Menopause care is evolving, and 2024 brought significant advancements in hormone therapy and women’s health care. In this video, Dr. Jim Simon of IntimMedicine Specialists highlights the latest research on hormone therapy, cognitive health, cardiovascular safety and treatment options for breast cancer survivors. Key insights include the safety of modern hormone therapies, potential cognitive benefits of early treatment and the role of testosterone in mood support. Additionally, new non-hormonal treatments like Elinzanetant are emerging to improve menopause symptoms. Watch the video or read on to explore how these findings are shaping the future of women’s healthcare.
Dr. Simon:
Hello, everyone. I’m Dr. Jim Simon, clinical professor at George Washington University and Medical Director at IntimMedicine Specialists here in Washington, DC. My goal today is to give you my personal uptake on the advances and changes that have come about in the menopause space in 2024. Thanks for being with me.
First I’d like to start with popular books, and I’ve highlighted four of them here because the popular space is, as in other arenas, driving research and paralleling research in terms of its focus. The four books I’ve highlighted here all came out in 2024.
The Menopause Brain , Dr. Lisa Mosconi, a popular author and also a clinical research investigator in California as it relates to hormones, cognition, menopause, and dementia. The New Menopause While this book is not the best nor far from the worst popular book on menopause, it has a unique place in this discussion because it was a number one bestseller on the New York Times list. Dr. Mary Claire Haver has more than a million followers in social media and as a driving force and influencer in that space, an important subject for a different day. The Longevity Imperative, an extremely interesting book by Andrew Scott, which follows, in the face of a very important book by Dr. David Sinclair on longevity and the lifespan, an important subject for our world as our world is aging. And then Estrogen Matters, the first edition of which was published several years ago, but it was so popular that my colleagues, Doctors Avram Bluming and Carol Tavris, revised and updated it for a second edition, published in 2024 to great acclaim.
Let’s dive in. Here is what I think is one of the more important subject papers published in the British Medical Journal at the end of last year called Contemporary Menopausal Hormone Therapy and Risk of Cardiovascular Disease. This is a huge Swedish nationwide trial, and I’ll take you through, very briefly, some of the highlights.
The goals of this study were to assess the relationship between contemporary doses of menopausal hormone therapy and cardiovascular disease, and to further isolate differences, if possible given the large sample size, between different forms of hormone therapy and those cardiovascular endpoints. Specifically, this involved more than 900,000 women ages 50 to 58 in the Swedish National Registry, of which almost 78,000 were hormone users, and they had a significant group of different types including oral therapies, oral and local progestogen or progestin, like an IUD, progestin-releasing IUD, tibolone, which is not available in the US but was part of their trial, and transdermal as opposed to oral therapies, both combined with progestin and given alone. The comparator group were individuals they called non-initiators who never used hormone therapy. The study was done over a significant period of time, about 138 bargains.
As you can see here, over time, since 2007 to 2020, use of hormone therapy has waned and then revised in Sweden. In 2007, about 25%, a decrease down to a minimum in 2013. Since that time, an increased use of hormone therapy of all types culminating in the end of the study in 2020. I’d like to point out the increasing use of the levonorgestrel IUD in Sweden in this group as a non-oral form of progestin for endometrial protection and the increase of transdermal therapies to a greater degree than oral therapies, a phenomenon we also see here in the US.
Despite the increase in hormone therapy, the incidence of all forms of cardiovascular disease basically either held steady or reduced, suggesting, at least, that menopausal women in Sweden are healthier or at least that hormone therapy is not making their cardiovascular reasoning worse.
Breaking it down by types, I’ll just summarize by saying none of the therapies had a dramatic effect, either in dramatic increase or a dramatic decrease, in cardiovascular risk. However, there was little or no risk from the transdermal forms, as illustrated here. In this figure, what you see is a top-line summation of these results. Where you see tibolone, oral estrogen, and anything red or pink, the degree of darkness of the red color showed an increased risk of stroke, blood clots to the lungs, thrombosis, or heart disease, heart attacks, whereas the transdermal forms of estrogen were not connected to those endpoints and had essentially a null effect on cardiovascular risk. These findings, quite to the contrary of what the labeling of systemic hormone therapy says in the US and in fact quite different from the findings in the Women’s Health Initiative study first published in 2002, and multiple times since then, give us reassurance that combination or estrogen-only therapy, particularly via the transdermal route of administration, is safe for cardiovascular risk.
Our second study that I found to be very important was a systematic review and meta-analysis on hormone therapy and cognition by a number of authors, including Dr. Mosconi, whose book I mentioned at the outset. This study looked at hormone therapy and its effect on cognitive function, not on dementia, per se, but on cognitive function, by hormone therapy formulation, as I just showed you in the Swedish study, and the timing of treatment, whether the initiation of hormone therapy was early in the menopausal transition or late, age 65 and over.
The goals were to determine its effect on several important endpoints, which I’ll mention in the moment. Well, why study cognition and menopause or cognition and menopausal hormone therapy? Well, there’s a number of reasons. First, there are major disruptions in thermal regulation, a CNS event, during the perimenopause and menopause. Hot flashes, night sweats, disturbed sleep, changes in mood, alterations in circadian rhythms and sensory processing, all well-documented in women who have changes in their hormone therapy around the menopause, with 60% or more of women reporting memory changes or other changes, which may be related to sleep, may be related to hormones or some other mechanism, but the goal here was to determine some of those findings.
The study design was as follows, but the endpoints were verbal memory, verbal memory delayed, visual memory, and working memory. Pretty standard endpoints for cognitive function testing, and the sample sizes from these 34 placebo control trials in this meta-analysis gave quite large sample sizes of almost 15,000 hormone-treated patients and about 13,000 placebo-treated patients. Each of these studies were randomized to the degree possible and placebo controlled.
Study endpoints looked like this. Rather than focusing on the specifics, I just want to say that the effects, whether they were improvements in memory or not, we’re small in either direction, and to me, quite variable. Not exactly predictable results from this unbelievably large, well-controlled meta-analysis. The implications were kind of all over the place consistent with my comment about variable. There were associations between hormone therapy and cognitive function in some domains, but they varied by both formulation and the timing of treatment. Menopausal hormone therapy had no overall effects on cognitive domain scores, but treatment with estrogen only for surgically menopausal women improved global cognitive function compared to placebo. There was a general tendency to show that when hormone therapy was initiated at midlife or closer to menopause, that estrogen was associated with improved verbal memory, while initiating estrogen late in life, say 65 years of age and older, had no effects, but minimal detrimental effects.
Overall, the combination of estrogen and progestogen for spontaneous menopause was associated with a decline in the Mini Mental State Exam scores compared to placebo, with most studies administering treatment in a late-life population. So not the typical place we’d want to use hormone therapy for prevention. This would be more of a treatment effect, in my opinion. Overall, starting early showed worse rather than after a short duration, and a lot of variability, both positive and negative in terms of these outcomes. A very important study, but one with difficult endpoints, both positive and negative, to my mind.
Another study, this is a single randomized prospective study, the so-called KEEPS study, this is the Kronos Early Estrogen Prevention Study, is now more than 10 years following the end of this study, and this 10-year follow-up is what’s reported in this paper by Gleason et al and a number of experts in hormone therapy.
This, as I mentioned, was a head-to-head comparison of early menopausal women who received, for about four years, either transdermal estradiol in the form of a patch or oral conjugated estrogen daily, which had no effect over the 10-year follow-up in terms of the issues of cognitive function. The findings were beautifully displayed in these distribution plots for verbal learning and memory, auditory attention and working memory, visual attention and executive function, speed of language processing and mental flexibility, and then, again, the Mini Mental State Examination.
Their conclusions were that there were no long-term cognitive effects of short-term, that would be the four years, of menopausal hormone therapy started early in menopause versus a comparable group of individuals randomized to placebo, and they could not find any long-term benefit, or more importantly given the point of view of the Women’s Health Initiative study, could not find any harm associated with short-term use of menopausal hormone therapy. And their conclusion was it should not be recommended to preserve cognitive function, at least in a similar population and of four years duration.
Next study on my list was a very important one looking at the possible use of menopausal hormone therapy in breast cancer survivors. This was a safety report on a systematic review and meta-analysis. This study, while one of the unique ones in our current discussion and unique in the literature, is far from perfect, but does give all of us some reassurance that hormone therapy can be safe in a subgroup of breast cancer survivors.
This is clearly not standard of care, and as a result, I would hope that those of you listening are very careful about the use of menopausal hormone therapy in breast cancer survivors, but it does provide some evidence that it can be safe in a subgroup of individuals. Without going into the details, that was their conclusion. And in particular, those with hormone receptor-negative cancers could users of menopausal hormone therapy in selected limited cases. That’s an important change from our normal approach, from the labeling of menopausal hormone therapy in the US, and does provide some shelter or benefit for those of us in the trenches treating severely-affected menopausal women who are breast cancer survivors.
The next study is menopausal hormone therapy beyond age 65, recalling that the Beers Criteria, which emanated from the current FDA approved-labeling of hormone therapy and the results of the Women’s Health Initiative, say that women over 65 should not be using hormone therapy. This study by Bake et al looked at this issue both by types of hormone therapy, routes of administration, and doses, and they concluded, showing here the results over the course of several years from 2007 to 2020, just how hormone therapy utilization has changed in the US, largely decreasing, transdermal therapy decreasing to a lesser degree than oral, but overall decreasing over that 13 or so year period.
But they found in their study that the risk reductions appear to be greater with low-dose therapy. Remember, we’re talking about women 65 years of age and older. Risk reductions, not risk increases, were low and better with low-dose therapy compared to medium or high-dose therapy, with vaginal or transdermal therapy compared to oral preparations, and estradiol compared to conjugated equine estrogens. These are all important endpoints and largely consistent with the first study I showed you vis à vis use of hormone therapy and cardiovascular disease. Their conclusion is that hormone therapy is relatively safe even in women receiving treatment who are over the age of 65.
Now, nobody ages exactly the same. I am fond of asking patients, “How old do you think I am?” Because I typically appear younger than my chronologic age. Well, this study by Liu and Li looked at age as biological age using a series of biomarkers rather than approaching age simply as a number based on your date of birth. They used biologic age in terms of assessing risks and benefits of hormone therapy. A very interesting approach, in my opinion. This also published in August of last year.
They wanted to ask the population, based on the UK Biobank, some 118,000 postmenopausal women, whether using a surrogate of age, both chronological and, in this case, biological, might make differences in our understanding of risks and benefits and menopausal hormone therapy. And to cut to the chase, the answer is, yes, chronological age predicts risk and benefit, but in fact, biologic age may predict it even better, and it turns out that the improvements or differences between chronological and biological age are easiest to find and largest in those of a lower socioeconomic status. Perhaps a sensitivity analysis on that endpoint is worth another paper.
A few other papers I wanted to briefly mention, this is tooting my own horn a little bit, but Elinzanetant, an NK-1 and NK-3 antagonist, not a hormonal, is being developed for the treatment of vasomotor symptoms associated with menopause. This study published in JAMA last year documents the efficacy studies from the two pivotal randomized clinical trials, OASIS 1 and OASIS 2, documenting that this compound, Elinzanetant, which is under review at FDA, could safely and effectively reduce both the frequency and severity of moderate to severe vasomotor symptoms in menopausal women compared to placebo.
This study, very interesting one, looked at the effect of transdermal testosterone, not on sexual desire, which is the single most commonly analyzed and most effective use of transdermal or oral testosterone, but in this case on mood and cognitive symptoms. I emphasize this study for two reasons. First, one, that it’s looking at two other endpoints, mood and cognitive symptoms, some of the patients were perimenopausal, some of them were postmenopausal, but more importantly, this is what can be done out of one’s private practice, not some big university center, not some large randomized clinical trial, and not some meta-analysis of published trials. This was done out of a large UK-based clinical practice, simply looking at the endpoints of a treatment in actual patients from the clinics.
It demonstrated that testosterone could reduce the prevalence of various peri and postmenopausal women’s mood and cognitive symptoms, reductions in feeling tired or loss of energy, reductions in mood problems, concentrating problems, feeling nervous, feeling irritable, feeling depressed, loss of interest in many things, attacks of anxiety or panic, crying spells, and loss of interest in sex, the most commonly investigated, all reduced by adding testosterone, transdermal in this case, to women already on hormone therapy.
In summary of all of this, what did we learn in 2024 that we might use going forward in 2025? First, that menopausal hormone therapy has significant cardiovascular benefits, particularly in younger, early menopausal women, that it’s relatively safe, transdermal being safer than oral, estrogen alone, safer than estrogen plus progestin, and that there are further some differences by the actual amounts and types of those therapies.
Menopausal hormone therapy is likely to improve some aspects of cognitive function when started near the last menstrual period, with estrogen having a better or more positive effect than estrogen plus progestin, but these endpoints on cognitive function seem to be highly variable and difficult to assess. Menopausal hormone therapy appears to be safe in healthy post-menopausal women, even those over age 65 and in a subgroup of breast cancer survivors. Good news for older breast cancer survivors. And hormone therapy may reduce biological age, and its benefits may be greater in those of lower socioeconomic groups compared to higher socioeconomic groups.
Elinzanetant 120 milligrams may be one of the newer agents that can significantly improve vasomotor symptoms. Secondary endpoints in those studies showed that it improved sleep and quality of life compared to placebo. And testosterone therapy, in the US we do not have an FDA-approved testosterone therapy, much to my dismay and despite 30 or more testosterone preparations for men, but transdermal testosterone therapy in post-menopausal women on estrogen may have improved mood and cognitive symptoms, and in addition to a reduction in their complaints about lower sex draw.
With that, I’d like to conclude and thank you all for listening to my opinions about what’s happened and what’s been of benefit to our knowledge and our future practice in menopause in 2024.
For more information about menopausal health, contact Dr. Simon at IntimMedicine Specialists. To schedule an appointment, call our office at (202) 293-1000 or message us here.
