Hey Team! 
Welcome to this special edition of Athletic Aging Medical Updates! Today, we are discussing the latest study published in the September 2025 issue of the journal Menopause, summarizing the data investigating the off-label use of the progesterone IUD for uterine protection as part of menopausal hormone therapy. 
Enjoy!
-Dr. Carla

The use of progesterone as part of menopausal hormone therapy (MHT) regimens began in the 1970s when it became apparent that the use of estrogen alone resulted in an increased risk of endometrial cancer. In the years that followed, progestins (progesterone derivatives) became a standard part of MHT regimens in women who had an intact uterus.

Fast-forward to today, where there is a variety of options for how we can choose to use our MHT.

The FDA-approved options for progesterone/progestin use in MHT include:

• Oral micronized progesterone (bioidentical): This is FDA-approved in combination with estrogen for the treatment of menopausal symptoms. Also has the most favorable safety profile for breast cancer risk. However, its use alone (ie, without estrogen) for this purpose is considered off-label, but is commonly prescribed this way as there is substantial safety and efficacy data behind it.

• Synthetic progestins: Medroxyprogesterone Acetate (MPA) alone or in combination pills such as Premphase and Prempro, Norethindrone Acetate in combination tablets with estrogen such as Activella, Levonorgestrel delivered with estradiol in a transdermal patch as Climara Pro and Combipatch, and oral Drosperinone in combination with oral estradiol as Angeliq.

What has gained traction over the last decade is the use of the progesterone intrauterine device (IUD) for uterine protection. There are 4 progesterone IUDs all containing varying doses of levonorgestrel - a synthetic progestin - that are FDA-approved for contraception: Mirena, Liletta, Kyleena, and Skyla.

Although Levonorgestrel is FDA-approved for uterine protection as a transdermal patch, it is not FDA-approved for uterine protection when delivered via an IUD. However, the off-label use of the Mirena IUD for uterine protection with MHT has been practiced for many years.

In this month’s issue of the journal “Menopause” an article reviewing the data surrounding the safety and efficacy of progesterone IUDs for uterine protection with MHT was published. This is a very important piece of literature as it lends guidance for clinicians and women taking HT in decision-making about the use of the IUD beyond contraception.

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Use of progestin-containing intrauterine systems in hormone therapy regimens: what are the data?

Voedisch, Amy J. MD, MS, MSCP

September 16, 2025. | DOI: 10.1097/GME.0000000000002672

Why It Matters

In combination with estrogen therapy (ET), progesterone IUDs help control bleeding and protect the endometrium, reducing the side effects associated with systemic progestins and progesterone. While this use is approved in over 100 countries, in the United States, it remains off-label, which can impact access and insurance coverage.

How It Works

The progesterone IUD releases levonorgestrel in small daily doses.

• Before menopause: it thickens cervical mucus, preventing pregnancy.

• After menopause: it acts locally on the endometrium, suppressing glandular growth and lowering the risk of overgrowth and malignant transformation of uterine lining cells.

Available Options in the U.S.

• 52 mg IUD (Mirena, Liletta):

  • FDA-approved for 8 years of contraception and 5 years of heavy menstrual bleeding control.

  • Strong evidence supports its use with MHT for up to 5 years to protect the endometrium.

• Lower-dose IUD (Kyleena, Skyla):

  • Primarily FDA-approved for contraception.

  • Limited data suggest they may not provide reliable endometrial protection throughout their full duration, especially beyond the first year of use.

What the Research Says

• Multiple randomized controlled trials and observational studies confirm that the 52 mg IUS prevents endometrial proliferation/pre-malignant transformation for up to 5 years when combined with estrogen therapy.

• There is no robust evidence to support its safety or effectiveness for longer than 5 years. While release rates beyond this period may still offer protection, the data are sparse.

• Lower-dose devices (Kyleena, Skyla) have not been adequately studied in the hormone therapy setting, and their declining hormone release makes them less reliable for endometrial protection.

Practical Takeaways

• The 52 mg IUD should be the first-line choice when considering an IUD for perimenopausal and menopausal patients using estrogen therapy and needing endometrial protection.

• Extended use beyond 5 years is not currently recommended for endometrial protetction, pending further research.

• Lower-dose devices (Kyleena, Skyla) should be reserved for unique cases and replaced earlier if used alongside MHT

• Because this use is off-label in the U.S., shared decision-making and patient counseling are essential to set realistic expectations about safety, efficacy, and insurance coverage.

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NOW TAKING NEW CLIENTS!

If you are an active woman or competitive midlife athlete who feels abandoned by mainstream medicine, I’m here for you!

It is with great excitement that after more than 2 years of preparation, I have FINALLY launched my Telehealth Consultation Medical practice focusing on the Reproductive Endocrine needs and Menopausal Care for active, athletic, and high-performing women.

Active and athletic midlife women have needs and risk profiles that are different from the general population. These needs often go unmet by the mainstream medical community due to a lack of understanding of fitness and sport and their impact on mid-life hormonal physiology or even a lack of acknowledgment that this dynamic exists. We put your health, fitness, and performance at the center of the equation so that you can achieve your healthiest, highest-performing self!

You will find all my service offerings on my website including a link to my calendar so that you can reserve your place in my schedule!

Happy New Year everyone, and what better way to start the year than with a commitment to better sleep! 

Sleep is the foundation of recovery from mental and physical activity, and helps keep our physiologic processes in balance for maintaining good health. But it is such a struggle for so many people - especially in midlife. Today we review of an excellent article published in the Journal Menopause that can help you on your way to better sleep! 

Enjoy! 
Dr. Carla

As a Menopause Specialist and a menopausal woman myself, I cannot think of anything more disruptive to the experience of life than poor sleep night after night after night. Even during my training as an OBGYN resident when we would work 36-hour shifts every third night, we at least knew that the shift would end and sleep was promised. In perimenopause and menopause (and postpartum, for that matter), you don’t know when (or if) the sleepless nights will end leading to exhaustion, depression, health issues, and overall poor quality of life.

Today’s post summarizes an excellent review published in the journal Menopause earlier this year. The authors discuss the latest knowledge surrounding sleep disturbance during perimenopause and menopause. I liked this review because it goes deeper than sleep hygiene and avoiding caffeine after 3pm. It discusses peri/menopausal sleep disturbance as a distinct entity from insomnia with respect to causes, physiology, and approach to intervention. As always, my editorial commentary will follow.

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REVIEW -Sleep disturbance associated with the menopause

Maki PM, Panay N, and Simon JA.

Menopause: The Journal of The Menopause Society 2024 Vol. 31, No. 8, pp. 724-733 DOI: 10.1097/GME.0000000000002386

Sleep disturbance during perimenopause and menopause is a frequent and disruptive problem second only to vasomotor symptoms (VMS) (“hot flashes”) in prevalence that can lead to significant disruption of life activities impacting personal and social relationships, work, and health. It is characterized by frequent sleep interruptions, nighttime awakenings and/or greater wakefulness after sleep onset (WASO), poor quality, and insufficient restorative sleep.

When associated with the menopause transition, disruptive sleep patterns can occur in women without a prior history of sleep problems with 40- 69% of midlife women reporting sleep disturbance. However, the proportion of women meeting the criteria for an insomnia diagnosis is much lower (4% and 40%).

Impact of menopausal sleep disruption

Over time, sleep disruption can have a significant impact on physical and mental health and quality of life including:

• Significant increases in the risk of unemployment

• Loss of approximately $2 billion per year in productivity in the US.

• Shift in nutrient utilization that promotes body fat gain, potential development of metabolic syndrome, and other related issues independent of changing estrogen levels during menopause.

• Links with subclinical markers of cardiovascular disease risk independently of VMS

• Association with deteriorating mental health, particularly with symptoms of depression and anxiety

• Studies of cognitive performance across the menopause transition identified sleep disruption as the major predictor of declines in verbal learning and memory areas and when persistent can result in impaired mental acuity and forgetfulness.

Defining Sleep Problems

A frustrating tendency in the mainstream medical community is that if a patient shares a concern with their provider and it doesn’t fit into a nice neat little diagnostic box, she may very well go untreated or even misdiagnosed. As we mentioned previously, 40-69% of perimenopausal and menopausal women report sleep disturbance but only 4-40% meet the diagnostic criteria for insomnia. This discrepancy underscores the need for a comprehensive conversation with our patients to understand their experiences, challenges, and goals.

Understanding the types of sleep disorders people experience creates a starting point of consideration when a woman shares her struggles with sleep. Below are three sleep disorder diagnoses that the authors cite as increasing in frequency among perimenopausal/menopausal women:

• Chronic Insomnia - The most severe form of sleep disturbance. It is defined by the DSM-V criteria as difficulty with initiating and maintaining sleep and/or early-morning awakening with the inability to return to sleep causing significant distress/impairment in daytime functioning 3 nights/week for at least 3 months.

• Sleep-Disordered Breathing (SDB)

  • Obstructive sleep apnea (OSA) is a condition where the upper airway repeatedly narrows or closes disrupting airflow. Treatment includes measures that relieve the obstruction such as positive airway pressure devices or oral appliances.

  • Central sleep apnea (CSA) is a condition where breathing repeatedly stops and starts during sleep due to improper signaling by the brain to the muscles that control breathing. Treatment targets the underlying cause (Medical conditions, medications, neurological causes, and use of continuous positive airway pressure.

• Restless Leg Syndrome (RLS) - A neurological disorder that causes discomfort in the lower extremities and the constant urge to move them. The cause is mostly unknown but is thought to be related to dopamine signaling in the brain. Treatments for RLS may include reducing aggravating factors, iron supplementation, or dopaminergic medications.

Sleep Disturbance Associated with Menopause

Studies of sleep disturbance in menopausal women identified increases in the number of night-time awakenings and the time spent awake after sleep onset (WASO). This varied from those with chronic insomnia in these studies in that total sleep time and hyperarousal seen in younger women were not observed.

Another difference between chronic insomnia and sleep disturbance associated with menopause is that a reduced ability to fall asleep (sleep-onset insomnia) is a less common complaint during the menopause transition where more nighttime awakenings are observed.

Lastly, menopausal sleep disturbance can be related to fluctuations in estradiol levels, hot flashes, and mood disorders whereas primary insomnia cannot be attributed to an underlying cause.

Physiology

The hallmark of the menopausal transition is the change in pattern and levels of estradiol production by the ovaries. These changes have a cascade of downstream physiological effects that frequently impact sleep:

• Decline in nighttime melatonin levels resulting in disturbance of circadian mechanisms that can impact sleep

• VMS (“hot flashes”) and changes in core body temperature follow a circadian pattern and can be more frequent at night.

• Eighty percent of menopausal/perimenopausal women experience vasomotor symptoms. When moderate to severe, women are 3 times more likely to experience awakenings from sleep. Interestingly, when VMS are objectively measured using instrumentation such as polysomnography, the results suggest that sleep can be disturbed even when VMS occur when women are unaware of them.

• Mood disorders such as anxiety and depression increase in perimenopausal and menopausal women. Those with a history of clinical anxiety or depression earlier in life are at particularly high risk. Sleep and mood have been found to have a bi-directional relationship where mood disturbance can disrupt sleep and disrupted sleep and can cause exacerbation of mood symptoms. Likewise, effective treatment of mood symptoms can improve sleep and improved sleep can result in better mood.

• The hormonal fluctuations associated with the menopause transition may cause sleep disturbance independently of other menopause symptoms due to a direct effect on the hypothalamic sleep center. Several studies have demonstrated that increased follicle-stimulating hormone (FSH) and decreasing estradiol levels are associated with difficulty staying and falling asleep.

• The positive effects of progesterone on sleep have been well-documented over the years. Further, estrogen administration can increase REM sleep and decrease sleep latency according to one study cited by the authors.

The common thread that ties many of these physiological elements together lies in the hypothalamus of the brain, which plays a central role in the control of body temperature, circadian rhythms, reproductive hormonal regulation, and mood, along with many other physiologic functions that keep the body in balance.

Within the hypothalamus are specialized nerve cells called KNDy neurons that play a role in temperature regulation and modulation of the reproductive hormones via Gonadotropin-releasing (GnRH) hormone. When estrogen declines, these nerve cells become hyperactive which is believed to be involved in the physiology behind temperature dysregulation and hot flashes. KNDy neurons also play a role in the stress response system and mood, co-localizing with corticotropin-releasing hormone (CRH), serotonin, and dopamine.

Recent studies of a new class of medications called NK1 and NK3 receptor antagonists have demonstrated effectiveness in improving sleep and mood symptoms in menopausal women. Fezolinitent is an NK3 receptor antagonist that was FDA-approved in May 2023 for the treatment of hot flashes.

Treatment of Sleep Disturbance Associated with Menopause

The authors review the current treatments for sleep disturbance associated with menopause and their limitations.

Identifying and treating medical causes of sleep disturbance and counseling on good sleep hygiene are recommended as initial approaches to address sleep disturbance, however these measures are frequently unsuccessful

Hormone therapy can be effective if sleep disturbance is related to hot flashes. However, in the absence of hot flashes, the effectiveness is uncertain. Oral micronized progesterone has been suggested to improve sleep, as well as decrease hot flash frequency.

Anti-depressant medications such as selective serotonin reuptake inhibitors (SSRIs), most notably, Paroxetine, have sedative effects and may benefit women with sleep disturbance associated with hot flashes and depression. However, some SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs) may actually worsen sleep disturbance in individuals with mood conditions.

Sedative-hypnotic medications such as benzodiazepines (ex - Diazepam (Valium), Xanax (Alprazolam) and non-benzodiazepines (Zolpidem (Ambien) can be effective for sleep disturbance in the short term, however, they are generally not recommended in postmenopausal women due to an increased risk of falls, bone fracture, and osteoporosis in this population. Further, use of these medications for more than 4 weeks can lead to the development of tolerance, addiction, dependence, and withdrawal symptoms

Cognitive Behavioral Therapy for insomnia (CBT-i) is the recommended first-line approach for insomnia disorder in peri/menopausal women, however, accessibility to trained providers is a challenge, and the treatment is time-intensive.

Supplements - Dietary supplements such as probiotics, omega-3, and herbal medicines (eg, isoflavones, pollen extracts, red clover) are used to manage menopausal symptoms including sleep disturbance. However, studies of their efficacy are conflicting and often of poor quality. Melatonin is frequently used to induce drowsiness and may be effective in reducing sleep disturbance among postmenopausal women, but results from clinical studies are mixed. Melatonin is only available over-the-counter in the United States.

NK-1 and NK-3 receptor antagonists modulate hypothalamic KNDy neuronal activity and have shown promising efficacy in addressing hot flashes and sleep disturbances in multiple studies.

In My Humble Opinion….

Although the authors paint a bleak picture of effective treatment options for managing sleep disruption during menopause, the silver lining lies in the knowledge that has been gained in understanding this problem:

1 - Sleep disruption in perimenopause and menopause is a distinct problem that is different from chronic insomnia, sleep-disordered breathing, and restless leg syndrome. Recognizing this distinction helps to focus efforts on the root cause of the sleep disturbance.

2 - There is a clearer understanding of the interplay between hot flashes, mood, sleep, and the changing hormonal paradigm of the menopause transition. Understanding how these factors interact in each individual helps target symptoms more effectively.

3 - The key discovery of the role of KNDy neurons and the development of neurokinin-3 (NK3) receptor antagonists have given us another FDA-approved pharmacologic tool for managing the symptoms that can result in sleep disturbance associated with menopause.

4 -Advances in wearable technology have given us a powerful tool to collect sleep data in the comfort of our own homes and even track associations with sleep patterns. The more information we have about our own sleep patterns, the better we can identify the factors that impact sleep for an individual and target interventions accordingly.

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NOW BOOKING APPOINTMENTS!

If you are an active woman or competitive midlife athlete who feels abandoned by mainstream medicine, I’m here for you!

It is with great excitement that after more than 2 years of preparation, I have FINALLY launched my Telehealth Consultation Medical practice focusing on the Reproductive Endocrine needs and Menopausal Care for active, athletic, and high-performing women.

Active and athletic midlife women have needs and risk profiles that are different from the general population. These needs often go unmet by the mainstream medical community due to a lack of understanding of fitness and sport and their impact on mid-life hormonal physiology or even a lack of acknowledgment that this dynamic exists. We put your health, fitness, and performance at the center of the equation so that you can achieve your healthiest, highest-performing self!

You will find all my service offerings on my website including a link to my calendar so that you can reserve your place in my schedule!

To celebrate the official launch, I’m offering $75 OFF my Health and Wellness Concierge service! Simply provide the code CONCIERGE75 in a message to us to redeem the discount once you request your appointment. The discount will be applied at the time the appointment request is processed.

The Women’s Health Initiative is one of the largest randomized trials focusing on women’s health in the US, beginning in 1993 and enrolling 161,808 women ages 50-79 with the goal being to inform clinical practice about the role of hormone therapy in preventing chronic diseases such as cardiovascular disease, cancer, and hip fractures. Many “sub-studies” emerged from this massive data collection, some still ongoing today.

This trial rocked the media headlines in 2002 when investigators terminated the estrogen/progestin arm of the trial due to what they interpreted as a statistically significant increase in breast cancer incidence found in the treatment group compared to the placebo group to the extent that risks of continuing the study outweighed any potential benefits. This led to a media firestorm leaving providers and patients fearful of prescribing and using hormone therapy to manage menopausal symptoms. Sadly, millions of women suffering from debilitating symptoms have gone untreated resulting in $1.8 billion in lost productivity every year according to a study from the Mayo Clinic.

Over the last 22 years since the discontinuation of this arm of the study, the debate still rages on. However, numerous studies have emerged lending more clarity to the nature and magnitude of risk and a clearer delineation of subgroups who may experience greater benefit or risk.

In May 2024, a group of WHI trials was reviewed in The Journal of the American Medical Association (JAMA) focusing on the health effects of menopausal hormone therapy, calcium plus vitamin D supplementation, and a low-fat dietary pattern. Here, we will review the pertinent points of the review with some editorial commentary to follow.

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The Women’s Health Initiative Randomized Trials and Clinical Practice - A Review

Manson JE, Crandall CJ, Rossouw JE, et al.

JAMA May 2024 online doi:10.1001/jama.2024.6542

GOAL: Review of the findings and conclusions of the WHI trials investigating the health effects of menopausal hormone therapy, calcium plus vitamin D supplementation, and a low-fat dietary pattern

METHODS: The review focused on the findings of the 4 WHI study arms below. :

• CEE + MPA (estrogen plus progestin) vs placebo (Uterus intact)- 16,608 participants; main outcome measure: Coronary heart disease (CHD)

• CEE (estrogen alone) vs placebo (After hysterectomy) - 10,739 participants; main outcome measure: CHD

• Calcium and Vitamin D supplementation vs placebo - 36,282 participants; main outcome measure: Hip fracture.

• Low-Fat Dietary Modification Trial: 20% reduction in dietary fat, increased fruits, vegetables, and grains vs usual diet - 48,835 participants; main outcome measure: invasive breast and colorectal cancer.

CEE: Conjugated equine estrogens, MPA: Medroxyprogesterone acetate

Rates of invasive breast cancer were monitored in the two hormonal trials as a safety measure. The intended length of the CEE alone and CEE + MPA trials was 9 years.

FINDINGS

CEE + MPA vs Placebo:

After 6 years the data safety monitoring board recommended discontinuing this arm of the study because they concluded that the risks of continuing the trial outweighed the benefits. They specifically cite a greater incidence of invasive breast cancer, CHD, stroke, and pulmonary embolism at 5.6 years. However, when analyzing the group ages 50-59 alone, the trends toward these risks appeared to be less. The death rate from breast cancer increased after 11-year follow-up, however, after 20 years, the differences were no longer significant.

Secondary outcome findings:

• There was an initial reduction in colorectal cancer however was no longer significant after long-term follow-up

• A reduction in the incidence of endometrial cancer was observed initially and through long-term follow-up.

• There was a significant reduction in the rate of hip fracture that persisted through long-term follow-up

• A decreased risk of diabetes and an increased risk of gallbladder disease was observed.

• There was a “Probable” increase in dementia risk

• A “Composite index” was defined as the risk of CHD, pulmonary embolism, stroke, breast cancer, colorectal and endometrial cancer, or death from other causes. In the treatment group, there were 20 excess cases per 10,000 women per year (12 excess cases ages 50-59) in the short term, however after a 13-year follow-up the differences were no longer significant.

CEE Alone vs Placebo

The trial was stopped 1 year early by the National Institutes of Health (NIH) due to an increased risk of stroke and no statistically significant benefit for the prevention of CHD.

Secondary outcome findings

• In the entire cohort, there was no effect of CEE alone on the Composite Index defined above. However, when stratified by age group, more favorable trends were seen in ages 50-59 with 19/10,000 fewer composite index cases, as compared to ages 70-79 where 51/10,000 excess events. After 13 years, these age differences persisted.

• The CEE group had a 14% lower risk of type 2 diabetes and 55% higher rates of gallbladder disease.

• In the study participants aged 65 and older receiving CEE alone showed a trend toward increased risk of dementia by in-person cognitive testing. A follow-up study of women aged 50-55 performed 7 years after the trial ended showed no difference in dementia risk.

Authors’ Conclusions from the CEE and CEE + MPA Trials

• Results from the WHI do not support either CEE plus MPA or CEE alone for preventing CHD, stroke, dementia, or other chronic diseases in postmenopausal women.

• Younger menopausal women (< age 60, within 10 years of the onset of menopause) have low absolute risk of many of these chronic diseases and low HT-related risk. These women may derive significant quality-of-life benefits from symptom relief achieved with HT.

• Differences in breast cancer outcome risk between CEE alone and CEE + MPA have clinical implications with risk increasing with longer duration of therapy and with CEE + MPA therapy.

• The findings from these trials cannot be extrapolated to women < age 45 experiencing premature menopause.

Calcium and Vitamin D Supplementation Trial

The WHI calcium and vitamin D supplementation trial investigated whether calcium plus vitamin D supplementation, compared with placebo, lowered the risk of hip fracture, (primary endpoint), total fractures, and colorectal cancer (secondary endpoints) in postmenopausal women at average risk of fracture.

36,282 women were randomly assigned to 1000 mg/d of elemental calcium carbonate with 400 IU/d of vitamin D3 or placebo.

Primary and Secondary outcomes

• During the 7-year trial period, Calcium and vitamin D supplementation did not significantly impact hip fracture rates in the entire study cohort.

• A reduction in hip fractures was seen in the cohort aged 60 and older, and an increase in fracture risk was seen in younger women.

*** These findings included women who were compliant AND non-compliant with therapy. In women who were compliant with therapy, a reduction in hip fracture risk was seen across the entire cohort (all ages).

• Women receiving calcium plus vitamin D supplementation had greater preservation of total hip BMD than women assigned to placebo but no statistically significant differences in bone density.

• Over the 11-year follow-up, there was no statistically significant effect of vitamin D and calcium supplementation on hip fracture risk, however in individuals compliant with therapy, there was a significant difference in the risk of hip fracture.

• During the 7-year intervention and over the 11-year follow-up period, Calcium and vitamin D supplementation did not impact the incidence of invasive colorectal cancer. This finding persisted when the analysis only included women compliant with the supplementation regimen.

• Compared with placebo, calcium plus vitamin D supplementation had no statistically significant effect on total mortality during the intervention period or 11-year follow-up.

• There was no statistically significant effect on cardiovascular events during the intervention period or cumulative follow-up.

• There was no significant effect on coronary artery calcium (CAC) scores during the intervention period or cumulative follow-up.

• Calcium plus vitamin D supplementation had no effect on invasive breast cancer risk.

• Compared with the placebo group, Calcium and vitamin D supplementation significantly increased the risk of kidney stones.

Authors’ Conclusions from the Calcium and Vitamin D Supplementation Trial

• Compared with placebo, calcium plus vitamin D supplementation had no effect on lower arm or wrist fracture, total fracture, colorectal cancer, CVD, or total mortality.

• In the overall study cohort, calcium plus vitamin D supplementation did not significantly reduce hip fractures in postmenopausal women compared with placebo.

• Greater preservation of total hip BMD and reduction in hip fractures was seen among women aged 60 years or older and among women adherent with study medications.

• The results of this trial do not support routine calcium plus vitamin D supplementation for postmenopausal women at typical risk of fracture.

Dietary Modification Trial

This trial investigated whether a low-fat diet (compared to a usual diet) rich in fruits, vegetables, and grains reduced the risk of invasive breast cancer or colorectal cancer (primary endpoints), and CHD (secondary endpoint).

The dietary program aimed to reduce fat consumption to 20% of total energy intake, increase vegetable and fruit intake to 5 or more servings per day, and increase grain intake to at least 6 servings per day.

Neither total caloric intake nor physical activity levels were considered in this study

The intervention period was a median 8.5- year behavioral intervention, delivered primarily by registered dietitians in small-group sessions.

Primary and secondary outcomes

• Compared with usual diet, the low-fat diet high in fruits and vegetables did not significantly reduce breast or colorectal cancer, however, all-cause mortality after a breast cancer diagnosis was decreased in the low-fat diet group. At 20-year follow-up, a reduction in breast cancer mortality was observed in the low-fat diet group.

• Coronary heart disease, defined as nonfatal myocardial infarction plus coronary death, was not significantly reduced by the low-fat dietary pattern. The author’s note that a differential rate of statin use in the comparison group as compared to the dietary intervention group may have skewed these findings.

• The low-fat dietary intervention did not significantly reduce endometrial, ovarian, or total cancer compared with the usual diet.

• The dietary intervention also did not significantly reduce stroke or total CVD outcomes compared with usual diet

Author’s Conclusions from the Dietary Modification Trial

A low-fat diet with increased fruits, vegetables, and grains has no impact on preventing breast or colorectal cancer, however, the potential role of a low-fat dietary pattern in reducing breast cancer mortality warrants further study.

In My Humble Opinion….

When I first read this study, my thought was that there was really nothing new pertaining to the hormone therapy trials. But to be fair, although the data itself is not new, the fresh perspective and interpretation that the authors put forth raise some points and nuances that may not have been appreciated when the data was initially released more than 20 years ago.

Regarding the hormone studies (CEE along, CEE + MPA), the debate over whether this data is relevant given that the HT preparations used in the study are different from what is typically used today is ongoing. While this is true, the intial findings raised these questions and led to investigations that have provided important information about how different formulations impact the clinical experience. Some examples include:

• There is evidence that the use of transdermal estrogen preparations is less thrombogenic (lower risk of blood clots) than oral preparations.

• Breast cancer risk may be impacted by the type of progestongen used in HT formuations with bioidentical micronized progesterone showing more favorable results.

The main observation that has stood the test of time and has appeared in every Menopause Society position statement from 2012 is the difference in risk of INITIATION of HT in women >age 60/>10 years since menopause onset and those <age 60, < 10 years since menopause onset. The findings surrounding the timing of HT start initially discovered in the WHI trials, still holds true today even across the use of different formuations. So I would humbly submit, that although there are critical differences in practice today, there is still much to appreciate about these original findings.

The other key finding that has emerged from further study of the use of HT in younger vs older women is that there does not need to be an arbitrary stopping point for the use of HT at any age if the individual’s benefits of using HT outweigh the risk. This is new as of the 2022 Menopause Society Hormone Therapy Position Statement and results from years of follow-up study from the initial observations of the WHI trials.

So, although there has been valid criticism of the messaging, results interpretation, and statistical analysis of the initial studies, some good came out of these initial findings and attempts to answer the criticisms from the studies that followed.

I found the Calcium and Vitamin D study interesting because of the multiple references to “the study population that was adherent to the supplementation regimen”. It puzzles me why subjects that were NOT compliant with the supplementation were included in the study. Those that were compliant with supplementation appreciated a lower fracture risk, particularly in the older population at greater fracture risk according to this study.

So at the end of the day after considering this data and the many studies that followed, my personal practice is to only recommend Calcium supplementation to those women at high risk of fracture by DEXA BMD, dietary calcium intake, prior medical history, family history, and physical activity patterns. I am not opposed to universal Vitamin D supplementation given the minimal apparent risk and reduced GI absorption of Vitamin D often seen in menopausal women.

The Dietary Modification Trial was equally puzzling, as many of the major risk factors for the primary and secondary outcomes were not considered. Physical activity level, BMI, and weight loss (study participants lost an average of 1.9kg, <5lbs) were not specifically addressed in the trial, nor was it mentioned by the authors of this review. In my opinion, the fact that few differences in the primary and secondary outcomes were seen between the study cohort (modified diet) and the controls (usual diet) may be because these other factors are indeed important. Had the study considered a more holistic approach to health habits rather than simply focusing on nutrition metrics, the study may have yielded different results.

Conclusion

I applaud the author’s for providing a renewed perspective on this very important and at times, controversial study. They did a very good job of clearly and concisely delineating the study methods, primary, and secondary outcome measures. As studies continue to emerge through the years, it will continue to shape the lens through which we see the original data and hopefully, yield additional insight and inspire continued study of these issues so critical for the health and well-being of women.

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The safety and efficacy of menopausal hormone therapy (MHT) have been under scrutiny since the day the Women’s Health Initiative study discontinued the estrogen/progestin treatment arm IN 2002 due to a statistically greater increase in breast cancer risk relative to the other treatment arms.

The messaging surrounding the interpretation of these results and the media frenzy that followed led to millions of women going untreated for their often debilitating symptoms. Fear of prescribing by providers and continued apprehension among symptomatic women continue to this day.

Fortunately, over the last 2 decades, a wealth of research has emerged that has more clearly defined the conditions for which MHT is effective and the parameters for patients at greater risk. Some examples of how this knowledge has evolved include:

• There is no longer a set duration of use after which MHT must be discontinued as compared to the 5-7 year recommendations issued 5-10 years ago.

• BRCA-positive women without a personal history of breast cancer do not incur any additional risk of breast cancer with MHT use compared to the BRCA-negative population.

• The severity and frequency of vasomotor symptoms (VMS) a.k.a “hot flashes” correlates with a greater risk of developing cardiovascular disease (CVD). This group may appreciate greater overall health benefits and risk reduction using MHT as compared to universal treatment of asymptomatic women for purposes of “disease prevention” or “longevity”.

The focus of this recent meta-analysis is on breast cancer survivors. According to the 2022 Menopause Society Position Statement on Hormone Therapy, systemic treatment with HT is not recommended in women with a prior history of breast cancer. However, these women have hot flashes too, and need relief.

This study is an important contribution to the literature because it defines risk categories based on tumor cell biology that can help providers and patients develop a risk/benefit analysis upon which to inform decision-making. Below is a summary and review of this study with my commentary to follow. Enjoy!

Eligibility criteria for using menopausal hormone therapy in breast cancer survivors: a safety report based on a systematic review and meta-analysis.

Coronado PJ, Gomez, A, Iglesias, E. et al. from the Women’s Health Institute Hospital Clinico San Carlos, Madrid, Spain.

Menopause: The Journal of the Menopause Society Vol 31 No. 3, 2024 pp 234-242

Goal of the study

Establish eligibility criteria for the use of MHT in breast cancer survivors

Study methods

Extensive literature search and review of MEDLINE, The Cochrane Library, and EMBASE up to June 2022. The evidence was graded according to grading quality of evidence and strength of recommendations.

Results

A total of 12 studies including 3 randomized controlled trials (RCTs), 3 prospective, and 6 retrospective studies were considered for evaluating the impact of MHT on breast cancer survivors. Below are the 3 RCTs included in this study:

• Stockholm

• Hormone Replacement Therapy After Breast Cancer - Is It Safe (HABITS)

• Livial Intervention Following Breast Cancer, Efficacy, Recurrence, and Tolerability Endpoints (LIBERATE)

BREAST CANCER RECURRENCE

When these studies were reviewed individually, there were conflicting results. The analyses that follow have strengths and limitations and should be interpreted with caution.

• The Stockholm study found no evidence of increased risk of recurrence in MHT users vs non-users/placebo at the 4 and 10-year follow-up periods.

• The HABITS study showed an increased risk of cancer recurrence in MHT users compared to non-users/placebo. It is worth noting that the group using MHT had a greater percentage (62.5%) of hormone receptor (HR)-positive tumors compared to the non-user group where 54.5% had a history of HR-positive tumors. The conclusion from this study is that the recurrence rate is greater in MHT users with HR-positive tumors and in those women taking Tamoxifen.

• When the results of the Stockholm study and the HABITS study were combined, there was no increased risk of recurrence after the 4-year follow-up and when incorporating the 10-year follow-up from the Stockholm study.

• The LIBERATE trial found an increased risk of cancer recurrence in women with a history of HR-positive tumors, however, there was no increased risk in women with a history of HR-negative tumors treated who were treated with tibolone.

It is important to note that the level of evidence of these trials is considered “moderate” because of the premature termination of these studies due to recruitment challenges and small sample sizes. These factors are important limitations to consider when applying this data in clinical practice.

• Incidentally, a combined analysis at the 10-year follow-up of the Stockholm, HABITS, and LIBERATE trials showed an increased risk of NEW breast cancer events.

• Whether only considering the RCT results or when all study types were considered (RCTs, retrospective, and prospective studies) no elevated risk of recurrence was observed.

  • However, the authors note that cohort studies (retrospective and prospective studies) need to be interpreted with extreme caution due to the high risk of confounding factors and selection bias that is inherent to these types of non-randomized studies.

ALL-CAUSE AND BREAST CANCER-RELATED MORTALITY (DEATH)

• A combined analysis of data from the Stockholm and HABITS trials showed no difference in overall mortality between MHT users and non-users. This finding was also true when the results of the RCTs and the prospective studies were pooled. Again, the authors recommend caution in interpretation due to the limitations of these studies noted above.

• Interestingly, a pooled analysis of 3 retrospective cohort studies showed a significant REDUCTION in breast cancer mortality rate in MHT users compared to non-users. This finding was maintained when data from the Stockholm and HABITS trials were added to the analysis.

• When all study types were pooled, there was no statistical difference in all-cause or breast cancer-related mortality rates in MHT users versus non-users.

Authors’ Discussion and Conclusions

The use of MHT in breast cancer survivors should not be considered as an absolute contraindication, particularly in cases of HR-negative tumors.

The results of these studies and this analysis need to be interpreted with caution due to a high degree of “heterogeneity” (variability) in MHT formulations, use of adjuvant therapies such as tamoxifen and aromatase inhibitors, differences in lymph node status, and varying patient characteristics among the studies.

The hormonal status of the tumor may influence breast cancer recurrence and is an important factor when considering the use of MHT. According to this analysis, HR-negative tumors pose less of a risk of recurrence. For women with HR-positive tumors, an excess risk of recurrence was noted. However, the pooled analysis did not show a significant difference in mortality (death) rates in HR-negative or HR-positive populations. Further analysis of the cohort studies showed some suggestion of a reduction in mortality rate in MHT users.

The data speaking to mortality (death) rate in MHT vs non-users should be interpreted with caution because this was a secondary endpoint of the study and because of the inherent biases and limitations of the studies analyzed.

In my humble opinion…..

This study is an invaluable contribution to the literature and lays the groundwork for continued study in breast cancer survivors. Here are my big takeaways:

• A personal history of breast cancer should not be considered an absolute contraindication to MHT use.

• HR status of the breast tumor matters with respect to recurrence rate.

• Future study would benefit from a focus on recurrence versus mortality rates, HT formulations with particular attention to progestin used, and the impact of HT use on women taking ancillary treatments such as aromatase inhibitors and Tamoxifen.

The use of ancillary treatments for breast cancer is also worth mentioning here. Aromatase inhibitors and tamoxifen have been used for decades as “maintenance” treatments that effectively reduce the level of systemic estrogen exposure to minimize stimulation or “activation” of estrogen-responsive cancer cells that may be present at subclinical levels in the tissues or circulation. More recently, a new class of pharmacotherapy has emerged called the tissue-specific estrogen receptor complex (TSEC). Bazedoxifene (a “SERM” or selective estrogen receptor modulator) combined with estrogens has emerged as a potential therapy that could be effective for the treatment of menopausal symptoms (hot flashes and bone loss) by selectively targeting some estrogen receptors while potentially providing a protective effect in other tissues such as the breast. There is definitely more to come on this front so stay tuned!

The last point that I would like to make is regarding all-cause mortality. We know from decades of research that when MHT is used in symptomatic women < age 60 and <10 years from the onset of menopause, there is a reduction in all-cause mortality. This reduction in mortality seen with MHT use needs to be entered into the equation because it is possible that the benefits of MHT use for mortality risk reduction may outweigh the risks of death that could result from cancer recurrence.

So, to only consider breast cancer recurrence rate as the determinant of whether or not MHT is safe is short-sighted; because at the end of the day, it’s all about living!

I am so encouraged by the direction of this research! My hope is that this work continues so that all women have options for managing their symptoms in this stage of life.

One of the most significant pivots in the hormone therapy (HT) recommendations that emerged from the North American Menopause Society (NAMS) 2023 Position Statement on Hormone Therapy is the notion that there is no set time when hormone therapy must be discontinued. This is in stark contrast to earlier position statements where a 5-7 year timeline, depending on HT formulation, (estrogen and progestin versus estrogen alone) was suggested. As more studies emerged over the last decade, there has been greater clarification surrounding the safety of HT in different patient populations as well as with different HT formulations. These results led to the decision in the 2023 position statement to continue HT based on an assessment of the benefits weighed against the risks rather than an arbitrary timeline.

When considering the “benefits” of HT, the recommendations set forth by the NAMS position statements include effective treatment of hot flashes, urinary and vaginal symptoms, disease prevention in women with premature menopause, and prevention of osteoporosis.

Through the last decade, the collective data surrounding HT use for the prevention of cardiovascular disease and cognitive decline remain mixed and thus the collective data does not support the use of HT for the sole benefit of disease prevention in women entering peri-menopause/menopause at the typical age according to NAMS.

But what about the woman who initiates HT for hot flashes, as an example, within the first 10 years of menopause onset but wishes to continue HT once the hot flashes resolve? The long-term use of HT continues to be a “gray area” in the medical literature as research has evolved beyond the initial long-term randomized controlled trials (RCTs) of the 1990’s such as the Women’s Health Initiative (WIH) and the Heart and Estrogen / Progestin Replacement Study (HERS).

Today, we will review an article published in the (October 2023) issue of Menopause that is a valuable contribution to the literature speaking to some of the questions surrounding the long-term use of HT.

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Benefits for cardiovascular system, bone density, and quality of life of a long-term hormone therapy in hysterectomized women: a 20-year follow-up study

Maria Isabel Lorite, MD, PhD, Angela Maria Cuadros, MD, PhD, Mario Rivera-Izquierdo, MD, PhD, Victoria Sanchez-Martin, PhD, and Marta Cuadros, PhD from Granada, Spain.

Goal of the study

Analyze the effects of 20 years of transdermal estradiol HT in women after hysterectomy, with respect to the symptoms of menopause, blood pressure, lipid profiles, bone density and quality of life.

Study methods

• This was a prospective (forward-looking) observational, longitudinal study of women taking HT.

• Menopausal women who had undergone a hysterectomy (86% for non-cancerous causes and 14% for gynecologic cancers) were managed at the Menopause Medical Unit at Hospital Universitario San Cecilio in Grenada, Spain. Participants were recruited from September 1989 to May 1998 and followed for 20 years. All but 5 women had reached menopause prior to hysterectomy.

• All women were started on an initial transdermal estradiol dose of 0.05 mg/day which continued for 20 years. Once a participant reached age 60, the dose was cut in half.

• Only women who completed the 20-year follow-up, including changes in doses at 60 years of age, were included in the study.

• Clinical data included cardiovascular parameters such as body mass index (BMI), lipid parameters, and systolic and diastolic blood pressure. Bone health metrics included bone mineral density and incidence of fractures. Breast cancer assessment was achieved through mammography and/or sonography. Quality of life metrics including menopause onset, symptom intensity, and lifestyle factors were assessed with the Kupperman Index (A self-reported 11-question survey of menopausal symptoms).

Results

• 259 hysterectomized women were treated with HT. During the 20-year follow-up period, 203 discontinued HT, 95 of whom were due to “misinformation as the main reason”, according to the authors. Other causes of dropout included “age” (median age of 65), heart disease, high blood pressure, 4 diagnoses of breast cancer, and 1 case of stroke. 56 women remained in the study cohort.

• Quality of life: Menopausal symptoms as assessed by the Kupperman Index showed a significant reduction in symptoms/severity after 20 years of HT use as compared to before initiation of HT.

• Cardiovascular health: Average BMI increased from 29 to 31 over the course of the 20-year follow-up period. LDL levels decreased even in older women after halving the HT dosage. Total cholesterol, VLDL levels, and diastolic blood pressure were also significantly decreased.

• Bone health: Significant bone mineral density increases were seen at the t3 follow-up timepoint even after HT doses were reduced. There were no reported fractures. The authors note that this population had a higher BMI, which is known to be protective of bone mineral density.

• Breast cancer risk: 0.02% of women dropped out of the study due to a breast cancer diagnosis. Two women were diagnosed in the first 10 years of follow-up with an average age of 59.5 years and two additional women were diagnosed 14-18 years into the study with an average age of 64. Population-based statistics of breast cancer incidence in Granda, Spain would predict 3 women would develop breast cancer during that time period.

Author’s Discussion and Conclusions

• Cardiovascular risk and bone fractures decreased in the study cohort as defined by favorable trends in diastolic blood pressure, lipid, and bone density parameters, which persisted even after dosage decrease at age 60.

• There was no association with an increased risk of breast cancer as compared to breast cancer incidence predicted in the general population.

• The authors contend that this study provides new data showing a “clinical benefit of prolonged HT in postmenopausal women older than 60 years as a primary preventive therapy for cardiovascular and bone diseases”.

• This data suggests the beneficial effects of long-term transdermal estradiol HT when initiated close to the beginning of menopause and maintained after 6age 60 in women after hysterectomy.

In My Humble Opinion….

• This study, although small (56 women) follows an important array of clinical and quality-of-life parameters in women taking HT for 20 years, which is much longer than most observational studies.

• It is important to note that 203 of the initial 259 discontinued HT use and thus dropped out of the study. The majority of “drop-outs” were due to “age” and “misinformation”, according to the authors. Four cases were due to cardiovascular disease and high blood pressure, and another 4 due to a breast cancer diagnosis. The final analysis was on the 56 women who completed the 20 years of follow-up, effectively “selecting out” the participants who are arguably at the lowest risk for continuing HT. Had this study been done on an “intention to treat” basis (all participants recruited into the study were analyzed regardless of whether they completed the 20 years of treatment), these data may have looked very different.

• The authors profoundly overstate the implications of this study in their statement regarding the “clinical benefit of prolonged HT in postmenopausal women older than 60 years as a primary preventive therapy for cardiovascular and bone diseases”.

  First, this is a very small, observational study of hysterectomized women from a single clinic on estrogen-only HT. To make such a claim would require a much larger, multi-center, randomized control trial that includes estrogen and estrogen/progesterone HT and controls for the many confounders noted by the authors in their statement of the limitations of their study.

  Second, their narrow demographic of hysterecomized women from one center on estrogen alone limits the applicability to the general population of women taking HT.

• To be fair, the Nurse’s Health Study, which was a much larger but prospective longitudinal cohort of hysterectomized women starting after surgery or within 2 years of menopause onset saw similar results to this study with respect to the benefits for cardiovascular risk and bone health.

Clearly, there continues to be no clear consensus. However, this study is a valuable contribution to the literature despite its limitations with its thorough clinical follow-up over 20 years of HT use. The findings of this study are consistent with the NAMS 2023 Position Statement on Hormone Therapy in that it is appropriate and possibly beneficial to continue HT over longer durations if the benefits continue to outweigh the risks.

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Last week the Menopause Society - formerly known as the North American Menopause Society (NAMS) - wrapped up the 2023 Annual Meeting in Philadelphia, PA. This meeting was full of some great science and clinical pearls, hanging with my friend and Feisty colleague, Selene Yeager (check out her awesome blog post 8 Hot Takes from the Menopause Society 2023 Annual Meeting), and reconnecting with the city where my career began.

There was a lot of heavy science at this meeting, so my goal today is to try to make sense of it all and translate it into actionable measures for me, as a clinician, and for the women I care for.

Opening Symposium - Precision Oncology for Midlife Women

Precision Medicine is the most recent evolution in clinical practice. With the advances in genome analysis technology, clinicians have tools that can analyze genetic sequences and methylation patterns that regulate these sequences and provide a profile of an individual’s disease risk and metabolic patterns. These findings guide specific recommendations for prevention, training, and nutrition unique to that individual. My colleagues at Wild Health have been doing this for years and excel at it!

But Precision Medicine goes beyond genetic analysis. It refers to utilizing all the clinical tools available to assess a patient’s risk and craft holistic treatment plans specific to their circumstances and their goals. Here are some of the discussion points raised during this symposium:

• Cancer prevention: Use of gene analysis technology and hereditary cancer gene screening panels to identify those at high risk.

• Risk stratification: Traditionally, screening has been less effective for low-risk individuals with a higher incidence of false positive results leading to additional procedures, risk, and patient anxiety. Advances in knowledge about cancer risk factors and gene analysis technology that can identify those with hereditary risk factors can better identify higher-risk populations and thus make screening more effective for these individuals.

• Early diagnosis: Use of cell-free DNA found in the bloodstream, tumor biomarkers, advanced “radiomics” such as PET/MRI scanning, high-resolution mammography, and analysis of the data using artificial intelligence (AI) to help to fully characterize cancer and identify them early.

• Individualized treatment: Using these tools to characterize a cancer with greater detail and precision can help oncologists tailor treatments that are most effective for that specific type of tumor.

• Detection of residual disease post-treatment: Cell-free DNA and gene analysis technology allow for the detection of tumor DNA and circulating tumor cells (CTCs) in the blood stream. The presence of these cells and tumor DNA in the bloodstream are associated with disease recurrence and allows targeted therapy to be initiated before the disease recurs or metastasis (spread) to other organs.

These general concepts were reviewed for breast, ovarian, cervical, and colon cancer. Each has its own limitations and effectiveness of screening.

• Ovarian cancer: No effective screening test. Depends more on identifying patients at high risk and strategic surveillance or in some cases, prophylactic surgery.

• Cervical cancer: Pap smear cytology and HPV continue to be the mainstay of screening and are effective. Decisions for treatment depend on risk stratification: HPV subtypes, length of time with abnormal screening tests, smoking status, etc.

• Breast cancer: Traditional mammography has limitations in low-risk populations with variability relative to the radiologist reading the images, increased false positive rate resulting in additional procedures and patient anxiety. False negative results also occur particularly in women with increased breast density. As a result, researchers are focusing on risk stratification using traditional models, such as the Gail Model, as well as higher-resolution breast imaging and image analysis using AI to reduce the false positive and false negative rates of mammographic screening.

• Colon cancer: Again, risk stratification is a primary focus. For low to average-risk individuals, there is a trend toward using less invasive screening modalities such as Cologuard, fecal occult blood gFOBT or immunochemical tests (FIT) first, then proceeding to colonoscopy in the event of a positive test.

New Kid on the Block - Estetrol (E4) for Contraception and Relief of Menopausal Symptoms

Estetrol is a type of estrogen that is naturally occurring and exclusively produced by the human fetal liver and is only seen during pregnancy in adult life.

E4 is a NEST: Natural/Native Estrogen with Selective Action on Tissues, meaning that the action of the estrogen is different from one tissue to the next. E4 has a favorable effect on the vagina, endometrium, bone, and cardiovascular system. It has a neutral effect on the liver with little impact on triglycerides, blood clotting factors, and sex hormone binding globulin, unlike estradiol (E2)derivatives. E4 has anti-estrogenic effects on breast tissue inhibiting the stimulatory effects on breast tissue proliferation seen with E2 derivatives.

In 2021, the FDA approved Nextstellis, an effective, oral contraceptive pill that contains 3mg of drosperinone (synthetic progestin) and 14.2mg of Estetrol (E4) for 24 days of active pills and 4 days of inactive pills. This presents a favorable alternative to traditional estrogen/progestin oral contraceptive pills for those women who may have specific risk factors.

Studies are underway evaluating the safety and efficacy of E4 for the treatment of menopausal symptoms such as hot flashes and vaginal dryness in menopausal women. So far, results have been favorable, however, there is not yet an FDA-approved formulation for menopausal HT.

Both Estetrol (E4) and estradiol (E2) derived contraceptive pills carry a similar risk for venous thromboembolism (VTE) or deep venous blood clots at 3.6 events per 10,000 women-years.

Hormone Therapy on the Molecular Level - Selective Targeting of Estrogen Action on Cells and Tissues

The general theme of “precision” therapy continued with this lecture series on selective estrogen receptor modulators (SERMs) and tissue-selective estrogen complexes (TSECs)

What is a SERM? A SERM is a compound that has differing effects on estrogen receptors of different tissues. For example, Tamoxifen, a common medication used for breast cancer treatment stimulates estrogen receptors in the uterus but has the opposite effect on estrogen receptors in the breast.

• The development of SERMs with different tissue and receptor characteristics is at the forefront of breast cancer research. Another type of compound, SERD’s (selective estrogen receptor “degraders") are also showing promise for targeted breast cancer treatment.

What is a TSEC? A TSEC is a combination of a SERM and an estrogen that creates a tissue-selective molecular complex that affords protection of a given tissue by the SERM but also provides the power of symptom relief afforded by the estrogen.

• Duavee (conjugated estrogen 0.45mg / bazedoxifene 20mg) is an FDA-approved medication for the treatment of menopausal hot flashes. Unlike traditional hormone therapy, a progesterone is NOT needed in combination with estrogen in women who have a uterus. The SERM (bazedoxifene) affords protection to the endometrial lining while the estrogen provides relief for menopausal symptoms.

• Bazedoxifene alone and in combination with estrogens have also been studied with favorable effects on breast and vaginal tissue, bone, and lipid parameters in a series of well-done randomized trials. (Selective Estrogens, Menopause and Response to Therapy (SMART) Trials).

• Bazedoxifene and conjugated estrogens may also be effective in the treatment of endometriosis, a common disorder that causes pelvic pain and is associated with infertility. More study is needed in this area.

Bone Health

Again, precision therapy is the theme. Osteoporosis and associated fracture is a leading cause of morbidity and mortality in aged women. More attention is being paid to identifying risk factors and early detection of bone loss so that interventions can occur earlier before bone loss becomes severe and fracture risk is high.

• FRAX tool - considers lifestyle factors, medical history, and other parameters in addition to bone mineral density (BMD) assessed by DEXA scan to assess risk.

  • A score of >/= 20% risk of major osteoporotic fracture or >/= 3% risk of hip fracture is diagnostic of osteoporosis even in the absence of a DEXA scan T score of -2.5

• Vertebral (spine) imaging to assess a “trabecular bone score (TBS)” as a measure of bone microstructure which can be coupled with the DEXA scan to provide an “adjusted” T-score.

• High-resolution peripheral quantitative CT scan (HRpQCT): Another measure of bone architecture that is more predictive of fracture than DEXA, but is not FDA-approved or widely available.

Treatment of osteroporosis - The “Step therapy” (fail first) method involves starting with the least expensive, widely available anti-resorptive medications and considering anabolic treatments only after the anti-resorptive medications have failed is a one-size-fits-all approach that managed care companies love. But in reality, this is not supported by the current research.

• Care should be individualized and the woman’s life stage considered when prescribing treatment. For example, younger women whose bone turnover rates are still high (due to cycling estrogen) can benefit more from anti-resorptive medications (bisphosphonates like Fosamax) whereas older, menopausal women whose bone turnover is lower can benefit more from anabolic therapy (such as Forteo or Prolia).

Miscellaneous “Pearls”

Premature Menopause - Although there is no FDA-approved testosterone product for women, the expert consensus is that testosterone can be considered for women with premature menopause who suffer from hypoactive sexual desire disorder (HSDD) or “low-libido”.

The “Statins” story - Treatment of high cholesterol with statins may be beneficial for intermediate to high risk for experiencing a cardiovascuar event such as heart attack or stroke in the next 10 years. A helpful risk assessment tool is the 10 year ASCVD risk calculator : <5% is considered low risk, 5-20% is considered intermediate risk and >20% is high risk.

Review of the 2023 Non-Hormone Therapy Position Statement - This statement received a lot of attention when it was released earlier this year following the FDA-approval of Fezolinetant, a non-hormonal, first in class treatment for hot flashes. You can find a review of this position statement in the Athletic Aging Archived Medical Updates. There are two FDA-approved, prescription non-hormonal options that are effective for freducing hot flashes:

• Paroxetine salt 7.5mg once daily

• Fezolinetant 45mg once daily

Disinformation and Misinformation in menopause - We have all seen some crazy stuff circulating on social media, TV news, and other outlets and it’s sometimes enough to make one’s head explode. I applaud the Menopause Society for approaching this head-on, however, everyone who publishes on this topic - including the Menopause Society - should be held to account through the exchange of respectful and constructive dialog.

• Bring back the microphones. Participants can no longer directly ask a speaker questions following a presentation. All questions were entered via an app and then filtered and pre-selected by the session moderator. There were topics raised by various presenters that were overlooked by the moderator and deserved a respectful exchange between participant and speaker.

• Get the word out. The Societies, to their credit, realize the need to utilize social media and other resources to better to reach women and connect with them so that they can deliver their message with credibility.

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Cognitive health is front and center along with cardiovascular, bone, muscle and metabolic health in maintaining our vitality as we enter life’s second half. The use of MHT and its impact on cognitive health has been the subject of interest and debate for more than two decades with no definitive answers and conflicting results among even the most well-done studies.

Today’s post reviews the latest contribution to this debate. This Danish study by Nelsan Pourhadi et. al. aimed to address some of the gaps in the current literature surrounding MHT use and dementia risk.

The Women’s Health Initiative (WHI) Memory Study is a landmark randomized, double-blind placebo controlled trial reported that MHT was associated with an increased risk of dementia. However, the study population only included women age 65 and older. Most commonly, MHT is prescribed for younger women < age 60 within 10 years of menopause onset, so the WHI memory study could not speak to the younger population using MHT. Further, only MHT containing conjugated estrogens was studied where estradiol is more commonly used in current MHT regimens.

The authors cite other large observational studies that have reported a positive association between MHT use and dementia risk, however, some of these studies lack a full MHT exposure history. Another question that has been raised by these studies is whether progestin use in MHT regimens plays a role in dementia risk independent of the estrogen component.

The current study is another very large observational study utilizing the Denmark National Registry, which has complete patient demographic information, follows diagnoses, types of medical therapy used and documents duration of therapy use.

Menopausal hormone therapy and dementia: nationwide, nested case-control study

Nelsan Pourhadi, Lina S Morch, Ellen A Holm, Christian Torp-Pedersen, Amani Meaidi

British Medical Journal 2023:382;e072770 (Free Full Text)

Goal of the study

To assess the association between MHT use and risk of dementia according to the type of MHT, duration of use, and participant age.

Study Design

• Nationwide nested case-control study (observational study)

• Danish women age 50-60 years from the Denmark National Registry with no history of dementia or contraindications for MHT at the start of the study in 2000.

• 5589 cases of dementia were included with 55,890 age-matched women without dementia identified between 2000 -2018.

• Outcome measure: All-cause dementia defined by a first-time diagnosis or first-time use of a dementia-specific medication.

Results

• The use of MHT was associated with an increased rate of all-cause dementia.

• Increasing duration of use yielded higher hazard ratios for dementia from 1 - 12 years of use.

• This positive association was seen for continuous and cyclic regimens of MHT.

• Positive associations persisted in women who received treatment at age 55 and younger.

• Findings persisted when restricted to late-onset dementia and Alzheimer’s Disease

Author’s Conclusions

• MHT was positively associated with the development of all-cause dementia and Alzheimer’s Disease, even in women who received treatment age 55 and younger.

• Rates of dementia were similar between continuous and cyclic MHT regimens.

• More study is needed to determine if these findings represent an effect of MHT on dementia risk or rather an underlying predisposition in women who present for treatment with MHT.

Definitions:

Nested case-control study: A study design where a cohort (group) of participants or case records are selected based on a disease of interest and matched with cases without the disease. Within this group, the magnitude of the exposure of interest is analyzed in those with and without the disease of interest.

Contraindication: A circumstance that poses a significant health risk to the use of an intervention or therapy.

Hazard Ratio: A measure of how often an event (or disease) happens in one group (ex - MHT use) compared to how often it happens in another group (ex- no MHT use). A hazard ratio of 1.0 indicates no difference between groups.

Observational vs randomized studies: Observational studies look at groups of individuals based on specified characteristics (ie dementia diagnosis, use of MHT, etc.) of interest and either follow them prospectively (going forward) or retrospectively (past history). A randomized study selects participants with specific characteristics (age, symptoms, medical history) and randomly assigns the participants treatment versus no treatment and follows them forward.

In My Humble Opinion….

My first observation in analyzing this study is the inherent differences in the two study populations with and without dementia. Table 1 of baseline characteristics of the two groups was notable for a statistically significant higher rate of thyroid disease and diabetes in the group with dementia. Diabetes is a known risk factor for developing dementia. Other risk factors such as smoking and obesity were not characterized in these two groups at baseline. It is, therefore, unknown if there were significant differences in smoking habits and obesity between these two groups that could have biased the results.

Further, 40% and 46% of patients with dementia and without dementia, respectively, had achieved an education level of elementary school only. However, 42% and 50% percent, respectively, were in the highest household income range. This seems like an inconsistency in socioeconomic demographics.

These observations raise questions about the inherent differences and inconsistencies in the baseline characteristics of these two populations with and without dementia before even considering MHT use. These potential differences in confounding risk factors between these two groups and their impact on developing dementia may extend way beyond whether or not these women used or did not use MHT.

Another potential bias inherent to any observational study is user bias. Women who use MHT are typically doing so to alleviate symptoms (such as hot flashes). The question, therefore, is whether the physiology behind the symptom is a risk factor in and of itself for developing a particular disease - in this case, dementia. Multiple studies have shown a positive association between the duration and severity of hot flashes and cardiovascular disease risk. One must ask, then, whether the duration and severity of hot flashes may also correlate with dementia risk, especially since dementia is often a vascular phenomenon. This remains to be seen.

In randomized controlled trials, this user bias is controlled for by randomizing users of the placebo and treatment. A well-done randomized, double-blind, placebo-controlled trial that is appropriately statistically powered is the highest level of evidence that supports a cause-effect relationship between variables. Because observational studies are not subject to this level of control and randomization, they are therefore unable to prove cause-effect relationships . They only show associations.

To be fair, this study is still a viable contribution to the collective literature with its very large number of study cases, use of a national registry with complete treatment histories, clinically relevant study population, and a valid method of identifying dementia cases. Although their study does not support a cause-effect relationship between MHT use and dementia, the associations noted were likely not random, as evidenced by their statistical analysis. Despite the potential confounders, these findings are worth considering in the design of future studies.

So where does this leave us? The collective literature to date, along with the recommendations of the North American Menopause Society (NAMS) as well as the British Medical Society and the Royal College supports the safety and efficacy of MHT use in women < age 60 within 10 years of menopause onset for appropriate indications (treatment of hot flashes, prevention of osteoporosis, genitourinary syndrome of menopause (GSM)) and that a reduction in all-cause mortality is seen in these individuals.

The collective body of evidence over the decades suggests, however, that there is not enough definitive evidence to support MHT use for general disease prevention as there are real risks in some populations. What is needed is to better define these populations with respect to disease processes, lifestyle habits, or other circumstances that pose the greatest risk and conversely, relay the greatest benefit. What we have seen since the original NAMS position statements on Hormone Therapy from 2010 to the most recent statement in 2022 is indeed more clarity surrounding the patient populations and conditions for which the benefits of MHT outweigh the risks and this research is continuing.

Additionally, the era of Precision Medicine is upon us which looks to our DNA for these clues. A recent study in Alzheimer’s Research & Therapy reviewed here in Athletic Aging was the first of its kind to look at the APOE allele genotype and its association with cognitive health in MHT users and non-users.

No study is ever perfect. But it’s important to take the “nuggets” of these studies with their strengths and weaknesses and keep them as puzzle pieces that will, with time, create a clearer picture of these very important issues (and inevitably, raise more questions!). Until next time! Thanks for reading!

My Friends...
Here it is! ... hot off the press from the North American Menopause Society (NAMS): The 2023 Position Statement on nonhormonal therapy. As we would expect, NAMS presents a thorough review of current and past literature. But the messaging behind the recommendations is a real head-scratcher. 
See what you think! 
-Carla 

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Hot Flashes and night sweats (a.k.a vasomotor symptoms (VMS)) are the most common symptoms women experience during the menopause transition and after menopause onset. They can range in severity from mild to outright debilitating, resulting in lost sleep which can lead to poor recovery, mood lability, poor health, and quality of life. VMS can last on average, 7-9 years, and in one-third of women, last more than 10 years.

Hormone therapy (HT) typically encompasses estrogen alone or estrogen plus progestogen as the mainstay of pharmacologic treatment with a long history of high-quality studies supporting its safety and efficacy for VMS. However, the debate about the safety of HT has been raging since the Women’s Health Initiative (WHI) discontinued the Estrogen/Progestin arm of their study due to a statistically greater incidence of breast cancer compared to the placebo and estrogen-only arms of the study back in 2002. Following the release of this data, HT use by women and prescriptions from healthcare providers have declined precipitously leaving many women untreated for their debilitating symptoms for fear of the risk of breast cancer. In the last 30 years, more study has emerged that has revealed the safety of HT for treating VMS in women <60 and within 10 years of menopause and even beyond in low-risk patients. However, apprehension still remains and many women prefer non-hormonal alternatives to treating their menopausal symptoms and some women have medical conditions where HT is not a safe or viable option.

NAMS recognizes the demand for non-hormonal treatment options for VMS and created its first position statement specifically addressing nonhormonal therapy for VMS in 2015. This year, NAMS published an update to the 2015 statement which was published in the June 2023 issue of Menopause.

Although I generally applaud NAMS for their rigorous and objective review of the vast body of literature surrounding menopause health, the messaging behind these two position statements on nonhormonal therapy does not do justice for the holistic and integrated approach required for effective menopause care. Further, the recommendations in these two statements are in direct conflict with their own patient information publication, MenoNotes on Hot Flashes, which was published at the same time as the original Position Statement on nonhormonal therapy published in 2015.

Below is a summary of the key points from the 2015 and 2023 Position Statements and my personal analysis to follow.

Definitions

Level I evidence: Good quality, randomized controlled trial (RCT)

Level II evidence: Moderate or poor RCT, good quality cohort study

Level III evidence: Moderate or poor quality cohort study, Case-control study

Level IV evidence: Case series

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The 2023 nonhormone therapy position statement of The North American Menopause Society

Menopause. Volume 30 No. 6 pp 573-590

Both the 2015 and 2023 Statements break down their analysis of the literature into categories of nonhormonal therapy to include lifestyle modifications, mind-body techniques, nonhormonal pharmacologic treatment, and dietary supplements.

NAMS on nonhormonal prescription therapies

• Anti-depressant medications - Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are two classes of commonly used anti-depressant medications that have also shown benefits for reducing VMS. Paroxetine salt is the only anti-depressant that is FDA-approved for the treatment of VMS, however, other medications in this class including escitalopram, citalopram, venlafaxine, and desvenlafaxine that have all been shown to significantly reduce VMS in large, double-blinded RCTs.

  • Conclusion: Anti-depressant medications in the SSRI and SNRI classes are an effective treatment for VMS. Level I evidence; Recommend.

• Gabapentiniods. Gabapentin is FDA-approved as an anti-epileptic drug that is commonly used to treat diabetic neuropathy and post-herpetic nerve pain. However, several trials have shown that 300mg three times daily can improve the frequency and severity of VMS. Adverse events at this dose include dizziness, headache, and disorientation, which can limit its utility. Gabapentin is often prescribed at night if there is also difficulty with sleep.

  • Conclusion: Gabapentin at doses of 900mg - 2400mg daily can be an effective treatment for VMS, although caution should be used due to side effects at these doses. Level I evidence; Recommend.

• Neurokinin B antagonists. Fezolinetant is a new therapy that was FDA-approved in May 2023 as a nonhormonal treatment for VMS. Its mechanism of action targets nerve pathways in the hypothalamus of the brain (a.k.a the “thermostat”) thus acting directly on the neural mechanisms underlying VMS. Phase 3 trials report headache as the most common side effect and rarely, elevation of liver enzymes. The effect of neurokinin B antagonists on other symptoms that commonly occur with VMS remains to be studied.

  • Conclusion: Fezolinetant is a first-in-class neurokinin B antagonist that is FDA approved for the management of VMS. Level I evidence; Recommend.

NAMS on dietary supplements

Assessing dietary supplements pertaining to the management of VMS is challenging because dietary supplements are unregulated and thus not standardized with respect to purity and safety. Further, there is limited, rigorous RCT data studying the effects of these supplements for the management of VMS.

• Conclusion: Of the dietary supplements reviewed in the position statement, none are recommended for the treatment of VMS with Level I-III evidence.

Below is a partial list of the most commonly used supplements that were reviewed in the Position Statement

• Soy foods and extracts

• Equol (soy metabolite)

• Black Cohosh

• Wild Yam

• Don Quai

• Evening Primrose

• Maca

• Ginseng

• Chasteberry

• Milk thistle

• Omega-3 fatty acid

• Vitamin E

• Cannabinoids

NAMS on mind-body techniques

• Cognitive behavioral therapy (CBT). CBT includes psychoeducation (physiology of VMS), training in relaxation and paced breathing techniques, and cognitive behavioral strategies to manage VMS. CBT has been shown to reduce the degree to which VMS is rated as a problem. Evidence of this began to emerge a decade ago with two randomized control trials (RCTs) in cancer survivors and subsequent follow-up studies extended the benefits to other populations.

  • Conclusion: The body of literature as a whole supports that CBT alleviates bothersome VMS for both survivors of breast cancer and menopausal women (Level I evidence; Recommended)

• Clinical hypnosis. Clinical hypnosis is a mind-body therapy that involves a deeply relaxed state and individualized mental imagery and suggestion. It has been widely used to manage pain and anxiety. The application of hypnosis to VMS has been studied in two RCTs involving breast cancer survivors. In both trials, 5 weekly, in-person sessions were compared to at-home self-hypnosis. These two studies and another involving 60 breast cancer survivors showed improvement in VMS as compared to no treatment.

  • Conclusion: Clinical hypnosis was better at reducing VMS and improving mood and sleep than no treatment. (Level I evidence; Recommended)

• Relaxation and Paced Respiration. Paced respiration was shown to be beneficial for reducing VMS in several small studies, however, in larger studies including a randomized trial involving 200 women, no benefit was found. There is limited and inconsistent evidence that relaxation techniques improve VMS.

  • Conclusion: Paced respiration and relaxation techniques did not show significant benefits for improving VMS. (Level I-II evidence; Not Recommended.)

NAMS on lifestyle modification

• Cooling techniques. These techniques include dressing in layers, breathable clothing, adjusting room temperature, and cooling aids such as fans, cold packs, and cooling mattresses. One small uncontrolled trial showed the benefit of using a forehead-cooling device and sleep hygiene instruction. In another 4-week randomized study of night-time comfort interventions, no improvements were seen in VMS, however, there were some self-reported improvements in sleep.

  • Conclusion: Cooling interventions must be tested in larger, randomized-placebo-sham controlled trials. Level II evidence; Not recommended.

• Avoiding triggers. VMS are sometimes reported by women to be associated with things like alcohol, stress, and spicy foods among other elements or circumstances. One study of more than 4500 Chinese women found a positive association between alcohol intake and VMS, however, this finding has not been reported in other studies.

  • Conclusion: There are no clinical trials assessing the effects of avoiding triggers for the relief of VMS. Level II evidence; Not recommended.

• Exercise and yoga. Observational studies report that women who exercise regularly report fewer VMS. Others have found no relationship and in some cases, exercise can be a trigger for VMS. Several Cochrane reviews have concluded that there is insufficient or poor evidence to consider exercise as a treatment for VMS. A systemic review of 12 randomized trials comparing yoga to no intervention, health education, exercise, and acupressure was difficult to interpret due to limitations of the study design. Yoga had limited benefits compared with exercise for the treatment of VMS and there was no benefit compared with no treatment.

  • Conclusion: Although there are other health benefits associated with exercise or yoga, the evidence supporting those interventions for the treatment of VMS is sparse. Level II evidence; Not recommended.

• Weight loss. Studies have found that women who struggle with obesity are more likely to report more frequent and severe hot flashes than women of normal weight. Randomized trials have found that weight loss from behavioral interventions is associated with a decrease in VMS. Evidence suggests that the role of adiposity and weight loss in VMS may vary depending on age or menopausal stage.

  • Conclusion: The limited available evidence suggests that weight loss may be used to improve VMS in some women. Level II-III evidence; Recommended.

In my humble opinion…..

The brilliant minds at NAMS have always been a reliable source of objective and thorough literature review to help guide clinical decision-making. The 2023 Position Statement on nonhormonal therapy for VMS is no different. However, what is sorely lacking in this statement is a perspective that applies these research findings in a common sense way to the holistic approach that is needed to manage not just VMS, but the menopausal woman as a whole person.

When I see menopausal patients, it is rare that they are seeking care for a single symptom. Invariably - even if VMS is the main complaint - there is a constellation of physical experiences that she is concerned about as well as her overall concern for her general health that are typically addressed at any client visit. Although the statement presented a methodical review of the literature speaking to the specific question of what nonhormonal means were effective for treating VMS, the messaging surrounding the recommendations was as if nothing else about the whole patient mattered except the VMS.

The best example of this is the recommendation against physical exercise and dietary modification (not specifically discussed here) as treatments for hot flashes. This is interesting because weight loss was seen, in this statement, as potentially beneficial for improving VMS. It is well-accepted that dietary modification and physical exercise are the cornerstones of effective weight loss strategies. Given that more than 50% of menopausal women in the US are overweight, how do recommendations against dietary modification and physical exercise make sense in the holistic approach to symptom management and overall health? My friend, professional writer, and esteemed host of the Hit Play Not Pause podcast, Selene Yeager, nailed this and other excellent points in her recent blog, NAMS Releases 2023 Position Statement on Nonhormone Therapies.

The other head-scratchers are the recommendations against, yoga, paced breathing, and cooling techniques as a way to manage VMS. At first glance, the question is what is the harm in trying these techniques? The 2015 Position Statement speaks to this question and states “Some therapies appear risk-free but do not have any evidence testing their effects on VMS and their use may lead to delay in receipt of more appropriate and efficacious treatment. These include cooling techniques and avoidance of triggers.”

Although there may be some logic behind this argument, NAMS's own MenoNotes patient information sheet entitled Treating Hot Flashes published the same year as the 2015 statement specifically recommends these same techniques that are not recommended in the 2015 and 2023 nonhormonal therapy Position Statements.

Although it seems like AI published this statement before the Humans had a chance to message it properly, let’s not throw the baby out with the bathwater. The data summary and background review are excellent and serve as useful foundational elements upon which patients and providers can apply these studies to their individual clients’ personal situations in a holistic, common-sense way. It is also a firm reminder that providers and patients alike need to approach these and any recommendations from even the most esteemed sources with a critical eye and not just take them at face value.

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The debate surrounding the risk of breast cancer and the use of menopausal hormone therapy (MHT) has been raging since 2002 when the combined estrogen (Conjugated Equine Estrogen (CEE))/progestin (Medroxyprogesterone Acetate (MPA)) arm of the Women’s Health Initiative (WHI) randomized controlled trial was terminated due to a statistically significant increase in the risk of breast cancer in the participants randomized to this arm of the study compared to the placebo group. This led to a media frenzy resulting in a sharp decline in prescriptions for MHT due to provider concerns over breast cancer risk as well as fear of the same in menopausal women experiencing symptoms.

Through the years, there has been rigorous follow-up study of these risks with increasing reassurance that the benefits of HT for treating menopausal symptoms in early menopause outweigh the risks of breast cancer, thromboembolism, and gallbladder disease. However, debate continues over the interpretation of the original WHI and subsequent follow-up studies with varying conclusions and perspectives.

The following article published in the April 2023 issue of Menopause presents the discordance between the results of the WHI randomized trials and other cohort studies describing the relationship between MHT and breast cancer. The authors also provide a rebuttal to many of the challenges to the original findings and interpretation of the WHI research.

Below is a summary of the article including highlights of the debate points presented. *Of note, the authors disclose that the entities that provide support for the WHI also partially supported their article. My personal opinion, commentary, and analysis follow the summary.

Definitions

Cohort study: Observational study of a group of individuals that share certain characteristics who have had a common “exposure” (in this case, MHT) and followed over a period of time.

Randomized controlled trial: A scientific study where participants are selected based on specific criteria/characteristics and then randomized and assigned to a “control” group (receives a “placebo” treatment) and an “experimental” group (receives the therapy of interest). These studies are designed to study cause-effect relationships between therapies and outcomes.

Progestogen: A term that refers to any natural progesterone or synthetic derivative of progesterone found in MHT formulations.

The Women’s Health Initiative randomized trials of menopausal hormone therapy and breast cancer: findings in context

Rowan T Chelbowski and Aaron K Aragaki. Menopause Vol 30 No 4 2023.

Goal of the study

Summarize the findings for the impact of MHT on breast cancer from cohort studies and the WHI randomized trials and address concerns raised regarding the WHI findings.

Study methods

The author’s referred to 2 analyses in their review of findings from cohort studies:

1. Collaborative Group on Hormonal Factors in Breast Cancer meta-analysis: 52,000 with and 108,000 women without breast cancer beginning in 1997 and updated in 2019.

2. Million Women Study: 1,084,110 post-menopausal women age 50-64, with 9,364 breast cancer cases beginning in 2003 and updated in 2019.

The Authors identified commentaries and editorials from the journals Menopause and Climacteric from 2002 to the present. A total of 30 commentaries challenged the conclusions of the WHI.

Highlights of the Discussion Points

The authors summarized the findings from the Collaborative Group and the Million Women Study and compared the findings to those of the WHI randomized trials.

• The Collaborative Group and Million Women Study report a statistically significant increase in breast cancer incidence in women taking combined estrogen/progestin MHT and MHT containing only estrogen.

• The WHI randomized trials reported a decrease in breast cancer incidence in the group taking MHT containing only estrogen.

• Findings from the WHI randomized trials and the findings from the Collaborative Group and Million Women study revealed an increased incidence of breast cancer in women taking MHT containing estrogen and a progestogen.

The authors address multiple challenges to the findings of the WHI randomized trials raised in the 30 editorials and commentaries they reviewed as part of their analysis. Below are excerpts addressing some of the more common arguments.

Challenge. The decrease in breast cancer incidence in the estrogen (CEE)-only group of the WHI randomized trial could be simply due to chance.

• Authors’ rebuttal: The lower breast cancer incidence seen with estrogen (CEE) alone was seen across all decades; 50s, 60s, and 70s in more than 10,000 randomized participants with the placebo and MHT groups having comparable baseline risk as defined by the Gail-5 year breast cancer risk tool. Given the robust size, the randomized structure of the study, and comparable baseline risk, these findings are unlikely due to chance.

Challenge: The increased incidence of breast cancer in the CEE + MPA group in women with prior hormone use was based on a lower breast cancer incidence among former hormone users in the placebo group rather than an increased incidence in the CEE + MPA group.

• Authors’ rebuttal: After long-term follow-up (20 years) there does not appear to be any significant difference in breast cancer incidence comparing prior hormone users to never-users taking estrogen/progestogen MHT.

Challenge: The WHI findings are not relevant for current practice because different types of progestogens may carry different risks for cancer outcomes.

• Authors’ Rebuttal: Micronized progesterone has been associated with lower breast cancer risk in some but not all observational studies. The Million Women study reported an “increased risk of breast cancer risk with estrogen plus progestin MHT use.” The study further states that “results varied little between different types of estrogen and progestogen”.

Challenge: Breast cancer risk with estrogen and progestin use is low.

• Rebuttal: The authors cite studies that reported a rapid and sustained reduction in age-adjusted breast cancer seen in the United States that followed the decrease in MHT use. A modeling study of this trend estimates that 126,000 fewer breast cancers occurred between 2002 and 2012 had the WHI trial results not been available. The authors cite another modeling study performed by Santen et al. that calculated attributable 5-year breast cancer incidence risk from the Collaborative Group findings in low, intermediate, and high-risk groups of women at 1.5%, 3.0%, and 6.0% baseline risk, respectively. Their findings report 12, 42, and 85 additional cases of breast cancer per 1000 women per year in the low, medium, and high-risk groups, respectively. “Against this background, individual women can decide whether such risks are “rare””.

Authors’ Conclusions

• The WHI randomized trials evaluating MHT provide reliable evidence regarding CEE alone and CEE + MPA influence on breast cancer incidence and breast cancer mortality.

• The North American Menopause Society (NAMS) 2022 position statement supports the distinction in breast cancer risk in women taking HT containing only estrogen as compared to combined estrogen / progestogen MHT.

• “For younger women with prior hysterectomy, besides the reduction in breast cancer incidence, and breast cancer mortality, it can be reassuring that in the WHI trial, there was a nominal decrease in all-cause mortality.” The authors further state that the same reduction in all-cause mortality was not seen in the combined CEE + MPA group of the WHI trial.

In My Humble Opinion….

The premise for this article is certainly warranted given the impact that the interpretation of the initial findings of the WHI trial had on the practice of menopausal medicine for the decades that followed and that continue today.

What stood out to me the most about this article was the Authors’ rebuttal to the challenge that breast cancer risk with estrogen and progestogen use is low. The Authors cite modeling studies that put forth numbers of excess breast cancer cases in estrogen/progestogen users literally orders of magnitude greater than what was reported in the WHI, which is the very study they are trying to defend. The WHI reported 8-10 additional cases per 10,000 women in the CEE + MPA users relative to the control group. The modeling studies cited by the authors suggest between 12-85 additional breast cancer cases per 1000 women using combined MHT, which is more than 10-fold higher than the risk suggested by the WHI findings.

It’s critically important to note that modeling studies are not randomized controlled trials and do not carry the same validity. Modeling studies are not studies of actual individuals but rather mathematical and statistical models based on findings from other studies and should be considered only at face value. These studies provide support more for the Authors’ sentiment about the level of risk associated with combined MHT rather than supporting the actual data in the WHI trial. However, in fairness, the observed reduction in breast cancer cases seen following the decrease in the MHT prescribing patterns should not be ignored.

Another point that is important to speak to is the Authors' statement that the WHI data did not see a decrease in all-cause mortality in women using CEE + MPA. Although this may be true of the study they cite, this contradicts the statement in the NAMS 2022 Position Statement on Hormone Therapy which states that in women < age 60 and <10 years from menopause taking combined estrogen/progestogen HT for appropriate indications, a reduction in all-cause mortality has, in fact, been observed for both combined estrogen/progestogen HT and HT containing only estrogen.

Where does this leave us?

In my opinion, the recommendations outlined in the NAMS 2022 Position statement as well as the combined statement from the British Menopause Society and the Royal College represent the most objective, evidence-based analysis of the safety and efficacy of MHT based on decades of study that was built upon the foundation of several well-done studies including the WHI randomized trials as well as the cohort studies of the Collaborative Group and the Million Women Study. Some of the points in the NAMS 2022 position statement that have stood the test of time are as follows:

• Benefits outweigh the risks of estrogen/progestogen MHT in healthy women <10 years since menopause onset, <60 years old taking MHT for appropriate indications. A decrease in all-cause mortality has been observed in these women taking combined estrogen/progestogen as well as estrogen-only MHT.

• Data does not support the general use of MHT for the sole purpose of disease prevention as risks often outweigh potential benefits.

• Choosing MHT requires an individualized, risk/benefit analysis for each woman’s specific situation. There should be no arbitrary limits on the duration of MHT use.

How this affects my personal practice

For every woman I see for menopausal care, the approach is highly individualized taking into account risks, benefits, and her personal goals for care. The foundation of my care begins with fitness, nutrition, appropriate supplementation, and lifestyle factors with the use of pharmacology when indicated.

Truth be told, in my opinion, I do not think the breast cancer risk is as low as the initial WHI suggests. I also take the thromboembolism (blood clot) risk very seriously, as this risk underlies cardiac events, stroke and dementia. But regardless of what the actual “numerical” risks are in the published literature, what is most important and has stood the test of time is that the benefits outweigh the risks in younger menopausal women and I have no hesitation in prescribing HT for these women with no set limits on duration.

For other women where it may not be so straightforward, the risk/benefit equation carries the day, taking into account her symptoms, the effectiveness of HT in resolving those symptoms, risks for fracture, and other components of her medical history.

My first line is bioidentical FDA-approved estrogen and progesterone and generally prefer the transdermal (skin patch) route for estrogen. For all women, I strongly recommend a mammogram prior to the start of HT and annually while taking HT.

They way forward

This debate is far from over, and with time, new questions will emerge. I applaud the task forces created by NAMS who have done an excellent job of objectively assessing the original literature and the follow-up studies that are the basis for their recommendations. The trends in the NAMS Position Statements over more than a decade have demonstrated increased reassurance of the safety of MHT in younger women, older women at low risk, and even women with genetic predispositions for heritable breast cancer without a personal history of cancer. So with every new article that emerges, the approach is the same. Give it credence, but always put it in the context of the “bigger picture”.

References

Ravdin PM et al. The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med 2007;356:1670-1674.

Hersh AL et al. National use of postmenopausal hormone therapy: annual trends and response to recent evidence. JAMA 2004;291:47-53.

Roth JA et al. Economic return from the Women’s Health Initiative estrogen plus progestin clinical trial: a modeling study. Ann Intern Med 2014;160:594-602.

Reference Santen RJ et al. Underlying breast cancer risk and menopausal hormone therapy. J Cln Endocrinol Metab 2020 (105) 105.

My Friends!
I'm very excited about this post today because it speaks to the incredibly important issue of cognitive function and Alzheimer's Disease risk and how hormone therapy (HT) fits into this equation. 
Enjoy!
-Carla DiGirolamo, MD

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The question of how hormone therapy (HT) impacts cognition has been a subject of intense debate with conflicting results in the medical literature.

A recent open-access article was published in January 2023 by RNM Saleh et al from Norwich Medical School in the UK entitled 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. Their findings make a valuable contribution to this debate.

Today’s post will summarize this study and include the official response from the North American Menopause Society (NAMS) as well as my own commentary.

____________________________________________________________________________________

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

Rasha N. M. Saleh, Michael Hornberger, Craig W. Ritchie, and Anne Marie Minihane

Alzheimer’s Research & Therapy (2023) 15:10

Goal of the Study

Investigate the role of APOE gene variant carrier status and age at HT initiation in the cognitive response to HT.

Background

• More than 2/3 of Alzheimer’s Disease (AD) patients are women and the hormonal changes of the menopause transition are emerging as a potential contributing factor.

• The APOE gene codes for the production of a special protein that combines with fat creating a lipoprotein. Lipoproteins aid in the transport of cholesterol throughout the body.

• A variant of the APOE gene called APOE4 has been associated with an increased risk of AD and cognitive decline. The risk of cognitive decline / AD has been reported to be greater in women who possess the APOE4 variant as compared to men with this same variant.

• The results of studies investigating the impact of HT on cognitive decline and AD risk have been mixed. However, there are trends suggesting that there may be a “window” of time during the menopause transition / early menopause where HT use may benefit cognitive function. Likewise, potentially harmful effects on cognitive function have been seen in women initiating HT later in menopause and at an older age. More investigation into these observations is needed.

Study Methods

• Data analysis of participants in the European Prevention of Alzheimer’s Dementia (EPAD) cohort.

• Participants: 1,906 of whom 1,178 (61%) were women.

• Statistical modeling (ANCOVA test) was used to test the independent and interactive impact of the APOE gene variants and HT on various cognitive performance tests and brain MRI findings.

• Additional statistical modeling (Multiple Linear Regression) was used to examine the impact of age of HT initiation in women possessing the APOE4 variant on cognitive testing and MRI findings.

Results

• Women possessing the APOE4 variant who were HT users had significantly higher memory scores (RBANS delayed memory index) compared with non-APOE4 carriers and non-users of HT.

• APOE4 / HT users also had greater maintenance of tissue volume in areas of the brain responsible for memory and cognition by MRI.

• Initiation of HT at a younger age was associated with greater maintenance of tissue volume in the memory/cognition areas of the brain in APOE4 carriers ONLY. This difference was not seen in APOE4 non-carriers.

Author’s Conclusions

• HT use is associated with improved memory scores and maintenance of tissue volume in areas of the brain responsible for memory and cognition in women who possess the APOE4 gene variant. This effect is not seen in women who do not carry the APOE4 variant.

• The presence of the APOE4 variant and the age of HT initiation are important modulators of the effect of HT on cognition. Consideration of these two factors may be an effective, targeted strategy to mitigate AD risk in this at-risk population of APOE4 variant carriers.

Study Limitations

• This study was a cross-sectional analysis that reveals associations among variables. This type of study cannot prove a cause-effect relationship.

• The small sample size of the APOE4 /HT user group did not allow stratification by type and dose of HT used (ie estrogen alone, estrogen plus progesterone, specific formulation, etc.).

NAMS Response

Because HT and cognition have been the subject of intense study with conflicting results, NAMS released an official commentary on the findings of this study and its significance within the existing medical literature. The main points of their response are below:

• The reviewers note that the APOE4 carrier/HT user population is small (29-31 participants).

• The average age of this patient group was 65 years. 91% were continuing the use of HT.

• The authors effectively demonstrated improved memory function using objective measures in APOE4 carrier HT users. They further demonstrate greater tissue volume in areas of the brain responsible for memory and cognition, particularly if HT was started at an earlier age.

• A causal relationship cannot be established in this type of study (cross-sectional). “Healthy user bias” is also a concern in observational studies where participants have chosen to use HT as compared to a study where the use of HT is randomized.

• So far, cognitive effects have not been demonstrated in two large randomized trials: the Early Versus Late Intervention Trial with Estradiol (ELITE) and the Kronos Early Estrogen Prevention Study (KEEPS).

• The APOE4 carrier status appears to be associated with an increased risk of AD and appears to be an important modifier of HT effects on the brain. An understanding of who is at risk for AD because of menopause-related factors needs further investigation. This study provides further evidence that APOE4 carrier status is an important factor.

In my humble opinion….

This study is an important contribution to the literature and provides a direction for further study. However, we must be cautious because there are studies that have shown harmful cognitive effects of HT in the same age group as the small number of APOE4 HT users in this study.

The author’s points are well-taken with respect to the “window” of therapeutic benefit for HT use. This has been a pattern seen in the study of the favorable effects of HT on cardiovascular disease risk and all-cause mortality in HT users within 10 years of menopause younger than 60 years old.

Although no cognitive effects have been observed thus far in the ELITE and KEEPS trials, these studies are not designed to stratify based on APOE4 carrier status. If the relationship between APOE4 and AD risk is significant as the literature currently suggests, the benefit for this population may not be appreciated in these larger trials designed to evaluate the effect of HT use in the general population.

All in all, this is great stuff! The area of personalized medicine and risk assessment based on genetics is growing rapidly. My colleagues at Wild Health are among the pioneers in this area and APOE genetic carrier status is part of their comprehensive genetic analysis. I have worked closely with the Wild Health physicians and coaches and they are top-notch!

Dear Friends! 
Welcome to Part 2 of our series on sleep! In Part 1, I shared my personal sleep solution for the 3am wake-up call in My Sleep Secrets Revealed. Today, Part 2 reviews a recent article published in the journal "Menopause" that focuses on the efficacy of behavioral interventions for improving sleep for those who prefer to minimize their use of pharmacology. 
Enjoy!
-Carla

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Sleep disturbance affects 40-48% of perimenopausal and menopausal women and increases throughout the menopausal transition. Difficulty sleeping is strongly associated with vasomotor symptoms and increased emotional and physical impairment, and can severely affect quality of life.

Common behavioral therapies for insomnia include exercise, cognitive behavioral therapy (CBT-I), sleep restriction therapy (SRT), stimulus control therapy, sleep hygiene, and relaxation/mindfulness techniques. These interventions are thought to work through the alteration of dysfunctional beliefs about sleep, adjustment of behaviors that contribute to poor sleep, and attenuation of arousal of the central nervous system.

The American College of Physicians recommends CBT-I as first-line treatment for adults with insomnia, however, studies report that practitioners still rely heavily on pharmacologic therapy. In fact, prescriptions for non-benzodiazepine sedative-hypnotics such as Ambien and Lunesta have increased 30-fold from 1994-2007. Side effects of these medications can include dizziness, lightheadedness, confusion, double vision, and memory impairment, as well as nausea, ataxia (loss of control of bodily movements), slurred speech, slow reflexes, loss of balance and coordination, and vertigo.

Christine M Lam and her colleagues at McMaster University in Ontario, Canada investigated the efficacy of behavioral interventions for sleep disturbance in menopausal women. This work was published in the October 2022 issue of the journal Menopause and is summarized below with my editorial comments to follow.

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Behavioral interventions for improving sleep outcomes in menopausal women: a systematic review and meta-analysis

Christine M Lam, Letician Hernandez-Galan, Lawrence Mbuagbaw, et al.

Menopause: The Journal of the North American Menopause Society 2022 Vol 29, No. 10, pp 1210-1221.

Goal of the study

• Assess the efficacy of behavioral interventions on sleep outcome among perimenopausal and menopausal women.

• Evaluate the safety of behavioral interventions through the incidence of adverse events.

Type of study

• Review and meta-analysis of the published literature evaluating the effects of behavioral interventions on objective and subjective measures of sleep quality using validated questionnaires and indices: polysomnography (PSG) or the Pittsburgh Sleep Quality Index (PSQI)

• 19 articles reporting results from 16 randomized controlled studies (RCTs) representing a total of 2,108 perimenopausal and menopausal women.

• Selected studies evaluated the effects of exercise, mindfulness/relaxation, CBT-I, and SRT on sleep outcomes. Exercise programs included yoga, pilates, moderate-intensity aerobic exercise, and walking.

Results

• Data from 19 articles including 16 RCTs were pooled and statistically analyzed showing that behavioral interventions were associated with a significant improvement in sleep outcomes.

• Analysis comparing the effects of the intervention subtypes found that CBT-I, exercise, and mindfulness/relaxation were associated with statistically significant improvement in sleep outcomes.

• When menopausal women were analyzed separately, behavioral intervention continued to show a statistically significant improvement in sleep outcomes.

• Nine studies measured adverse events. Six reported no adverse events. All study-related adverse events reported were not significantly different from their respective control groups. Reported events included muscle aches, low back pain, changes in strength/sensation in the limbs, and modification of exercise due to a pre-existing condition.

• Risk of bias: 18 of the 19 studies were judged to be at high risk for bias in at least 1 domain - most often “outcome measurement” due to the fact that self-reported surveys were used, and, thus the study subjects could not be blinded.

• Certainty of evidence was evaluated as very low quality due to the risk of bias as noted above, inconsistency, and publication bias.

Author’s Discussion and Conclusions

• CBT-I, physical exercise, and mindfulness/relaxation therapy show promise in improving sleep outcomes in perimenopausal and menopausal women.

• These interventions may be considered safe as no serious adverse events were reported.

• Barriers to CBT-I can include limited access to qualified providers, and time and transportation constraints. More study is needed on alternative delivery methods for CBT-I.

• Study limitations included the heterogeneity within study designs due to the non-standardized nature of behavioral interventions and the use of multiple different sleep scales among the selected studies.

***To learn more about CBT-I, check out this link to resources from the Mayo Clinic!

In my Humble Opinion…..

This study is valuable because it illustrates the effectiveness of an alternative to prescribed medications that can potentially have side effects worse than insomnia itself - such as daytime somnolence (which compounds the already apparent brain fog that mid-life women often experience), slow reflexes (which is NOT good if you are an athlete) and impaired coordination and balance which can lead to falls and potentially fractures.

Just like anything else, interventions that require some investment of time and engagement potentially yield greater long-term results. However, these are certainly not as easy or attractive as a pill that you just need to swallow.

I’m certainly not against medication - I’m an allopathic physician. I write hundreds of prescriptions every year. But if we use a variety of sleep strategies and engage in good health practices as our foundation, this may be enough to manage our symptoms. But if we do need to use medication, they will work a whole heck of a lot better on a foundation of lifestyle modifications and healthy habits than they will by themselves.

As the medical and fitness communities learn more about the physiology of the changes during the menopause transition, resistance training is a subject that is gaining much attention!

This Systematic Review was performed by a team in Brazil and published in the journal Menopause ahead of print in October 2022. This study reviews the current literature investigating the “benefits and harms” of resistance training in menopausal women.

A summary of the findings of this study are below with my editorial commentary to follow.

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Resistance training for post-menopausal women: systematic review and meta-analysis

Martins Sa KM, Resende da Silva G, Martins UK, Colovati MES, Crizol GR, Riera R, Pacheco RL, Martimbianco ALC

October 2022 Menopause: The Journal of the North American Menopause Society - e-pub ahead of print.

Goal of the Study

Assess the effects (benefits and harms) of resistance training in postmenopausal women.

Methods

An extensive literature review was undertaken and 12 randomized control trials (RCT) were included in the analysis and assessed for bias pertaining to blinding, randomization, and incomplete outcome data. The GRADE approach was used to integrate bias calculations and assess the certainty of the evidence.

(GRADE is a systematic approach to rating the certainty of evidence in systematic reviews and other evidence syntheses.)

Results

• 12 RCTs were found range in unclear to high levels of bias. Using the GRADE approach, evidence certainty was graded as low to very low.

• RCTs were published between 2008-2020 and included 452 menopausal women. Most participants had no comorbidities and were not taking hormone therapy (HT).

• Compared with no exercise, up to 16 weeks of resistance training promoted an improvement in functional capacity, bone mineral density and reduction in hot flash frequency.

• Between groups, there was no difference in abdominal circumference or body mass index (BMI).

• When compared to aerobic exercise, resistance training may result in a reduction of hot flash frequency and fat mass with no difference in quality of life and BMI.

• No serious adverse events were reported.

Author’s Conclusions

• This review of 12 RCTs suggests that resistance training may improve postmenopausal symptoms and functional capacity.

• Because the GRADE approach revealed low to very low certainty of evidence, further RCTs with higher quality methodology and better reporting are needed.

• Health practitioners should take an individualized approach to resistance training in their patients taking into account previous exercise history, physical capacity and adaptation period.

In My Humble Opinion…..

I find it refreshing that menopause health investigators are paying attention to resistance training in light of the physiologic changes common to mid-life women resulting in declining muscle mass and function, osteoporosis, weight gain, and the like. I applaud the authors for demonstrating how incomplete the body of research is regarding the impact of resistance training in menopausal women and that better studies are needed in this area.

What continues to puzzle me is why would any practitioner NOT recommend physical exercise for all menopausal women? The benefits of exercise - resistance training, HIIT training and the like - are well known as outlined in a brilliant review by Grindler and Santoro (Menopause and Exercise, Menopause 2022; 22(12) pp 1351-1358).

While we embrace studies that explore the benefits of exercise in this population, we must keep a clear perspective that exercise is a lifestyle whose benefits are as sure as the sunrise every day. Just like smoking cessation is an automatic recommendation -exercise should be the same.

The quest for quality of life and longevity is front and center in the medical and fitness communities and is the Holy Grail for all of us! This article published in the September 2022 issue of the journal Menopause focuses on the factors that impact longevity in 1158 mid-life women in Chile who were followed for a 30-year period!  This article is summarized below with my personal and professional analysis to follow. 
Enjoy! 
-Carla DiGirolamo, MD

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Health screening of middle-aged women: what factors impact longevity?

Blümel, Juan E.; Aedo, Sócrates; Murray, Nigel; Vallejo, María S.; Chedraui, Peter

Menopause. 29(9):1008-1013, September 2022.

Goal of the Study

The goal of this study was to measure the impact of various risk factors on longevity in middle-aged women over a 30-year period.

Type of Study

This was a prospective cohort study (a study where a group of individuals is followed over time) of 1158 female public service officials in Chile who were followed for 30 years.

Methods

The following characteristics were defined at the start of the study:

• Age

• Body mass index (BMI)

• Postmenopausal status

• Type 2 diabetes

• Arterial hypertension (chronically elevated systolic blood pressure - the top number!)

• Cigarette use

• Physical activity (walks >1 hour/day)

• Active sexual intercourse

• Parity (having birthed one or more children)

• Unskilled job (not requiring higher or technical education)

• Personal history of fracture or heart disease

• Lipid levels (total cholesterol, HDL, LDL, Triglycerides)

At the end of the 30 years, the registry was reviewed for whether participants were living or dead, if dead, cause of death, and date of death.

Results

• Average age at the time of admission into the study was 47.4 years with an average BMI of 26 +/- 4.

• Total survival over the 30-year follow-up period was 75.6%.

• Top 3 causes of death: cancer (33.8%), cardiovascular disease (21.2%), infectious disease (15.8%).

An important point made by the authors was the concept of association vs causation. There were a number of variables associated with higher mortality at the end of the 30-year follow-up period: higher BMI, older age, postmenopausal status at the time of entry into the study, history of diabetes or arterial hypertension, and elevated triglycerides. This simply means that these factors were found more often in those who were deceased at the end of the 30-year period as compared to those who were still alive.

The authors went further using a thorough and statistically validated flexible parametric (FP) survival model to identify variables that could predict future mortality, thus implying a causative relationship between those variables and the risk of death:

• Personal history of fracture

• Type 2 diabetes mellitus

• Personal history of heart disease

• Chronic arterial hypertension

• Postmenopausal status

• Unskilled job

• Cigarette smoking

• Older age

• Higher BMI

The most notable finding of the study was that a history of fracture in women <age 60 was the risk factor that most decreased life expectancy - exceeding diabetes and hypertension.

• The FP survival model identified parity and active sexual intercourse correlated with longevity at a level of statistical significance.

• Obesity is an independent risk factor for death but decreases with age implying that it plays more of a role in the mortality risk in younger women than in older women.

• The lipid profile did not serve as a predictor for mortality.

Author’s Conclusions

Most of the known risk factors for mortality were present. However, a history of fracture, particularly when present in younger women, is a strong predictor of mortality surpassing diabetes mellitus and chronic hypertension. Multiparity and sexual activity were protective factors.

In My Humble Opinion….

The strengths of this study were the rigorous statistical analysis of variables and the long duration of follow-up of the participants. Using the Civil Registry of the Chilean government ensured accurate and complete documentation of death and associated causes.

This study illustrates the impact of fracture history - particularly in younger women - on mortality. This finding underscores the well-known correlation of fracture with poor health outcomes and a decline in quality of life.

However, caution must be exercised when extrapolating these results to other populations. For example, the average BMI of the participants of this study was 26 +/- 4. According to the National Center for Health Statistics, 42.4% of American women and men age 20 and older have a BMI of 30 or higher. This percentage is likely even higher in the middle-aged population that this study represents. One could speculate that in America, the impact of cardiovascular disease and diabetes mellitus may play an even greater role in mortality than what was reported in this study.

I find it interesting that physical activity was defined as “walking >1 hour per day”. Given their findings, it seems that further stratifying those individuals who actually “exercised” intentionally may have yielded some interesting results. Sadly, this is the status quo in many studies looking at quality of life, health outcomes, and longevity.

As a strong believer that evolution is the tool by which Mother Nature has designed the continued existence of living things since their inception on planet Earth, I find it philosophically interesting (and not surprising) that procreative fitness correlates significantly with survival.

So where does this leave us?

• Take care of those bones! Especially if you are a leaner individual such as those represented in this study.

  • Sound nutrition with plenty of protein!

  • Physical activity and exercise - maximize muscle mass and mobility

  • Prevent falls with physical fitness!

• Maintain a healthy weight, sound nutrition, and exercise strategies to promote cardiovascular health and minimize the risk of diabetes mellitus.

It’s important to realize and accept that there are always variables that are beyond our control such as age and menopausal status. However, focusing on the things we can control will help us to live the best lives we possibly can!

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Joint pain is one of the most common symptoms that midlife women experience -especially active women! And for good reason! As estrogen and estrogen receptor activity decline, changes in the muscles, tendons, bone, and even pain receptors result in discomfort, stiffness, and many times reduced function.

This review published in the June 2022 issue of Menopause from the Department of Physical Medicine and Rehabilitation at Spaulding Rehabilitation Hospital in Charlestown, Massachusetts discusses the physiology, prevention, and management of knee osteoarthritis (KOA) in midlife women. I have summarized the key points of this article here.

Knee osteoarthritis in midlife women: unique considerations and comprehensive management

Curry ZA et al. Menopause vol 29, No. 6, pp 748-755 2022

Goal of this study:

To describe the unique pathophysiology of KOA and treatment considerations for menopausal women.

Type of study:

Review of the peer-reviewed medical literature related to the pathophysiology, diagnosis, and treatment of KOA with a focus on menopausal women.

Some stats:

KOA affects up to 16% of adults age 50 and over in the US with up to 60% of patients with KOA being women. KOA can be disabling in older menopausal women with mobility issues, difficulties with self-care, and performing usual activities of daily living.

The normal knee joint:

• The knee joint provides articulation between the femur (thigh bone), tibia (shin bone) and the patella (knee cap).

• Movements include flexion, extension and a small degree of rotation.

• The knee joint is stabilized by ligaments (connective tissue from bone to bone) on both sides (medial and lateral collateral ligaments) and front and back (anterior and posterior cruciate ligaments).

• The articulating surfaces of the femur and tibia are lined with cartilage, which serves as shock absorption and provides a smooth articulating surface and is lubricated by synovial fluid.

• Knee extensors (ex quadriceps muscles) absorb shock to the knee and stabilize the joint.

Pathophysiology of KOA:

• Due to age-related degenerative changes in cartilage and bone.

• Chronic inflammation is thought to play a key role in degrading the cartilage that lines the articulating surface of the joint. Pain results from local tissue damage and possibly through the accumulation of immune cells and mediators in the nerve roots leading to the central nervous system.

• Recent studies suggest a role for the bone underlying the cartilage surface (subchondral bone) in the pathogenesis of KOA where lower bone mineral density was associated with high-grade KOA seen on X-ray. With the declining bone density noted in menopause, midlife women are at particular risk.

• The changing hormones of the menopause transition also impact pain perception.

• Interestingly, the age of menopause onset is not associated with the risk of KOA which raises questions about the role of hormones in this process.

• Newer studies show a lower prevalence of KOA in menopausal hormone therapy (HT) users, likely related to the preservation of subchondral bone and cartilage. However, significant discordance remains among studies, again underscoring the complexity surrounding the role of hormonal change in KOA development.

• The angle of weight/biomechanical force transmission from the hips to the knees in women as compared to men plays a significant role in joint instability and cartilage damage to the medial (toward the middle/inside) aspect of the knee joint. Obesity exacerbates these effects resulting in hip pain and reduced physical activity and mobility.

Diagnosis and Assessment

• Dull pain in one or both knees. Pain may be in the whole knee or localized and is worse with activity and better with rest. Knee pain may be accompanied by hip pain affecting walking stride, mobility, and activity level.

• Knee pain may be accompanied by vasomotor symptoms (hot flashes) that may impact sleep which in turn may impact pain perception.

• A thorough physical exam of the knee and attention to the hip along with x-rays are standard of care. Functional testing such as sit-to-stand without the use of the arms and single-leg squats are also helpful in the initial assessment.

Management

Prevention is King! Regular physical activity, weight management, lower body muscle strengthening, aerobic exercise, sound nutrition and minimizing inflammation are the mainstay for optimal knee health.

• Physical therapy that targets specific deficiencies.

• Neoprene sleeves: Increase proprioception, and support knee alignment.

• Topical therapeutics: Topical non-steroidal anti-inflammatory (NSAID) cream (ex- Diclofenac)

• Oral therapeutics: NSAIDs for acute flares. Caution must be exercised with longer-term use due to gastrointestinal effects and impact on kidney function. Pain control with serotonin-norepinephrine reuptake inhibitors (SNRIs) or GABA targets nervous system pain transmission/perception. Improvement in sleep may also improve pain perception.

• Injections: May be considered when conservative measures fail and should be used sparingly. Steroid and local anesthetic injections are the most common. Although effective for short durations, these agents may be toxic to cartilage. Alternatives include injections with hyaluronic acid and its derivatives, prolotherapy, platelet-rich plasma, bone marrow aspirate, and adipose transfer. However, these alternative therapies have limited evidence of effectiveness and some may not be FDA approved.

• Knee Replacement: When all other conservative management strategies have failed, when pain and functional limitation are severe.

In My Humble Opinion….

The physical changes that accompany midlife have widespread effects on physical functioning - and our joints are a significant part of that equation. As with other physical changes of menopause, the foundation of optimal joint (and overall health) is sound nutrition and varied physical activity with a central focus on aerobic training and muscle strengthening. Not only do physical exercise and nutrition support the muscles and bones, but it is the cornerstone of a healthy metabolism and weight management, which reduces undue stress on joints, and promotes long-term mobility and functionality until late in life.

If you have established KOA, there are a multitude of interventions that are available to help you manage pain, improve function and have your knees working for you for life!

Last month in Athletic Aging we reviewed the British Menopause Society and the Royal College of Obstetricians and Gynecologists joint position statement on the appropriate use of hormone therapy in the post Best Practices for Menopausal Care - Is There Any Consensus? This month - hot off the press - The North American Menopause Society (NAMS) issued an update to the 2017 position statement on the use of hormone therapy in a new and improved 2022 position statement. The highlights from the 2022 version issued directly from NAMS are below.

In My Humble Opinion….

Having reviewed both the 2017 and 2022 statements, there appears to be a refreshing shift in multiple key elements of critical importance to mid-life women:

• A considerable openness to the extended duration of HT without any clear time limits with the determining factor lying centrally with the risk/benefit equation individualized for each woman and the effective doses needed to relieve her symptoms.

• Transdermal (via the skin) and lower doses of HT may decrease the risk of venous blood clots and stroke.

• Statements on breast cancer risk emphasize that this is rare and that select breast cancer survivors may be candidates (in consultation with a woman’s oncologist) for low-dose HT.

• Reaffirmation of the following:

  • The risk/benefit ratio for using HT is most favorable when initiated in women under the age of 65 within 10 years of the onset of menopause.

  • HT is recommended in women with premature ovarian insufficiency until at least the mean age of menopause onset.

  • HT remains the most effective treatment for hot flashes, genitourinary syndrome of menopause, and prevention of bone loss and fracture.

For the official, complete highlights issued by NAMS, please see below.

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Highlights From The 2022 Hormone Therapy Position Statement of The North American Menopause Society    

• Hormone therapy remains the most effective treatment for vasomotor symptoms (VMS) and the genitourinary syndrome of menopause (GSM) and has been shown to prevent bone loss and fracture. 

• Personalization with shared decision-making remains key, with periodic reevaluation to determine an individual woman’s benefit-risk profile, with recommendations for the use of the appropriate dose, duration, regimen, and route of administration required to manage a woman’s symptoms and to meet treatment goals. 

• Risk stratification by age and time since menopause is recommended. 

• The benefits of hormone therapy outweigh the risks for most healthy symptomatic women who are aged younger than 60 years and within 10 years of menopause onset. 

• Transdermal routes of administration and lower doses of hormone therapy may decrease risk of blood clots in the deep veins and stroke. 

• Women with primary ovarian insufficiency and premature or early menopause have higher risks of bone loss, heart disease, and cognitive or affective disorders associated with estrogen deficiency. It is recommended that hormone therapy can be used until at least the mean age of menopause unless there is a contraindication to its use. 

• There is a paucity of randomized, controlled trial data about the risks of extended duration of hormone therapy in women aged older than 60 or 65 years, although observational studies suggest a potential rare risk of breast cancer with increased duration of hormone therapy. 

• For select survivors of breast and endometrial cancer, observational data show that use of low-dose vaginal estrogen therapy for those who fail nonhormone therapy for treatment of GSM appears safe and greatly improves quality of life for many. 

• Breast cancer risk does not increase appreciably with short-term use of estrogen-progestogen therapy and may be decreased with estrogen alone. 

• Compounded bioidentical HT presents safety concerns, such as minimal government regulation and monitoring, overdosing or underdosing, presence of impurities or lack of sterility, lack of scientific efficacy and safety data, and lack of a label outlining risks. 

• Hormone therapy does not need to be routinely discontinued in women aged older than 60 or 65 years and can be considered for continuation beyond age 65 for persistent VMS, quality-of-life issues, or prevention of osteoporosis after appropriate evaluation and counseling of benefits and risks. 

• For women with GSM, vaginal estrogen (and systemic if required) or other non-estrogen therapies may be used at any age and for an extended duration, if needed.     

The 2022 Hormone Therapy Position Statement of The North American Menopause Society has been endorsed by more than 20 well-respected international organizations.

My Friends! 
The sea of information on how to manage the menopausal experience is vast and often confusing with media messaging that is all over the map. Three of the world's most reputable women's health societies have created position statements to help us make sense of it all. Their efforts are summarized here. 
Enjoy!
Carla DiGirolamo, MD

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One of the greatest challenges that mid-life women face is navigating the vast landscape of information on how to lead their best lives during menopause. The internet and social media have promoted widespread access to information. However, this has proven to be a double-edged sword.

The media frenzy surrounding the release of the Women’s Health Initiative was damaging because it invoked fear in menopausal women and their providers of using hormone therapy (HT) for the treatment of often debilitating menopausal symptoms. HT includes estrogens, progestogens, and in some cases, androgen (testosterone, DHEA) therapy. Societal stigmas and lack of study and understanding of the menopausal experience have created barriers for women seeking care or even just achieving a basic understanding of this stage of life. As a result, women have had difficulty receiving the care they need and providers have lacked resources upon which to base safe and effective care.

We have also seen the emergence of providers and services that promise “superior”, “safe” and easy access to hormonal products often involving expensive tests and the notion of the magic bullet for “curing” your “hormone deficiency” - this “disease” that we call “Menopause”. This is of particular concern in some geographies where there are shortages of hormonal treatment for menopausal symptoms, further feeding the desperation of some women.

In response to these challenges, some of the greatest minds in menopausal medicine have convened to objectively evaluate the scientific evidence and issue recommendations for providers and patients as a resource for safe and effective management of this stage of life where women will spend nearly half of their lives.

On June 9, 2022 the British Menopause Society (BMS) and the Royal College of Obstetricians and Gynaecologists (RCOG) issued a joint position statement on the best practices for the care of menopausal women. This statement - along with the North American Menopause Society 2017 position statement on hormone therapy - provides evidence-based recommendations based on a careful review of the peer-reviewed literature by experts in menopausal medicine who treat menopausal women every day.

Below is a summary of the key recommendations from the June 2022 BMS / RCOG Joint Position Statement and the 2017 NAMS Position Statement on Hormone Therapy.

General Considerations

• Optimal management of menopause involves an individualized, holistic approach that includes lifestyle modifications, nutrition and exercise recommendations, disease prevention, and the use of hormone therapy based on a careful benefit/risk analysis specific to the individual.

• BMS/RCOG and NAMS are aligned in abandoning specific age and duration limits for the use of HT. Rather, an individualized benefit/risk assessment at periodic intervals drives the decision for the duration of HT use.

• BMS/RCOG and NAMS agree that HT should not be used without a clear indication and should not be prescribed for generalized, primary prevention of disease. However, when used for appropriate indications, HT is effective and may reduce all-cause mortality when used within the first 10 years of the onset of menopause in women < age 60.

• Appropriate indications for HT based on the reviewed scientific evidence includes:

  • Vasomotor symptoms (hot flashes)

  • Prevention of osteoporosis

  • Genitourinary symptoms of menopause (vaginal dryness, painful intercourse, urinary symptoms)

  • Premature Menopause

  • Hypoactive Sexual Desire Disorder

Osteoporosis

• HT is effective and FDA-approved for the prevention of osteoporosis.

• BMS/RCOG promotes HT as an effective treatment for osteoporosis, however, in agreement with NAMS, recommends bisphosphonates as the first-line treatment of established osteoporosis.

Breast Cancer Risk

• NAMS and BMS/RCOG do not recommend systemic HT in breast cancer survivors, however, there are possible exceptions in consultation with an oncologist, for debilitating menopausal symptoms when all non-hormonal treatments have failed.

• For breast cancer survivors, NAMS states that low-dose vaginal estrogen therapy is likely a safe option, in consultation with the woman’s oncologist, for vaginal and urinary symptoms when non-hormonal measures have failed.

• For women within the first 10 years of menopause and <age 60, breast cancer risk is extremely low and the benefits of HT for appropriate indications outweigh the risks.

• Evidence suggests that breast cancer risk is linked to the type of progestogen (ie synthetic progestins) in combination HT products.

• NAMS reports that although studies are limited, HT does not increase the risk of breast cancer in women with a family history or who possess BRCA gene mutations.

For more information on HT and breast cancer risk, check out last week’s Athletic Aging post: Breast Cancer Risk and Hormone Therapy - New Data Emerges

Thromboembolism (Blood clots in the deep veins)

• For healthy women within 10 years of menopause and age <60, the risk of thromboembolism is small and the benefits of HT for appropriate indications outweigh the risks.

• Several studies have suggested (but not definitively shown) that the transdermal route (skin patch, cream, spray) of HT administration may be less thrombogenic than the oral route. BMS/ROC supports the use of transdermal preparations as first-line for HT.

Premature Menopause

• NAMS and BMS/RCOG are aligned in their recommendation that women who become menopausal before the age of 45 (due to either natural or iatrogenic (medical treatment) causes, be prescribed HT.

• NAMS reports that HT reduces the risk for osteoporosis and related fractures, vaginal symptoms, and dyspareunia, with benefits seen in observational studies for atherosclerosis, cardiovascular disease, cognition, and dementia in women with premature menopause.

• Estrogen/progesterone-containing oral contraceptive pills are commonly prescribed for prematurely menopausal women until the age of natural menopause at which time the decision is made to wean or transition to menopausal doses of HT.

Cardiovascular Disease Prevention

• HT prescribed for appropriate indications in women <10 years since the onset of menopause and age <60 shows favorable effects on cardiovascular risk and all-cause mortality in many rigorous studies.

• Data are mixed when considering HT for the sole indication of reducing cardiovascular risk. For this reason, NAMS and BMS/RCOG jointly recommend that HT should not be prescribed for the primary prevention of cardiovascular disease.

Dementia

• NAMS and BMS/RCOG are aligned in their recommendation that HT should not be used for the primary prevention of dementia or Alzheimer’s Disease.

• Cognitive benefits are seen when HT is prescribed for women with premature menopause. However, the results of studies of women within 10 years of the normal onset of menopause and age <60 are neutral in relation to cognitive effects. In those > age 65, caution is advised given a small but notable increased risk of dementia in this older age group.

Testosterone

• NAMS and BMS/RCOG report evidence that testosterone therapy is effective for the treatment of hypoactive sexual desire disorder in menopausal women.

• BMS/RCOG reports a lack of evidence to support testosterone supplementation for the purpose of prevention or improving cognitive function, musculoskeletal health, improving bone density, or fracture prevention

Compounded Therapies

• NAMS and BMS/RCOG are aligned in the recommendation that compounded hormonal therapies should be avoided due to issues related to purity, potency, safety, lack of oversight, and rigorous study of specific custom formulations.

• Both organizations recommend that FDA-regulated and conventionally licensed products be used as a first-line for any treatment.

For a review of this issue, check out my previous post in Athletic Aging: An Objective Look at Compounding Pharmacies and Their Role in Menopausal Medicine

In My Humble Opinion (IMHO)…..

Interpreting scientific literature is challenging - even for those of us in the field trained to do it. Compelling arguments can be made on both sides of many of these issues and are the subject of ongoing controversy. There is no clear “right” or “wrong”. Just data and a variety of interpretations.

So how do we as mid-life women make sense of it all?

• Find reliable resources with reputable credentials and an evidence-based approach. The more you read, the more of a sense you will get for whether a piece is “opinion” or evidence-based.

• Seek providers who will actively work with you to individualize your care.

• Know that there is not always just one answer or option.

• Find your tribe! You are not alone.

• View yourself as the powerful, bad-ass woman that you are, ready to take on this next stage of life with a vengeance! .. not as a victim of a “disease” or a “deficiency.”

BMS / RCOG says it best….

“Menopause is a life stage and does not represent a deficiency state. Menopause should not be compared with conditions such as hypothyroidism or type 1 diabetes mellitus”

So, Game-On, my Friends! I hope you found this helpful.

Cheers!
Carla

My Friends, 
This highly charged topic is by no means a closed book. This article published just days ago investigates an important question that any woman and her provider should consider in the decision to use HT. 
Enjoy the review! 
-Carla DiGirolamo, MD

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Since the publication of the Women’s Health Initiative (WIH) study in 2002, patients and the medical community have exercised caution surrounding the use of hormone therapy (HT) for peri-menopausal and menopausal women due to concerns about breast cancer risk. When the results of the WIH went public, a media firestorm created a narrative that, frankly, petrified the general public and health care providers alike, casting a dark cloud over the use of HT for menopausal symptoms. As a result, women with life-altering symptoms have gone without treatment jeopardizing their quality of life and overall health and wellness.

After years of continued study and challenges to this damaging narrative by many in the medical community, most notably, Dr. Avrum Bluming in his provocative book Estrogen Matters, the field of menopausal medicine is re-setting the table on this important issue. The North American Menopause Society (NAMS) convened a task force to critically evaluate the collective body of evidence surrounding the risks and benefits of HT and issued a comprehensive position statement in 2017. Over time, the menopausal population and the medical community have gained a more informed perspective on the risks and benefits of HT, however, there is more work to be done.

One of the limitations of the WIH study was that only two hormonal formulations (conjugated equine estrogen with or without medroxyprogesterone acetate) were studied.

In the June 2022 issue of Obstetrics and Gynecology, researchers from McGill University investigated whether HT formulation impacts breast cancer risk.

Menopausal Hormone Therapy Formulation and Breast Cancer Risk

Haim A. Abenhaim, MD MPH, Samy Suissa, PhD, Laurent Azoulay, PhD, Andrea R Spence, PhD, Nicholas Czuzoj-Shulman, MMA, and Togas Tulandi MD MHCM

Obstetrics and Gynecology Vol 139, No. 6, June 2022

The Study:

• Type of study: Case-Control using data from the UK Clinical Practice Research Datalink.

• Timeframe: Women were followed from the time they were registered in the database starting in 1995-ending in 2014.

• Participants: 43,183 women who developed breast cancer after registration in the database were matched with 431,830 women without breast cancer in the database as the control group.

• Exclusions: age 75 or greater or breast cancer diagnosis at the time of entry into the registry.

• Covariates: Data on obesity, smoking status, alcohol use, medical history of endometrial cancer, hysterectomy, oophorectomy (removal of ovaries), Oral Contraceptive Pill (OCP) use, and family history of breast cancer were also collected and included in statistical analysis.

• Main Outcome Measure: Risk of developing breast cancer in women using the following HT formulations: bioidentical estrogens, animal-derived estrogens, micronized (bioidentical) progesterone, and synthetic progestin compared to HT non-users.

Results

• The Case group (those that developed breast cancer) had a statistically higher incidence of obesity (BMI of 30 or >), those reporting smoking and alcohol use, history of endometrial cancer, use of OCPs, and family history of breast cancer.

• HT use was associated with an increased risk of breast cancer, with an odds ratio of 1.12 after adjustment for the above covariates (obesity, smoking, etc). This translates into a 12% increased risk above the control group (no HT use). This is comparable to the magnitude of risk observed in the WHI report for the estrogen/progesterone arm of the study.

When the data were stratified by type of HT formulation and controlled for the above covariates:

• Use of Estrogens alone (bioidentical or animal-derived) was not associated with an increased risk of developing breast cancer compared to HT non-users.

• The use of synthetic progestins showed an increased risk of breast cancer whereas micronized progesterone (bioidentical progesterone) did not show an increased risk.

When the data analysis was restricted to women aged 50-60 years and controlled for the above covariates, the same statistically significant associations were observed.

Authors Discussion - Key Points

• Previous studies including WHI suggest that the use of estrogens alone - regardless of formulation - did not confer a higher risk of breast cancer. However, the risk appears to be related more to progestin use.

• Other studies support the notion that synthetic progestins have very different biological effects on breast tissue and may incur a greater breast cancer risk.

• HT may be related to breast cancer in promoting the growth of occult (not yet detected) cancers vs de-novo (new-onset) cancers.

Study limitations:

• Administrative study of registry entries as compared to medical chart review.

• Other relevant covariate data such as race, ethnicity, socioeconomic class, and education level were not available.

Study Strengths:

• Large study

• Rigorous statistical analysis and validity testing.

• Reflected actual prescribing practices allowing for the analysis of different HT formulations and age-appropriate use.

In My Humble Opinion (IMHO)

This study reiterates the findings in prior studies - including the WHI - that the risk of developing breast cancer related to HT use is SMALL, but it is not zero. Just as there is an increased risk of developing deep venous blood clots (DVT) with HT use, HT can be used safely in women when their personal risks and benefits are assessed by a qualified provider. That being said, be wary of anyone who tries to tell you that HT is no different from supplements. HT is safe for most women - but it’s not like candy that can be taken indiscriminately as many suggest!

The second key takeaway is the distinction between the risks associated with bioidentical vs. synthetic progestins. There are a wide variety of HT formulations and routes of administration from which women and their providers can choose. My personal practice is to prescribe FDA-approved, bioidentical estradiol (17-beta estradiol) and micronized progesterone whenever possible. Before deciding on HT, work with your provider to learn exactly what types of estrogens and progestogens comprise their recommended therapy.

But what about the progesterone IUD? Mirena, Skyla, Kylena, and Liletta all secrete the synthetic progestin, Levonorgestrel. However, the exposure of the progestin is largely limited to the uterus, and rarely are these progestins detectable in the bloodstream. Although there has been very little, if any, study specifically looking at breast cancer risk as it relates to progesterone IUD use, I would speculate that the low to undetectable presence of the progestin in the circulation favors a much safer situation than the orally ingested synthetic progestins found in other types of HT. If you are in a country where oral micronized progesterone is not available in HT formulations, your safest bet may be a Mirena IUD combined with 17-beta estradiol skin patches or 17-beta estradiol oral pills.

But what about oral contraceptive pills (OCPs)? Most OCPs on the market contain synthetic progestins. They are also most commonly prescribed in pre/peri-menopausal women - a younger age group than the participants in the studies noted previously. It has been suggested that a possible mechanism by which HT increases the risk of breast cancer is through stimulating the growth of an existing, occult (undetected) cancer rather than causing a new cancer. Because younger women are at a significantly lower risk of breast cancer compared to postmenopausal women, breast cancer risk in those taking OCPs is less apparent. My personal practice is to insist that any woman age 40 and over have a negative mammogram prior to starting HT and yearly mammograms while taking HT.

My Friends, 
I have dedicated my career to studying hormones in women - it’s one of my favorite subjects (along with fitness!). So let’s continue the conversation with a review of this very provocative article in Obstetrics and Gynecology.
Cheers!
-Carla

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The use of Testosterone (T) therapy in mid-life women has been the subject of great debate in recent years. Off-label use of T therapy targeting pre-menopausal physiologic blood levels has been studied for the treatment of hypoactive sexual desire disorder in menopausal women with good evidence for safety and efficacy. However, there are no FDA-approved testosterone products dosed for use in women. As a result of this and many other factors, women are resorting to alternative sources to obtain testosterone and other types of hormone therapy.

This article published in the November 2021 issue of Obstetrics and Gynecology provides a provocative but well-accounted, evidence-based review of the current landscape of the use of T in mid-life women. After their publication, there were rebuttals and re-rebuttals further fueling this heated debate.

Testosterone Therapy in Women

A Clinical Challenge

Rebecca Dunsmoor-Su, MD MSCE, Ashley Fuller, MD, NCMP, and Amy Voedisch, MD, MS

Obstetrics and Gynecology VOL. 138, NO. 5, NOVEMBER 2021

This article is an editorial from the Swedish OBGYN Specialists—First Hill, Seattle, Washington; and the Division of Family Planning, Department of Gynecologic Specialties, Stanford University, Stanford, California with no significant disclosed conflicts of interest.

The authors summarize the current clinical landscape surrounding the use of T therapy in mid-life women with the following main points:

• There is great variability in the evaluation and prescribing practices outside the clinical guidelines published in the peer-reviewed literature for allopathic menopausal medical practice.

• The prevalence of permanent adverse reactions and uterine malignancies is often understated and unaccounted for.

• Hormone preparations are often obtained through compounding pharmacies at doses and formulations that have not been thoroughly studied for safety or efficacy.

• There is evidence of safe and effective use of pre-menopausal, physiologic T therapy in postmenopausal women with hypoactive sexual desire disorder. However, longer-term safety studies are needed with the longest trials to date extending only 4 years.

• Adverse events are most often seen when testosterone blood levels exceed the pre-menopausal physiologic ranges and can include acne, hair growth, weight gain, alterations in high-density lipoprotein (HDL) and low density-lipoprotein (LDL) levels, irreversible deepening of the voice, temporal balding, development of an “Adam’s Apple”, clitoromegaly and potentially uterine malignancy.

The authors go on to describe “where the blame lies” for this “current crisis”:

• Inadequate medical education

• Failure of the FDA to approve testosterone products dosed for women despite peer-reviewed evidence supporting safety and efficacy at doses targeting physiologic, pre-menopausal blood levels.

• Deceptive marketing practices by those groups that promote these formulations as safer and more effective than FDA-approved products without supporting peer-reviewed evidence.

• Inconsistent insurance coverage for FDA-approved products for female use.

In My Humble Opinion…

The authors present a compelling case supported by evidence and do so very methodically. Their positions are supported by consensus from the various respected medical societies and the peer-reviewed medical literature.

What I take issue with is the provocative, authoritarian tone of this article, which chastises (and in some cases, maybe justifiably so) other providers who are practicing outside the consensus for the safe and effective use of T.

Although the authors do an excellent job of stating the problem and providing supporting evidence, they do very little to put forth solutions to these problems thus creating more division in the totality of the mainstream and alternative medical community.

Although I agree that there are indeed predatory practices of some medical providers, the mainstream medical community isn’t much better when they either shrug off the symptoms that women present or refuse to consider thinking “outside the box” to find reasonable solutions and interventions. Surely there is something in between predatory, unsafe medical practices and suggesting a cup of Ashwagandha tea to calm anxiety even if there isn’t a double-blind placebo-controlled randomized control trial to support it.

I also take issue with the portrayal of the mid-life woman as a victim. Predatory marketing practices are apparent in every industry. We’re big girls... this isn’t our first rodeo. So while the “ruling” medical bodies, FDA, and insurance companies throw grenades at one another, let’s try empowerment as a strategy and take matters into our own hands.

Here’s what you can do to make the most informed decisions you can about your health and wellness:

• Speak to your health care providers. As faulty as the system is, most providers do care about your health and well-being, even if the tools and sometimes the knowledge are incomplete. Get second opinions and different perspectives.

• Research your health care providers! Investigate if they receive direct monetary gain from the therapies they prescribe. This conflict of interest incentivizes the provider to prescribe their therapy... not the most appropriate therapy.

• Evaluate “studies'“ critically. A study showing the benefits of a therapy that is funded by the same company producing the therapy presents a financial conflict of interest. The most reliable studies are those where the authors have no financial interest in the results of the study. So before you look at the data, look at who funded the study.

• Research your compounding pharmacy. Although they are not overseen by the FDA, there is oversight from the global pharmacy community that has clear standards of best practice. Ideally, seek PCAB-certified pharmacies.

• Be wary of the dreaded “Google” search. There is a lot of unhelpful information out there. A great “go-to” for reliable information for mid-life women is the North American Menopause Society. It is a great start for learning about health and wellness issues important for mid-life women.

• Find your tribe. You are not alone. There is lots of support out there. For fitness-minded women, check out Feisty Menopause. This is my tribe. The work they do and the community of women they serve are second to none!

So remember... you are your own best advocate. You’re smart, you’re resilient and you are not alone! ..and most of all you are NOT DEFICIENT! All the tools you need are out there to help you live your best years ever from mid-life and beyond!

For more great talk about hormones and hormone therapy, check out my latest appearance on Hit Play Not Pause and register for the FREE 10-day Master Class Series, Perimenopausal Athletes and Beyond with former pro triathlete Tenille Hoogland.

For more fun stuff check out my Facebook, Instagram and Linked In!

The menopausal transition includes a complex interplay of physical, emotional and societal factors that influence our perception of this experience and our quality of life. A major frustration among mid-life women is the absence of empathy and medical knowledge specific to this stage of life which arguably has led to over 70% of women not seeking care from traditional medical practice. Instead, women are turning to the internet, social media and other health professionals to find relief from their symptoms. This article published in the January 2022 issue of the journal Menopause provides evidence of the importance of management of the menopausal experience and potential health implications for leaving symptoms untreated.

Treatment of menopausal symptoms: concomitant modification of cortisol

Cagnacci, Angelo MD, PhD1; Xholli, Anjeza MD1; Fontanesi, Francesca MD2; Neri, Isabella MD3; Facchinetti, Fabio MD3; Palma, Federica MD3

Author Information

Menopause: January 2022 - Volume 29 - Issue 1 - p 23-27

Cortisol is a hormone secreted by the adrenal glands in response to stress. It is part of a cascade of hormonal responses that helps us contend with an immediate threat. Once the inciting event is gone, this hormonal cascade returns to baseline.

Chronic stressors, which can include environmental/life stressors, alcoholism, anxiety, depression, among others, can result in an ongoing stress response and chronically elevated cortisol levels. It is well-known that long-term elevation of cortisol has been associated with elevated blood sugar, high blood pressure, low bone mass, decreased cognitive function, and accelerated aging.

The menopausal transition is associated increases in anxiety and depression, physiological changes that can be bothersome including hot flashes, weight gain, relationship strain along with a whole host of difficulties. This study seeks to determine if there is a relationship between the symptoms of menopause and 24 hour urinary cortisol levels and if effectively treating those symptoms results in a decline in urinary cortisol.

Goal of the Study:

Evaluate the association between menopausal symptoms and 24 hour urinary cortisol and whether treatment of these symptoms results in a concomitant change in 24 hour urinary cortisol levels.

Study Participants:

• 72 healthy menopausal women

• Average age of 52.8 years

• Average 3 years since onset of menopause.

• Experiencing symptoms of menopause who were not undergoing formal treatment of these symptoms.

Methods:

• Menopausal symptoms were evaluated using Greene’s Climacteric Scale scoring system. This includes 21 symptoms including hot flashes, anxiety, physical symptoms and sexuality.

• 24 hour urinary cortisol was collected before and after the 12 week study period.

• 72 study subjects were randomized to receive treatment with either hormone therapy, phytoestrogens or acupuncture over a 12 week period.

Results

• At the start of the study period, Greene’s Climacteric Scores correlated strongly with 24- hour urinary cortisol levels. The higher the score, the higher the cortisol levels.

• Most notable associations seen with anxiety, depression and physical symptoms (somatization).

• After 3 months of treatment, Green’s Climacteric Scores and 24- hour urinary cortisol levels significantly decreased.

• Sexuality related symptoms did NOT exhibit the same decrease.

• There were no differences seen with the type of treatment that the test subjects received.

Author’s Conclusions

“The data indicate that improvements of symptoms, induced by any means, can reduce cortisol exposure, and possibly its deleterious effect on a woman's health. This can be of particular importance for those women with severe and long-lasting menopausal symptoms”.

In My Humble Opinion....

The big take-away from this study is that the menopausal experience matters! Quality of life and physical well-being go hand in hand. What we experience every day needs to be listened to and effectively addressed. The fact that the correlation with cortisol levels was significant only when the entire Climacteric score was considered (as compared to looking at symptoms individually) supports this notion that what matter most is the total experience and not just individual symptoms.

Further, active treatment and symptom relief is associated with a change in cortisol levels. Whether relief is achieved with hormone therapy, acupuncture, counseling, supplements - or whatever else - improvement in symptoms was strongly associated with a reduction in cortisol levels, which may have implications for long term risk of cardiovascular disease, cognition, blood sugar levels among other chronic conditions.

So the next time your provider gives you the “eye roll”... or the “shoulder shrug” and you feel like they are telling to you “just deal with it”, find a new provider who specializes in menopausal medicine and take your experience into your own hands.

All for now!

Carla DiGirolamo, MD