Menopausal Hormone Replacement Health Benefits

Susan is a 54 year old accountant suffering from many diverse health problems, such as vague aches and pains in the muscles and joints, difficulty remembering things or finding words, insomnia, dry skin and hair, chronic fatigue, mood disturbance, night sweats and hot flashes. To make things worse, Susan’s primary care doctor ordered a DEXA bone density scan which showed osteopenia (low bone density) and offered Susan a drug called fosamax. I explained to Susan all of her symptoms are due to menopausal estrogen deficiency, very treatable with HRT (Hormone Replacement Therapy). I advised against the fosamax drug, as estrogen is more effective for improving bone density with none of the side effects of fosamax.

Susan replied that her other doctor did not mention hormone replacement. Also, her sister had been treated for breast cancer in the past, and she is worried the hormone replacement therapy might cause breast cancer. I then spent the time to explain to Susan the health benefits of menopausal hormone replacement.  The increased risk for breast cancer is associated with the use of carcinogenic synthetic hormones called progestins, such as MPA (medroxyprogesterone), a drug known to be carcinogenic. We avoid these, instead and use human bioidentical hormones found to be safe in multiple studies. In addition to hormone replacement, we use a separate breast cancer prevention program with iodine supplementation, testosterone and DIM (Di-indole methane).

Eighty Per Cent Decline in women using HRT

Susan’s story is not unusual. Since 2002, there has been an 80 per cent decline in use of  menopausal hormone replacement, a result of the bad press after the 2002 WHI (Women’s Health Initiative Study) which convinced menopausal women and their doctors to abandon hormone replacement leading to needless suffering.  Worse, since 2002, there has been complete loss of trained health care workers to even dispense menopausal HRT. Thankfully, this insanity has finally ended. Menopausal hormone replacement (HRT) is now recognized as key for maintaining health after menopause. HRT is first line management for menopausal symptoms. In 2019, Dr. Santiago Palacios  writes:

Reluctance to treat menopausal symptoms has derailed and fragmented the clinical care of midlife women, creating a large and unnecessary burden of suffering. Clinicians who stay current regarding hormonal and non-hormonal treatments can put menopause management back on track by helping women make informed treatment choices. In addition, we must train and equip the next generation of health care providers with the skills to address the current and future needs of this patient population.(1-2) Emphasis Mine

A Situation Detrimental to Women’s Health

In 2014 Dr. Richard Santen laments that internists should be providing menopausal HRT to their menopausal patients, yet fail to do so, lacking the core competency and experience in this field. It is clear this situation is detrimental to women’s health. Dr. Richard Santen writes:

Most internists currently lack the core competencies and experience necessary to address menopausal issues and meet the needs of women who have completed their reproductive years. We believe that this situation is detrimental to women’s health, leads to fragmented care, and should change.(3)

Standard of Care until 2002

In 2014, Dr. R.D. Langer writes in Climacteric, menopausal hormone replacement therapy was standard of care until release of the 2002 WHI study (Women’s Health Initiative Study) which created unfounded fears of cancer and heart disease, not supported by the data. The actual data shows HRT (Hormone Replacement Therapy) reduces all-cause mortality and reduces risk of coronary disease, osteoporosis, and dementia. Dr. R.D. Langer writes:

HRT use plummeted following the WHI in 2002 and has remained low…Unfortunately, among many women and clinicians, the perception of HRT benefit/risk is distorted, and its use avoided, leading to unnecessary distress. Following the WHI, many clinicians have not received adequate training to feel comfortable prescribing HRT. When initiated within 10 years of menopause, HRT reduces all-cause mortality and risks of coronary disease, osteoporosis, and dementias. (4) (12-13)

What Are the Health Benefits of Hormone Replacement ?

There are considerable heath benefits of menopausal hormone replacement involving all organ systems, the bones, joints, heart and brain.

HRT Reduces Over All Mortality, Risk for Coronary Artery Disease, Osteoporosis and Dementia

Hormone Replacement Therapy (HRT) with bioidentical hormones reduces all cause mortality, reduces risk for coronary artery disease, reduces bone loss and prevents osteoporosis and reduces risk for dementia. (5-13)

In 2023, Dr. Guilherme Renke writes:

Recent evidence suggests that, when initiated within 10 years of menopause, HRT reduces all-cause mortality and risks of coronary disease, osteoporosis, and dementia. (5)

Loss of Bone Density / Osteoporosis Prevention: Estrogen therapy prevents the annual loss of  bone density caused by estrogen deficiency, thus reducing fracture risk. Estrogen replacement therapy is now accepted as first line for prevention and treatment of osteoporosis.(14-23)  In 2018, Dr. V.A. Levin writes:

Menopause predisposes women to osteoporosis due to declining estrogen levels. This results in a decrease in bone mineral density (BMD) and an increase in fractures. Osteoporotic fractures lead to substantial morbidity and mortality…The Women’s Health Initiative (WHI) randomized controlled trial first proved hormonal therapy (HT) [with estrogen] reduces the incidence of all osteoporosis-related fractures in postmenopausal women. ..These studies support that HT [estrogen] improves BMD [bone mineral denisty] and reduces fracture risk in women with and without osteoporosis…we propose that HT should be considered for the primary prevention and treatment of osteoporosis in appropriate candidates. HT should be individualized and the once “lowest dose for shortest period of time” concept should no longer be used. … low-dose and transdermal HT that have been shown to be safer than oral standard-dose HT. (23)

In 2021, Dr. Anna Gosset states that menopausal hormone therapy is the only anti-osteoporotic therapy with proven efficacy for prevention of osteoporotic fracture and should be considered as the first option for maintenance of bone health, writing:

MHT [menopausal hormone therapy containing estrogen] prevents bone loss and the degradation of the bone microarchitecture but it significantly reduces the risk of fracture at all bone sites by 20 to 40%. It is the only anti-osteoporotic therapy that has a proven efficacy regardless of basal level of risk, even in low-risk women for fracture…In the absence of contraindication, use of MHT should be considered as a first option for the maintenance of bone health in those women where specific bone active medications are not warranted. (16)

Coronary Artery Disease: Menopausal HRT using estradiol and progesterone reduces risk of coronary artery disease. One must avoid MPA medroxyprogesterone and other synthetic forms which increase heart disease risk. (24-25)

In 2022, Dr. Howard Hodis states that when initiated within 10 years of menopause, menopausal hormone replacement significantly reduces all cause mortality and cardiovascular disease, while other therapies such as statin drugs for lipid lowering fail to do so, writing:

Initiated in women <60 years of age and/or at or near menopause, HRT significantly reduces all-cause mortality and cardiovascular disease (CVD) whereas other primary CVD prevention therapies such as lipid-lowering [with statin drugs] fail to do so. Magnitude and type of HRT-associated risks, including breast cancer, stroke and venous thromboembolism are rare (<10 events/10,000 women), not unique to HRT and comparable with other medications. (24)

In 2012, Dr. Louise Lind Schierbeck reported a Danish randomized study showing 52 percent reduction in cardiovascular disease after 10 years of hormone replacement therapy (HRT, estrogen with or without progestogen) relative to no HRT, writing:

Survival curve from the Danish Osteoporosis Study showing a statistically significant reduction of cardiovascular disease by 52% (HR, 0.48; 95% CI, 0.27–0.89) after 10 years of randomized hormone replacement therapy (HRT) (estrogen with or without progestogen) relative to no HRT…(25)

In 2020, Dr. Schipper states menopausal hormone replacement eliminates the increased cardiovascular mortality associated with menopause, and advises starting HRT as soon as possible after the menopause transition, writing:

It has been substantiated that hormone replacement therapy (HRT) decreases the risk for ischemic heart disease and eliminates the increased cardiovascular disease mortality. It is therefore crucial to start HRT as soon as possible, particularly in women with premature ovarian insufficiency. (31)

In 2023, Dr. Guilherme Renke discusses the mechanism of estrogen’s cardioprotective properties, proposing a novel insight that estrogen promotes mitochondrial biogenesis and modulates the renin-angiotenisn-aldosterone system (RAAS). Dr. Guilherme Renke advises using human-identical hormone replacement to receive these benefits, writing:

E2 mediates its cardioprotective actions by increasing mitochondrial biogenesis, angiogenesis, and vasodilation, decreasing reactive oxygen species (ROS) and oxidative stress, and modulating the renin-angiotensin-aldosterone system (RAAS). In this review, we assess whether it is prudent to develop an approach to managing postmenopausal women based on modifying the patient’s CV risk that includes human-identical hormone replacement therapy (HRT), modulation of RAAS, and stimulating mitochondrial biogenesis. (33)

Breast Cancer: Menopausal HRT with estradiol, progesterone and testosterone actually reduces the risk of invasive breast cancer. However, synthetic progestins such as MPA are known carcinogens which increase risk for breast cancer. Testosterone is breast cancer preventive, decreasing breast cancer risk by 40 percent. Iodine supplements prevent and treat breast cancer. (36-53)

In 2020, Dr. Rowan Chlebowski reviewed breast cancer incidence and mortality in the two arms of the WHI finding in the second arm using Premarin alone, there was a 22 percent reduction in breast cancer and a 40 percent reduction in breast cancer mortality. However, in the first arm using Premarin and Medroxyprogesterone combined had a 28 percent increased risk of breast cancer. Clearly, a synthetic progestin called medroxyprogesterone (MPA) a known carcinogen,was the culprit. Dr. Rowan Chlebowski writes:

In long-term follow up of 2 placebo-controlled randomized clinical trials involving 27, 347 postmenopausal women, prior randomized use of conjugated equine estrogen (CEE), compared with placebo, among women with prior hysterectomy was significantly associated with lower risk of breast cancer (annualized incidence, 0.30% vs 0.37%; hazard ratio [HR], 0.78); and breast cancer mortality (annualized mortality, 0.031% vs 0.046%; HR, 0.60), whereas prior randomized use of CEE plus medroxyprogesterone acetate (MPA), compared with placebo, among women with an intact uterus, was significantly associated with higher risk of breast cancer (annualized incidence, 0.45% vs 0.36%; HR, 1.28) and no significant difference in breast cancer mortality (annualized mortality, 0.045% vs 0.035%; HR, 1.35). (36)

In 2022, Dr. D.A. Tan agrees that the carcinogenic culprit is the synthetic progestin, and should be avoided by using natural bioidentical progesterone instead. Fear of and failure to use menopausal hormone replacement puts women in harm’s way. Dr. Tan suggests women should no longer fear breast cancer risk from hormone replacement. It is obvious that women should avoiding carcinogenic synthetic progestins such as MPA to reduce risk of breast cancer. Instead of using MPA, human bioidentical progesterone is advised. Dr. D.A. Tan writes:

The threat that women may develop breast cancer is the major reason why both physicians and women are afraid to use menopausal hormone therapy (MHT). The fear pertains to estrogen-progestin replacement therapy (EPRT) as estrogen-alone replacement therapy has no, or even a reduced, breast cancer risk... avoiding MHT use when indicated puts a woman in harm’s way. (40)

In 2021, Dr. Irene Lambrinoudaki reviewed breast cancer risk from menopausal hormone therapy, stating  the excess risk of breast cancer associated with menopausal hormone therapy is mainly conferred by use of a synthetic progestin such as medroxyprogesterone (MPA), levonorgestrel and norethisterone. Synthetic progestins are known carcinogens. Again, synthetic progestins can be avoided by using human bioidentical progesterone.  Dr. Irene Lambrinoudaki writes:

Estrogen-only therapy for up to 9 years increased only marginally the risk of breast cancer (OR 1.14, CI 1.08–1.21), whereas estrogen–progestin combination therapy for the same duration was associated with a more pronounced increase in breast cancer risk (OR 1.70, CI 1.64 to 1.76). The risk differed according to the progestin used, being higher with medroxyprogesterone acetate, levonorgestrel and norethisterone (OR 1.87 CI 1.71 to 2.05, 1.79 CI 1.68 to 1.90 and 1.88 CI 1.79 to 1.99 respectively) and lower with dydrogesterone (OR 1.24 CI 1.03 to 1.48) for more than 5 years of therapy. The excess risk dissipated in past users.  The excess risk of breast cancer associated with MHT is mainly conferred by the progestin. (41)

In 2020, Dr.John Stevenson discussed selection of the safest progestogen agent for menopausal hormone replacement, stating micronized progesterone is the safest option, advising against use of synthetic progestins,writing:

Micronized progesterone and dydrogesterone appear to be the safest options, with lower associated cardiovascular, thromboembolic, and breast cancer risks compared with other progestogens, and are the first-choice options for use in ‘special situations,’ such as in women with high-density breast tissue, diabetes, obesity, smoking, and risk factors for venous thromboembolism, among others. (45)

In 2017, Dr. Allan Lieberman reviewed the literature on human bioidentical progesterone, stating progesterone is protective and prevents breast cancer, and should be used instead of the synthetic progestins, writing:

A meta-analysis of 3 studies involving 86,881 postmenopausal women reported that the use of natural progesterone was associated with a significantly lower risk of breast cancer compared with synthetic progestins. Anovulation and low levels of serum progesterone have been associated with a significantly higher risk of breast cancer in premenopausal women. Use of progesterone has been linked to lower rates of uterine and colon cancers and may also be useful in treating other cancers such as ovarian, melanoma, mesothelioma, and prostate. Progesterone may also be helpful in preventing cardiovascular disease and preventing and treating neurodegenerative conditions such a stroke and traumatic brain injury…Physicians should have no hesitation prescribing natural progesterone. The evidence is clear that progesterone does not cause breast cancer. Indeed, progesterone is protective and preventative of breast cancer. (47)

HRT for Breast Cancer Survivors

Breast cancer survivors who suffer from menopausal symptoms and seek HRT are denied treatment by the mainstream medical system over misplaced concerns for cancer recurrence. Quite to the contrary, studies show breast cancer survivors treated with menopausal hormone replacement actually enjoy reduced all cause and reduced breast cancer related mortality. Again, avoiding the use of carcinogenic progestins such as norethisterone is advisable, since the only study to demonstrate increased breast cancer recurrence, the HABITS trial from Finland, used norethisterone, a known carcinogen.

In 2022, Dr. Avrum Zvi Bluming reviewed hormone replacement after breast cancer suggesting “it is time”. Of 25 studies using hormone replacement after breast cancer, only one, the HABITS trial in Finland, showed increased cancer recurrence. This HABITS trial used estradiol and synthetic progestin norethisterone, known to be carcinogenic. The French Cohort study showed the use of carcinogenic progestin, norethisterone, doubles the risk for breast cancer. (38)

By avoiding the carcinogenic progestin, and using natural progesterone instead, cancer risk can be eliminated.

Next, Dr Bluming looked at only those studies in which the breast cancer cells were estrogen receptor positive. Of 17 studies of hormone replacement after breast cancer with positive estrogen receptors in the cancer cells, NONE of 17 showed increased risk for breast cancer recurrence. (54-61)

Dr. Avrum Zvi Bluming writes:

Twenty-five studies of HRT after a breast cancer diagnosis, published between 1980 and 2013…Only 1 of the 25 studies, the HABITS trial, demonstrated an increased risk of recurrence, which was limited to local or contralateral, and not distant, recurrence. None of the studies, including HABITS, reported increased breast cancer mortality associated with HRT…Of the 25 studies reporting the risk of HRT administered to breast cancer survivors, 17, including HABITS, listed those with positive estrogen receptor assays...None of those reports identified an increased risk of breast cancer recurrence associated with a positive receptor assay... (57)

Osteoarthritis Prevention / Bone Density:

Animal Studies show rendering the animal estrogen deficient induces cartilage degeneration and arthritis. Restoring estrogen levels in the animal experiments stimulates cartilage regeneration. We have found this to true in menopausal women as well. We have found that estrogen replacement prevents joint degeneration, and for those post menopausal women who already have arthritis, they have considerable improvement with the use of estrogen applied topically over the joint. (62-77)

Cognitive Function/ Dementia: Menopausal HRT improves cognitive function (concentration and focus) and reduces long term risk for dementia and Alzheimer’s Dementia. (78-98)

Vasomotor Symptoms Hot Flashes Night Sweats: Estrogen is the most effective treatment for menopausal estrogen deficiency symptoms of hot flashes and night sweats, also called vasomotor symptoms.(99-102)

Vaginal Atrophy: Menopausal HRT with estrogen (estradiol) is the most effective treatment for vaginal atrophy, vaginal dryness, pain, vaginal itching, and discomfort. Note: vaginal atrophy is thinning of lining caused by menopausal estrogen deficiency. (103-107)

Sleep Quality / Insomnia: Menopausal hormone replacement therapy (HRT) improves sleep quality. (108-118)

Libido: Testosterone improves libido for menopausal women. Currently, testosterone is the mainstream accepted treatment for “Hypoactive Sexual Desire Disorder” (HSDD). (199-123)

Urinary Tract Symptoms: Estrogen and Testosterone strengthen the pelvic floor and bladder muscles, preventing recurrent urinary tract infections, incontinence, treating the “genitourinary syndrome of menopause”. (124-126)

Weight Gain / Bio-Energetics:  Menopausal estrogen deficiency causes weight gain and visceral fat accumulation. However, postmenopausal hormone replacement prevents weight gain, with less accumulation of visceral fat.This effect is thought to be due to estrogen’s ability to stimulate mitochondrial biogenesis.(127-133)

In 2014, Dr Jamaica Rettberg reviewed estrogen as the master regulator of energy production for the brain and body, thus explaining protection against weight gain, and protection against cognitive dysfunction, writing:

After menopause, when estrogen levels drop, women experience a general increase in weight as well as a redistribution of adipose tissue leading to increased abdominal fat deposition. Importantly, the increased abdominal fat in postmenopausal women tends to be visceral and not subcutaneous fat (Lovejoy et al., 2008)….meta-analysis conducted by the Endocrine Society reported that HT [Hormone Therapy] was associated with less accumulation of weight, fat mass, and/or centrally located fat mass …postmenopausal HT protects against weight gain, and also promotes less adipose tissue deposition in visceral fat stores….Results from several imaging studies support the idea that postmenopausal HT can modulate brain bioenergetics, likely leading to the maintenance of cognitive function and reduced risk of AD [Alzheimer’s Dementia]...HT users showed increased rCBF [regional cerebral blood flow with PET imaging] over time compared to nonusers in the hippocampus, parahippocampal gyrus, and temporal lobe, regions that are critical for memory formation and are also vulnerable to decreased glucose metabolism in preclinical AD (Maki and Resnick, 2000). As before, the HT users scored higher on a battery of memory tests than nonusers (Maki and Resnick, 2000). (130)

In 2023, Dr. Jing Zhu reviewed estrogen’s regulation of energy production in relation to menopause, stating estrogen deficiency of menopause triggers decreased energy production in the brain and organs leading to type 2 diabetes mellitus, hypertension, and cardiovascular disease and dementia, writing:

Within the brain, central estrogen via ER [estrogen receptor] regulates appetite and energy expenditure and maintains cell glucose metabolism, including glucose transport, aerobic glycolysis, and mitochondrial function. In the whole body, estrogen has shown beneficial effects on weight control, fat distribution, glucose and insulin resistance, and adipokine secretion. As demonstrated by multiple in vitro and in vivo studies, menopause-related decline of circulating estrogen may induce the disturbance of metabolic signals and a significant decrease in bioenergetics, which could trigger an increased incidence of late-onset Alzheimer’s disease, type 2 diabetes mellitus, hypertension, and cardiovascular diseases in postmenopausal women. (131)

Mood Swings, Depression: Menopasual HRT treats mood swings, and the depression commonly reported during menopause. Both testosterone and estrogen serve as effective antidepressants. Progesterone has anti-anxiety effects. (134-136)

Skin: menopausal HRT improves the skin by increasing skin collagen content, thickness, elasticity, and hydration, serving as anti-aging treatment for skin with less wrinkles and sagging. (137-145)

Hair: 50% of post-menopausal women report alterations in hair quality, loss of hair, hair thinnin etc. (196-198)

In 2022, Dr. Bob Kronemyer writes:

More than half of postmenopausal women experience female pattern hair loss (FPHL), according to results of a cross-sectional study published in Menopause. The authors attributed their findings to the pathophysiological changes in FPHL involving progressive miniaturization of hair follicles and subsequent conversion of terminal follicles into velluslike follicles. Furthermore, alterations in growth, diameter, and pigmentation of the hair progressively increase, along with scalp hair thinning, thus indicating that FPHL strongly correlates with menopause. (197)

Colorectal Cancer risk is reduced by 63 percent in menopausal hormone replacement users. (146-149)

Diabetes: Menopausal HRT decreases risk of developing diabetes and improves diabetic control. (150-153)

Healing: Menopausal HRT enhances wound healing, and reduces the incidence of wound complications. (154)

Musculoskeletal System: Menopsausal HRT with estrogen and testosterone maintain muscle mass, and muscle strength, and eliminates muscle aches and pains. (155-158)

Migraines: Estrogen helps with migraine symptoms. Triptan drugs may be needed as well. We have found the nasal spray version of Sumatriptan more effective than the oral tablets. (159-170)

Generalized Inflammation: Menopausal estrogen deficiency causes generalized inflammation in the body and brain. Inflammation within the hypothalamus may cause cognitive dysfunction,  hypothalamic dysfunction, metabolic syndrome and obesity. This can be relieved with use of estrogen HRT. (171-175)

Macular Degeneration / Retinopathy: The retina is a hormonal organ, has estrogen receptors, and itself manufactures estrogen involved in mitochondrial energy production. Estrogen deficiency leads to retinopathy and macular degeneration. Menopausal hormone replacement with estrogen prevents retinopathy and macular degeneration.  Retinopathy has been described as an adverse effect of estrogen blocking drugs such as clomiphene, tamoxifen and aromatase inhibitors such as letrazole. (177-190)

Dry Eye / Dry Skin Syndrome: Lubrication of the eye and skin is controlled by testosterone, and dry eyes and skin are the result of testosterone deficiency. Treatment with testosterone may be curative if treated early enough in the course of disease. (191-195)

Conclusion: The health benefits of menopausal hormone replacement extend beyond alleviation of menopausal symptoms of hot flashes and night sweats to involve improvement in all-cause mortality, bone density, sleep quality, cognition, depression, mood, body weight, diabetic control, skin quality, retina, eye lubrication, muscle strength, protection from cardiovascualar disease and prevention of osteoarthritis.

In 2023, Dr. Lawrence Nelson described menopause as a “waning of ovarian function” with low estradiol (estrogen) levels. Early menopausal estrogen deficiency is associated with significant morbidity and early mortality, Dr. Lawrence Nelson writes:

The essential biology of this physiologic midlife transition in women is a waning of ovarian endocrine function. The physiologic midlife transition to so-called menopause is a state of low serum E2 [estradiol], and early E2 deficiency is associated with significant morbidity and early mortality…The physiologic midlife transition to menopause is a state of low serum E2, and early menopause is associated with significant morbidity and early mortality. A few prospective population-based cohort studies provide convincing evidence that women with early onset menopause, and the associated E2 deficiency, have 1) a shorter life expectancy, 2) increased risk of type II diabetes, 3) adverse effects on cognitive function, 4) significant correlation between age at menopause and age at diagnosis of dementia, and 5) a significant correlation between age at menopause and age at death…Evidence is clear, extremely low E2 [estradiol] levels increase the risk for some women. For example, there is a 2.5-fold increase in hip and vertebral fractures in older women with total E2 levels less than 5.0 pg/ml. …Intriguingly, even minimal increases in E2 serum concentrations have a proven beneficial effect on bone mineral density in menopausal women, with little effect on endometrial proliferation. …This same therapeutic window of low doses of E2, proven to improve bone mineral density, could theoretically also improve health for menopausal women regarding their cardiovascular health, central nervous system health, mood, and related cosmetic benefits to skin and hair. (176)

Articles with related interest:

All Articles on Menopausal Bioidentical Hormone Replacement

Estrogen for Osteoporosis Prevention and Treatment

Safety and Adverse Effects of Natural Progesterone.”

Testosterone reduces Risk of Breast Cancer

Iodine for prevention of Breast Cancer

Iodine for Treatment of Breast Cancer

Morning Rounds With Steven G. Economou MD by Jeffrey Dach MD

Bioididentical Hormones for Breast Cancer Survivors

Bioidentical Hormone Replacement Prevents Osteoarthritis

Estrogen for Osteoarthritis Prevention and Treatment

Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314
954-792-4663
my blog: www.jeffreydachmd.com 

Header image: PET scans of brain. Left Image: Normal patient, and Right Image: Alzheimer’s Dementia patient. Courtesy of NIH and Wikimedia Commons.

References:

hormone replacement menopause

free pdf GOOD
1) Palacios, Santiago, et al. “Hormone therapy for first-line management of menopausal symptoms: Practical recommendations.” Women’s Health 15 (2019): 1745506519864009.

In 2016, to atone for the turmoil caused by the inappropriately communicated findings of the WHI trials, two WHI investigators published a request for forgiveness:

Reluctance to treat menopausal symptoms has derailed and fragmented the clinical care of midlife women, creating a large and unnecessary burden of suffering. Clinicians who stay current regarding hormonal and non-hormonal treatments can put menopause management back on track by helping women make informed treatment choices. In addition, we must train and equip the next generation of health care providers with the skills to address the current and future needs of this patient population.7

2) Clinically Speaking: Do I Need Hormone Replacement Therapy?
MEEFRO  January 11, 2023

80 per cent decline in HRT after 2002 WHI

3) Santen, Richard J., et al. “Competency in menopause management: whither goest the internist?.” Journal of women’s health 23.4 (2014): 281-285.

After publication of the Women’s Health Initiative study in 2002, use of menopausal hormone therapy (HT) has declined by nearly 80% worldwide and internists now play only a limited role in menopause management. Over the past decade, new data have increased our knowledge of the multiple effects and mechanisms of HT.  Methods: Existing literature was reviewed.

Results: A consensus has emerged that the benefits of HT outweigh the risks for the relief of symptoms in women who have recently undergone menopause and are not at excess risk of breast cancer and cardiovascular disease. Non-hormonal agents, selective estrogen receptor modulators (SERMs), and tibolone are also useful in management. Factors entering into the decision-making process regarding menopause management are increasingly complex and involve consideration of effects on multiple systems and potential disease-related events. These considerations suggest that internists trained to evaluate and integrate factors influencing multiple organ systems should re-engage in menopause management. Most internists currently lack the core competencies and experience necessary to address menopausal issues and meet the needs of women who have completed their reproductive years. We believe that this situation is detrimental to women’s health, leads to fragmented care, and should change.

Conclusions: We propose that the multidimensional expertise that characterizes the internist may provide the most comprehensive approach to menopause management. For the internist to meet this need, a set of core competencies must be attained, which will require new didactic programs to be developed for medical students, residents and practicing physicians.

4)  Langer, R. D., et al. “Hormone replacement therapy–where are we now?.” Climacteric 24.1 (2021): 3-10. references

Hormone replacement therapy (HRT) was the standard of care for menopause management until 2002, when perceptions changed following release of the initial results from the Women’s Health Initiative (WHI) trial. Fears of breast cancer and heart attacks engendered by that report were not supported by the data, especially for recently menopausal women. Clinically, HRT is usually initiated near menopause. The WHI tested something different – the effects of HRT started a decade or more after menopause. As it turned out, age at starting HRT is critical in determining benefit/risk. HRT use plummeted following the WHI in 2002 and has remained low, prompting strong interest in alternative treatments. None provide the range of benefits across multiple organ systems offered by estrogen. Most have concerning adverse effects in their own right. HRT can provide effective relief for a wide range of health conditions, potentially avoiding the need for multiple treatments for separate problems. Unfortunately, among many women and clinicians, the perception of HRT benefit/risk is distorted, and its use avoided, leading to unnecessary distress. Following the WHI, many clinicians have not received adequate training to feel comfortable prescribing HRT. When initiated within 10 years of menopause, HRT reduces all-cause mortality and risks of coronary disease, osteoporosis, and dementias.

Heart

5) Renke, Guilherme, et al. “Cardio-metabolic health and HRT in menopause: novel insights in mitochondrial biogenesis and RAAS.” Current Cardiology Reviews 19.4 (2023): 1-5.

Recent evidence suggests that, when initiated within 10 years of menopause,
HRT reduces all-cause mortality and risks of coronary disease, osteoporosis, and dementia. [24-27].

6) Hodis, Howard N., and Wendy J. Mack. “Menopausal hormone replacement therapy and reduction of all-cause mortality and cardiovascular disease: it is about time and timing.” The Cancer Journal 28.3 (2022): 208-223.

7) Stute, Petra, A. Stadler, and A. Heufelder. “The impact of menopausal hormone therapy on overall mortality–a comprehensive review.” Climacteric 23.5 (2020): 447-459.

in postmenopausal women, MHT appears to confer a (significant) reduction in overall mortality; the benefit especially applies to women who initiate long-term MHT early after menopause;

8) Akter, N., et al. “The effect of hormone replacement therapy on the survival of UK women: a retrospective cohort study 1984− 2017.” Bjog 129.6 (2022): 994.

Combined HRT was associated with a 9% lower risk of all‐cause mortality and estrogen‐only formulation was not associated with any significant changes.

9) Langer RD, Hodis HN, Lobo RA, Allison MA. Hormone replacement therapy – where are we now? Climacteric 2021; 24(1): 3-10.

10) Harman SM, Brinton EA, Cedars M, et al. KEEPS: The kronos early estrogen prevention study. Climacteric 2005; 8(1): 3-12.

11) Ventura-Clapier R, Piquereau J, Veksler V, Garnier A. Estrogens, estrogen receptors effects on cardiac and skeletal muscle mitochondria. Front Endocrinol 2019; 10: 557.  estrogen receptors have been identified within mitochondria.

12)  447-459.

13) Akter, N., et al. “The effect of hormone replacement therapy on the survival of UK women: a retrospective cohort study 1984− 2017.” Bjog 129.6 (2022): 994.

Combined HRT was associated with a 9% lower risk of all‐cause mortality and estrogen‐only formulation was not associated with any significant changes.
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14) Estrogen for Osteoporosis Prevention and Treatment

15) Na, Zhao, et al. “Role of menopausal hormone therapy in the prevention of postmenopausal osteoporosis.” Open Life Sciences 18.1 (2023): 20220759.

16) Gosset, Anna, Jean-Michel Pouillès, and Florence Trémollieres. “Menopausal hormone therapy for the management of osteoporosis.” Best Practice & Research Clinical Endocrinology & Metabolism 35.6 (2021): 101551.

MHT prevents bone loss and the degradation of the bone microarchitecture but it significantly reduces the risk of fracture at all bone sites by 20 to 40%. It is the only anti-osteoporotic therapy that has a proven efficacy regardless of basal level of risk, even in low-risk women for fracture…In the absence of contraindication, use of MHT should be considered as a 1st option for the maintenance of bone health in those women where specific bone active medications are not warranted.

17) Anagnostis, Panagiotis, et al. “Estrogen and bones after menopause: A reappraisal of data and future perspectives.” Hormones 20 (2021): 13-21.

18) Rozenberg, Serge, et al. “Is there a role for menopausal hormone therapy in the management of postmenopausal osteoporosis?.” Osteoporosis International 31 (2020): 2271-2286.

19) Chang, Cherry Yin-Yi, et al. “Timing and dosage of and adherence to hormone replacement therapy and fracture risk in women with menopausal syndrome in Taiwan: A nested case-control study.” Maturitas 146 (2021): 1-8.

20) Newson, Louise, Sarah Ball, and Rebecca Lewis. “Letter to Editor: Our concerns about HRT not having a priority as a treatment for osteoporosis in the NOGG guidelines.” Osteoporosis International 34.4 (2023): 815-816.

21) Stepan, Jan J., Hana Hruskova, and Miloslav Kverka. “Update on menopausal hormone therapy for fracture prevention.” Current Osteoporosis Reports 17 (2019): 465-473.

22) Gamsjaeger, Sonja, Erik F. Eriksen, and Eleftherios P. Paschalis. “Effect of hormone replacement therapy on bone formation quality and mineralization regulation mechanisms in early postmenopausal women.” Bone reports 14 (2021): 101055.

23) Levin, V. A., X. Jiang, and R. Kagan. “Estrogen therapy for osteoporosis in the modern era.” Osteoporosis International 29 (2018): 1049-1055.

Menopause predisposes women to osteoporosis due to declining estrogen levels. This results in a decrease in bone mineral density (BMD) and an increase in fractures. Osteoporotic fractures lead to substantial morbidity and mortality, and are considered one of the largest public health priorities by the World Health Organization (WHO). It is therefore essential for menopausal women to receive appropriate guidance for the prevention and management of osteoporosis. The Women’s Health Initiative (WHI) randomized controlled trial first proved hormonal therapy (HT) reduces the incidence of all osteoporosis-related fractures in postmenopausal women. However, the study concluded that the adverse effects outweighed the potential benefits on bone, leading to a significant decrease in HT use for menopausal symptoms. Additionally, HT was not used as first-line therapy for osteoporosis and fractures. Subsequent studies have challenged these initial conclusions and have shown significant efficacy of HT in various doses, durations, regimens, and routes of administration. These studies support that HT improves BMD and reduces fracture risk in women with and without osteoporosis. Furthermore, the studies suggest that low-dose and transdermal HT are less likely associated with the adverse effects of breast cancer, endometrial hyperplasia, coronary artery disease (CAD), and venous thromboembolism (VTE) previously observed in standard-dose oral HT regimens. Given the need for estrogen in menopausal women and evidence supporting the cost effectiveness, safety, and efficacy of HT, we propose that HT should be considered for the primary prevention and treatment of osteoporosis in appropriate candidates. HT should be individualized and the once “lowest dose for shortest period of time” concept should no longer be used. This review will focus on the prior and current studies for various HT formulations used for the prevention and treatment of osteoporosis, exploring the safety profile of low-dose and transdermal HT that have been shown to be safer than oral standard-dose HT.

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24) Hodis, Howard N., and Wendy J. Mack. “Menopausal hormone replacement therapy and reduction of all-cause mortality and cardiovascular disease: it is about time and timing.” The Cancer Journal 28.3 (2022): 208-223.

Totality of evidence indicates menopausal hormone replacement therapy (HRT) effects are determined by timing of initiation according to age and/or time-since-menopause, underlying health of target tissue and duration of therapy. Initiated in women <60 years of age and/or at or near menopause, HRT significantly reduces all-cause mortality and cardiovascular disease (CVD) whereas other primary CVD prevention therapies such as lipid-lowering fail to do so. Magnitude and type of HRT-associated risks, including breast cancer, stroke and venous thromboembolism are rare (<10 events/10,000 women), not unique to HRT and comparable with other medications. HRT is a sex-specific and time dependent primary CVD prevention therapy that concomitantly reduces all-cause mortality as well as other aging-related diseases with an excellent risk profile. Keeping in mind that prevention strategies must be personalized, health-care providers and patients can use cumulated HRT data in making clinical decisions concerning chronic disease prevention including CVD and mortality reduction.

25) Schierbeck, Louise Lind, et al. “Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial.” Bmj 345 (2012).
Survival curve from the Danish Osteoporosis Study showing a statistically significant reduction of cardiovascular disease by 52% (HR, 0.48; 95% CI, 0.27–0.89) after 10 years of randomized hormone replacement therapy (HRT) (estrogen with or without progestogen) relative to no HRT and reduction by 39% (HR, 0.61; 95% CI, 0.39–0.94) after 16 years of total follow-up (10 years of randomized treatment and 6 years of postintervention follow-up)

26) Anagnostis, Panagiotis, et al. “Menopause-associated risk of cardiovascular disease.” Endocrine Connections 11.4 (2022).

27) Lorga, Andrea, et al. “The protective role of estrogen and estrogen receptors in cardiovascular disease and the controversial use of estrogen therapy.” Biology of sex differences 8.1 (2017): 1-16.AMH measurement helps estimate when a woman will undergo her FMP, and, in general, does so better than FSH.

free pdf
28) Renke, Guilherme, et al. “Cardio-metabolic health and HRT in menopause: novel insights in mitochondrial biogenesis and RAAS.” Current Cardiology Reviews 19.4 (2023): 1-5.

Recent evidence suggests that, when initiated within 10 years of menopause,
HRT reduces all-cause mortality and risks of coronary disease, osteoporosis, and dementia. [24-27].

29) Thamman, Ritu. “Are we there yet? Menopausal hormone therapy for primary cardiovascular disease prevention.” Heart (2021).

30) Anagnostis, Panagiotis, et al. “Menopause-associated risk of cardiovascular disease.” Endocrine Connections 11.4 (2022).

31) Schipper, I., and Y. V. Louwers. “Premature and Early Menopause in Relation to Cardiovascular Disease.” Seminars in Reproductive Medicine. Vol. 38. No. 4-05. 2020.
It has been substantiated that hormone replacement therapy (HRT) decreases the risk for ischemic heart disease and eliminates the increased cardiovascular disease mortality. It is therefore crucial to start HRT as soon as possible, particularly in women with premature ovarian insufficiency.

32) Anagnostis, Panagiotis, et al. “Menopausal hormone therapy and cardiovascular risk: where are we now?.” Current Vascular Pharmacology 17.6 (2019): 564-572.

33) Renke, Guilherme, et al. “Cardio-metabolic health and HRT in menopause: novel insights in mitochondrial biogenesis and RAAS.” Current Cardiology Reviews 19.4 (2023): 1-5.

E2 mediates its cardioprotective actions by increasing mitochondrial biogenesis, angiogenesis, and vasodilation, decreasing reactive oxygen species (ROS) and oxidative stress, and modulating the renin-angiotensin-aldosterone system (RAAS). In this review, we assess whether it is prudent to develop an approach to managing postmenopausal women based on modifying the patient’s CV risk that includes human-identical hormone replacement therapy (HRT), modulation of RAAS, and stimulating mitochondrial biogenesis.

34) Prabakaran, Sindhu, Arielle Schwartz, and Gina Lundberg. “Cardiovascular risk in menopausal women and our evolving understanding of menopausal hormone therapy: risks, benefits, and current guidelines for use.” Therapeutic Advances in Endocrinology and Metabolism 12 (2021): 20420188211013917.

35) Maas, Angela HEM. “Hormone therapy and cardiovascular disease: Benefits and harms.” Best Practice & Research Clinical Endocrinology & Metabolism 35.6 (2021): 101576.

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36) Chlebowski, Rowan T., et al. “Association of menopausal hormone therapy with breast cancer incidence and mortality during long-term follow-up of the women’s health initiative randomized clinical trials.” Jama 324.4 (2020): 369-380.

In long-term follow up of 2 placebo-controlled randomized clinical trials involving 27 347 postmenopausal women, prior randomized use of conjugated equine estrogen (CEE), compared with placebo, among women with prior hysterectomy was significantly associated with lower risk of breast cancer (annualized incidence, 0.30% vs 0.37%; hazard ratio [HR], 0.78); and breast cancer mortality (annualized mortality, 0.031% vs 0.046%; HR, 0.60), whereas prior randomized use of CEE plus medroxyprogesterone acetate (MPA), compared with placebo, among women with an intact uterus, was significantly associated with higher risk of breast cancer (annualized incidence, 0.45% vs 0.36%; HR, 1.28) and no significant difference in breast cancer mortality (annualized mortality, 0.045% vs 0.035%; HR, 1.35).

37) De Lignieres, B., et al. “Combined hormone replacement therapy and risk of breast cancer in a French cohort study of 3175 women.” Climacteric 5.4 (2002): 332-340.

38) Fournier, Agnès, Franco Berrino, and Françoise Clavel-Chapelon. “Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study.” Breast cancer research and treatment 107 (2008): 103-111.

39) Campagnoli, Carlo, et al. “Progestins and progesterone in hormone replacement therapy and the risk of breast cancer.” The Journal of steroid biochemistry and molecular biology 96.2 (2005): 95-108.

40) Tan, D. A., and A. R. B. Dayu. “Menopausal hormone therapy: why we should no longer be afraid of the breast cancer risk.” Climacteric 25.4 (2022): 362-368.

The threat that women may develop breast cancer is the major reason why both physicians and women are afraid to use menopausal hormone therapy (MHT). The fear pertains to estrogen-progestin replacement therapy (EPRT) as estrogen-alone replacement therapy has no, or even a reduced, breast cancer risk. We reviewed the way breast cancer risk with EPRT was reported in some major publications since 2002 and tried to put the use-risk association in context. We hope this will make it easier for the physician and the menopausal woman to understand the risk involved and allow more confident and more informed decision-making regarding MHT use. We conclude that there are five interrelated reasons why physicians and women should no longer be afraid of the breast cancer risk with EPRT. We submit that breast cancer related to EPRT use is rare because the risk is very low; the reported increase in breast cancer risk with EPRT is not relevant to current practice; modifiable lifestyle factors, not EPRT, are the real risks for breast cancer; breast cancer-specific mortality is reduced in women who develop breast cancer while on EPRT; and avoiding MHT use when indicated puts a woman in harm’s way.

41) Lambrinoudaki, Irene. “Menopausal hormone therapy and breast cancer risk: all progestogens are not the same.” Case Reports in Women’s Health 29 (2021).

Estrogen-only therapy for up to 9 years increased only marginally the risk of breast cancer (OR 1.14, CI 1.08–1.21), whereas estrogen–progestin combination therapy for the same duration was associated with a more pronounced increase in breast cancer risk (OR 1.70, CI 1.64 to 1.76). The risk differed according to the progestin used, being higher with medroxyprogesterone acetate, levonorgestrel and norethisterone (OR 1.87 CI 1.71 to 2.05, 1.79 CI 1.68 to 1.90 and 1.88 CI 1.79 to 1.99 respectively) and lower with dydrogesterone (OR 1.24 CI 1.03 to 1.48) for more than 5 years of therapy. The excess risk dissipated in past users.  The excess risk of breast cancer associated with MHT is mainly conferred by the progestin.

42) Climént-Palmer, María, and David Spiegelhalter. “Hormone replacement therapy and the risk of breast cancer: How much should women worry about it?.” Post reproductive health 25.4 (2019): 175-178.

43) Vinogradova, Yana, Carol Coupland, and Julia Hippisley-Cox. “Use of hormone replacement therapy and risk of breast cancer: nested case-control studies using the QResearch and CPRD databases.” Bmj 371 (2020).

Progesterone Vs. Progestins

44) Hipolito Rodrigues, Marcio Alexandre, and Anne Gompel. “Micronized progesterone, progestins, and menopause hormone therapy.” Women & Health 61.1 (2021): 3-14.

45) Stevenson, John C., et al. “Progestogens as a component of menopausal hormone therapy: the right molecule makes the difference.” Drugs in context 9 (2020).
Micronized progesterone and dydrogesterone appear to be the safest options, with lower associated cardiovascular, thromboembolic, and breast cancer risks compared with other progestogens, and are the first-choice options for use in ‘special situations,’ such as in women with high-density breast tissue, diabetes, obesity, smoking, and risk factors for venous thromboembolism, among others.

46) Ferretti, Gianluigi, Alessandra Felici, and Francesco Cognetti. “The protective side of progesterone.” Breast Cancer Research 9 (2007): 1-1.

47) Allan Lieberman, M. D., and M. D. Luke Curtis. “In Defense of Progesterone: A Review of the Literature.” Alternative Therapies in Health and Medicine 23.6 (2017): 24-32.

The medical literature on the use of progesterone in postmenopausal women is often confusing and contradictory. Some physicians implicate natural progesterone in an increase in the risk of breast cancer. The chemical structure of natural progesterone (P4) is quite different from chemically altered, synthetic chemicals called progestins, which results in different actions at the cell level.
Objective  The research team intended to review the literature to examine the benefits and safety of natural progesterone and determine whether it can cause an increase or decrease in breast cancer risk.
Design  A review of the medical literature to examine the benefits and safety of natural progesterone as compared with synthetic progestins.
Intervention: Studies examined compared controls not receiving hormone therapy with women receiving estrogen alone and in combination with natural progesterone and with various synthetic progestins, such as medroxyprogesterone acetate-the most commonly used synthetic progestin.
Outcome Measures : Outcome measures included factors such as progression and survival of breast and other cancers and other epidemiological and laboratory data.
Results : A meta-analysis of 3 studies involving 86 881 postmenopausal women reported that the use of natural progesterone was associated with a significantly lower risk of breast cancer compared with synthetic progestins. Anovulation and low levels of serum progesterone have been associated with a significantly higher risk of breast cancer in premenopausal women. Use of progesterone has been linked to lower rates of uterine and colon cancers and may also be useful in treating other cancers such as ovarian, melanoma, mesothelioma, and prostate. Progesterone may also be helpful in preventing cardiovascular disease and preventing and treating neurodegenerative conditions such a stroke and traumatic brain injury.
Conclusions : Physicians should have no hesitation prescribing natural progesterone. The evidence is clear that progesterone does not cause breast cancer. Indeed, progesterone is protective and preventative of breast cancer.

48) Dach, Jeffrey. “Safety and Adverse Effects of Natural Progesterone.”

49) Testosterone reduces Risk of Breast Cancer

50)  Iodine for prevention of Breast Cancer

51) Iodine for Treatment of Breast Cancer

History of HRT

52) Cagnacci, Angelo, and Martina Venier. “The controversial history of hormone replacement therapy.” Medicina 55.9 (2019): 602.

53) Kohn, Grace E., et al. “The history of estrogen therapy.” Sexual medicine reviews 7.3 (2019): 416-421.

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54) Ugras, Stacy K., and Rakhshanda Layeequr Rahman. “Hormone replacement therapy after breast cancer: yes, no or maybe?.” Molecular and Cellular Endocrinology 525 (2021): 111180.

55) Deli, Tamás, Mónika Orosz, and Attila Jakab. “Hormone replacement therapy in cancer survivors–review of the literature.” Pathology & Oncology Research 26 (2020): 63-78.

56) Bluming, Avrum Z. “Safety of systemic hormone replacement therapy in breast cancer survivors.” Breast Cancer Research and Treatment 191.3 (2022): 685-686.

57) Bluming, Avrum Zvi. “Hormone replacement therapy after breast cancer: it is time.” The Cancer Journal 28.3 (2022): 183-190.

Of the 25 studies reporting the risk of HRT administered to breast cancer survivors, 17, including HABITS, listed those with positive estrogen receptor assays.62,65–67,69–72,75–79,82,84,86,88 None of those reports identified an increased risk of breast cancer recurrence associated with a positive receptor assay.

Twenty-five studies of HRT after a breast cancer diagnosis, published between
1980 and 2013…Only 1 of the 25 studies, the HABITS
trial, demonstrated an increased risk of recurrence, which was limited to local
or contralateral, and not distant, recurrence. None of the studies, including
HABITS, reported increased breast cancer mortality associated with
HRT.

HABITS study used estradiol and synthetic progestin norethisterone, known to be carcinogenic.

2008 – Norethisterone Doubles Breast Cancer- French Cohort Study

58) Fournier, Agnès, Franco Berrino, and Françoise Clavel-Chapelon. “Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study.” Breast cancer research and treatment 107 (2008): 103-111.

59) Lyytinen, Heli, et al. “Do the dose or route of administration of norethisterone acetate as a part of hormone therapy play a role in risk of breast cancer: National‐wide case‐control study from Finland.” International journal of cancer 127.1 (2010): 185-189.

In Finland, the most common progestagen as a part of EPT is norethisterone acetate (NETA), which can be given both orally and transdermally.3

60) Morning Rounds With Steven G. Economou MD by Jeffrey Dach MD

61) Bioididentical Hormones for Breast Cancer Survivors

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62) Gilmer, Gabrielle, et al. “A network medicine approach to elucidate mechanisms underlying menopause-induced knee osteoarthritis.” bioRxiv (2023): 2023-03.

63) Gulati, Malvika, et al. “The influence of sex hormones on musculoskeletal pain and osteoarthritis.” The Lancet Rheumatology 5.4 (2023): e225-e238.

64) Castañeda, Santos, and Esther F. Vicente-Rabaneda. “Disentangling the molecular interplays between subchondral bone and articular cartilage in estrogen deficiency-induced osteoarthritis.” Osteoarthritis and Cartilage 31.1 (2023): 6-8.

65) Ge, Yuxiang, et al. “Estrogen prevents articular cartilage destruction in a mouse model of AMPK deficiency via ERK-mTOR pathway.” Annals of translational medicine 7.14 (2019).

66) Dreier, Rita, et al. “Estradiol inhibits ER stress-induced apoptosis in chondrocytes and contributes to a reduced osteoarthritic cartilage degeneration in female mice.” Frontiers in Cell and Developmental Biology 10 (2022): 913118.

67) Burkard, Theresa, et al. “Risk of hand osteoarthritis in new users of hormone replacement therapy: A nested case-control analysis.” Maturitas 132 (2020): 17-23.

68) Mei, Yixue, et al. “Roles of hormone replacement therapy and menopause on osteoarthritis and cardiovascular disease outcomes: a narrative review.” Frontiers in Rehabilitation Sciences (2022): 45.

69) Felson, David T., and Michael C. Nevitt. “The effects of estrogen on osteoarthritis.” Current opinion in rheumatology 10.3 (1998): 269-272.

70) Pang, Huiwen, et al. “Low back pain and osteoarthritis pain: a perspective of estrogen.” Bone Research 11.1 (2023): 42.

71) Tang, Jinshuo, et al. “Estrogen-related receptors: novel potential regulators of osteoarthritis pathogenesis.” Molecular Medicine 27.1 (2021): 1-12.

72) Wu, Yuyun, et al. “Combination of estrogen deficiency and excessive mechanical stress aggravates temporomandibular joint osteoarthritis in vivo.” Archives of Oral Biology 102 (2019): 39-46.

73) Yang, Xiaohui, et al. “Meta-Analysis of Estrogen in Osteoarthritis: Clinical Status and Protective Effects.” Alternative Therapies in Health and Medicine 29.1 (2023): 224-230.

74) Kohler, Minna J. “Does menopausal hormonal therapy have a role in treatment of knee osteoarthritis?.” Menopause 26.6 (2019): 576-577.

75) Roman-Blas, Jorge A., et al. “Osteoarthritis associated with estrogen deficiency.” Arthritis research & therapy 11 (2009): 1-14.

76) Bioidentical Hormone Replacement Prevents Osteoarthritis

77) Estrogen for Osteoarthritis Prevention and Treatment

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78) Luine, Victoria, and Maya Frankfurt. “Estrogenic regulation of memory: the first 50 years.” Hormones and Behavior 121 (2020): 104711.

it is now clear that estradiol also influences the higher order neural function of cognition. We provide a brief overview of estradiol’s regulation of memory and some mechanisms which underlie its effects. Given systemically or directly into the hippocampus, to ovariectomized female rodents, estradiol or specific agonists, enhance learning and/or memory in a variety of rodent cognitive tasks. Acute (within minutes) or chronic (days) treatments enhance cognitive functions. Under the same treatment conditions, dendritic spine density on pyramidal neurons in the CA1 area of the hippocampus and medial prefrontal cortex increase which suggests that these changes are an important component of estrogen’s ability to impact memory processes. Noradrenergic, dopaminergic and serotoninergic activity are also altered in these areas following estrogen treatments.

79) Russell, Jason K., Carrie K. Jones, and Paul A. Newhouse. “The role of estrogen in brain and cognitive aging.” Neurotherapeutics 16 (2019): 649-665.

80) Torromino, Giulia, Adriana Maggi, and Elvira De Leonibus. “Estrogen-dependent hippocampal wiring as a risk factor for age-related dementia in women.” Progress in Neurobiology 197 (2021): 101895.

81) Pertesi, S., et al. “Menopause, cognition and dementia–A review.” Post reproductive health 25.4 (2019): 200-206.

82) Georgakis, Marios K., et al. “Surgical menopause in association with cognitive function and risk of dementia: A systematic review and meta-analysis.” Psychoneuroendocrinology 106 (2019): 9-19.

Current evidence is limited, but suggests surgical menopause induced by bilateral oophorectomy at ≤45 years of age to be associated with higher risk of dementia and cognitive decline. Additional large-scale cohort studies are necessary to replicate these findings.

83) Nerattini, Matilde, et al. “Systematic review and meta-analysis of the effects of menopause hormone therapy on risk of Alzheimer’s disease and dementia.” Frontiers in Aging Neuroscience 15 (2023): 1260427.
protective effects noted with ET [RR = 0.86, 95% C.I. 0.77–0.95, p = 0.002] but not with EPT [RR = 0.910, 95% C.I. 0.775–1.069, p = 0.251].

84) Gava, Giulia, et al. “Cognition, mood and sleep in menopausal transition: the role of menopause hormone therapy.” Medicina 55.10 (2019): 668.

85) Stute, Petra, et al. “Cognitive health after menopause: does menopausal hormone therapy affect it?.” Best Practice & Research Clinical Endocrinology & Metabolism 35.6 (2021): 101565.

The majority of studies found a risk reducing impact of MHT by 11-33%. However, results may vary depending on MHT type, age at initiation and study design. For example, the Women’s Health Initiative Memory Study (WHIMS) reported an approximately 2-fold increased risk of dementia/Alzheimer’s disease if MHT comprising conjugated equine estrogens and medroxyprogesterone acetate was initiated in predominantly comorbid postmenopausal women above age 65.

86) Saleh, Rasha NM, et al. “Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer’s Disease (EPAD) cohort.” Alzheimer’s research & therapy 15.1 (2023): 10.

HRT introduction is associated with improved delayed memory and larger entorhinal and amygdala volumes in APOE4 carriers only. This may represent an effective targeted strategy to mitigate the higher life-time risk of AD in this large at-risk population subgroup.

87) McCarthy, Micheline, and Ami P. Raval. “The peri-menopause in a woman’s life: a systemic inflammatory phase that enables later neurodegenerative disease.” Journal of neuroinflammation 17 (2020): 1-14.

It has been demonstrated that ER-β is localized and involved in regulation of mitochondrial function in neurons

Emerging evidence is showing that peri-menopause is pro-inflammatory and disrupts estrogen-regulated neurological systems. Estrogen is a master regulator that functions through a network of estrogen receptors subtypes alpha (ER-α) and beta (ER-β). Estrogen receptor-beta has been shown to regulate a key component of the innate immune response known as the inflammasome, and it also is involved in regulation of neuronal mitochondrial function. This review will present an overview of the menopausal transition as an inflammatory event, with associated systemic and central nervous system inflammation, plus regulation of the innate immune response by ER-β-mediated mechanisms.

88) Zimmerman, Benjamin, et al. “Longitudinal effects of immediate and delayed estradiol on cognitive performance in a spatial maze and hippocampal volume in menopausal macaques under an obesogenic diet.” Frontiers in Neurology 11 (2020): 539.

89) Klinge, Carolyn M. “Estrogenic control of mitochondrial function.” Redox biology 31 (2020): 101435.

90) Mohajeri, Mohammad, et al. “Effects of estrogens and androgens on mitochondria under normal and pathological conditions.” Progress in Neurobiology 176 (2019): 54-72.

91) Zhao, Wei, et al. “Estrogen deficiency induces mitochondrial damage prior to emergence of cognitive deficits in a postmenopausal mouse model.” Frontiers in Aging Neuroscience 13 (2021): 713819.

92) Guo, Hang, et al. “The critical period for neuroprotection by estrogen replacement therapy and the potential underlying mechanisms.” Current Neuropharmacology 18.6 (2020): 485-500.

93) Marchant, Ivanny Carolina, et al. “Estrogen, Cognitive Performance, and Functional Imaging Studies: What Are We Missing About Neuroprotection?.” Frontiers in Cellular Neuroscience 16 (2022): 866122.

94) Russell, Jason K., Carrie K. Jones, and Paul A. Newhouse. “The role of estrogen in brain and cognitive aging.” Neurotherapeutics 16 (2019): 649-665.

There are 3 common physiological estrogens, of which estradiol (E2) is seen to decline rapidly over the menopausal transition. This decline in E2 has been associated with a number of changes in the brain, including cognitive changes, effects on sleep, and effects on mood. These effects have been demonstrated in both rodent and non-human preclinical models. Furthermore, E2 interactions have been indicated in a number of neuropsychiatric disorders, including Alzheimer’s disease, schizophrenia, and depression. In normal brain aging, there are a number of systems that undergo changes and a number of these show interactions with E2, particularly the cholinergic system, the dopaminergic system, and mitochondrial function. E2 treatment has been shown to ameliorate some of the behavioral and morphological changes seen in preclinical models of menopause; however, in clinical populations, the effects of E2 treatment on cognitive changes after menopause are mixed.

95) Salinero, Abigail E., et al. “Brain Specific Estrogen Ameliorates Cognitive Effects of Surgical Menopause in Mice.” bioRxiv (2023).

We examined whether we could enhance cognitive performance by delivering estrogen exclusively to the brain in post-menopausal mice. We modeled surgical menopause via bilateral ovariectomy (OVX). We treated mice with the pro-drug 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), which can be administered systemically but is converted to 17β-estradiol only in the brain. Young (2.5-month) and middle-aged (11-month-old) female C57BL/6J mice received ovariectomy and a subcutaneous implant containing vehicle (cholesterol) or DHED. At 3.5 months old (young group) and 14.5 months old (middle-aged group), mice underwent behavior testing to assess memory. DHED did not significantly alter metabolic status in middle-aged, post-menopausal mice. In both young and middle-aged mice, the brain-specific estrogen DHED improved spatial memory. Additional testing in middle-aged mice also showed that DHED improved working and recognition memory.

96) Ali, Noor, et al. “The role of estrogen therapy as a protective factor for Alzheimer’s disease and dementia in postmenopausal women: A comprehensive review of the literature.” Cureus 15.8 (2023).

Estrogen prevents dementia by augmenting Hippocampal and prefrontal cortex function, reducing neuroinflammation, preventing degradation of estrogen receptors, decreasing oxidative damage to the brain, and increasing cholinergic and serotonergic function. According to the window phase hypothesis, estrogen’s effect on preventing dementia is more pronounced if therapy is started early, during the first five years of menopause…brain mitochondria are believed to be the targets for estrogen’s neuroprotective effect..Despite the promising positive cognitive effects estrogen therapy has displayed in laboratory studies, this has yet to be strongly and unequivocally replicated in human studies.

 

Thus far, estrogen therapy prescribed alone, i.e., without progesterone, solely for preventing Alzheimer’s disease and dementia, appears to best benefit healthy, cognitively intact peri-menopausal women under the age of 65 years.

we noted estrogen’s involvement in neuroprotective signaling pathways. All signaling pathways require enzymes and/or co-factors, and those require vitamins. Accordingly, correcting vitamin deficiencies before studying the effects of estrogen on cognition is pivotal.

97) Moran, Valentina Echeverria, et al. “Estrogenic plants: to prevent neurodegeneration and memory loss and other symptoms in women after menopause.” Frontiers in pharmacology (2021): 993.

98) Rana, Anil Kumar, et al. “Lithium therapy subdues neuroinflammation to maintain pyramidal cells arborization and rescues neurobehavioural impairments in ovariectomized rats.” Molecular Neurobiology 59.3 (2022): 1706-1723.

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99) Archer, D. F., et al. “Menopausal hot flushes and night sweats: where are we now?.” Climacteric 14 (2011): 515-528.

Estrogen replacement therapy is the most effective treatment for hot flushes.

100) Steingold, Kenneth A., et al. “Treatment of hot flashes with transdermal estradiol administration.” The Journal of Clinical Endocrinology & Metabolism 61.4 (1985): 627-632.

101) Liu James, et al. “SAT-239 Bioidentical estradiol and progesterone improved hot flushes, night sweats and sweating.” Journal of the Endocrine Society 3.Supplement_1 (2019): SAT-239.

102) Nelson, Heidi D. “Commonly used types of postmenopausal estrogen for treatment of hot flashes: scientific review.” Jama 291.13 (2004): 1610-1620.

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103) Nelson, Lawrence M. “The truth about 17-beta estradiol: menopause beyond “old wives’ tales”.” Frontiers in Endocrinology 14 (2023): 1229804.

104) Tanmahasamut, Prasong, et al. “Effect of estradiol vaginal gel on vaginal atrophy in postmenopausal women: A randomized double‐blind controlled trial.” Journal of Obstetrics and Gynaecology Research 46.8 (2020): 1425-1435.

105) Donders, Gilbert GG, et al. “Pharmacotherapy for the treatment of vaginal atrophy.” Expert Opinion on Pharmacotherapy 20.7 (2019): 821-835.

106) Villa, Paola, et al. “Local ultra-low-dose estriol gel treatment of vulvo-vaginal atrophy: efficacy and safety of long-term treatment.” Gynecological Endocrinology 36.6 (2020): 535-539.

107) Simon, James, et al. “Effective treatment of vaginal atrophy with an ultra–low-dose estradiol vaginal tablet.” Obstetrics & Gynecology 112.5 (2008): 1053-1060.

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108) Tandon, Vishal R., et al. “Menopause and sleep disorders.” Journal of Mid-life Health 13.1 (2022): 26.

109) Hachul, Helena, et al. “Sleep During Menopause.” Sleep Medicine Clinics 18.4 (2023): 423-433.

110) Bashir, Kiran, et al. “Prevalence of Insomnia in Menopausal Women: Prevalence of Insomnia.” Pakistan Journal of Health Sciences (2023): 43-46.

110) Caretto, Marta, Andrea Giannini, and Tommaso Simoncini. “An integrated approach to diagnosing and managing sleep disorders in menopausal women.” Maturitas 128 (2019): 1-3.

111) Lee, Jinju, et al. “Sleep disorders and menopause.” Journal of Menopausal Medicine 25.2 (2019): 83-87.

112) Li, Caixia, et al. “Analysis of the long‑term beneficial effects of menopausal hormone therapy on sleep quality and menopausal symptoms.” Experimental and Therapeutic Medicine 18.5 (2019): 3905-3912.

113) Andenæs, Randi, et al. “Associations between menopausal hormone therapy and sleep disturbance in women during the menopausal transition and post-menopause: data from the Norwegian prescription database and the HUNT study.” BMC women’s health 20.1 (2020): 1-9.

114) Pan, Zhuo, et al. “Different regimens of menopausal hormone therapy for improving sleep quality: a systematic review and meta-analysis.” Menopause (New York, NY) 29.5 (2022): 627.

115) Dias, Rejane Camila Alvarenga, et al. “Fibromyalgia, sleep disturbance and menopause: Is there a relationship? A literature review.” International Journal of Rheumatic Diseases 22.11 (2019): 1961-1971.

116) Zhou, Qian, et al. “Investigation of the relationship between hot flashes, sweating and sleep quality in perimenopausal and postmenopausal women: the mediating effect of anxiety and depression.” BMC Women’s Health 21.1 (2021): 1-8.

117) Kagan, Risa, et al. “Improvement in sleep outcomes with a 17β-estradiol–progesterone oral capsule (TX-001HR) for postmenopausal women.” Menopause (New York, NY) 26.6 (2019): 622.

118) Geiger, Paul J., et al. “Effects of perimenopausal transdermal estradiol on self-reported sleep, independent of its effect on vasomotor symptom bother and depressive symptoms.” Menopause (New York, NY) 26.11 (2019): 1318.

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119) Parish, Sharon J., and Juliana M. Kling. “Testosterone use for hypoactive sexual desire disorder in postmenopausal women.” Menopause 30.7 (2023): 781-783.

120) Uloko, Maria, et al. “The clinical management of testosterone replacement therapy in postmenopausal women with hypoactive sexual desire disorder: a review.” International Journal of Impotence Research 34.7 (2022): 635-641.

121) Nappi, Rossella E. “Testosterone for women: green light for sex, amber light for health?.” The Lancet Diabetes & Endocrinology 7.10 (2019): 738-739.

122) Davis, Susan R., and Jane Tran. “Testosterone influences libido and well being in women.” Trends in Endocrinology & Metabolism 12.1 (2001): 33-37.

123) Basson, Rosemary. “Testosterone therapy for reduced libido in women.” Therapeutic advances in endocrinology and metabolism 1.4 (2010): 155-164.

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124) Rahn, David D., et al. “Vaginal estrogen for genitourinary syndrome of menopause: a systematic review.” Obstetrics & Gynecology 124.6 (2014): 1147-1156.

125) Ferrante, Kimberly L., et al. “Vaginal estrogen for the prevention of recurrent urinary tract infection in postmenopausal women: a randomized clinical trial.” Female pelvic medicine & reconstructive surgery 27.2 (2021): 112-117.

126) Buck, Emory S., Vanessa A. Lukas, and Rachel S. Rubin. “Effective prevention of recurrent UTIs with vaginal estrogen: pearls for a urological approach to genitourinary syndrome of menopause.” Urology 151 (2021): 31-36.

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127) Marlatt, Kara L., et al. “Body composition and cardiometabolic health across the menopause transition.” Obesity 30.1 (2022): 14-27.

128) Chmouliovsky, L., et al. “Beneficial effect of hormone replacement therapy on weight loss in obese menopausal women.” Maturitas 32.3 (1999): 147-153.

129) Tchernof, A., E. T. Poehlman, and J. P. Despres. “Body fat distribution, the menopause transition, and hormone replacement therapy.” Diabetes and Metabolism 26.1 (2000): 12-21.

130) Rettberg, Jamaica R., Jia Yao, and Roberta Diaz Brinton. “Estrogen: a master regulator of bioenergetic systems in the brain and body.” Frontiers in neuroendocrinology 35.1 (2014): 8-30.

After menopause, when estrogen levels drop, women experience a general increase in weight (Davis et al., 2012a; Pimenta et al., 2013) as well as a redistribution of adipose tissue leading to increased abdominal fat deposition (Bjorkelund et al., 1996; Toth et al., 2000; Zamboni et al., 1992). Importantly, the increased abdominal fat in postmenopausal women tends to be visceral and not subcutaneous fat (Lovejoy et al., 2008)….meta-analysis conducted by the Endocrine Society reported that HT was associated with less accumulation of weight, fat mass, and/or centrally located fat mass (Santen et al., 2010)….Overall, in non-overweight and non-obese women, results from the Endocrine Society meta-analysis indicate that postmenopausal HT protects against weight gain, and also promotes less adipose tissue deposition in visceral fat stores (Santen et al., 2010)….Results from several imaging studies support the idea that postmenopausal HT can modulate brain bioenergetics, likely leading to the maintenance of cognitive function and reduced risk of AD. In the earliest study of brain metabolism in healthy postmenopausal women who were or were not receiving HT, patterns of regional cerebral blood flow (rCBF) were measured during various memory-related tasks (Resnick et al., 1998). Women taking HT showed a different pattern of rCBF than women not taking HT that was particularly evident in brain regions involved in memory systems, and the women taking HT also had superior performance on memory tasks (Resnick et al., 1998). In a follow-up study of the same women two years later, HT users showed increased rCBF over time compared to nonusers in the hippocampus, parahippocampal gyrus, and temporal lobe, regions that are critical for memory formation and are also vulnerable to decreased glucose metabolism in preclinical AD (Maki and Resnick, 2000). As before, the HT users scored higher on a battery of memory tests than nonusers (Maki and Resnick, 2000).

131) Zhu, Jing, et al. “Role of estrogen in the regulation of central and peripheral energy homeostasis: from a menopausal perspective.” Therapeutic Advances in Endocrinology and Metabolism 14 (2023): 20420188231199359.
Within the brain, central estrogen via ER regulates appetite and energy expenditure and maintains cell glucose metabolism, including glucose transport, aerobic glycolysis, and mitochondrial function. In the whole body, estrogen has shown beneficial effects on weight control, fat distribution, glucose and insulin resistance, and adipokine secretion. As demonstrated by multiple in vitro and in vivo studies, menopause-related decline of circulating estrogen may induce the disturbance of metabolic signals and a significant decrease in bioenergetics, which could trigger an increased incidence of late-onset Alzheimer’s disease, type 2 diabetes mellitus, hypertension, and cardiovascular diseases in postmenopausal women.

132) Chopra, Sakshi, et al. “Weight management module for perimenopausal women: A practical guide for gynecologists.” Journal of mid-life health 10.4 (2019): 165.
Menopause-related weight gain is a consequence of low circulating estrogen levels due to progressive loss of ovarian function.

133) Fenton, Anna. “Weight, shape, and body composition changes at menopause.” Journal of Mid-life Health 12.3 (2021): 187. BMI and waist circumference decreased in women taking estrogen and progestin therapy compared to those taking placebo in the WHI study.

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134) Halbreich, Uriel, and Linda S. Kahn. “Role of estrogen in the aetiology and treatment of mood disorders.” CNS drugs 15 (2001): 797-817.
There is growing evidence suggesting that estrogen may be efficacious as a sole antidepressant for depressed perimenopausal women.

135) Wieland, Scott, et al. “Anxiolytic activity of the progesterone metabolite 5α-pregnan-3α-ol-20-one.” Brain research 565.2 (1991): 263-268.

136) Picazo, O., and A. Ferna. “Anti-anxiety effects of progesterone and some of its reduced metabolites: an evaluation using the burying behavior test.” Brain research 680.1-2 (1995): 135-141.

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137) Lephart, Edwin D., and Frederick Naftolin. “Menopause and the skin: Old favorites and new innovations in cosmeceuticals for estrogen-deficient skin.” Dermatology and Therapy 11 (2021): 53-69.

138) Lephart ED. A review of the role of estrogen in dermal aging and facial attractiveness in women. J Cosmet Dermatol (2018) 17(3):282–8. doi: 10.1111/jocd.12508

139) Wilkinson, Holly N., and Matthew J. Hardman. “The role of estrogen in cutaneous ageing and repair.” Maturitas 103 (2017): 60-64.

140) Rzepecki, Alexandra K., et al. “Estrogen-deficient skin: The role of topical therapy.” International Journal of Women’s Dermatology 5.2 (2019): 85.

141) Hall, Glenda, and Tania J. Phillips. “Estrogen and skin: the effects of estrogen, menopause, and hormone replacement therapy on the skin.” Journal of the American Academy of Dermatology 53.4 (2005): 555-568.

142) Kendall, Alexandra C., et al. “Menopause induces changes to the stratum corneum ceramide profile, which are prevented by hormone replacement therapy.” Scientific Reports 12.1 (2022): 21715.

143) Zouboulis, C. C., et al. “Skin, hair and beyond: the impact of menopause.” Climacteric 25.5 (2022): 434-442.

144) Borda, Luis J., Lulu L. Wong, and Antonella Tosti. “Bioidentical hormone therapy in menopause: relevance in dermatology.” Dermatology online journal 25.1 (2019).

145) Reus, Thamile Luciane, et al. “Revisiting the effects of menopause on the skin: functional changes, clinical studies, in vitro models and therapeutic alternatives.” Mechanisms of ageing and development 185 (2020): 111193.

146) Rennert, Gad, et al. “Use of hormone replacement therapy and the risk of colorectal cancer.” Journal of clinical oncology 27.27 (2009): 4542.

Two thousand four hundred sixty peri/postmenopausal women were studied from among 2,648 patients with colorectal cancer and 2,566 controls. The self-reported use of HRT was associated with a significantly reduced relative risk of colorectal cancer (odds ratio [OR], 0.67; 95% CI, 0.51 to 0.89).

The use of oral HRT was associated with a 63% relative reduction in the risk of colorectal cancer in postmenopausal women after adjustment for other known risk factors.

147) Botteri, Edoardo, et al. “Menopausal hormone therapy and colorectal cancer: a linkage between nationwide registries in Norway.” BMJ open 7.11 (2017).

148) Williams, Cecilia, et al. “Estrogen receptor beta as target for colorectal cancer prevention.” Cancer letters 372.1 (2016): 48-56.

149) Lin, Kueiyu Joshua, et al. “The effect of estrogen vs. combined estrogen‐progestogen therapy on the risk of colorectal cancer.” International journal of cancer 130.2 (2012): 419-430.

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150) Xu, Youhua, et al. “Combined estrogen replacement therapy on metabolic control in postmenopausal women with diabetes mellitus.” The Kaohsiung journal of medical sciences 30.7 (2014): 350-361.

This systemic review and meta-analysis provides evidence that postmenopausal women taking low-dose combined ERT have a decreased risk of developing diabetes and have better diabetic control.

151) Anagnostis, Panagiotis, et al. “Early menopause and premature ovarian insufficiency are associated with increased risk of type 2 diabetes: a systematic review and meta-analysis.” European journal of endocrinology 180.1 (2019): 41-50.

152) Mauvais-Jarvis, Franck. “Is estradiol a biomarker of type 2 diabetes risk in postmenopausal women?.” Diabetes 66.3 (2017): 568.

153) Pu, D., et al. “Metabolic syndrome in menopause and associated factors: a meta-analysis.” Climacteric 20.6 (2017): 583-591.

154) El Mohtadi, Mohamed, et al. “Estrogen deficiency–a central paradigm in age-related impaired healing?.” EXCLI journal 20 (2021): 99.

155) Collins, Brittany C., Eija K. Laakkonen, and Dawn A. Lowe. “Aging of the musculoskeletal system: How the loss of estrogen impacts muscle strength.” Bone 123 (2019): 137-144.

156) Pellegrino, Andrea, Peter M. Tiidus, and Rene Vandenboom. “Mechanisms of estrogen influence on skeletal muscle: mass, regeneration, and mitochondrial function.” Sports Medicine 52.12 (2022): 2853-2869.

157) Dam, Tine Vrist, et al. “Transdermal estrogen therapy improves gains in skeletal muscle mass after 12 weeks of resistance training in early postmenopausal women.” Frontiers in physiology 11 (2021): 596130.

158) Tian, Xu, Shujie Lou, and Rengfei Shi. “From mitochondria to sarcopenia: role of 17β-estradiol and testosterone.” Frontiers in Endocrinology 14 (2023): 1156583.

159) Raffaelli, Bianca, et al. “Menstrual migraine is caused by estrogen withdrawal: revisiting the evidence.” The Journal of Headache and Pain 24.1 (2023): 131.
This hypothesis was first introduced by Brian W. Sommerville in 1972 [7], based on his experimental studies suggesting that the precipitous drop in estrogen shortly before menstruation increases the risk of developing a migraine attack [7–9].
Since the early work by Sommerville [7–9], several clinical trials have been performed to evaluate the effectiveness of treating migraine with estradiol [6]. The administration of perimenstrual estradiol gel in small cohorts of women with menstrual migraine yielded a noteworthy reduction in migraine frequency when compared with placebo [32, 33].

160) Nappi, Rossella E., et al. “Role of estrogens in menstrual migraine.” Cells 11.8 (2022): 1355.

161) Reddy, Nihaal, et al. “The complex relationship between estrogen and migraines: a scoping review.” Systematic reviews 10 (2021): 1-13.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197159/
162) Ornello, Raffaele, et al. “Acute and preventive management of migraine during menstruation and menopause.” Journal of Clinical Medicine 10.11 (2021): 2263.

Abstract: Migraine course is influenced by female reproductive milestones, including menstruation and perimenopause; menstrual migraine (MM) represents a distinct clinical entity. Increased susceptibility to migraine during menstruation and in perimenopause is probably due to fluctuations in estrogen levels. The present review provides suggestions for the treatment of MM and perimenopausal migraine. MM is characterized by long, severe, and poorly treatable headaches, for
which the use of long-acting triptans and/or combined treatment with triptans and common analgesics is advisable. Short-term prophylaxis with triptans and/or estrogen treatment is another viable option in women with regular menstrual cycles or treated with combined hormonal contraceptives; conventional prevention may also be considered depending on the attack-related disability and the
presence of attacks unrelated to menstruation. In women with perimenopausal migraine, hormonal treatments should aim at avoiding estrogen fluctuations. Future research on migraine treatments will benefit from the ascertainment of the interplay between female sex hormones and the mechanisms of migraine pathogenesis, including the calcitonin gene-related peptide pathway.

163) Gilmore, Katherine Louise, and Diana Mansour. “A case vignette describing management of menopausal symptoms and migraine in the perimenopause.” BMJ Sexual & Reproductive Health (2021).

164) MacGregor, E. Anne. “Migraine, menopause and hormone replacement therapy.” Post reproductive health 24.1 (2018): 11-18.

165) Silberstein, S. D., and B. De Lignières. “Migraine, menopause and hormonal replacement therapy.” Cephalalgia 20.3 (2000): 214-221.

166) Nappi, Rossella E., et al. “Hormonal management of migraine at menopause.” Menopause international 15.2 (2009): 82-86.

167) Loder, Elizabeth, Paul Rizzoli, and Joan Golub. “Hormonal Management of Migraine Associated With Menses and the Menopause: A Clinical Review: CME.” Headache: The Journal of Head and Face Pain 47.2 (2007): 329-340.

168) Ibrahimi, Khatera, Emile GM Couturier, and Antoinette MaassenVanDenBrink. “Migraine and perimenopause.” Maturitas 78.4 (2014): 277-280.

169) Pavlović, Jelena M. “The impact of midlife on migraine in women: summary of current views.” Women’s midlife health 6.1 (2020): 1-7.

To compare patterns of ovarian hormone changes over the menstrual cycle for women with migraine and controls, we recently examined daily urinary concentrations of estrogen, progesterone, luteinizing hormone, and follicle stimulating hormone over the menstrual cycle for women enrolled in the Study of Women’s Health Across the Nation (SWAN) Daily Hormone Study [35]. These women were entering midlife with an average age of 47 years. Women with migraine history were observed to have a 30% more rapid rate of estrogen decline than controls, specifically within the late luteal phase of the menstrual cycle. This difference was independent of whether women in the migraine group experienced a headache in the cycle studied [35]. This suggested a “two-hit” hypothesis of peri-menstrual migraine attack triggering such that among women with history of migraine, more rapid estrogen decline following the late luteal peak may confer neuroendocrine vulnerability that facilitates initiation of migraine attack(s) by common triggers such as stress, disrupted sleep, foods, wine, etc. [25, 26].

For example, migraine attacks are generally stabilized during states of stable and high estrogen (as in the 2nd and 3rd trimester of pregnancy) [37] and exogenous estrogens have been effectively used to stabilize migraine in women with menstrually related attacks [24]. However, in contrast, treatment with exogenous estrogens has been associated with more frequent migraine attacks or even a precipitation of new onset migraine in some women [38].

The few available epidemiological studies suggest that the increase in frequency and severity of migraine attacks in peri-menopause are due to peri-menopausal hormonal fluctuations [7, 8]. The limited data available suggest that more frequent estrogen withdrawal in peri-menopause is the primary driver of increased headache frequency during the menopausal transition.

170) Yuan H, Spare NM, Silberstein SD. Targeting CGRP for the Prevention of Migraine and Cluster Headache: A Narrative Review. Headache. 2019;59(Suppl 2):20–32.

171) McCarthy, Micheline, and Ami P. Raval. “The peri-menopause in a woman’s life: a systemic inflammatory phase that enables later neurodegenerative disease.” Journal of neuroinflammation 17 (2020): 1-14.

It has been demonstrated that ER-β is localized and involved in regulation of mitochondrial function in neurons

Emerging evidence is showing that peri-menopause is pro-inflammatory and disrupts estrogen-regulated neurological systems. Estrogen is a master regulator that functions through a network of estrogen receptors subtypes alpha (ER-α) and beta (ER-β). Estrogen receptor-beta has been shown to regulate a key component of the innate immune response known as the inflammasome, and it also is involved in regulation of neuronal mitochondrial function. This review will present an overview of the menopausal transition as an inflammatory event, with associated systemic and central nervous system inflammation, plus regulation of the innate immune response by ER-β-mediated mechanisms.

172) Yang, Hye Rim, et al. “Obesity induced by estrogen deficiency is associated with hypothalamic inflammation.” Biochemistry and Biophysics Reports 23 (2020): 100794.

Occurrence of obesity during the postmenopausal period is closely associated with inflammatory processes in multiple peripheral organs that are metabolically active. Hypothalamic inflammation has been recognized as one of the major underlying causes of various metabolic disorders, including obesity. The association between menopause-related obesity and hypothalamic inflammation remains poorly understood. We observed an elevation in hypothalamic inflammation in the ovariectomized mice, which displayed altered metabolic phenotypes and visceral obesity. Furthermore, we confirmed that ovariectomized mice displayed microglial activation accompanied by the upregulation of multiple genes involved in the inflammatory responses in hypothalamic microglia. Collectively, the current findings suggest that hypothalamic inflammation associated with microglial functioning could be a major pathogenic element in disruption of energy homeostasis during the postmenopausal period.

173) Vegeto, Elisabetta, Valeria Benedusi, and Adriana Maggi. “Estrogen anti-inflammatory activity in brain: a therapeutic opportunity for menopause and neurodegenerative diseases.” Frontiers in neuroendocrinology 29.4 (2008): 507-519.

174) Abu-Taha, May, et al. “Menopause and ovariectomy cause a low grade of systemic inflammation that may be prevented by chronic treatment with low doses of estrogen or losartan.” The Journal of Immunology 183.2 (2009): 1393-1402.

175) Au, April, et al. “Estrogens, inflammation and cognition.” Frontiers in neuroendocrinology 40 (2016): 87-100.

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! Important !!!!!!!!!!!!!!!!!!!!!!!!!!!!

Estrogen Deficiency Increased Morbidity and Mortality

176) Nelson, Lawrence M. “The truth about 17-beta estradiol: menopause beyond “old wives’ tales”.” Frontiers in Endocrinology 14 (2023): 1229804.

The physiologic midlife transition to menopause is a state of low serum E2, and early menopause is associated with significant morbidity and early mortality (28, 29). A few prospective population-based cohort studies provide convincing evidence that women with early onset menopause, and the associated E2 deficiency, have
1) a shorter life expectancy,
2) increased risk of type II diabetes,
3) adverse effects on cognitive function,
4) significant correlation between age at menopause and age at diagnosis of dementia, and
5) a significant correlation between age at menopause and age at death (6, 30, 31).
This midlife transition to ultra-low serum E2 levels is associated with significant cardiovascular morbidity and mortality. Prospective epidemiologic studies correlate earlier menopause with earlier death, ischemic stroke, and a combined effect of earlier menopause and high-risk factors on death and cardiovascular disease, osteoporosis, and fragility fracture (32–34).

Evidence is clear, extremely low E2 levels increase the risk for some women. For example, there is a 2.5-fold increase in hip and vertebral fractures in older women with total E2 levels less than 5.0 pg/ml. Men have a similar association between E2 levels and fractures (18). Intriguingly, even minimal increases in E2 serum concentrations have a proven beneficial effect on bone mineral density in menopausal women, with little effect on endometrial proliferation (19, 20). These observations suggest a potentially safe therapeutic window of low physiologic E2 replacement may exist in other areas of a woman’s health. This same therapeutic window of low doses of E2, proven to improve bone mineral density, could theoretically also improve health for menopausal women regarding their cardiovascular health, central nervous system health, mood, and related cosmetic benefits to skin and hair (21, 22).

Actions of E2 in the brain

Evidence associates shorter cumulative life exposure to E2 in women with a higher risk of dementia (44). Notably, the scientific community now recognizes the neuromodulator effects of the potent sex steroid hormone E2 (24). E2 induces both spinogenesis and synaptogenesis (45, 46). These actions are mediated not only by classical slow-acting genomic effects by ER α and ER β receptors but also by rapid activity by membrane-bound ER α, ER β, and G protein-coupled estrogen receptor 1 (GPER1) mediating immediate nongenomic effects (47).

In female animal models, considerable evidence supports the crucial role of E2 in regulating learning and memory. A growing body of literature indicates a similar role in male animals. In animal models, E2 signaling affects spatial memory, object recognition memory, social memory, and fear memory (24). In female mice, E2 reduces anxiety by activating estrogen receptor-β (ERβ) (48). These laboratory science findings may have important clinical implications for managing E2 deficiency in women across the lifespan. In female rodents, E2 rapidly activates numerous cellular events in the brain, including cell signaling, histone modification, and local protein translation. This rapid E2 action in the brain consolidates spatial and object recognition memories (49). E2 also facilitates higher cognitive functions by exerting effects on the prefrontal cortex.

Actions of E2 in the heart and cardiovascular system

The Multi-Ethnic Study of Atherosclerosis (MESA), a prospective cohort study, used Cox hazard models to evaluate associations of E2 with the outcome. After adjusting for demographics, risk factors, and use of hormone therapy, they found higher E2 levels associated with a lower risk of coronary artery disease (57). A longitudinal study of midlife women over up to 9 years showed that those with lower endogenous E2 levels had increased subclinical atherosclerosis progression (58). Vasomotor symptoms (hot flashes and night sweats) related to E2 deficiency are an independent indicator of increased risk of coronary artery disease after correcting for traditional cardiovascular risk factors (59).

den Ruijter HM, Kararigas G. Estrogen and cardiovascular health. Front Cardiovasc Med (2022) 9:886592. doi: 10.3389/fcvm.2022.886592

Actions of E2 in bone

While little recognized and little employed, published evidence demonstrated many years ago that there is a very low dose of E2 (only 14 micrograms per day) administered by a transdermal patch that effectively protects bone density in menopausal women (19, 20). Long-term studies confirm that women in midlife who regularly use menopausal hormone therapy have greater bone mass and fewer osteoporotic fractures (69). A recent meta-analysis clarified the effects of transdermal E2 replacement on BMD in menopausal women. According to pooled estimates, transdermal E2 significantly increased lumbar spine BMD one and two years after initiation of therapy (70).

Physiologic replacement of 17-Beta Estradiol is administered transdermally or transvaginally to avoid adverse “hepatic first-pass effects” of oral administration of estrogens (71). Oral estrogens are known to increase the risk of potentially fatal thromboembolic events (71).

Bone Density

Popat VB, Calis KA, Kalantaridou SN, Vanderhoof VH, Koziol D, Troendle JF, et al. Bone mineral density in young women with primary ovarian insufficiency: results of a three-year randomized controlled trial of physiological transdermal estradiol and testosterone replacement. J Clin Endocrinol Metab (2014) 99(9):3418–26. doi: 10.1210/jc.2013-4145

Over the three-year study, the NIH-IRP hormone replacement regimen restored bone mineral density to normal. Women tolerated the treatment well.

“Physiologic Primary Ovarian Insufficiency” is a unifying scientific term describing the physiology and trajectory of ovarian hormone function across a woman’s lifespan into her later years. To improve understanding and provide better care, a new perspective and this more accurate biologic terminology is needed for “menopause.” The essential biology of this physiologic midlife transition in women is a waning of ovarian endocrine function. The physiologic midlife transition to so-called menopause is a state of low serum E2, and early E2 deficiency is associated with significant morbidity and early mortality. A change in terminology away from the culturally defined menopause and to the scientifically defined Physiologic Primary Ovarian Insufficiency (P-POI) is needed to increase awareness of the underlying biology and endocrinology, improve communication, and provide more effective evaluation and management of the associated role of physiologic E2 replacement in maintaining a woman’s health.

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Estrogen and the Retina, Macular Degeneration, Dry Eye Syndrome

177) Wergenthaler, Nousal, et al. “Etiology of Idiopathic Macular Holes in the Light of Estrogen Hormone.” Current Issues in Molecular Biology 45.8 (2023): 6339-6351..

Fovea cone energy production most likely depends on estrogen. Due to the presence of OR [estrogfen receptor] in cone mitochondria, it may be possible that the fovea cones, through their sensibility to estrogen and high rates of energy consumption, are very vulnerable to damage through a sudden change in the systemic levels of estrogen in females.

178) Korpole, Nilay Reddy, Padma Kurada, and Madhukar Reddy Korpole. “Gender difference in ocular diseases, risk factors and management with specific reference to role of sex steroid hormones.” Journal of Mid-life Health 13.1 (2022): 20.

premature ovarian insufficiency, ocular surface damage and dry eye symptoms.

Hormonal therapy in post-menopausal women might be protective against AMD [macular degeneration] and glaucoma. Estrogen is considered to have a prophylactic effect against eye diseases

179) Patnaik, J. L., et al. “Hormone Therapy as a Protective Factor for Age-Related Macular Degeneration.” Ophthalmic Epidemiology 27.2 (2019): 148-154.

Our case-control study found that the use of HT was associated with a lower odds of all AMD [age-related macular degeneration]stages studied: NV-AMD, GA and early/intermediate.

180) Wei, Qingquan, et al. “17β-estradiol ameliorates oxidative stress and blue light-emitting diode-induced retinal degeneration by decreasing apoptosis and enhancing autophagy.” Drug Design, Development and Therapy 12 (2018): 2715.

181) Cascio, Caterina, et al. “The estrogenic retina: The potential contribution to healthy aging and age-related neurodegenerative diseases of the retina.” Steroids 103 (2015): 31-41.

The retina, like the brain, is a target of sex steroid hormones and a site of E2 production from cholesterol-based steroid synthesis and testosterone aromatization.

show that the retina is programmed to provide E2 from a cholesterol-based biosynthetic pathway or from circulating testosterone, thus being capable
to adjust synthesis and metabolism of E2 to its local needs.

182) Bazvand, Fatemeh, et al. “Tamoxifen retinopathy.” Survey of ophthalmology: S0039-6257.

183) Tenney, Stephen, et al. “Tamoxifen retinopathy: A comprehensive review.” Survey of Ophthalmology (2023).

184) VINDING, TROELS, and NIELS VESTI NIELSEN. “Retinopathy caused by treatment with tamoxifen in low dosage.” Acta ophthalmologica 61.1 (1983): 45-50.

185) Mckeown, Craig A., et al. “Tamoxifen retinopathy.” The British Journal of Ophthalmology 65.3 (1981): 177.

186) Tunc, M. “Maculopathy following extended usage of Clomiphene citrate.” Eye 28.9 (2014): 1144-1146.

187) Russom, Mulugeta, et al. “Blindness and retinal disorder associated with clomifene citrate: Cases series assessment.” Clin Med Invest 2.3 (2017): 1-4.

188) Feng, Zhao Xun, et al. “Risk of ocular adverse events with aromatase inhibitors.” Canadian Journal of Ophthalmology (2023).

189) Azeem, Sitara, et al. “A case report on letrozole-related maculopathy.” Oman Journal of Ophthalmology 16.2 (2023): 322-325.

190) Almafreji, Ibrahim, et al. “Review of the literature on ocular complications associated with aromatase inhibitor use.” Cureus 13.8 (2021).

191) Supalaset, Sumet, et al. “A randomized controlled double-masked study of transdermal androgen in dry eye patients associated with androgen deficiency.” American Journal of Ophthalmology 197 (2019): 136-144.

192) Connor, C. G. “Treatment of dry eye with a transdermal 3% testosterone cream.” Investigative Ophthalmology & Visual Science 44.13 (2003): 2450-2450.

193) Connor, C. G. “Symptomatic relief of dry eye assessed with the OSDI in patients using 5% testosterone cream.” Investigative Ophthalmology & Visual Science 46.13 (2005): 2032-2032.

194) Testosterone for Dry Eye Syndrome by Jeffrey Dach MD

195) Aryani, Inda Astri, Cayadi Sidarta Antonius, and Suroso Adi Nugroho. “Role of Androgen on Physiological Function of Pilosebaceous Unit.” Bioscientia Medicina: Journal of Biomedicine and Translational Research 5.6 (2021): 545-551.

Hair

196) https://www.mdpi.com/2227-9059/11/11/3041
Rinaldi, Fabio, et al. “The Menopausal Transition: Is the Hair Follicle “Going through Menopause”?.” Biomedicines 11.11 (2023): 3041.

197) https://www.proquest.com/openview/123e8269547aa36f036088563621875c/1?pq-origsite=gscholar&cbl=48920
Kronemyer, Bob. “Female pattern hair loss in postmenopausal women.” Contemporary OB/GYN 67.4 (2022): 26-26. More than half of postmenopausal women experience female pattern hair loss (FPHL), according to results of a cross-sectional study published in Menopause.

The authors attributed their findings to the pathophysiological changes in
FPHL involving progressive miniaturization of hair follicles and subsequent
conversion of terminal follicles into velluslike follicles.
Furthermore, alterations in growth, diameter, and pigmentation of the hair
progressively increase, along with scalp hair thinning, thus indicating that FPHL
strongly correlates with menopause.

198) https://pubmed.ncbi.nlm.nih.gov/35357365/
Chaikittisilpa, Sukanya, et al. “Prevalence of female pattern hair loss in postmenopausal women: A cross-sectional study.” Menopause 29.4 (2022): 415-420.
Objective: To identify the prevalence of female pattern hair loss (FPHL), hair characteristics, and associated factors in healthy postmenopausal women.
Methods: Two hundred postmenopausal women aged 50 to 65 years were recruited. Each participant was evaluated for FPHL according to Ludwig’s classification using standardized global photography in all six views and trichoscopy for hair density and diameter. Three dermatologists re-evaluated all pictures for confirmation of FPHL. The time since menopause, levels of scalp sebum, serum testosterone, estradiol, thyroid stimulating hormone, and hemoglobin; family history of hair loss, as well as an evaluation of low self-esteem were evaluated. Women who underwent recent hair loss treatments were excluded. We used simple and multivariable logistic regression analysis to identify the factors affecting FPHL.
Results: In total, 178 postmenopausal women were evaluated for hair-loss patterns. The average age and time since menopause were 58.8±4.1 and 9.2 ± 5.6 years, respectively. The prevalence of FPHL was 52.2% (95% CI, 44.6-59.8). Severity of FPHL by Ludwig grades I, II, and III was 73.2% (95% CI, 62.9-81.8), 22.6% (95% CI, 14.6-32.4), and 4.3% (95% CI, 1.2-10.7), respectively. Logistic regression analysis revealed that age, time since menopause, and body mass index were all significantly associated with FPHL. After adjusting for age and family history of FPHL, only body mass index ≥25 kg/m2 was significantly associated with FPHL (adjusted OR = 2.65, 95% CI, 1.23-5.70). Conclusion: The prevalence of FPHL was high in postmenopausal women, raising the need for hair loss awareness in menopause clinics. Early detection and proper treatment of FPHL may increase the quality of life in postmenopausal women.

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https://www.tandfonline.com/doi/full/10.1080/13697137.2023.2258783

Davis, S. R., et al. “The 2023 practitioner’s toolkit for managing menopause.” Climacteric 26.6 (2023): 517-536.

Endometriosis

Zanello, Margherita, et al. “Hormonal replacement therapy in menopausal women with history of endometriosis: a review of literature.” Medicina 55.8 (2019): 477.

Prevention of Chronic Disease

Gambacciani, M., A. Cagnacci, and S. Lello. “Hormone replacement therapy and prevention of chronic conditions.” Climacteric 22.3 (2019): 303-306.

women with Fibroids

Moro, Elisa, et al. “The impact of hormonal replacement treatment in postmenopausal women with uterine fibroids: a state-of-the-art review of the literature.” Medicina 55.9 (2019): 549.

Unscheduled Bleeding

Dave, Fulva Gajjar, et al. “Unscheduled bleeding with hormone replacement therapy.” The Obstetrician & Gynaecologist 21.2 (2019): 95-101.

Longevity and AntiOxidant status

Borrás, C., et al. “Estrogen replacement therapy induces antioxidant and longevity-related genes in women after medically induced menopause.” Oxidative medicine and cellular longevity 2021 (2021).

AMH

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067546/
Finkelstein, Joel S., et al. “Antimullerian hormone and impending menopause in late reproductive age: the study of women’s health across the nation.” The Journal of Clinical Endocrinology & Metabolism 105.4 (2020): e1862-e1871.

AUCs for predicting that the FMP will occur within the next 24 months were significantly greater for AMH-based than FSH-based models. The probability that a woman with an AMH <10 pg/mL would undergo her FMP within the next 12 months ranged from 51% at h<48 years of age to 79% at ≥51 years. The probability that a woman with an AMH >100 pg/mL would not undergo her FMP within the next 12 months ranged from 97% in women <48 years old to 90% in women ≥51 years old.

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Last updated on April 21st, 2024 by Jeffrey Dach MD