Activity Transcript

Segment 1

Tobie de Villiers, MBChB, MMed (O&G), FRCOG (UK), FCOG(SA)​: Hello. I'm Tobie de Villiers. I'm a consultant gynecologist in private practice and part-time consultant at the Department of Obstetrics and Gynecology, Stellenbosch University, Cape Town, South Africa. Welcome to this first talk of this activity and this is about the benefits of menopausal hormone therapy.

Menopausal hormone therapy (MHT) is indicated in menopausal women when the expected benefits of the treatment are anticipated to be greater than any possible adverse effects. It is thus essential that the prescriber be able to judge expected benefit in an individual menopausal woman when on menopausal hormone therapy. This section will be based on the global consensus statement regarding menopausal hormone therapy. Although this was published in 2016, it still embodies the opinions of all the major menopause societies in the world. The consensus statement states that menopausal hormone therapy including tibolone and the combination of the conjugated equine estrogens and bazedoxifene (CE/BZA), are the most effective treatments for vasomotor symptoms associated with menopause at any age. But benefits are more likely to outweigh possible risks if it is initiated for symptomatic women and before the age of 60 years, or within 10 years after menopause. It further states that quality of life, sexual function, and other menopause-related complaints such as joint and muscle pains, mood changes and sleep disturbances, may improve during hormone therapy.

The uncontested evidence illustrating the beneficial effects on the reduction of these symptoms is illustrated in the following slides. In this study of a 6-month double-blind, placebo-controlled crossover study, we can clearly see the beneficial effects of estrogen in the first 3 months in contrast to that of the placebo patients, whereas the opposite happens when they crossover after 3 months. We also see that hormone therapy works in a dose-responsive manner. In other words, on placebo there's virtually no effect except the placebo effect, but as the dosage is increased, we see increasing improvement in the reduction of symptoms. We also see that when menopausal hormone therapy is compared to placebo again, as well as to black cohosh, as well as red clover.

How does this happen? Recent research has shown that a chemical pathway involving neurokinin B and neurokinin-3 receptors is involved in the development of hot flashes, where it interacts with the temperature controlling center in the brain. Neurokinin B binds to the neurokinin-3 receptor to stimulate its effects. In postmenopausal women, estrogen deficiency increases neurokinin B, so that the pathway is overstimulated, leading to flashes and sweats. Estrogen therapy prevents or reverses overstimulation of this pathway and thus prevents the vasomotor symptoms. New non-hormonal agents, which act against this pathway, are currently in development.

The statement further says that menopausal hormone therapy is effective in the treatment of vulvovaginal atrophy, also called VVA, now considered as a component part of the genitourinary syndrome of menopause or GSM. Local low-dose estrogen therapy is preferred for women whose symptoms are limited to vaginal dryness or associated discomfort with intercourse, or for the prevention of recurrent urinary tract infections. Some women on systemic MHT may also require additional local vaginal estrogen.

How does it work? Well, menopausal hormone therapy reverts vaginal tissue back to the premenopausal state. This study using tibolone also shows the effect of menopausal hormone therapy on lowering the incidents of vulvar or vaginal symptoms, sexual symptoms, as well as GSM. In terms of bones, menopausal hormone therapy has been shown to significantly lower the risk of vertebral and other osteoporosis-related fractures in postmenopausal women. It can be initiated in postmenopausal women at risk of fracture or osteoporosis, or even osteopenia if they fall within the window of opportunity. If they're above the age of 60, it is considered second-line therapy and use requires individually calculated benefit-to-risk ratios compared to other approved drugs.

We can see here how the placebo results in the loss of bone density in postmenopausal women whereby in a dose-responsive way, menopausal hormone therapy increases bone mineral density. These are the results from the Women’s Health Initiative (WHI) study, which showed how the combination of CE and medroxyprogesterone acetate in this case significantly reduced the risk of all osteoporosis-related fractures.

In terms of cardiovascular benefit, we know that in estrogen-alone dosages, menopausal hormone therapy may decrease the risk of myocardial infarction and all-cause mortality when initiated in the window of opportunity. This is supported by randomized clinical trials and observational data. When we get to progestogen plus estrogen therapy, we have less compelling evidence for both the benefit and the cardioprotection. The evidence here is less robust with inconsistent results compared to the estrogen-alone group.

It works by lowering the LDL cholesterol, triglycerides and raising the good guys, the HDLs. In body composition, MHT prevents accumulation of central and visceral adiposity. It improves glucose tolerance, lowers the risk of metabolic syndrome and actually reduces blood pressure. The ELITE study from Howard Hodis showed that hormone therapy significantly reduces the progression of subclinical atherosclerosis only if started in the early menopause, but not if started in the late menopause. The WHI study also showed us the addition of medroxyprogesterone acetate, the progestin actually attenuated the beneficial effects of estrogen alone.

We now also know from the 18 years cumulative data of the WHI, that all-cause mortality is not raised by menopausal hormone therapy, and it's actually reduced if started in the window of opportunity with younger patients. In terms of this cognition and depression, we know that menopausal hormone therapy has no real substantial effect on cognition, but if started early enough, it can or maybe prevent Alzheimer's disease in later life. It is beneficial in improving mood in early menopause and women with depression or anxiety. If major depression is present, it will help, but an antidepressant therapy remains first-line treatment. Colorectal cancer is also reduced in the setting of menopausal hormone therapy and that's true for any formulation. We also know that menopausal hormone therapy reduces gum disease in a study of 492 osteoporotic women treated for osteoporosis with menopausal hormone therapy. The treatment was associated with significantly lower rates of gum disease resulting in a lower risk of tooth loss.

That, ladies and gentlemen, are the substantial benefits that can be gained by hormone therapy in the menopause. It is now up to Tommaso Simoncini in the next session to draw attention to some of the negative effects. Thank you very much for the opportunity to present.

Segment 2

Tommaso Simoncini, MD, PhD: Hello. I'm Tommaso Simoncini, professor and chair of obstetrics and gynecology at the University of Pisa, Italy, and the past president of the European Menopause and Andropause Society. Welcome to this session, "Valid Concerns: Breast Cancer and VTE, the Evidence in Perspective."

So menopausal hormone therapy (MHT) has been used for many years because of the many advantages, but the publication of a trial from the WHI showing the risk of breast cancer and deep vein thrombosis, drove reduction in use. Let's see why this is of concern. So why is estrogen favoring deep vein thrombosis and pulmonary embolism? One of the major reasons is because most estrogen preparations are taken orally, so it goes into the gut and from the gut, it goes directly to the liver. This drives the synthesis of clotting factors, fibrinogen, von Willebrand factor, and reductions in clotting inhibitors. This drives activated protein C resistance, which facilitates blood clotting. And in most studies, if you put them together, the relative risk for this phenomenon is about 2 with a range between 1.5 and 4. So this hepatic first-pass metabolism is very important.

However, the characteristics of the patient also have an impact. The first one is age. So, if you look at the prevalence of venous thromboembolism (VTE) in the population, you can see that in the graph, the incidence of VTE is basically stable up to the age of 60, both in males and in females, and then it tends to go up afterwards. The usual age range when we use MHT is between 50 and 60. So most women will be candidates for this therapy in this age range. So, if you apply that relative risk of 1.5 to 4 to the baseline risk of a 50-year-old woman, you will find that you have about the risk of 1 out of a 1,000 cases of women per year of DVT or pulmonary embolism, which would go up to 1.5 to 4 if these women use MHT. Now, the numbers change significantly with increasing ages. So, the first concept is that younger women have lower risks.

Then there's also a matter of the route of administration. So, if estrogens are not provided orally, but they're provided transdermally with gels and patches, then all these phenomena linked to the liver activation disappear, and you do not have any increased risk of a venous thromboembolism. This is actually shown in this slide quite well. This is the summary of the 4 major trials, comparing the effects on deep vein thrombosis of oral estrogens, as compared to transdermal estrogens. And it is quite clear that in all these studies, women receiving menopausal hormone therapy through the skin did not have any increased risk of pulmonary embolism or DVT, which is very important. And last but not least, MHT is also, in general performance, a combination of estrogens and a progestin in those women who have a uterus. Now, you all know that progestins are many different types of molecules. They have different chemical variations. And it's very important to appreciate that the type of progestin used in MHT, may also make a difference in terms of deep vein thrombosis risk. For instance, this is one of the major studies conducted on more than 80,000 women, the E3N French trial, where you can see that women receiving oral menopausal hormone therapy containing progesterone, did not show any increase in the risk of DVT, while those receiving pregnanes while it was not significantly increased, it was slightly higher, and with the norpregnanes it was significantly higher. So, the progestin makes a difference, you have to be aware of that.

So, the other part of the presentation is on breast cancer. Is it a matter of concern? Of course it does, because estrogen and progesterone are hormones that are tightly involved in breast development. And there is, from a mechanistic standpoint, a multitude of ways that can explain how estrogen and progesterone would promote breast cancer cell growth. So recently, a very large meta-analysis confirms the data of the Women's Health Initiative Trial, showing that the impact of estrogen alone in menopause hormone therapy, is not there. But showing also that women receiving, in all the trials conducted so far, a combination of estrogens and progestins, do have a much sharper increase in breast cancer. There's a statistical difference between these groups of women, highlighting that the progestin might be very important in terms of breast cancer development.

And do we have any data on whether it makes a difference whether you use a certain type of progestin? We are starting to have this data. This is a very interesting and recent study showing that depending on the type of progestin, there's a difference in the incidence in breast cancer. Indeed, women receiving MHT containing MPA, levonorgestrel or norethisterone acetate, show depending on the length of the therapy, different but increased risk of breast cancer. But in those receiving dydrogesterone, which is a very commonly used progestin that is more similar to natural progesterone, there was no risk seen up to at least 4 years of administration, while just a slight risk and much less than with those other progestins for those women using dydrogesterone in the UK for more than 5 years. So, this is very significant and calls for future investigation into these differences.

So, I'd like to conclude with providing you also with some concepts of communication, because when we communicate the risk of a disease, it's very important the way we do it. For instance, if you take some of the most important studies that have highlighted an increased risk of breast cancer, and you communicate the risk in terms of risk ratio or percentage, say a 1.5 risk ratio or a 50% increase in the risk, we communicate a certain type of message to the patient, to the woman. But if we actually translate that into absolute numbers, this is in excess of 2 additional cases for each 1000 women receiving hormone therapy for 5 years.

So let's try to translate this into numbers. So these small women are actually a 1,000 women in a single slide. Those in red, are those women who will actually develop breast cancer risk at 70. So the relative risk in these 1,000 women, when they're 50, to develop breast cancer up to the time when they get 70 in terms of age, is 63 over 1,000. So this is the baseline number. So if you actually provide to all these 1,000 women menopausal hormone therapy for 5 years, you have 5 additional cases. So the risk moves from 63 to 68. Not that impressive in terms of the big picture. And if you actually provide menopausal therapy for 10 years, then the additional cases are 10 as compared to those 63. This is the effect based on the studies that we have with MHT. So let's try to compare with some of the common risk factors. For instance, being overweight means drives an additional risk of 26 cases. So this is much more important in absolute terms in driving and increasing the risk of developing breast cancer in this group of a 1,000 women. And if you drink 2 drinks every day for between age 50 to age 70, then the additional cases would be 26. So again, much more important than the impact of 5 years of menopausal hormone therapy. Now, what is most important, if those women would be regularly physically active, then there would be a reduction of 18 cases. So being physically active and being overweight or drinking alcohol carries a modification of risk of breast cancer, which is far more important than the risk attributable to the use of MHT.

Thank you for your attention, and please continue on to watch the next session with Professor Susan Davis.

Segment 3

Susan Davis, AO, MBBS, FRACP, PhD, FAHMS: Hello, my name is Susan Davis. I'm an endocrinologist and I'm professor of women's health and director of the Women's Health Research Program at Monash University in Melbourne Australia. Welcome to this section where I'm going to be talking about some of the myths and practicalities around menopausal hormone therapy.

So, our patients have a number of fears and concerns when we bring up the topic of hormone therapy and managing menopause. And it's really important to address these concerns and to reassure women. So, women are extremely uncertain about menopausal hormone therapy, primarily because there have been years of conflicting and confusing information. In order for you to reassure your patients, you need to be comfortable about the facts yourself. You need to listen to women's concerns with empathy and then confidently reassure them about the safety for them as an individual. It's really important that you can prescribe with confidence because that in itself will reassure your patients about the appropriateness of the treatment you are recommending.

So, to begin with, there's a lot of internet chatter about natural hormone therapy. And it's really important to explain to patients that there's no such thing as an estrogen or a progesterone plant and that all hormone therapy is made in the laboratory, even when claims are made that the hormone alternative is natural. I often talk to my patients about vitamin C being so-called natural, but you'd have to eat a large number of oranges to get the amount of vitamin C that's in a single tablet and that the tablet is made in a laboratory. But then I explain to my patients that progesterone was first made from a Mexican yam, and the alternative for example of dydrogesterone is also synthesized and manufactured by treatment of progesterone with UV light. So, most of the hormones we are prescribing do have a natural origin.

One of the most common concerns women also express is the fear of weight gain. It's important to step patients through this. Menopause itself causes an increase in subcutaneous fat and redistribution of fat from the hip and the thigh into the waist. This will occur even if women do not gain weight. So, on average, women have an increase in their central abdominal fat in the order of 20% to 40%. It's important to reassure patients that menopausal hormone therapy does not increase weight. And in fact, does the reverse, it reduces central fat accumulation. One of the best examples of this comes from a study over 3 years, that was undertaken to determine whether hormone replacement therapy would reduce the risk of cardiovascular events in women with preexisting heart disease. Now, in this study, women were randomly allocated to either estrogen tablets with progestin or placebo, and they took the treatment for 3 years. The women on the hormone therapy arm had less weight gain, less central abdominal fat increase and less increase in hip circumference. So, it is one of the classic examples that proves that estrogen therapy, if anything, protects against weight gain and certainly does not increase central abdominal fat or cause weight gain.

Now, many women actually would like to continue to have regular menstrual cycles. So, it's important to discuss with the patient what their expectation is with respect to hormone therapy, ask them if they feel more comfortable having a regular cycle or whether they would like their bleeding to stop. Now, of course, women who have very heavy menstrual bleeding are going to want to generally stop having menstrual cycles. What I have found is very pragmatic in approaching this is that when I first commence women on hormone replacement therapy, even if they're more than 12 or 24 months from menopause, I tend to initiate with a cyclical regimen. I have found personally that this reduces the patient calling back and saying, "I have breakthrough bleeding on the continuous combined therapy." So, I start with 1 or 2 cycles of cyclical therapy induce a bleed and then move the patient onto continuous combined therapy, if they are more than 12 months from the last menstrual period.

Your patients might also ask you whether menopausal hormone therapy causes heart disease and high blood pressure. I reassure my patients that this is indeed not the case. And as you have just heard, MHT is not associated with either increased cardiovascular disease or stroke mortality. So, you can be quite definite about reassuring your patients that this is a myth, not a reality that there's any connection. Now, some women might experience fluid retention with menopausal hormone therapy. And the trick here is to defer to using a progestogen that has a mild diuretic effect. And these include progesterone and drospirenone and indeed, dydrogesterone also has a borderline diuretic effect. But importantly, it is vital that even before commencing hormone replacement therapy, you identify and treat any cardiovascular disease risk factors your patient might have. As oral estrogen does tend to increase triglycerides, we would generally prefer to use a non-oral estrogen in any woman with preexisting diabetes, but these women can certainly have estrogen replacement therapy. 

So, what there is a lot of confusion about is the duration of therapy. The concept of stopping menopausal hormone therapy after 5 years was a bit of a knee jerk reaction in response to the very early papers from the Women's Health Initiative study that suggested that 5 years of menopausal hormone therapy increased breast cancer risk. And as a hangover from this, so many doctors are still telling their patients that they must stop after 5 years or that they must stop when they reach the age of 65. What we do know is that estradiol alone was not associated with an increased risk of breast cancer in women who have had a hysterectomy with an average duration of use of 7 years in the WHI studies. For women with a uterus who need estrogen plus progestin, it's very reassuring to be aware that there was no increased risk of breast cancer in the WHI studies in the women who had not previously used hormone therapy before entering the study. So, in a nutshell, the idea that a woman must have her hormone therapy stopped at 5 years is very arbitrary and really not strongly supported by the available evidence. What matters is the duration of use should be related to whether or not a woman's symptoms have resolved. And in addition, one should take into account a woman's long-term risk of bone loss after cessation of therapy. And that's more likely in a woman that is of normal or low body weight that you'll have more rapid bone loss as a consequence of menopause and hormone therapy in that instance is highly protective.

So, the duration of use depends on the individual symptoms and their risk in terms of bone loss. Finally, the duration of risk for someone who's experienced menopause before the age of 45 is universally agreed to be at least until the average age of menopause, which in most countries is around the age of 50. This to prevent premature bone loss and premature cardiovascular disease and death. So, I emphasize when with early menopause should continue therapy, at least until the average age of menopause in the community.

So, just finally concluding with some general tips, women often come with many questions, or sometimes they're not even sure of the questions that they should be asking. It's very difficult to take in a vast amount of information that you are likely to impart during the consultation. So, I suggest you refer your patients to reliable information sources. For example, the International Menopause Society has a YouTube channel with short information videos that cover the array of issues women often raise as questions. You can refer women to your national menopause society website, where again, there is likely to be credible information. Suggest that your patients might write down questions after the consultation so that they can bring them to the next consultation so they can ask again in person. I think it's also valuable to advise your patients to be wary of uncredentialed websites and therefore unreliable internet information, which is often scaremongering and can be misleading, and therefore refer them back to websites or resources that you feel confidence will give credible information.

Thank you for your attention. And please continue on to watch the next section with Doctors Antonina Smetnik and Yu Qi.

Segment 4

Antonina Smetnik, MD, PhD: Hello, I'm Antonina Smetnik, head of the Department of Gynecological Endocrinology in Moscow, Russia.

Yu Qi, MD: And I'm Professor Yu Qi from Peking University College Hospital. I'm a professor of gynecological endocrinology and reproductive medicine. Welcome to this section, "Case Studies in Menopausal Hormone Therapy." We have 2 cases here, the first case is a 50-year-old woman, menopausal of course, frequently experiencing hot flushes and sweating. She had no personal history of VTE, but is concerned about it. The second case is a woman of 53 years old. She has a personal history of venous thromboembolic disease 1 year ago. She also has hot flushes, sweating, and GSM symptoms. So how should we deal with these 2 cases?

We all know that the risk factors of VTE occupy a lot of aspects and MHT (menopause hormone therapy) is one of them. The absolute risk of oral MHT is rare below the age of 60 years old, far less than the risk of VTE in a normal pregnancy. In order to mitigate risk with routes of administration, we can use transdermal estrogen. There's a lower risk of VTE with use this route, but oral estrogen is contraindicated in women with personal history of VTE. And the dosage of estrogen is also a big factor. The higher the dose, the higher risk of VTE. The duration of progesterone may also contribute to the risk of VTE, and the type of progesterone may also influence the VTE risk.

There is a unique characteristic that Chinese woman, including the Asian woman, the incidence of VTE is lower, much lower than the rest of the world. This is due to the genetic factors. Population screening of thrombophilia is not indicated prior to MHT use, especially in Asia. Selective screening may be indicated in the basis of personal and family history.

In this 50-year-old woman, she has frequent hot flushes, but no history of VTE. So, we can tell the patient the absolute risk of venous thromboembolic events with oral MHT is low below age 60 years old. And the incidence of VTE is less frequent among Asian women. So, if she is an Asian woman, she has no concern or minimal concerns about a VTE event. And third thing we should tell the patient is that without a high risk of VTE, they can be treated with oral estrogen. So that's our recommendation.

For the case with history of VTE, she has a history of VTE 1 year ago, but has already been cured. So, in this case, we can tell the patient that active venous or arterial thromboembolic diseases in the past 6 months, are contraindications to MHT. So, if she had the history of thrombosis within the last 6 months, she cannot use any kind of MHT. Transdermal estrogen can be considered if it is more than 6 months after VTE. So, oral estrogen therapy is contraindicated in that woman with personal history of VTE and transdermal estrogen does not increase the risk of VTE. So transdermal estrogen can be considered.

Dr Smetnik: Thank you, Dr Yu for that interesting case. We will move on now to a case involving breast cancer risk. A 53-year-old patient is experiencing bothersome vasomotor symptoms and poor sleep that leads to mood swings and poor concentration at work. She's postmenopausal for 2 years. She's otherwise healthy and physically active. Her BMI is 22. Her past history is significant for wrist fracture at age 47, following a fall. She has 1 healthy daughter, who is 26 years of age. Family history is significant for osteoporosis (via her maternal grandmother) and breast cancer (via her mother at age 60). The patient is anxious regarding possibility of height loss, similar to her grandmother, but is even more concerned about her risk for breast cancer, given her maternal history of breast cancer at age 60. How should we counsel this patient at what management options are available to address the patients concerns and minimize the risks?

So definitely this woman has the indications for menopausal hormone therapy. In terms of safety, we should take into consideration: the type of menopausal hormone therapy, dose, duration of use, regimen, route of administration, prior exposure, and individual characteristics. First of all, we should consider if she has any contraindications for menopausal hormone therapy. Of course, the breast cancer risk should be evaluated before MHT prescription. Greater risks of breast cancer are observed in some cases with MHT, however this may be decreased by selecting women with a lower individual baseline risk, including low breast density, and by providing education about preventive lifestyle measures.

The results of her mammogram, BI-RADS assessment category is 2. Any BI-RADS category 2, it is a defined benign finding, and it is not expected to change over the follow up interval. The usual screening follow up is recommended. And the breast density is normal, ACR-B. And the pelvic examination, pap smear and routine blood tests are without pathology. We perform DXA (dual x-ray absorptiometry) and find the T-score in the lumbar spine and femoral neck as -1.9. And we can calculate FRAX (fracture risk assessment).

This patient is not a candidate for BRCA1 or -2 gene mutation testing, since she has only 1 blood relative with breast cancer at the age of 60, which is not at a young age. Our patient even doesn't need to change the frequency of her mammograms due to menopausal hormone therapy. Since this woman is postmenopausal and has a uterus, I would suggest continuous combined estrogen progestogen therapy or as an option conjugated equine estrogen with bazedoxifene, which is not available in all countries. Low dose, but not ultra-low as we need not only symptoms reduction, but also a fracture risk reduction. And of course, we need to make the right choice of progestogen.

Three studies suggest that micronized progesterone or dydrogesterone could be associated with a lower risk than synthetic progestogen. According to the latest nested case control studies for women aged from 50 to 59 years using estradiol with dydrogesterone, there is no increased risk of breast cancer for up to 5 years. I would suggest oral route of administration as one of the easiest for the patient to take and adhere. And there is no difference in terms of breast cancer risk between oral or transdermal estrogens. For example, a fixed combination of 1 mg of estradiol and 5 mg of dydrogesterone, 1 tablet a day.

Next time we can meet in a few months to discuss the efficacy, adherence and any side effects. Women taking MHT should have at least an annual consultation to include a physical examination, update of medical and family history, relevant laboratory and imaging investigations, a discussion on lifestyle and strategies to prevent or reduce chronic disease. There is currently no indication for increased mammographic or cervical smear screening for these women. No arbitrary limits should be placed on the dose or duration of usage of MHT. Individualization with shared decision making remains key with periodic reevaluation to determine an individual woman's benefit risk profile.

Thank you, Dr Yu for your interesting case, and thank you for your attention. Please continue on to answer the questions and complete the evaluation.