defined as being low in  saturated fat  and high in vegetable oils, showed improvement in aspects of cognitive function. This diet consists of low intake of sweets and eggs, moderate intakes of meat and fish, dairy products and red wine, and high intake of  leafy green vegetables , pulses/legumes and nuts, fruits, cereal, and cold pressed extra virgin olive oil. [ 7 ]  Further analysis concluded that the Mediterranean diet supplemented by olive oil resulted in better cognition and memory as compared to the Mediterranean diet plus mixed nuts combination. [ 26 ]


Soy isoflavones  (SIF), a type of  phytoestrogen  which can be found in soybeans, fruits and nuts, has been shown to improve cognitive outcomes in recent postmenopausal women of less than 10 years. This suggests that the initiation of SIF may have a critical margin of opportunity when used at a younger age in postmenopausal women. In addition to improved cognitive functions and visual memory, no evidence of harm from SIF supplementation was revealed with the dose ranges tested in multiple trials. [ 8 ]


Analysis of multiple randomized controlled trials have brought attention to  black cohosh  and  red clover  (which contain  phytoestrogen ) and its potential as an efficacious treatment of menopausal symptoms. Black cohosh did not reveal any evidence of risk of harm, but lack of good evidence cannot firmly conclude its safety. [ 27 ]  Overall, the results suggested that neither botanical treatments provided any cognitive benefits. [ 28 ]


Resveratrol , another bioactive compound derived from plants, has also shown to improve cognitive performance in postmenopausal women. There are ongoing trials studying the cognitive benefits of resveratrol in early versus late postmenopausal women. [ 9 ]


Chronic  ginkgo biloba  supplementation has been shown to improve "mental flexibility" in "older and more cognitively impaired" postmenopausal women. However, a combined ginkgo biloba and  ginger  supplementation had no effect on memory or cognitive performance in postmenopausal women. [ 29 ]


Dehydroepiandrosterone  ( DHEA ) supplementation may improve cognition in women with postmenopausal confusion but does not benefit those without cognitive impairment. [ 30 ]  More long-term studies are required to study the efficacy of DHEA and its role in cognition and postmenopausal women. [ 31 ]


Regular  physical exercise  may prevent symptoms of postmenopausal confusion. Studies have shown an association between exercise and "lower rates of cognitive decline" in postmenopausal women. On the other hand, an inactive lifestyle has been strongly associated with "higher rates of cognitive decline" in postmenopausal women. [ 6 ]


Studies have shown benefits of mind-body therapies in women with postmenopausal symptoms including cognitive impairment.  Mindfulness ,  hypnosis , and  yoga  may help decrease symptoms of insomnia, depression, or hot flashes in postmenopausal women which leads to better cognitive performance. [ 3 ]


Primary ovarian insufficiency  ( POI ), also called  premature ovarian insufficiency  and  premature ovarian failure , is the partial or total loss of  reproductive  and  hormonal  function of the  ovaries  before age 40 because of  follicular  ( egg  producing area) dysfunction or early loss of eggs. [ 1 ] [ 4 ] [ 6 ]  POI can be seen as part of a continuum of changes leading to  menopause [ 7 ]  that differ from age-appropriate menopause in the age of onset, degree of symptoms, and sporadic return to normal ovarian function. [ 8 ]  POI affects approximately 1 in 10,000 women under age 20, 1 in 1,000 women under age 30, and 1 in 100 of those under age 40. [ 6 ]  A  medical triad  for the diagnosis is  amenorrhea ,  hypergonadotropism , and  hypoestrogenism . [ 5 ]


Physical and emotional symptoms are similar to those seen during menopause and can include  hot flashes ,  night sweats ,  dry skin ,  vaginal dryness , irregular or absent  menstruation ,  anxiety ,  depression ,  mental fog , irritability, nervousness, decreased  libido , and increased  autoimmune disruption . [ 9 ]  The sense of  shock and distress on being informed of the diagnosis can be overwhelming. [ 1 ]  Hormonal therapy with  estrogen  and  progesterone  is the first line treatment and is associated with improvement of symptoms and possibly improvement in other parameters such as bone density, mortality and cardiovascular risk. [ 10 ]  The general treatment is for symptoms,  bone protection , and  mental health . [ 1 ] [ 11 ]  Although 5 to 10% of women with POI may  ovulate  sporadically and become pregnant without treatment, [ 12 ]  others may use  assisted reproductive technology  including  in vitro fertilization  and  egg donation [ 13 ]  or decide to  adopt  or remain childless. [ 14 ]


The causes of POI are heterogeneous and are unknown in 90% of cases. [ 6 ]  It can be associated with  genetic  causes,  autoimmune disease ,  enzyme deficiency , infection,  environmental factors ,  radiation , or surgery in 10%. [ 15 ]  Two to 5% of women with POI and a premutation in  FMR1 , a genetic abnormality, are at risk of having a child with  fragile X syndrome , the most common cause of inherited  intellectual disability . [ 8 ] [ 6 ]


The diagnosis is based on ages less than 40, amenorrhea, and  elevated  serum   follicle-stimulating hormone  (FSH) levels. [ 4 ]  Typical serum FSH levels in POI patients is in the post-menopausal range. [ 2 ]  Treatment will vary depending on the symptoms. It can include hormone replacement therapy, fertility management, and psychosocial support, as well as annual screenings of  thyroid  and  adrenal  function. [ 16 ]


The signs and symptoms of POI can be seen as part of a continuum of changes leading to menopause. [ 7 ]  POI contrasts with age-appropriate menopause in the age of onset, degree of symptoms and sporadic return to normal ovarian function. [ 8 ]  As some women retain partial ovarian function, symptoms may not be as severe as regular menopause. [ 8 ]  In others, particularly with coexistent depression, symptoms such as decreased  quality of life  can be severe. [ 9 ]


Hormonally, POI is defined by abnormally low levels of estrogen and high levels of  FSH , which demonstrate that the ovaries are no longer responding to circulating FSH by producing estrogen and developing fertile eggs. The ovaries will likely appear smaller than normal. [ medical citation needed ]  The age of onset can be as early as 11 years. [ 17 ]  POI can be seen as part of a continuum of changes leading to menopause [ 7 ]  that differ from age-appropriate menopause in the age of onset, degree of symptoms, and sporadic return to normal ovarian function. [ 8 ]  A contrasting problem can be when a girl never begins menstruation due to a genetic condition causing primary amenorrhea. [ 15 ]


The cause of POI is  idiopathic  in 39-67% of cases. [ 10 ]  Some cases of POI are attributed to autoimmune disorders such as  autoimmune oophoritis , [ 19 ]   Hashimoto thyroiditis ,  Addison disease ,  type I diabetes mellitus ,  pernicious anemia , genetic disorders such as  Turner syndrome  and  Fragile X syndrome , metabolic defects, and enzyme defects. [ 15 ]  One study showed a strong correlation between incidence of POI and certain variants in the  inhibin alpha  gene. [ 20 ]  Chemotherapy and radiation treatments (especially radiation to the pelvis) for cancer can sometimes cause POI. The effect of chemotherapy or radiation is variable and in a mouse model, with results consistent with observations in humans, cyclophosphamide can result in an 87% reduction in primordial follicles 72 hours after administration. [ 15 ]   Women who have had a  hysterectomy  tend to go through menopause early and have a nearly twofold increased risk of POI. [ 15 ]  Almost any pelvic surgery has the potential to damage the ovary by affecting its blood supply or causing inflammation in the area resulting in POI, especially surgery to the ovaries themselves (e.g. for treatment of  ovarian cysts  or  endometriosis ). [ 15 ] [ 10 ]  Certain environmental toxins such as  phthalates ,  bisphenols , and  dioxins  are also associated with POI. [ 10 ]  Certain infectious diseases, such as  mumps  or  HIV  may also damage the ovaries, leading to POI. [ 10 ]


Women who have inherited  classic galactosemia  ( galactose intolerance ) may develop primary ovarian insufficiency. [ 21 ]


The pathogenic mechanisms of POI are highly heterogeneous and can be divided into four major categories: follicular migration defect early in embryogenesis; an early decrease in the primordial follicles; increased follicular death; and altered maturation or recruitment of primordial follicles. [ 15 ]   These result in a decrease of the ovaries' general supply of eggs that normally lasts until an average age of 51 for age of age-appropriate  menopause . [ 22 ]