Topical treatment with estrogen is effective when the symptoms are severe and relieves the disruption in pH to restore the microbiome of the vagina. When symptoms include those related to the urinary system, systematic treatment can be used. Recommendations for the use of the lowest effective dose for the shortest duration help to prevent adverse endometrial effects. [ 29 ]  Treatment is generally with  estrogen cream  applied to the vagina. [ 1 ]  The use of estrogen for treatment do come at some risk. Those who are treated with estrogen may be at a higher risk of developing vaginal candidiasis since estrogen allows lactobacilli to increase in levels. [ 27 ]  Additionally, it is recommended that soaps and other irritants are avoided. [ 2 ]


Some treatments have been developed more recently. These include  selective estrogen receptor modulators , vaginal  dehydroepiandrosterone , and  laser therapy . [ 20 ]  Other treatments are available without a prescription such as vaginal lubricants and moisturizers.  Vaginal dilators  may be helpful. Since GSM may also cause urinary problems related to pelvic floor dysfunction, the person may benefit from pelvic floor strengthening exercises. The individual and their partners have reported that estrogen therapy resulted in less painful sex, more satisfaction with sex, and an improvement in their sex life. [ 1 ]  If a person cannot tolerate or use estrogen therapy, topical hyaluronic acid can be used as another option which has been shown to be safe and effective. [ 31 ]  For mild atrophic vaginitis, hyaluronic acid can be used as a treatment first. [ 31 ]  However, if it is moderate to severe atrophic vaginitis, estrogen therapy is recommended to be used first. [ 31 ]  Vitamin E vaginal suppositories were also found to be helpful in relieving symptoms of GSM, but further studies need to be done to evaluate how safe and effective this treatment is for this condition. [ 32 ]  Other studies have discussed using vaginal oxytocin as a treatment, but there has been no significant effect on GSM in either helping alleviate signs and symptoms or improving the condition. [ 33 ]


Atrophic vaginitis develops in 10-50% of postmenopausal women. Of those who are postmenopausal and have developed atrophic vaginitis, 50-70% develop symptoms. [ 1 ] [ 23 ]  Around 30% of women with atrophic vaginitis discuss their symptoms with their primary healthcare provider. It is likely to be under diagnosed and under treated due to lack of awareness of those who are affected by atrophic vaginitis and of healthcare providers. [ 6 ]  Symptoms of genitourinary syndrome of menopause (GSM) are seen in 65% women one year post-menopause versus 87% six years post-menopause. [ 23 ]


Vulvovaginal atrophy  and  atrophic vaginitis  have been the preferred terms for this condition and cluster of symptoms until recently. These terms are now regarded as inaccurate in describing changes to the entire genitourinary system occurring after menopause. The term  atrophic vaginitis  suggests that the vagina is inflamed or infected. Though this may be true, inflammation and infection are not the major components of postmenopausal changes to the vagina. The former terms do not describe the negative effects on the lower urinary tract which can be the most troubling symptoms of menopause for women. [ 3 ]   Genitourinary syndrome of menopause  (GSM) was determined to be more accurate than  vulvovaginal atrophy  by two professional societies. [ 1 ] [ 19 ] [ a ]  The term atrophic vaginitis does not reflect the related changes of the  labia ,  clitoris , vestibule,  urethra  and  bladder . [ 19 ]  Overall, the current preferred term is Genitourinary syndrome of Menopause (GSM). It is an umbrella term for vulvovaginal atrophy, atrophic vaginitis, urogenital atrophy and vaginal atrophy. [ 34 ]


In 2018, the FDA issued a warning that lasers and other high energy devices were not approved for "rejuvenating" the vagina, and it has received many reports of injuries. [ 35 ]  Such devices are scams and have been shown to only cause  necrosis  and extreme pain to lead to  suicidal ideation . [ 36 ]  In a 2021 systematic review, fractionated type CO2 laser therapy used for GSM was shown to be effective and safe in the studies the researchers reviewed. However, there is a lot of evidence still needed to determined how effective this therapy is compared to other treatments for GSM such as hormonal, non-hormonal, and topical treatments. In addition, further studies conducted can also help determine which groups of patients would benefit from CO2 laser therapy. [ 37 ]


In addition, there were several studies that looked into whether vaginal oxytocin was an alternative hormone treatment for atrophic vaginitis. In 2023, a systematic review found that there was no significant effect using vaginal oxytocin for this condition. The article explored vaginal maturation index, vaginal pH, endometrial thickness, and dyspareunia. Even though there were lack of evidence to support using vaginal oxytocin for atrophic vaginitis, further studies should be conducted to gain a better understanding of oxytocin's effects and its efficacy on this condition. [ 33 ]


A 12-week randomized controlled clinical trial conducted in Ardabil, Iran, in 2018 evaluated the effectiveness of fenugreek extract on atrophic vaginitis in 60 postmenopausal women. [ 38 ]  Research participants were dividied into an intervention group, which received fenugreek vaginal cream, and a control group, which received conjugated estrogen vaginal cream. [ 38 ]  The study measured clinical signs and the Vaginal Maturation Index (VMI). [ 38 ]  The results indicated that while fenugreek extract showed some efficacy in treating atrophic vaginitis, it was significantly less effective that ultra-low-dose estrogen as evidenced by higher VMI scores and greater improvement in clinical signs in the control group. [ 38 ]


A 2021 study examined the effectiveness of aloe vera vaginal cream for the treatment of atrophic vaginitis. This randomized, double-blind, controlled trial compared the effectiveness of Aloe Vera vaginal cream to estrogen vaginal cream in treating vaginal atrophy in 60 postmenopausal women. [ 39 ]  Over six week, both treatments significantly improved symptoms, including vaginal health index (VHI), maturity valve (MV), and overall symptoms of vaginal atrophy. [ 14 ]  The Aloe Vera group showed a notable increase in superficial cells and superior results in fluid volume compared to the estrogen group. [ 14 ]  The study concluded that Aloe Vera cream is as effective as estrogen cream, presenting a viable alternative for women who cannot use estrogen therapy. [ 14 ]


A 2021 systematic review studied the use of hyaluronic acid for those with postmenopausal vaginal atrophy. From the 833 studies identified, the comparisons of hyaluronic acid to vaginal estrogen treatments appear to have similar safety, tolerability, and efficacy based on outcomes such as vaginal pH and cell maturation. Thus, hyaluronic acid may be a suitable treatment for those who cannot tolerate hormonal treatment. [ 40 ]


A 2022 systematic review evaluated randomized controlled trials to see if there were evidence to support the effectiveness of using vaginal Vitamin E and whether it helped alleviate GSM symptoms in postmenopausal individuals. The authors looked into 31 studies and found four of the studies met the requirements for inclusion criteria. One of the trials showed that there was a significant impact in helping alleviate GSM symptoms with using 1 mg vitamin E in the experimental group compared to the placebo group. Another trial showed 5 mg vaginal hyaluronic acid had a greater impact than 1 mg vitamin E. Two of the other trials showed there were no difference between using 0.5 g vaginal estrogen and 100 IU of vaginal vitamin E. Since the authors were only able to use four studies, they encountered some limitations such as using a small number of studies and not having as much evidence. In conclusion, the review article found that vaginal vitamin E can be used to helping with GSM symptom but further studies need to be conducted to confirm its efficacy and safety. [ 32 ]


Bellergal  is a combination of levorotatory  alkaloids  of  belladonna ,  ergotamine tartrate , and  phenobarbital , [ 1 ] [ 2 ]  used for the treatment of functional  menopause , such as  hot flashes  and  night sweat .


Belladonna, including atropine, hyoscyamine and scopolamine, are antimuscarinic agents. They block acetylcholine from binding to its receptors. It generally reduces the secretion of the body, including mouth, nose, and skin, causes drowsiness and other anticholinergic effects. Phenobarbital provides  sedative  and anesthetic effects through depressing the central nervous system. 24 Ergotamine constricts blood vessels in the brain and alleviates headache through stimulating alpha-1, dopamine and serotonin receptors.


Common  side effects  of bellergal include  drowsiness , flushing,  nausea ,  vomiting ,  diarrhea ,  constipation , decreased  sweating , visual disturbances, unusual  fatigue  or  weakness  and  dry mouth . [ 3 ] [ 4 ]  Bellergal has a high potential for potentially serious  drug interactions  due to strong  CYP3A4   inhibition  by  ergotamine . Ergotamine is a  vasoconstrictive  CYP3A4  substrate .


Bellergal was widely used during the 1970s and 1980s. [ 5 ]  Its limited efficacy on decreasing hot flashes frequency and severity were demonstrated by several  randomized controlled trials . On 6 June 2018, Bellergal was discontinued by  Paladin Labs  due to its raw material availability and limited efficacy. There are no bellergal tablets available in the markets now.


The primary use of bellergal is for the treatment of alleviating menopause associated symptoms, include  hot flashes ,  perspiration ,  palpitations ,  dizzy spells , restlessness, apprehension,  fatigue ,  insomnia , and  headache .


This combination is contraindicated in those with hypersensitivity to the three active ingredients, and in those with narrow-angle glaucoma, hypertension, cardiovascular, liver, kidney, or circulation problems. People with high temperature, pregnant women, nursing mothers should also avoid this medication.


Prolong use of bellergal is not recommended due to the risk of ergotism and rare fibrotic complications. Patients should be informed of the maximum doses allowed and of the first symptoms of overdosage: hypoesthesia, paresthesia in the fingers and toes, nausea and vomiting, symptoms of myocardial ischemia and symptoms of ergotism including cerebral ischemia.


Ergotamine is a vasoconstrictive CYP3A4 substrate. The concurrent use of vasoconstricting ergot derivatives and strong CYP3A4 inhibitors, such as HIV protease or reverse transcriptase inhibitors, azole antifungals, or macrolide antibiotics, was associated with ergot toxicity. The inhibition of CYP3A4 leads to an increased level in serum concentration of Ergot derivatives. Extreme ischemia, coma or even death is the result. For this reason, the use with potent CYP3A4 inhibitors should be avoided when prescribing. Moderate CYP3A4 inhibitors such as berotralstat, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, fedratinib, fluconazole, fosnetupitant, grapefruit juice, imatinib, isavuconazonium sulfate, and lefamulin, should also be monitored closely. Cramping, pain and angina were reported. Patient should be monitored closely for ergot toxicity and the use with this treatment should be done with cautions.


Belladonna alkaloids, ergotamine tartrate, and phenobarbital are the three main components of Bellergal. The belladonna plant, which has numerous alkaloids with anticholinergic properties, yields the belladonna alkaloids. A fungus that lives on specific grains produces ergot alkaloids, of which ergotamine tartrate is a synthetic derivative. Barbiturate phenobarbital is an anticonvulsive and sedative drugs.


Three active components cooperate to alleviate menopausal symptoms. The belladonna alkaloids which is an anticholinergic drug acting on the autonomic nervous system. It could inhibit the parasympathetic nerve system by blocking the neurotransmitter, acetylcholine, from binding to chlolinergic receptor to lessen sweating and assist in body temperature regulation. Ergotamine tartrate could act as a vasoconstrictor that reduce the blood flow to the area of hot flash and hence lessens its intensity and frequency. The effects of the other two components are strengthened by the sedative phenobarbital.


Bellergal was widely used during the 1970s and 1980s. Its limited efficacy on decreasing hot flashes frequency and severity were demonstrated by several randomized controlled trials. After 2 weeks of therapy, bellergal significantly reduced hot flashes, according to a randomized controlled experiment from the 1980s. The difference between the therapy and placebo, however, vanished after 8 weeks with decreases of 68% and 75%, respectively. Although Bellergal reduced hot flashes compared to placebo, there was a considerable amount of toxicity, with more than 30% of users discontinuing the medication owing to side effects as dry mouth, drowsiness, dizziness, and rash.


There were shortage reports related to phenobarbital from 18 July 2017 to 1 March 2018, disrupting the flow of the production process with quality, time and cost control. With all the factors considered, on 6 June 2018, Bellergal was discontinued by Paladin Labs due to its raw material availability and limited efficacy; while the remaining supply date was on 1 October 2017.


There are no bellergal tablets available in the markets now. Sandoz in Spain, France and Germany, Novartis in Switzerland, Thailand, Turkey and South Africa and Paladin in Canada discontinued the preparations. Instead, it is replaced by a new and similar formulation named as Bellegal-S, manufactured by Novartis in the United States of America. One of the active ingredients is changed to bellafoline (levorotatory alkaloids of belladonna).


Bioidentical hormone replacement therapy  ( BHRT ), also known as  bioidentical hormone therapy  ( BHT ) or  natural hormone therapy , is the use of  hormones  that are identical on a  molecular  level with  endogenous  hormones in  hormone replacement therapy . [ 1 ]  It may also be combined with blood and  saliva testing  of hormone levels, and the use of pharmacy  compounding  to obtain hormones in an effort to reach a targeted level of hormones in the body. A number of claims by some proponents of BHT have not been confirmed through scientific testing. Specific hormones used in BHT include  estrone ,  estradiol ,  progesterone ,  testosterone ,  dehydroepiandrosterone  (DHEA), and  estriol .


Custom-compounded BHT is a practice almost wholly restricted to the United States [ 2 ]  and is a form of  alternative medicine . It has been promoted as a  panacea  for many diseases and for relieving the symptoms of  menopause  beyond the medical objective of reducing the risk of  osteoporosis . There is little evidence to support these incremental claims; the hormones are expected to have the same risks and benefits as comparable approved drugs for which there is evidence based on extensive research and regulation, except for progesterone, which may have an improved safety profile than artificial progestogens, though direct comparisons with  progestins  have not been made. Risks associated with the less-controlled process of compounding bioidentical hormones are not clearly understood. In addition, the accuracy and efficacy of saliva testing have not been definitively proven, and the long-term effects of using blood testing to reach target levels of hormones have not been researched.


The International Menopause Society,  American Congress of Obstetricians and Gynecologists ,  Society of Obstetricians and Gynaecologists of Canada ,  The Endocrine Society ,  the North American Menopause Society (NAMS) ,  United States Food and Drug Administration , American Association of Clinical Endocrinologists,  American Medical Association ,  American Cancer Society , and the  Mayo Clinic  have released statements that there is a lack of evidence that the benefits and risks of bioidentical hormones differ from well-studied non-bioidentical counterparts; until such evidence is produced the risks should be treated as if they are similar; and that compounded hormone products may have additional risks related to compounding. A major safety concern in compounded BHT is that there is no requirement to include package inserts, despite the potential for serious adverse effects (including life-threatening adverse effects) associated with HRT, which can harm consumers as they are misled into believing that any hormone-related problems and dangers are exclusively related to non-bioidentical hormones, and that compounded BHT is safe and has no side effects. In reality, the risks of bioidentical hormones have not been studied to the extent of non-bioidentical hormones, so the risks are not well-understood. Regulatory bodies require pharmacies to include important safety information with conventional hormone replacement therapy (CHRT) via package inserts.


Bioidentical hormones were first used for menopausal symptom relief in the 1930s, [ 2 ]  after Canadian researcher  James Collip  developed a method to extract an orally active estrogen from the urine of pregnant women and marketed it as the active agent in a product called Emmenin. [ 3 ]  It was supplanted on the market when its manufacturer, Ayerst (later  Wyeth  Pharmaceuticals), began producing the more-easily manufactured  conjugated [ clarification needed ]   equine  estrogens in 1941 under the brand name  Premarin ; by 1992, Premarin was the most widely prescribed drug in the United States. [ 4 ]


In the 1970s, research and reports indicating risks from synthetic conjugated estrogens began to appear. Investigations determined that the addition of a  progestogen  to estrogen treatment reduced the risks. As early as 1980, the  British Medical Journal  (now  The BMJ ) recommended oral bioidentical progesterone as an option when side effects from synthetic progestogens otherwise mandated discontinuing treatment. In May 1998 the FDA approved  Prometrium , an oral bioidentical progesterone product produced by  Solvay Pharmaceutical . [ 5 ]


Physicians John R. Lee and Jonathan Wright were pioneers in the field of BHT. [ 6 ]  Lee authored several popular books on BHT [ 7 ]  and promoted custom-compounded BHT, with the goal of achieving what he called a "natural hormone balance". He based this goal on the clinical testing of saliva to establish where "deficiencies" existed, though agencies such as the FDA and the  American Congress of Obstetricians and Gynecologists  state that blood and saliva testing is unreliable and biologically meaningless. [ 2 ]  Lee also believed that progesterone acted as a  panacea [ 8 ]  and general health tonic for many health conditions, basing his claims on anecdotal data rather than peer-reviewed research, [ 7 ]  which has not been supported by any clinical trials. [ 8 ]  Wright also authored a popular book on BHT. [ 6 ]  Compared to previous bioidentical formulas that only used estradiol, he promoted a triple-estrogen formula called Triest, which combined three estrogens found in human females:  estriol ,  estradiol  and  estrone . It was based on an unpublished study whose conclusions did account for how estrogens are processed and excreted in the body—particularly how the liver processes oral estrogens, converting most of them to estrone. No follow-up was performed by Wright to replicate these observations. [ 2 ]  Wright may have been the first proponent of BHT to use the term  bioidentical —the word he coined to describe unpatentable, plant-derived molecules he believed were identical to human hormones. However, no  structural crystallographic  evidence has been used to support the idea that these molecules are identical to endogenous human hormones. When the  Women's Health Initiative 's reports on the unappreciated risks of equine estrogens were released, many prescribers of BHT used Wright's assertions (and his terminology) to proclaim the superiority of bioidentical molecules despite a lack of scientifically supported evidence. Following the publication of a popular book written by  Suzanne Somers  in 2006, the term  bioidentical  gained more prominence in popular consciousness as a "poorly understood new adjective" regarding hormone replacement therapy. [ 6 ]


There is no single definition for the term  bioidentical hormone replacement therapy ; it is generally used to refer to 17β-estradiol, but other uses include plant-based or compounded estrogen products that blend estradiol with estriol and sometimes with estrone. [ 9 ]  A  bioidentical hormone  is defined as a molecule identical to a hormone  produced by the human body [ 2 ]  (though not all allegedly bioidentical hormones sold by custom-compounding pharmacies are necessarily molecularly identical to endogenous humans [ 10 ] ). The FDA considers BHT as currently used by BHT advocates to be a marketing term, not a scientific term, and does not recognize its use. [ 11 ]  The meaning of  plant-derived  has also been attached to the term  bioidentical , [ 12 ]  and it may also mean that the hormones are "natural"; throughout the 1990s plant-derived, compounded hormones were referred to as "natural hormone therapy". [ 6 ]  However, the term  natural  can be applied to all products where the principal ingredient originates from an animal, plant, or mineral source, and both bioidentical and non-bioidentical hormones can be produced from the same plant sources. [ 13 ]


BHT is often used to refer to a set of diagnostic, prescribing, preparation and marketing practices including  compounding , saliva testing, and an emphasis on countering the effects of aging rather than relieving the symptoms of menopause. This compounded BHT package has been promoted by Somers,  Oprah Winfrey , and other proponents as safer and more effective than CHRT, [ 14 ] [ 15 ] [ 16 ] [ 17 ] [ 18 ] [ 19 ] [ excessive citations ]  though there is no evidence to support these claims. Compounded BHT has been marketed on the internet by pharmacies that make unfounded claims for its safety and its effectiveness for a variety of conditions. [ 12 ]


There are a variety of FDA-approved products, made using bioidentical estrogens and micronized progesterone, used to treat the symptoms of menopause: [ 13 ]


The term  synthetic  is also used incorrectly in two ways: to refer to the process used to manufacture all estrogens, including bioidentical estrogens, and to compounds that interact with estrogen receptors similarly to estrogen molecules but are not found in nature. Examples of the latter two include  diethylstilbestrol  and  ethinylestradiol . [ 9 ]


BHT is used to reduce the symptoms of menopause. It is also promoted by some practitioners for anti-aging purposes providing benefits beyond menopausal symptom relief, such as improving quality of life, though there is  little evidence to support these claims . [ 2 ] [ 20 ]


Compounded preparations of bioidentical hormones usually include  estriol ,  estrone ,  estradiol ,  testosterone ,  progesterone , and sometimes  dehydroepiandrosterone  (DHEA), either individually or combined. [ 2 ]  They are promoted as natural, safer and (in some cases) more efficacious than CHT; however, there are no scientific studies to support claims of superiority of BHT over CHRT. [ 2 ]  Estimates from sales of bulk hormones for compounding suggest that more than one million women may be using compounded BHT in the United States. [ 15 ]  Bioidentical hormones are expected to have the same risks as conventional hormones made with the same categories of hormones. [ 21 ]


In premenopausal women the majority of  estrogen  produced by the body is estradiol (produced primarily in the ovaries), while in postmenopausal women estrone (produced in fat cells) is the type of primary estrogen present; however, the body is able to convert one type of estrogen into another to a certain extent. Because of the limited research into potency, delivery methods, and conversion of the various estrogens, a valid scientific understanding of compounded estrogen products has not been achieved. [ 22 ]  Synthetic estradiol, taken orally,  decomposes  when absorbed in the  gastrointestinal tract  and delivers bioidentical estradiol to the bloodstream. [ 23 ]


The hormone  estriol , produced during  pregnancy , is frequently compounded into bioidentical preparations in the United States. While some think it to be a weaker estrogen, with a more limited period of effectiveness than estradiol, it has been demonstrated to be a stronger estrogen in certain ways. [ 22 ]  Though initial research in the 1970s suggested possible use, follow-up studies have failed to confirm this potential. [ 8 ] [ 24 ] [ 25 ]  Estriol is not found in any FDA-approved drug, and its safety and effectiveness as a hormone supplement is unknown. [ 21 ]


Estriol was part of the  United States Pharmacopeia  before FDA approval was needed for its use. Its approval was grandfathered in by the FDA until 2008 when the agency banned its use, stating that manufacturers of estriol would have to create a new application and estriol would be treated as a new drug. [ 11 ]  Its use is not approved by  Health Canada ; estriol is not available as a pharmaceutical preparation in Canada or the United States, but is a commonly prescribed conventional treatment in other countries and is available as a cream or vaginal suppository in the  United Kingdom  and the  European Union . [ 8 ] [ 26 ]  Estradiol is available as brand-name products in both oral and transdermal forms. [ 26 ]


Progesterone  is used both orally and transdermally. Oral progesterone is micronized (ground) to increase availability and is approved by the FDA to treat endometrial hyperplasia when used in opposition to estrogen. It has also been approved to relieve menopausal symptoms, either alone or in combination with estrogen. It is more reliable in treating menopausal sleep disorders than synthetic progestins. Transdermal progesterone is often used as a component of compounded BHT but has not been clinically proven to prevent endometrial hyperplasia, as oral progesterone has. [ 25 ]  The editors-in-chief of the scientific journal  Climacteric  state that the greatest difference in function between bioidentical and synthetic hormones may be found in progesterone's behavior compared with  progestin . Laboratory studies have suggested that bioidentical progesterone binds primarily to progesterone  receptors , while synthetic  progestins  activate other receptors with a variety of effects. The editors suggested that progesterone may have neutral to positive effects on the cardiovascular system, and induce  apoptosis  in breast epithelial cells. These compounds have not been directly compared with each other in appropriate scientific tests, though as of 2010 trials had begun. [ 23 ]  Progesterone is approved for use by both the FDA and Health Canada as a brand-name oral preparation. [ 26 ]  The  French   epidemiological  study "Etude Epidemiologique aupres de femmes de l'Education Nationale" suggested micronized progesterone may offer a reduced risk of breast cancer compared to other progestins, though large-scale clinical trials have not been conducted. [ 27 ]  A 2012 practice advisory published by  Canadian Family Physician  concluded "there is no convincing evidence that bioidentical hormones are safer or more effective than synthetic HRT". [ 28 ]


Testosterone  supplementation can improve libido in postmenopausal women, but can also reduce levels of  high-density lipoproteins . [ 20 ]  Commercial sources for testosterone for women in the United States are limited and include the estrogen-testosterone mixture  Estratest ; compounding pharmacies are the main source of testosterone-only preparations for women. [ 24 ]  A testosterone patch has been approved for use in the United Kingdom and European Union, but in Canada and the United States there is no long-term safety data on it. [ 26 ]


DHEA is an androgen  precursor  that lacks FDA and Health Canada approval for use in women, and is not available in Canada as a pharmaceutical preparation; [ 26 ]  it is sold as an  over-the-counter drug  or incorporated into compounded preparations in the United States. In the body, it can be converted into testosterone then estrogen; there are no consistent scientific findings or safety information supporting its use. High levels of DHEA have been linked to breast cancer. [ 25 ]


Compounding pharmacies use commercially available bulk drugs to create new formulations which differ in form or dosage from those manufactured on a large scale by pharmaceutical companies. [ 8 ]  Custom-compounded BHT is almost wholly restricted to the United States, where pharmacy compounding is governed at the state level while the FDA has regulatory authority over the compounded product. Some internet-based compounding pharmacies understate harm and claim benefits of compounded BHT beyond what can be proven by  evidence-based medicine , and many of their claims exceed those made by other BHT practitioners. [ 2 ]


BHT benefits and adverse effects are expected to be the same for bioidentical and synthetic hormones. [ 29 ]  Dosages used in BHT can be as high as ten times the oral dose provided by comparable HRT regimens; the hormones used are known to adversely impact biological markers of cardiovascular disease and may produce a substantially higher risk of heart attack or stroke. [ 30 ]  There are potentially serious adverse effects and important safety information that is required to be given with FDA approved HRT as package inserts; however, they are typically not given (or required) with compounded bioidentical preparations, [ 31 ] [ 32 ] [ 33 ]  which has caused consumers to falsely assume that bioidenticals are safer than FDA-approved hormones or lack any adverse effects—one of the concerns expressed about the hormones. [ 34 ]  BHT has also been associated with  endometrial cancer . [ 21 ]


Less common (but serious) side effects of all post-menopausal estrogens include increased risk or severity of  breast ,  ovarian  or  uterine cancer ;  stroke ;  heart attack ;  blood clots ;  dementia ;  gallbladder disease ;  high blood pressure ,  liver  problems;  high blood sugar ,  fluid retention , enlargement of benign tumors ( fibroids ) of the uterus; a spotty darkening of the skin, especially on the face ( melasma ); and vaginal  yeast infection . [ 29 ]


Estradiol only recommended for use for the shortest period of time and at the lowest effective dose due to its adverse-effects profile. [ 29 ]  There is the potential for a range of adverse effects in  breasts , skin, eyes,  cardiovascular ,  gastrointestinal ,  genitourinary  or  central nervous systems . [ 29 ]


Progesterone can cause the emergence (or significant worsening) of  abdominal pain ,  constipation , yeast infections,  breast cancer ,  cystitis ,  acne ,  conjunctivitis ,  thrombotic disorders  resulting in  pulmonary embolus ,  strokes  or  heart attacks ,  epilepsy ,  migraine ,  asthma , and cardiac or renal dysfunction. Psychiatric reactions can include emotional instability,  depression , aggression, decreased  libido , and  drowsiness . Adverse effects can also occur in the urinary, central or  peripheral nervous , or  musculoskeletal systems . [ 35 ]  A review of clinical trials studying bioidentical progesterone use found that it was ineffective in managing  vasomotor  symptoms of menopause, but had mild and self-limiting side effects. [ 36 ]


Hormones can be administered in a variety of ways, including percutaneous skin and vaginal creams, oral pills,  topical gels , vaginal rings and tablets, and transdermal patches. Although all preparations of a given type of estrogen may be molecularly identical before their introduction into the human body, estrogens administered orally are modified by the liver before entering the  bloodstream  and most of it is converted to estrone; estrogen bypassing the digestive tract and liver via the skin is not converted to a new form before entering the bloodstream. Creams and gels applied to the skin also enter the blood directly and without modification but absorption of the gels, creams, and patches can vary from application to application, depending on the temperature and condition of the skin. [ 13 ]


Advocates for BHT have claimed that commonly compounded BHT preparations are not commercially available, but there are many FDA-approved hormone preparations containing bioidentical molecules available both as proprietary or generic brands. The exception is estriol, used in the compounded bioidentical preparations Triest and Biest—in 2008, the FDA banned estriol until a  New Drug Application  was completed; these preparations are not approved by the FDA or  Health Canada . [ 21 ]  Some advocates of compounding have also claimed that customized compounding provides customized results, but the claim is weak since compounding is aimed at producing a single hormone profile with absolute blood or saliva levels—which has not been demonstrated to be better than CHRT—and does not consider the rate at which individuals will differ in the activity, metabolism and excretion of the hormones. There have been no clinical trials directly comparing the effectiveness or efficacy of bioidentical versus non-bioidentical compounds. [ 2 ]


A 2010 article published in  The Medical Letter on Drugs and Therapeutics  concluded that "[t]here is no acceptable evidence that 'bioidentical' hormones are safe or effective. Patients should be discouraged from taking them." [ 21 ]


BHT is frequently associated with the testing of saliva to establish a baseline hormone level and compounding of the substances by pharmacists (according to a doctor's advice) to produce preparations (and blood levels) of hormones that are specific to each patient. There is no research demonstrating any benefit to either of these practices. [ 8 ] [ 16 ] [ 20 ] [ 21 ] [ 37 ]  Although promoters of BHT claim that saliva testing can be used to customize hormone levels for individuals, and tests are used to determine which hormones are supposed to be deficient and require supplementation, there is no scientific basis to support the use of saliva testing. Estrogens are secreted in pulses within and over days, resulting in varying levels in saliva. [ 2 ] [ 19 ] [ 21 ]  Certain compounding formulations also attempt to use a single profile for all women, with no evidence that a specific profile is beneficial in all cases and no recognition that women differ in their sensitivity to hormones and metabolic rate. Testing-based customizing also does not account for much of the effects, and synthesis of hormones occurs within  tissues  rather than in the blood, so blood or saliva hormone levels may not necessarily reflect the actual biological activity. [ 2 ]  Other concerns include lack of evidence that samples are stable during storage and transportation, poor replication of results and considerable variation among  assays . [ 2 ] [ 19 ]  There are also no studies that link symptoms with blood or saliva hormone levels. [ 2 ] [ 8 ]  The FDA recommends adjusting hormone therapy to the symptoms of the patient, [ 12 ] [ 22 ] [ 38 ]  and that there is no reason to adjust the dosing or monitor patients receiving BHT. [ 39 ]  BHT skeptics have also pointed out that there is no certainty regarding hormone levels in the body. [ 13 ]  The  North American Menopause Society  has supported warnings about the potential harm BHT could cause, as it unnecessarily compounds drugs that are already FDA-approved in ways that lack an evidence base of safety or harm. [ 40 ]  The warnings are supported by the  Society of Obstetricians and Gynaecologists of Canada . [ 41 ]


Although promoted as a way of customizing treatment, hormone therapy does not require customization; [ 38 ]  the use of testing to determine the number of hormones administered could result in the dose being higher than the minimum recommended level to alleviate symptoms, [ 2 ] [ 8 ]  or the administration of unnecessary hormones to asymptomatic women may result in greater risks to the patient. [ 8 ] [ 22 ]  Analysis of the material used to promote BHT suggests that rather than basing hormone doses on saliva results, practitioners are adjusting dosage based on symptoms. [ 19 ]  Different bioidentical preparations result in mixtures with different strengths, and practitioners using compounded formulations may be unaware of the total dose of hormones their patients receive. [ 22 ]  In a 2001 test of compounded bioidentical hormone products, the FDA found that 10 out of 29 products failed their quality tests; nine out of ten failed potency tests (comparable rates for drug manufacturers were less than 2% and 0.13%, respectively). [ 2 ] [ 26 ]  A 2006 test found potency levels ranging from 67.5% to 268.4% of the potency specified on the label; some samples were mixtures of different hormones with some being above, and others below, the specified potency. [ 21 ]  The failure of potency testing could be problematic and dangerous for progesterone products, where specific levels of progesterone are required to protect the endometrium against precancerous hyperplasia. [ 26 ]


Boothby, Doering, and Kipersztok summarize the issue as being a poor effort to apply principles of  pharmacokinetics  to achieve individualized dosing for drugs that do not require it. [ 19 ]


Saliva testing has not been shown to accurately measure blood-bound hormone levels. The FDA recommends the lowest dose of hormones that effectively relieve symptoms and does not recommend custom compounding, blood or saliva testing. [ 12 ]


Bioidentical hormones have been advertised, marketed and promoted as a risk-free  panacea  that is safer than standard HRT. [ 22 ]   Literature reviews  by private practitioners who sell bioidentical preparations suggest benefits and advantages of BHT over its conventional counterpart, but there is skepticism over claims made about BHT; there is no peer-reviewed evidence that compounded bioidentical hormones are safer or more effective than FDA-approved formulations or that they carry less risk. [ 42 ] [ 2 ] [ 6 ] [ 8 ] [ 20 ] [ 25 ] [ excessive citations ]  The hormones are expected to carry the same risks as their conventional counterparts, while the risks of including estriol—a hormone normally produced in large amounts only in pregnant women—have not been studied. [ 21 ]  The United States FDA warned that claims about compounded BHT products are unsupported by medical evidence. [ 18 ]  Bioidentical hormones have been described as a form of marketing; [ 43 ] [ 44 ]  the chief medical editor of  Endocrine Today  called compounded BHT a "marketing concept" with no scientific backing, [ 13 ] [ 15 ]  and the FDA warned that pharmacies use these terms to imply that the drugs are natural and have the same effects as endogenous hormones. Other claims include compounded BHT's ability to prevent or treat conditions such as heart disease, stroke, Alzheimer's disease, endometrial and breast cancer; fewer side effects; and custom blending to uniquely address individuals. There is no credible evidence to support these claims. Bioidentical hormones and compounded BHT are expected to have the same risks and benefits as CHRT; the latter benefits from years of study and regulation, while compounded BHT has no scientific data to support claims of superior safety or efficacy. [ 2 ] [ 8 ] [ 9 ] [ 12 ] [ 13 ] [ 14 ] [ 20 ] [ 38 ] [ excessive citations ]  The following specific claims have been made for the efficacy of bioidentical hormones and compounded BHT, with varying evidence to support or contradict them: [ 20 ]


In 2006, Somers released the book  Ageless: The Naked Truth About Bioidentical Hormones  endorsing the use of bioidentical hormones. The book was criticized by a group of doctors who (though generally supportive of BHT) state that more research is required, and object to protocols mentioned in the book—because of their potential danger and the promoters' lack of qualifications. [ 45 ]  Somers' book may have increased awareness of the existence of BHT for a growing number of menopausal women, but also may have caused confusion by making unsubstantiated claims for BHT and referring to bioidentical hormones as non-drug products with fewer risks. [ 2 ]  Bioidentical hormones have also been discussed on  The Oprah Winfrey Show , with Somers as a guest. [ 46 ]


Michael Cirigliano and Judi Chervenak have stated in reviews of the literature on BHT that large-scale, peer-reviewed studies should be used to establish the safety, efficacy and beliefs about the use of bioidentical hormones. [ 2 ] [ 22 ]  Two 2008 studies conducted in France found that estradiol plus micronized progesterone did not increase the incidence of breast cancer, while a comparison of estradiol plus different types of progestins found a reduced risk of invasive breast cancer with micronized progesterone. Christine Derzko stated that the evidence supported the use of bioidentical estrogen plus progesterone, but since the trial was an observational cohort study rather than a  randomized controlled trial  that compared different types of hormones head-to-head, more data was required before concluding bioidentical hormones were safer and preferred. Derzko concluded that there was weak (but promising) preliminary evidence that bioidentical hormones may present equal (or possibly lower) risks than conventional HRT; however, there was no data supporting the use of compounding. Derzko recommended following evidence-based medicine and cited concerns over BHT by numerous medical organizations—requirements for oversight over compounding,  black box warnings  for all bioidentical products, and the establishment of mandatory adverse-events registry. [ 26 ]


M. Sarah Rosenthal, Director of the  University of Kentucky  Program for Bioethics and Patients' Rights, has stated that she believes BHT is an experimental therapy that is often prescribed by practitioners who sell the products, and are thus in an unethical position of  conflict of interest . Rosenthal has also described problematic issues with BHT including patients receiving information from popular books while lacking the scientific literacy to separate rhetoric from evidence about hormone replacement, illegitimate claims of a " big pharma " conspiracy to suppress bioidentical prescribing, the extra and unnecessary cost of the products that are often not covered by insurance plans, and the inaccurate depiction of bioidentical prescribing as "cutting edge science" rather than unproven alternative medicine. [ 6 ]


Bioidentical hormones are frequently marketed as being "natural", or more natural than conventional HRT. The term  natural  can be used to suggest or emphasize a variety of different ideas—similarity with endogenous hormones, extraction from a plant-based source, and that the hormones are not manufactured or synthesized. [ 47 ]


The monthly newsletter  Harvard Women's Health Watch , published by  Harvard Medical School , states that  natural  does not automatically mean  safe , and that it can be used to indicate any product with an animal, plant, or mineral source—including hormones that are not bioidentical (such as  Premarin ), as well as the molecules extracted from soybean and yam sources used in many bioidentical and non-bioidentical commercial preparations. [ 13 ]


Compounded BHT may be more expensive than conventional, FDA-approved HRT, and is often not covered by health insurance. [ 6 ] [ 49 ]


Bioidentical hormones are expected to carry the same risks and benefits as their non-bioidentical counterparts, but there have been no studies that directly compare compounded bioidentical hormones with their non-bioidentical counterparts. [ 2 ] [ 20 ]  Hormones—as used in CHRT—have been studied for years and their risk, benefit, and effectiveness profiles are known and demonstrated through considerable research. [ 12 ]


In 2002, the  Women's Health Initiative  study (WHI) that was designed to demonstrate additional benefits of conventional hormone therapy (study participants were given Prempro or a placebo) was terminated prematurely after preliminary data indicated small increases in the risks of breast cancer, heart attack and stroke in older women using Prempro. [ 50 ]  Its early termination and the subsequent publicity about these previously unappreciated risks led to a decline in prescriptions for CHRT. [ 51 ]  The results from the study were used by BHT prescribers to promote bioidentical hormones as safer than the FDA-regulated preparations despite a lack of evidence; [ 6 ]  according to the FDA, the results found by the study apply to all estrogens. [ 12 ]  BHT has since been strongly promoted as a natural alternative with fewer risks than CHRT, though there is no evidence to support this claim. BHT practitioners recommend compounded products due to their claim that they more closely mimic the composition and ratio of circulating hormones in a woman's body than do commercially manufactured products. [ 20 ]


The Endocrine Society  issued a position statement that bioidentical hormones carry essentially the same risks and benefits as non-bioidentical molecules. [ 14 ]  In February 2009 the American Congress of Obstetricians and Gynecologists reiterated its position (from November 2005) that there are no proven benefits in regard to the safety or efficacy of compounded bioidentical hormones, nor are there any benefits in salivary testing of hormone levels or customized dosing of hormones. [ 38 ]  The  Mayo Clinic  states that there is no evidence that pharmacy-compounded BHT is safer or more effective than conventional hormone replacement, and that some bioidentical hormones are already available in certain FDA-approved products. [ 37 ]  The  American Cancer Society  also stated that "natural" and "bioidentical" hormones present the same risks as synthetic hormone replacement therapy such as heart disease, blood clots, strokes and an increased risk of breast cancer with long-term use. [ 52 ]


The  U.S. Food and Drug Administration  has warned several pharmacies about making unsubstantiated claims about the safety and effectiveness of compounded hormone products. [ 18 ]  The  North American Menopause Society  has stated that compounded bioidentical hormones have not been approved by the FDA; there is no guarantee of purity, potency, efficacy or safety, and they may contain unknown contaminants. [ 37 ]  The Australian Menopause Society has similarly stated that there is no evidence that bioidentical hormones administered using  lozenges  are any safer than their approved counterparts. [ 53 ] [ 54 ]  The International Menopause Society has stated "There are no medical or scientific reasons to recommend unregistered 'bioidentical hormones'. The measurement of hormone levels in the saliva is not clinically useful. These 'customized' hormonal preparations have not been tested in studies and their purity and risks are unknown." [ 55 ]


In November 2006, the  American Medical Association  adopted a policy requesting that the FDA better monitor and regulate bioidentical hormones, [ 56 ]  releasing an editorial stating that compounded bioidentical molecules were expected to have the same risks as conventional hormones until proven otherwise. [ 57 ]


Deborah Moskowitz published an article suggesting that some forms of bioidentical hormones may be safer than non-bioidentical hormones in safety and effectiveness, [ 58 ]  though this review was criticized for "[attempting] to demonstrate that BHT has a good safety profile, but the data presented only serve to demonstrate similar risks to conventional HRT." [ 6 ]


Quackwatch  recommends against the use of bioidentical hormones due to lack of quality control over compounding, posing the same risks as conventional hormones, the use of unnecessary saliva testing, and including the non-FDA-approved hormone  estriol .  Stephen Barrett , the site's owner, concludes his review with: "The bottom line for consumers is very simple: Steer clear of anyone who prescribes "bioidentical" hormones or recommends saliva testing as the basis for evaluating hormone status." [ 59 ]


Compounded BHT is used almost exclusively in the United States, [ 2 ]  and many FDA-approved formulations that are wholly or partially made of bioidentical hormones are available. [ 13 ]  Topical hormone preparations such as progesterone, estrogen and DHEA creams can be purchased in stores or over the internet and are not regulated by the FDA, as they are generally considered cosmetic. [ 8 ]


When prescribed by a licensed practitioner, the compounding of bioidentical hormones is controlled by the state pharmacy boards rather than the FDA, [ 60 ]  and  pharmacists  are permitted to adjust dose and delivery method according to the prescription. [ 61 ]  However, the FDA does have authority over the compounded product. [ 2 ]  In 2001 the FDA surveyed a limited number of compounded preparations, including eight hormone compounds. All three estradiol products passed every test; however, two out of five progesterone products failed at least one test of potency, content or uniformity. [ 2 ]


In October 2005  Wyeth  Pharmaceuticals, a manufacturer of both FDA-approved bioidentical and non-bioidentical HRT preparations, filed a citizen petition with the FDA asking for enforcement action against compounding pharmacies that dispensed BHT and to investigate labelling and advertising guidelines. Soon after, the FDA took a number of enforcement actions against several (primarily Internet-based) pharmacies that were producing compounded BHT and in 2008, banned the use of estriol in the US. [ 18 ] [ 39 ]  The FDA stated that it did not take these regulatory actions against compounded bioidentical hormones in response to Wyeth's request, since that is not the purpose of a citizen petition. They said that they had an ongoing investigation when they received the petition. [ 12 ]  The FDA ordered pharmacies to discontinue use of estriol. The agency's Assistant Director of the Office of Compliance stated that the use of estriol would require a permit for research and a new drug application. The FDA also stated that it has not approved any drug containing estriol and that no information had been submitted to the FDA regarding its safety and effectiveness. [ 11 ]  The FDA's concerns over the marketing and use of bioidentical hormones were supported by the American Association of Clinical Endocrinologists. [ 62 ]  In response to the FDA's actions, the International Academy of Compounding Pharmacists began a letter-writing campaign to the FDA to reverse this action, citing Wyeth's attempt as a "self-serving, and at times duplicitous, campaign to restrict patients' access to alternatives to its own products". [ 63 ]


In November 2006, the  American Medical Association  adopted a policy urging the FDA to survey compounded BHT products for purity and dosage; to maintain a registry and require mandatory adverse event reporting by manufacturers and compounding pharmacies related to bioidentical hormones; to mandate the inclusion of uniform patient information, including warnings and precautions regarding bioidentical products; and to prohibit the use of the term  bioidentical hormones  unless the agency has approved the preparation. [ 56 ]


On July 18, 2008, a US Appeals Court issued a ruling stating that new drug approval processes should not be applied to compounded drugs that complied with established guidelines, and also that provisions of the regulations relevant to the use of estriol were still in effect, preventing the FDA from taking action against pharmacies using estriol in compounded products. [ 64 ]


The Wiley Protocol is a version of compounded BHT endorsed by  T. S. Wiley . Its goal is to produce serum levels of estradiol and progesterone that are identical to those of a young woman with a normal menstrual cycle. It has been criticized for a variety of reasons. [ 17 ] [ 45 ] [ 65 ] [ 66 ]


Bionovo  (NASDAQ: BNVI.OB) was an American  biotechnology   company  focused on the discovery and development of botanically derived treatments for women's health and cancer based in  Emeryville ,  California . The company had multiple drug candidates in U.S.  Food and Drug Administration  (FDA)  clinical trials -  Menerba  (formerly known as MF101) a selective  estrogen receptor beta  agonist for  hot flashes  associated with  menopause  Seala (formerly VG101) a selective estrogen receptor beta agonist for menopausal vaginal dryness and Bezielle (formerly BZL101) for advanced  breast cancer . The company has ceased activity after filing for Chapter 7 bankruptcy protection in California. Bionovo's stock is no longer listed.


Bionovo used  traditional Chinese medicine  (TCM) as its discovery engine, isolating, purifying and testing potent  active ingredients  from  herbs  and other botanicals, then formulating them into products which can be packaged as powders or pills for easy use by patients.


The company identified the active chemical components underpinning the mechanism of action for all of their lead drug candidates, [ 2 ] [ 3 ]  and in some cases, has developed synthetic  methods of production . They are developing their drugs in accordance with the U.S. FDA's botanical drug guidelines. [ 4 ]


Bionovo's  drug pipeline  had two drug candidates in clinical trials and several additional candidates positioned to enter clinical trials upon the receipt of funding or partnership.


Bionovo’s lead drug candidate, Menerba (formerly known as MF101), is a novel selective  estrogen receptor beta  (ERβ) agonist designed to treat vasomotor symptoms ( hot flashes ) associated with  menopause . [ 5 ]


Although Menerba is a  selective estrogen receptor modulator  (SERM), it is distinct from the other FDA-approved SERMs, such as  tamoxifen  and  raloxifene , since these drugs have mixed agonist/antagonist activity and are not selective in transcriptional regulation to one of the two known  estrogen receptor  subtypes.


Menerba completed its Phase II clinical trial, showing the drug to be safe, clinically efficacious and well tolerated. [ 6 ]  The drug will begin its Phase III clinical trial pending FDA approval. [ 7 ]


Bezielle (also called BZL101) is an oral drug designed for the treatment of advanced  breast cancer . The drug is derived from the herb, Scutellaria Barbata, which is used in  traditional Chinese medicine  to treat  cancer . [ 8 ]   Bezielle is selectively cytotoxic to most of twelve breast cancer cell lines examined [ 3 ]  as well as to a number of cancer cell lines of different tissue origins such as prostate, lung, colon, ovarian and pancreatic cancers. [ 3 ] [ 9 ]


Bezielle’s  mechanism of action  targets diseased cells while leaving normal cells healthy and intact by inhibiting  glycolysis  production. Normal cells depend primarily on the  citric acid cycle  (>85%) and very little on  glycolysis  (<7%) for energy production. In contrast,  cancer cells  depend largely on  glycolysis  (>85%) for energy production. [ 10 ]  Bezielle induces strong  oxidative stress  in cancer cells leading to severe  DNA damage , but in normal cells the effect is blunted due to their different metabolic profile.  Cancer cells attempt but ultimately fail to repair DNA damage that results in the inhibition of glycolysis and cancer cell death while normal cells remain unharmed. [ 3 ]  Bezielle has completed Phase 1A [ 10 ]  and 1B [ 11 ]  clinical trials for advanced metastatic breast cancer. [ 12 ]


Seala (also known as VG101) for  vaginal atrophy  was approved by the FDA to begin a Phase I/II  clinical trial [ 13 ]  upon receipt of funding.


BN107 and BN108, both designed to treat advanced breast cancer, are slated to begin Phase I/II  clinical trials  upon funding. [ 14 ] [ 15 ]


Bezielle was scheduled to begin a Phase I/II  clinical trial  for the treatment of  pancreatic cancer  upon funding. [ 16 ]


Broken Light  is a 2023 novel by English-French author  Joanne Harris . It is in the  psychological thriller  genre, with aspects of  magical realism , and deals with a woman approaching  menopause  who develops paranormal abilities. [ 1 ]


The book is written in a  multiple-narrative  technique, alternating first-person accounts between Bernie Moon and her old school friend Katie Hemsworth.


Bernie Moon is nearing fifty, lonely and menopausal. She lives in London with her husband Martin, has one son whom she seldom sees, works in a local bookshop and has virtually no friends. But the murder of a woman in a nearby park re-awakens a latent talent, and she begins to experience "flashes" that allow her to enter - and in some cases, influence - the minds of others. [ 2 ]


She first uses this talent to identify a predator, Jim "Woody" Wood, a friend of Martin's, who she thinks may be the murderer of the woman in the park. She realizes that he is not, but that he does mean to spike the drink of a young woman, Iris, who works in a local coffee shop. Bernie follows Iris and Woody to their date, and intervenes psychically to protect Iris, with the result that Woody passes out, and continues to do so every time he thinks about harming a woman. Iris and Bernie become friends. When she finds out about Bernie's " superpower ", Iris is eager for Bernie to use it again.


As Bernie starts to understand her powers, we find that she developed them as a child, and has suppressed them, following an early incident involving a boy called Adam Price, and a later one, in which a predatory schoolteacher took his own life. We also learn that Bernie shared her ability with a friend, Katie, from whom she is now estranged. Katie still lives in Bernie's home town, and has an apparently perfect life, which Bernie envies. We also learn that Martin, whom Bernie met while they were at school, nurses a secret infatuation for Katie. Bernie and Martin married when Bernie fell pregnant at eighteen, and Bernie sacrificed her chance of going to university to look after their son. Now, as their 30-year high school reunion party approaches, she realizes that she has spent her life looking after other people.


Encouraged by Iris, and motivated by the approach of the high school reunion, Bernie sets out to change. She uses her powers benignly to help the bookshop sell more books, and enjoys vicarious experiences by observing the habits of others. She joins a running club and discovers the comradeship of other women. Meanwhile, Woody is still suffering unexplained episodes of  narcolepsy . Martin invites him to stay for a few days, and he moves in, to Bernie's dismay. Weeks pass, and Woody, increasingly dysfunctional, becomes convinced that he was drugged as part of a nefarious plan by women to emasculate and enslave men. His social media accounts and podcast are filled with these conspiracy theories, which begin to gain a following, especially among young men.


Woody makes his dislike of Bernie clear, although he has no memory of her intervention. Bernie wants to make him leave, but is afraid of doing further damage. Finally, emboldened by her friendship with Iris, she finds the courage to tell him to go without using her superpowers, and he moves out, though he remains convinced that she is connected to the conspiracy. Meanwhile, Martin is making plans for the 30-year high school reunion, during which he intends to reform his high school band, and recreate the set they played at the original graduation party, when he first became attracted to Katie.


As the date of the reunion party approaches, Bernie, encouraged by Iris, begins to enjoy her powers. She runs a 5k with her running group, gets singing lessons, gets a tattoo and becomes reunited with her son. But when Iris steals a designer dress for her during a shopping expedition, she begins to suspect that Iris's personality change is a result of her own intervention. Her suspicions are confirmed when a client of Martin's, an author known for his misogynistic behaviour, begins to behave erratically following a visit to their home, and when Woody, whose own behaviour has become increasingly strange, is killed in a stabbing incident in a women-only gym.


Convinced now that her powers are both toxic and somehow infectious, Bernie tries to concentrate on the reunion party, which she hopes will bring her closer to Martin. She lets him travel to their home town of Malbry without her, meaning to surprise him later with her transformation. She disconnects from Iris, breaking the psychic link between them, and travels to Malbry, where she appears at the party and performs the song she has been practicing. On stage, she enters Katie's mind and understands why her friend abandoned her. She too is a victim of date rape, this time by Martin when they were both at university, and Katie has internalized the guilt, believing herself to be at  fault.


But Adam Price, the boy on whom their first psychic experiment was directed, has never forgotten the incident. Obsessed with Woody's podcast and his conspiracy theories, he is certain that Bernie and Katie are responsible for the failures in his life. He attempts to stab Katie onstage, but Bernie intervenes, and sacrifices herself in the attempt, having realized that Adam is a victim, and not a predator.


The backdrop of lockdown, the  #MeToo  campaign and the murder of  Sarah Everard  during the  Covid pandemic  has been cited as the context for Harris' writing of  Broken Light . [ 3 ]  The novel also deals with the theme of women in menopause and the invisibility of the older woman. [ 4 ]  In an interview with Dr Louise Newson, Harris speaks about Bernie's superpowers as "a metaphor for the anger of women in later life who are too often silenced in art and reality". [ 5 ]  It also deals with the impact of social media, gender politics, [ 6 ]  friendship and self-discovery. [ 7 ]


In a guest post for the  Nerd Daily , Harris acknowledges the debt of  Broken Light  to  Stephen King 's  Carrie , saying:


...menopause triggers Bernie's powers just as puberty triggers Carrie's: both are a metaphor for rage, though Carrie's rage is reactive, directed against the bullies at school, her mother and ultimately herself, whilst Bernie's rage, though quieter, is both feminist and political; the rage of a woman forced to endure forty years of gaslighting from a patriarchy that insists that women's experience doesn't count; that we are somehow in a minority. [ 8 ]


In an interview with  The Guardian ,  Harris says  she began the book after re-reading  Carrie  during lockdown, and during her cancer treatment, which she says was "like menopause, but worse". [ 9 ]


Publishers Weekly  called  Broken Light  "an intricate, brilliantly plotted thriller". [ 10 ]   The Telegraph  said that the book "landed polemical blows", but dismissed the concept as "cartoonish". [ 11 ]  Author  Ian Rankin  named  Broken Light  as one of his best books of the year in the  New Statesman ,  saying, "This is Angela Carter meets  Carrie  and it is done with dizzying aplomb. Bernie Moon is a compelling and complex creation." [ 12 ]


The audiobook of the novel, narrated by  Imogen Stubbs , was selected as one of the Best Summer Audiobooks of 2023 by the  Financial Times . [ 13 ]


The  Centre for Menstrual Cycle and Ovulation Research (CeMCOR)  is a health research centre in  Vancouver . According to the  University of British Columbia , CeMCOR is the only centre in the world that focuses on  ovulation  and the causes and consequences of ovulation disturbances. [ 1 ]   CeMCOR is known for research on  progesterone -only therapy for menopausal  hot flushes , [ 2 ] [ 3 ]   research on  perimenopause  as distinct from  menopause , [ 4 ]   and for a focus on women's perspectives and self-knowledge. [ 5 ]


The Centre was founded by  Dr. Jerilynn Prior [ 2 ]  in May 2002 as a  charity  affiliated with the University of British Columbia. The stated vision was to "reframe scientific knowledge of the menstrual cycle and ovulation in a woman-centered context." [ 6 ]


CeMCOR is now located at  Vancouver General Hospital [ 2 ]  in the Gordon and Leslie Diamond Health Care Centre. [ 7 ]  Staff includes 15 clinicians and 9 trainees. It is guided by both a Community Advisory Council and a Scientific Advisory Council composed of  endocrinologists ,  epidemiologists ,  gynecologists ,  nutritionists ,  psychologists , and  sociologists . [ 7 ] [ 5 ]


CeMCOR published over 50 scientific papers in its first 10 years, as well as 4 books. [ 7 ]  Areas of research include  menstruation  and ovulation,  bone health , premenopausal  breast cancer ,   polycystic ovary syndrome (PCOS) , and perimenopause. [ 8 ]   CeMCOR has stated that its research shows overall that regular menstrual cycles with ovulation help prevent osteoporosis, breast cancer, and  heart disease . [ 6 ]  Dr. Prior has called menstrual cycles "a vital sign". [ 9 ]


CeMCOR does not conduct research funded by the  pharmaceutical industry . [ 6 ]


Climacteric  is a bimonthly  peer-reviewed   medical journal  that covers all aspects of aging in women, especially during the  menopause . [ 1 ]  As the official journal of the  International Menopause Society ,  Climacteric  also publishes position statements and workshop proceedings from the society.


Climacteric  was established in 1998. According to the  Journal Citation Reports , the journal has a 2022  impact factor  of 2.800. [ 2 ]  The  Editor-in-chief  is Rodney Baber ( Sydney Medical School ).


An  estrogen patch , or  oestrogen patch , is a  transdermal  delivery system for  estrogens  such as  estradiol  and  ethinylestradiol  which can be used in  menopausal hormone therapy ,  feminizing hormone therapy  for  transgender women ,  hormonal birth control , and other uses. [ 1 ]  Transdermal preparations of estrogen are  metabolized  differently than  oral  preparations. Transdermal estrogens avoid the  first pass  through the  liver  and thus potentially reduce the risk of  blood clotting  and  stroke . [ 2 ]


An estrogen patch is applied directly to the skin, preferably near the lower abdomen, hips, or buttocks, and is usually changed once or twice per week. For women who have not undergone a  hysterectomy , it is often suggested that they take  progestogen  in addition to an estrogen patch in order to protect the  endometrium  of the  uterus . [ 1 ] [ 2 ]  Transdermal estrogens are not recommended for all women; there are important precautions and side effects that should be considered before use. [ 2 ]


An estrogen patch may be recommended for women experiencing moderate to severe symptoms of  menopause , such as  vasomotor symptoms  and  vaginal atrophy . During menopause, the ovaries stop producing estrogen which causes estrogen levels to fall. The sudden change in estrogen levels may cause vasomotor symptoms, such as hot flashes. Research suggests that the estrogen patch can relieve both the frequency and severity of vasomotor symptoms by increasing estrogen levels. An estrogen patch may also be used to treat vulvar and vaginal atrophy, another symptom of menopause associated with the sudden change in estrogen levels. [ 1 ]


Hypoestrogenism, or estrogen deficiency, may suggest menopause is approaching for middle aged women. Other causes of hypoestrogenism are excessive exercise, restrictive diet, underactive  pituitary gland ,  ovarian failure ,  Turner Syndrome , and  kidney disease . Symptoms of hypoestrogenism may include pain during sex, irregular periods, mood swings, hot flashes, breast tenderness, headache,  depression , fatigue, weak bones, and an increase risk of  urinary tract infections . Estrogen therapies, including the use of an estrogen patch, can be used to alleviate these symptoms by increasing estrogen levels to a normal state. Premenopausal women may be recommended to take progestin with estrogen therapy. [ 2 ]


Estrogen patches may be effective in preventing osteoporosis in postmenopausal women. Research suggests that estrogen patches can significantly increases  bone mineral density  and reduce risks of fractures in postmenopausal women by raising estrogen levels and avoiding first-pass metabolism. [ 5 ]


There is evidence that the combination of an estrogen patch with a progestin pill can improve bone mineral density in young, premenopausal  amenorrheic  athletes, and may be more effective than an oral estrogen with progestin. [ 6 ]


Contraceptive patches  such as  norelgestromin/ethinylestradiol  are a form of estrogen patch which are used for  hormonal birth control .


Estrogen patches are commonly used for  feminizing hormone therapy  for  transgender  women as part of  gender-affirming care . [ 7 ]


Taking a progestogen in addition to an estrogen patch should be considered for women who have not undergone a hysterectomy to regulate the thickness of the  endometrial lining [ 2 ]  and reduce the risk of  endometrial cancer . Hysterectomized women rarely need a progestogen, however it may be considered if a history of  endometriosis  exists. [ 1 ]  There are different types of delivery systems of progestogens that can be used in addition to an estrogen patch, including pills, injections, [ 8 ]  and patches, among others. [ 9 ]


Research has suggested that estrogen plus progestogen therapy may increase the risk of  heart attacks , stroke,  breast cancer , blot clots, and  dementia  in postmenopausal women. Taking the lowest effective dose of both estrogen and a progestogen may reduce risks. [ 1 ]


Depending on the brand, patches are applied to the skin once or twice weekly. Patches should be placed on clean skin where hair and moisture is not present. Preferred areas of application include lower  abdomen ,  hip , and  buttocks . Patches should never be applied to the  breasts . To reduce the risk of the patch detaching from the skin and skin irritation, skin care products, sun exposure, damaged skin, and tight-fitting clothing should be avoided where the patch is placed. [ 2 ]


Headache , breast pain or tenderness,  nausea , vomiting, hair loss, vaginal discharge or irritation, and mood changes are some of the common side effects that may occur while using an estrogen patch. [ 10 ]  More serious side effects may include fever, loss of appetite, joint pain, difficulty breathing or swallowing, and yellowing of the skin or eyes. [ 10 ] [ 11 ]


Seeing a health professional regularly, taking progestin, having pelvic and breast exams, lowering blood pressure, and lowering cholesterol may reduce the likelihood of developing severe side effects while using an estrogen patch. [ 1 ]


Women who have experienced vaginal bleeding post menopause, certain cancers, stroke, heart attack, blood clotting, or uncontrollable bleeding, and women who are pregnant or allergic to ingredients in estrogen patches should not use an estrogen patch as serious adverse effects may occur. [ 1 ]


Estrogen patches are available in multiple brand names in different countries. Some patches are available with a progestin such as  levonorgestrel ,  norethisterone acetate , or  norelgestromin . [ 4 ] [ 12 ]


The  European Menopause and Andropause Society  is an institution that promotes the study, and encourages research of midlife health. Founded in 1998.


The official journal of EMAS,  Maturitas , is published on a monthly basis by   Elsevier Science  It covers a variety of disciplines, including management of  chronic diseases ,  epidemiology , therapeutic techniques, and  alternative medicine . The journal impact factor is 5.110. [ 1 ]  Irene Lambrinoudaki and Leon Flicker are the Editors-in-Chief. [ 2 ]
EMAS is now affiliated with Case Reports in Women's Health, also published by Elsevier. The Editor-in-Chief is Margaret Rees.


EMAS participates in a variety of medical congresses related to  menopause ,  gynecology , and  obstetrics  each year. The society hosts its own European Congress  [ 3 ]  every two years. EMAS also organises educational schools on menopausal health.


EMAS provides online education on its website with the textbook EMAS Care Online 2020 accompanied by PowerPoint presentations.


The aim of the mentorship programme, JuMP, is to encourage career development of junior clinicians and researchers in the field of post-reproductive health by pairing one expert mentor with a mentee, based on mutual research interests. The last round, 2021 – 2023, is completed.


The 12th European Congress on Menopause and Andropause was held in Berlin, in May 2019.


The 13th EMAS Congress took place virtually 8-10 September 2021 starting  on 7 September with the launch of the first-ever World Menopause & Work Day.


Few animals have a  menopause : humans are joined by just four other species in which females live substantially longer than their ability to reproduce. The others are all  cetaceans :  beluga whales ,  narwhals ,  orcas  and  short-finned pilot whales . [ 1 ]   There are various theories on the origin and process of the  evolution of menopause . These attempt to suggest evolutionary benefits to the human species stemming from the cessation of women's reproductive capability before the end of their natural lifespan. Explanations can be categorized as adaptive and non-adaptive:


The high cost of female investment in offspring may lead to physiological deteriorations that amplify susceptibility to becoming infertile. This hypothesis suggests the reproductive lifespan in humans has been optimized, but it has proven more difficult in females and thus their reproductive span is shorter. If this hypothesis were true, however, age at menopause should be negatively correlated with the amount of energy expended to maintain the reproductive organs, [ 2 ]  and the available data does not support this. [ 3 ]


A recent increase in female  longevity  due to improvements in the standard of living and social care has also been suggested. [ 4 ]  It is difficult for selection, however, to favor aid to offspring from parents and grandparents. [ 5 ]  Irrespective of living standards, adaptive responses are limited by physiological mechanisms. In other words,  senescence  is programmed and regulated by specific genes. [ 6 ]


While it is fairly common for extant hunter-gatherers to live past age 50 provided that they survive childhood, fossil evidence shows that mortality in adults has decreased over the last 30,000 to 50,000 years and that it was extremely unusual for early  Homo sapiens  to live to age 50. This discovery has led some biologists to argue that there was no selection for or against menopause at the time at which the ancestor of all modern humans lived in  Africa , suggesting that menopause is instead a random evolutionary effect of a  selection shadow  regarding aging in early  Homo sapiens . It is also argued that since the population fraction of post-menopausal women in early  Homo sapiens  was so low, menopause had no evolutionary effect on mate selection or social behaviors related to mate selection. [ 7 ] [ 8 ]


This hypothesis suggests that younger mothers and offspring under their care will fare better in a difficult and predatory environment because a younger mother will be stronger and more agile in providing protection and sustenance for herself and a nursing baby. The various biological factors associated with menopause had the effect of male members of the species investing their effort with the most viable of potential female mates. [ 9 ] [ page needed ]


A problem with this hypothesis is that, if true, we would expect to see menopause exhibited among many species in the animal kingdom, [ 10 ]  and another problem is that in the case of extended child development, even a female who was relatively young, still agile, and attractive when producing a child would lose future support from her male partner due to him seeking out fertile mates when she reaches menopause, while the child is still not independent. This would be counterproductive to the supposed adaptation of getting male support, as it would significantly decrease the survival for children produced over much of the female's fertile and agile life, unless children were raised in ways that did not rely on support from a male partner, which would eliminate the supposed evolutionary benefit anyway. [ 11 ] [ 12 ]


The young female preference hypothesis proposes that changes in male preferences for younger mates allowed late-age acting fertility  mutations  to accumulate in females without any evolutionary penalty, giving rise to menopause. A computer model was constructed to test this hypothesis, and showed that it was feasible. [ 13 ]   However, in order for deleterious mutations that affect fertility past roughly age fifty to accumulate, human maximum lifespan had to first be extended to about its present value. As of 2016 it was unclear if there has been sufficient time since that happened for such an evolutionary process to occur. [ 14 ]


The male-biased  philopatry  theory proposes that if human social groups were originally based around women leaving their birth communities at sexual maturity more frequently than men, then reproductive females would become more closely related to other group members as they grew older, making the  inclusive fitness  benefits older females receive from helping the group greater than what they would receive from continued reproduction. This in turn would lead to the evolution of menopause. [ 15 ]  By contrast, in a pattern of male-biased dispersal and local mating, the relatedness of the individuals in the group decreases with female age, leading to a decrease in  kin selection  with female age. [ 15 ]  This occurs because a female will stay with her father in her birth community throughout life, initially being closely related to the males and females. Females are born and stay in the group, so relatedness to the females stays about the same. However, throughout time, the older male relatives will die and any sons she gives birth to will disperse, so that local relatedness to males, and therefore the whole group, declines. The situation is reversed in species where males are philopatric and either females disperse, or mating is non-local. [ 15 ]  Under these conditions, a female's reproductive life begins away from her father and paternal relatives because she was either born into a new group from non-local mating or because she dispersed. In the case of female-biased dispersal, the female is initially equally unrelated with every individual in the group, and with non-local mating, the female is closely related to the females of the group, but not the males since her paternal relatives are in another group. As she gives birth, her sons will stay with her, increasing her relatedness to males in the group over time and thus her relatedness with the overall group. The common feature that connects these two otherwise different behaviors is male-biased philopatry, which leads to an increase in kin selection with female age.


While not conclusive, evidence does exist to support the idea that female-biased dispersal existed in pre-modern humans. The closest living relatives to humans,  chimpanzees ,  bonobos , and both  mountain gorillas  and  western lowland gorillas , are female-biased dispersers. [ 16 ]  Analysis of sex specific genetic material, the non-recombining portions of the Y chromosome and mitochondrial DNA, show evidence of a prevalence of female-biased dispersal as well; however, these results could also be affected by the effective breeding numbers of males and females in local populations. [ 17 ]  Evidence of female-biased dispersion in hunter-gatherers is not definitive, with some studies supporting the idea, [ 16 ]  and others suggesting there is no strong bias towards either sex. [ 18 ]  In  orcas , both sexes mate non-locally with members of a different pod but return to the pod after copulation. [ 19 ]  Demographic data shows that a female's mean relatedness to the group does increase over time due to increasing relatedness to males. [ 20 ]  While less well-studied, there is evidence that  short-finned pilot whales , another menopausal species, also display this behavior. [ 21 ]  However, mating behavior that increases local relatedness with female age is prevalent in non-menopausal species, [ 16 ]  making it unlikely that it is the only factor that determines if menopause will evolve in a species.


The mother hypothesis suggests that menopause was selected for humans because of the extended development period of human offspring and high costs of reproduction so that mothers gain an advantage in reproductive fitness by redirecting their effort from new offspring with a low survival chance to existing children with a higher survival chance. [ 22 ]


The Grandmother hypothesis suggests that menopause was selected for humans because it promotes the survival of grandchildren. According to this hypothesis, post-reproductive women feed and care for children, adult nursing daughters, and grandchildren whose mothers have weaned them. Human babies require large and steady supplies of glucose to feed the growing brain. In infants in the first year of life, the brain consumes 60% of all calories, so both babies and their mothers require a dependable food supply. Some evidence suggests that hunters contribute less than half the total food budget of most hunter-gatherer societies, and often much less than half, so that foraging grandmothers can contribute substantially to the survival of grandchildren at times when mothers and fathers are unable to gather enough food for all of their children. In general, selection operates most powerfully during times of famine or other privation. So although grandmothers might not be necessary during good times, many grandchildren cannot survive without them during times of famine.
Post-reproductive female orcas tend to lead their pods, especially during years of food scarcity. [ 23 ]  Furthermore, the increased mortality risk of an orca due to losing a grandmother is stronger in years of food scarcity [ 24 ]


Analysis of historical data found that the length of a female's post-reproductive lifespan was reflected in the reproductive success of her offspring and the survival of her grandchildren. [ 25 ]  Another study found comparative effects but only in the maternal grandmother—paternal grandmothers had a detrimental effect on infant mortality (probably due to paternity uncertainty). [ 26 ]  Differing assistance strategies for maternal and paternal grandmothers have also been demonstrated. Maternal grandmothers concentrate on offspring survival, whereas paternal grandmothers increase birth rates. [ 27 ]


Some believe variations on the mother, or grandmother effect fail to explain longevity with continued spermatogenesis in males (oldest verified paternity is 94 years, 35 years beyond the oldest documented birth attributed to females). [ 28 ]  Notably, the survival time past menopause is roughly the same as the maturation time for a human child. That a mother's presence could aid in the survival of a developing child, while an unidentified father's absence might not have affected survival, could explain the paternal fertility near the end of the father's lifespan. [ 29 ]   A man with no certainty of which children are his may merely attempt to father additional children, with support of existing children present but small. Note the existence of partible paternity supporting this. [ 30 ]  Some argue that the mother and grandmother hypotheses fail to explain the detrimental effects of losing ovarian follicular activity, such as  osteoporosis ,  osteoarthritis ,  Alzheimer's disease  and  coronary artery disease . [ 31 ]


The theories discussed above assume that evolution directly selected for menopause. Another theory states that menopause is the byproduct of the evolutionary selection for  follicular atresia , a factor that causes menopause. Menopause results from having too few ovarian follicles to produce enough estrogen to maintain the ovarian-pituitary-hypothalamic loop, which results in the cessation of menses and the beginning of menopause. Human females are born with approximately a million oocytes, and approximately 400 oocytes are lost to ovulation throughout life. [ 32 ] [ 33 ]


In social  vertebrates , the sharing of resources among the group places limits on how many offspring can be produced and supported by members of the group. This creates a situation in which each female must compete with others of the group to ensure they are the one that reproduces. [ 34 ]  The reproductive conflict hypothesis [ 35 ]  proposes that this female reproductive conflict favors the cessation of female reproductive potential in older age to avoid reproductive conflict, increasing the older female's fitness through  inclusive  benefits. Female-biased dispersal or non-local mating leads to an increase in relatedness to the social group with female age. [ 15 ]  In the human case of female-biased dispersal, when a young female enters a new group, she is not related to any individual and she reproduces to produce an offspring with a  relatedness  of 0.5. An older female could also choose to reproduce, producing an offspring with a relatedness of 0.5, or she could refrain from reproducing and allow another pair to reproduce. Because her relatedness to males in the group is high, there is a fair probability that the offspring will be her grandchild with a relatedness of 0.25. The younger female experiences no cost to her inclusive fitness from using the resources necessary to successfully rear offspring since she is not related to members of the group, but there is a cost for the older female. As a result, the younger female has the advantage in reproductive competition. Although a female orca born into a social group is related to some members of the group, the whale case of non-local mating leads to similar outcomes because the younger female relatedness to the group as a whole is less than the relatedness of the older female. This behavior makes more likely the cessation of reproduction late in life to avoid reproductive conflict with younger females.


Research using both human and orca demographic data has been published that supports the role of reproductive conflict in the evolution of menopause. Analysis of demographic data from pre-industrial Finnish populations found significant reductions in offspring survivorship when mothers-in-laws and daughters-in-laws had overlapping births, [ 36 ]  supporting the idea that avoiding reproductive conflict is beneficial to offspring survivorship. Humans, more so than other primates, rely on food sharing for survival, [ 37 ]  so the large survivorship reduction values could be caused by a straining of community resources. Avoiding such straining is a possible explanation for why the reproductive overlap seen in humans is much lower than other primates. [ 35 ]  Food sharing is also prevalent among another menopausal species, orcas. [ 38 ]  Reproductive conflict has also been observed in orcas, with increased calf mortality seen when reproductive overlap between a younger and older generational female occurred. [ 20 ]


The  grandmother hypothesis  is a hypothesis to explain the existence of  menopause  in human life history by identifying the adaptive value of extended kin networking. It builds on the previously postulated " mother hypothesis " which states that as mothers age, the costs of reproducing become greater, and energy devoted to those activities would be better spent helping her offspring in their reproductive efforts. [ 1 ]  It suggests that by redirecting their energy onto those of their offspring, grandmothers can better ensure the survival of their genes through younger generations. By providing sustenance and support to their kin, grandmothers not only ensure that their genetic interests are met, but they also enhance their social networks which could translate into better immediate resource acquisition. [ 2 ] [ 3 ]  This effect could extend past kin into larger community networks and benefit wider  group fitness . [ 4 ]


One explanation to this was presented by  G.C. Williams  who was the first to posit [ 5 ]  that menopause might be an adaptation. Williams suggested that at some point it became more advantageous for women to redirect reproductive efforts into increased support of existing offspring. Since a female's dependent offspring would die as soon as she did, he argued, older mothers should stop producing new offspring and focus on those existing. In so doing, they would avoid the age-related risks associated with reproduction and thereby eliminate a potential threat to the continued survival of current offspring. The evolutionary reasoning behind this is driven by related theories.


Kin selection provides the framework for an adaptive strategy by which altruistic behavior is bestowed on closely related individuals because easily identifiable markers exist to indicate them as likely to reciprocate. Kin selection is implicit in theories regarding the successful propagation of genetic material through reproduction, as helping an individual more likely to share one's genetic material would better ensure the survival of at least a portion of it. Hamilton's rule suggests that individuals preferentially help those more related to them when costs to themselves are minimal. This is modeled mathematically as

 r
 b
 >
 c

 {\displaystyle rb>c}

 . Grandmothers would, therefore, be expected to forgo their own reproduction once the benefits of helping those individuals ( b ) multiplied by the relatedness to that individual ( r ) outweighed the costs of the grandmother not reproducing ( c ).


Evidence of kin selection emerged as correlated with climate-driven changes, around 1.8–1.7 million years ago, in female foraging and food sharing practices. [ 6 ]  These adjustments increased juvenile dependency, forcing mothers to opt for a low-ranked, common food source ( tubers ) that required adult skill to harvest and process. [ 6 ]  Such demands constrained female IBIs (Inter Birth Intervals) thus providing an opportunity for selection to favor the grandmother hypothesis.


Parental investment, originally put forth by  Robert Trivers , is defined as any benefit a parent confers on an offspring at a cost to its ability to invest elsewhere. [ 7 ]  This theory serves to explain the dynamic sex difference in investment toward offspring observed in most species. It is evident first in gamete size, as eggs are larger and far more energetically expensive than sperm. Females are also much more sure of their genetic relationship with their offspring, as birth serves as a very reliable marker of relatedness. This paternity uncertainty that males experience makes them less likely than females to invest, since it would be costly for males to provide sustenance to another male's offspring. This translates into the grandparental generation, as grandmothers should be much more likely than grandfathers to invest energy into the offspring of their children, and more so in the offspring of their daughters than sons.


Evolutionary theory  dictates that all organisms invest heavily in reproduction in order to replicate their genes. According to parental investment, human females will invest heavily in their young because the number of mating opportunities available to them and how many offspring they are able to produce in a given amount of time is fixed by the biology of their sex. This inter birth interval (IBI) is a limiting factor in how many children a woman can have because of the extended developmental period that human children experience. Extended childhood, like the extended post-reproductive lifespan for females, is relatively unique to humans. [ 8 ]  Because of this correlation, human grandmothers are well-poised to provide supplemental parental care to their offspring's children. Since their grandchildren still carry a portion of their genes, it is still in the grandmother's genetic interest to ensure those children survive to reproduction.


The mismatch between the rates of degradation of  somatic cells  versus  gametes  in human females provides an unsolved paradox. Somatic cells decline more slowly, and humans invest more in somatic  longevity  relative to other species. [ 9 ]  Since natural selection has a much stronger influence on younger generations,  deleterious mutations  during later life become harder to select out of the population. [ 10 ]


In female  placentals , the number of ovarian  oocytes  is fixed during embryonic development, possibly as an adaptation to reduce the accumulation of  mutations , [ 11 ]  which then mature or degrade over the life course. At birth there are, typically, one million  ova.  However, by menopause, only approximately 400 eggs would have actually matured. [ 12 ]  In humans, the rate of  follicular atresia  increases at older ages (around 38–40), for reasons that are not known. [ 13 ]  In chimpanzees, our closest nonhuman, genetic relatives, recent research indicates a menopausal age of roughly 50, similar to that of human females, in captive chimpanzees ( [ 14 ] ), with similar findings reflected in a study of the Ngogo (Uganda) wild chimpanzee community reported in October 2023 ( [ 15 ] ). The report of the latter study questioned the grandmother hypothesis by observing that "...chimpanzees have very different living arrangements than humans. Older female chimpanzees typically do not live near their daughters or provide care for grandchildren, yet females at Ngogo often live past their childbearing years." Previously, a very similar rate of oocyte atresia until the age of 40 had been posited in chimps and humans, at which point humans experienced a far accelerated rate compared to chimpanzees. [ 16 ]


The aging process in humans leaves a dilemma in that females live past their ability to reproduce. The question poised to evolutionary researchers then becomes, why do human bodies live on so robustly and for so long past their reproductive potential, and could there be an adaptive benefit to abandoning one's own attempts at reproduction to assist kin?


The practice of dividing parenting responsibilities among non-parents affords females a great advantage in that they can dedicate more effort and energy toward having an increased number of offspring. While this practice is observed in several species, [ 17 ]  it has been an especially successful   strategy for humans  who rely extensively on social networks. One observational study of the Aka foragers of Central Africa demonstrated how allomaternal investment toward an offspring increased specifically during times that the mother's investment in subsistence and economic activities increased. [ 18 ]


If the grandmother effect were true, post-menopausal women should continue to work after the cessation of fertility and use the proceeds to preferentially provision their kin. Studies of  Hadza  women have provided such evidence. A modern hunter-gatherer group in Tanzania, the post-menopausal Hadza women often help their grandchildren by foraging for food staples that younger children are inefficient at acquiring successfully. [ 8 ]  Children, therefore, require the assistance of an adult to gain this crucial version of sustenance. Often, however, mothers are inhibited by the care of younger offspring and are less available to help their older children forage. [ 8 ]  In this regard, the Hadza grandmothers become vital to the care of existing grandchildren, and allow reproductive-age women to redirect energy from existing offspring into younger offspring or other reproductive efforts.


However, some commentators felt that the role of Hadza men, who contribute 96% of the mean daily intake of protein, was ignored, [ 8 ]  though the authors have addressed this criticism in numerous publications. [ 8 ] [ 19 ] [ 20 ] [ 21 ]  Other studies also demonstrated reservations about behavioral similarities between the Hadza and our ancestors. [ 22 ]


Because grandmothers should be expected to provide preferential treatment to offspring she is most certain of her relationship to, there should be differences in the help she provides to each grandchild according to that relationship. Studies have found that not only does the maternal or paternal relationship of the grandparent affect whether or how much help a grandchild receives, but also what kind of help. Paternal grandmothers often had a detrimental effect on infant mortality. [ 23 ] [ 24 ]  Also, maternal grandmothers concentrate on offspring survival, whereas paternal grandmothers increase birth rates. [ 25 ]   These finding are consistent with ideas of parental investment and paternity uncertainty.  Equally, a grandmother could be both a maternal and paternal grandmother and thus in division of resources, a daughter's offspring should be favored.


Other studies have focused on the genetic relationship between grandmothers and grandchildren.  Such studies have found that the effects of maternal / paternal grandmothers on grandsons / granddaughters may vary based on degree of genetic relatedness, with paternal grandmothers having positive effects on granddaughters but detrimental effects on grandsons, [ 26 ]  and paternity uncertainty may be less important than chromosome inheritance. [ 27 ]


Some critics have cast doubt on the hypothesis because while it addresses how grandparental care could have maintained longer female post-reproductive lifespans, it does not provide an explanation for how it would have evolved in the first place. One theory is that the number of caregivers has a positive relationship on the likelihood of offspring reaching adulthood, suggesting that grandparents who contribute to the care of their grandchildren are more likely to have their genes passed down. Some versions of the grandmother hypothesis asserted that it helped explain the longevity of human  senescence . However, demographic data has shown that historically rising numbers in older people among the population correlated with lower numbers of younger people. [ 28 ]  This suggests that at some point grandmothers were not helpful toward the survival of their grandchildren, and does not explain why the first grandmother would forgo her own reproduction to help her offspring and grandchildren.


In addition, all variations on the mother, or grandmother effect, fail to explain  longevity  with continued  spermatogenesis  in males.


Another problem concerning the grandmother hypothesis is that it requires a history of female  philopatry . Though some studies suggest that hunter-gatherer societies are  patriarchal , [ 29 ]  mounting evidence shows that residence is fluid among hunter-gatherers [ 30 ] [ 31 ]  and that married women in at least one patrilineal society visit their kin during times when kin-based support can be especially beneficial to a woman's  reproductive success . [ 32 ]  One study does suggest, however, that maternal kin were essential to the fitness of sons as fathers in a patrilocal society. [ 33 ]