Menopause Updates

As a functional medicine practitioner, the #menopause transition is viewed by me as a physiologic state, much like pregnancy and puberty, and any symptomology that results in discomfort is thought of as a reflection of one's overall health and wellness. Entering these stages of life in an unhealthy state, with fatigued adrenals or gut dysbiosis for example, will certainly provide a less than optimal experience. Guiding a client back into an optimal state of being would be my primary goal in managing menopausal symptoms and certainly my focus as one begins perimenopause, as to avoid any negative experiences; however, for a variety of reasons, it may be helpful to understand a more conventional approach. Potentially more acute relief is required or the woman's overall state of health is more critical and in need of more aggressive medical management. This post will address those states, more so than review how one might optimize their foundational health from a functional medicine perspective.

The Women's Health Initiative released results of their #hormone therapy research in 2002 and it received tremendous media attention, scaring the hell out of the entire women's health profession. Prempro (combination of estrogen and progesterone) scripts dropped by 66% and Premarin (estrogen) scripts dropped by 33%.

Since this time, there has been some evolution in the mindset of supporting women with hormones through what can be an exceedingly difficult life transition. In 2012, the North American Menopause Society (NAMS) revised its position and stated that the risk-benefit analysis of menopausal hormone treatment should be individualized and that the benefits of hormone therapy may outweigh risks when initiated around the time of menopause and used for three to five years.

Later, in 2015, NAMS released an updated statement saying that for women older than 65 years, hormone therapy should not be discontinued solely on the basis of age, but should instead be individualized based on consideration of risks and symptoms. The American College of Obstetricians and Gynecologists (ACOG) updated its position in 2014 to reflect a more liberal approach to hormone therapy during this menopausal transition.

Midwives & Menopause

The #midwifery profession is often thought of as a speciality limited to catching babies to the point that the scope of practice seems to be even less broad than the entry level registered nurse. More often than is even comical, I had to respond to people who belittled the profession that we are capable of much more than simply boiling water.

Midwives are ideally suited to provide care to women through and beyond the menopausal transition, because we are clinicians who place emphasis on women-centered care, shared decision making, non-biased counseling, and extend incredible priority to detailed informed consent.

Menopause is defined as the last menstrual period which is unknown until that first year passes, which averages at about 51 years of age. Perimenopause is the time prior to that last menses when which women are experiencing symptoms, typically two to eight years prior to menopause, and postmenopause is the time following that last menstrual flow. The menopausal transition is climacteric, referring to both the perimenopausal and early postmenopausal stages when vasomotor symptoms are most likely to occur.

Our ovaries contain a finite number of follicles, and menopause occurs when follicular reserve reaches a critical lower threshold of about 1000 follicles. As the ovarian follicles are unable to respond to the hypothalamic-pituitary stimulation, estrogen and progesterone production decreases in the ovary and pituitary gonadotropin (follicule-stimulating hormone) increases. Progesterone is the first to decline. Generally this happens prior to the onset of one's menses, as progesterone is typically highest at this time. During that perimenopausal transition then, these women will start to see more significant premenstrual syndrome symptoms.

Estrone (E1), Estradiol (E2), and Estriol (E3) are our primary estrogen hormones with estrone being the most dominant of the group after menopause, but it is weaker overall. Estradiol is the dominant estrogen during our childbearing years, offering protection to our cardiac health. Estradiol is the cause of breast development and ovulation. This is also the form of estrogen which essentially disappears with menopause, bringing about our symptoms and inviting increased cardiac risk.

Typical symptoms of menopause include changes in the spacing between each menstrual flow, as well changes in the duration and amount of flow. Night sweats without daytime vasomotor symptoms may occur early in the perimenopausal stages, and then later, menses begins to space to as much as two months apart. Changes in bone metabolism, reproductive function, vasomotory symptoms, atrophy of the smooth triangular area at the base of the bladder between the openings of the ureters and urethra (trigone) are changes that are ominous with loss of reproductive steroids.

Hormone Therapy

Hormone therapy is the administration of systemic or local #estrogen with or without progestogen used to treat the symptoms of menopause. Progestogen is a broad term that includes both natural progesterone and synthetic progestins, and when both are being discussed, the more specific term is typically used. When providing systemic estrogen, a progestogen is used to prevent endometrial hyperplasia and cancer in women who have an intact uterus. Low-dose, topical, vaginal estrogen may be given without a progestogen, but any vaginal bleeding after menopause must be thoroughly investigated if it occurs.

After the WHI study, experts theorized that potentially they were simply prescribing too potent of a regime, so potentially, decreasing estrogen to just 14 days may prove advantageous? Some clients do have the low progesterone though, and may even suffer insomnia due to it, so supplementing progesterone on days that estrogen is withdrawn may be helpful. Medroxyprogesterone acetate (MPA) 2.5-10mg, 2.5mg daily if continuous estrogen, or for 14 days is an option, as is norethindrone acetate 0.1-1mg by mouth daily. Progesterone micronized 100-200mg at bedtime for at least 12 days out of every month as a vaginal suppository can help provide endometrial protect if applied at least 10 days/month at 4% (45mg/day) or every other day at 100mg/day for three to five years. My clients have shared that this does help them sleep when taken prior to bed, but also that it is quite messy. Transdermal micronized progesterone does not provide the endometrial protection. There are providers, particularly those who specialize in bioidentical hormones, who will pack a great deal into these vaginal suppositories, which is super convenient, but this can not protect the uterus. These clients will be at risk of endometrial carcinoma if not offered additional support.

Selective estrogen receptor modulators (SERMs) are emerging as an alternative to progestogens, having the potential to prevent endometrial hyperplasia without increasing breast cancer risk. Bazedoxifene is a great option, at 0.45mg/20mg daily, which is a conjugated equine urine product, but evidence is quite supportive of its use. This product is tissue-selective, providing estrogen without the progestin, without inviting risk to the uterus while reducing breast cancer risk. Osphena (Ospemifene) is another SERM, which is specific to vulvaginal dryness, at 60mg each day, with food. This is estrogen-like, but is not in fact, hormones.

Previously, I shared a bit about E1 and E2, neither of which are FDA-approved for supplementation. E2 is well known for increasing the risk of breast cancer in those who are overexposed, which may mean these women initiated their menses at a really young age or endured those years longer than most, such as beyond the age of 55 years, or they did not undergo pregnancy or #breastfeeding which would have reduced exposure to E2. Estrone or E1 is developed in our adipose or fatty tissue so those with higher adiposity or obesity are at greater risk for breast cancer because of this ongoing exposure.

#Estriol or E3 is the dominant estrogen when we are pregnant, made by our #placenta, and this is really where the controversy comes with regards to supplementation. This is not currently FDA-approved in the United States for supplementation, but it is in Europe and Asia. There are hundreds of research articles available on this particular estrogen, primarily as a vaginal estrogen, but no FDA-approval. It is therefore only available by compound pharmacies, via prescription.

Interestingly, when one is pregnant, they find they have better hair growth, a pregnancy glow, and even increased vaginal discharge, which is likely why there is more research on vaginal estrogen E3. Pregnancy also offers improved immunomodulary responses or pro-inflammatory cytokines. We see that women with autoimmune diseases, such as #Lupus, seem to improve during pregnancy. Soon after pregnancy resolves however, relapse often return abruptly. E3 is not as potent as E2 and so it is not as cardioprotective, nor is it as good for the bones.

There are a number of benefits women may attain from hormone replacement therapy. Therapy can also be pertinent for those with increased cardiovascular risk or with various cancer risks, bone disease, or even diabetes. One meta-analysis found combined hormone therapy reduced type two diabetes almost 40 percent with lower fasting glucose levels and levels of HgbA1c. Weight gain increases by about five pounds upon entering menopause even when eating and exercising the same. This gain was abdominal as well, so the conclusion here is that hormone therapy can improve metabolic syndrome.

Vasomotor Symptoms

Otherwise understood as hot flashes or flushes, vasomotor symptoms involve an abrupt sensation of heat and flushing in the upper body followed by perspiration and chills, occasionally with associated #anxiety and heart palpitations. These might disrupt sleep, work, and overall quality of life. Eight percent of women experience some level of symptoms during their menopausal transition, and half of all women experience these frequently enough to disrupt their daily well-being. When experienced, these symptoms typically endure for an average of 7.4 years, but can last well into the seventh decade for some women.

The gold standard treatment here, is the conventional combination birth control pill, offering the client ethinyl estradiol supplementation. The concern is that this amount and type of estrogen is really quite potent, which might not be optimal for someone in their later childbearing years, who may already have higher cholesterol, maybe even hypertension or pre-diabetes. For this reason, although the current gold standard, this isn't my first choice for women.

Genitourinary Syndrome of Menopause

This is otherwise known as vulvovaginal atrophy or atrophic #vaginitis. GSM is the broader term, which includes vaginal dryness, vulvovaginal atrophy, and the urogenital changes related to the local tissue effects of loss of estrogen on the trigone. These symptoms are chronic and progressive, causing loss of tissue elasticity and decreasing aperture and length of the vagina, which can lead to discomfort, even pain, with intercourse. Many women notice a reduced desire for sex, increased urinary tract infections, and urinary incontinence. While many women do continue regular sexual activity utilizing a water-soluble lubricant, most women without any supplemental vaginal estrogen will find these symptoms worsen with age.

Both systemic hormone therapy and low-dose vaginal estrogen replacement can increase lubrication, blood flow, and sensation of the vaginal tissues. Systemic hormone therapy does not improve sexual function, sexual interest, arousal, or orgasmic response in women without menopause symptoms. If sexual function or libido are concerns in women with menopause symptoms, transdermal estrogen therapy may be preferable over oral estrogen therapy because of less effect on sex hormone binding glubulin (SHBG) and free testosterone levels. Low dose vaginal estrogen therapy improves sexual function in postmenopausal women. For those women who seek to avoid hormone therapy, there are non-estrogen alternatives approved for dyspareunia, including ospemifene and intravaginal DHEA (Intrarosa). Given vaginally, these have had the same effects of estrogen and testosterone. These are synthetic, but the evidence demonstrates that these have not increased systemic levels.

Osteoporosis

As reproduction steroids decrease with age, bone mineral density declines. Osteoporosis is diagnosed when the T-score is -2.5 (test question), which occurs in twice as many women as men because of the relatively sudden and absolute reproductive hormone loss, rather than gradual loss that men experience. Screening begins at age 50 years in women with risk factors. The US Preventive Task Force and National Osteoporsis Foundation recommends beginning dual-energy x-ray absorptiometry bone density scans at 65 years for those without high risk.

Evaluating for Menopause Clinically

Menopause is generally thought of as a state of diminishing estrogen, but in the transition, women can have elevated estradiol levels during the luteal phase of their menstrual cycle, which could give false reassurance of fertility. During perimenopause, FSH can vary as well, from month to month. Serum results are unreliable diagnostic tools.

Women typically visit their care provider during their menopausal transition for changes in libido, mood, cognition, or due to weight gain. Although these concerns may be secondary to #vasomotor symptoms and subsequent insomnia, they are not necessarily specific to menopause and so, the clinician should be diligent in ruling out other underlying causes. Obesity, coronary vascular disease, venous thrombotic events, reproductive organ cancers, depression, and dementia are other potential causes, independent of menopause. A thorough health evaluation really is necessary, so unfortunately, although many clients do call requesting I recommend labs, this is a very dangerous approach to managing this stage in a woman's life.

When one is initiating menopause and their estrogen is declining, they may experience increased anxiety, arthritis, decreasing breast size, decrease in memory, decrease in sexual interest, depression, elevated cholesterol, more wrinkles, osteoporosis, stress incontinence, and vaginal dryness, whereas, when estrogen is high, women experience bloating, fatigue, elevated risk of breast cancer, fibrocystic breasts, heavy periods, irritability, mood swings, poor sleep, swollen breasts, and weight gain. This latter scenario can occur when a client is prescribed too high a dose of estrogen replacement, but some women are just naturally a little higher. This may result from hormone imbalance for whatever reasons related to diet and lifestyle choices as well. Low progesterone will present like high estrogen, most especially just prior to menses. Supplementation at this time can be helpful.

Progesterone declines as we enter menopause as well, which also invites anxiety and depression, excessive menstruation, insomnia, irritability, mood swings, pain and inflammation, as well as weight gain. High progesterone can cause incontinence, increased appetite, increased #carbohydrate cravings, and relaxes the smooth muscles of the gut leading to constipation and bloating. These are quite similar to premenstrual symptoms. High progesterone is true to pregnancy as well.

Systemic hormone therapy is indicated within conventional medicine for treatment of vasomotor symptoms that interfere with one's quality of life and do not respond to other alternative options, such as behavioral interventions (removing layers of clothing, paced breathing, avoiding triggers). It is also indicated for prevention of osteoporosis in women who cannot take bisphosphonates. If a woman's only concern is GSM, then a low-dose estradiol can be prescribed in a vaginal cream, tablet, or ring. This management doesn't have an appreciable effect on the uterine endometrium and may be used without a progestogen. ACOG has even shared that women who have a history of estrogen-dependent breast cancer can even be offered this regimen, if other non-hormonal treatments are not effective. Topical estrogen can be added even when systemic treatment is being used, and sometimes even in breastfeeding women, as a local therapy for better tissue effect on the trigone.

Hormone therapy is generally started after the age of 45 years, although one must be aware that if pregnancy is still a possibility, #contraception should be considered. Combined oral contraceptives, such as the ring or patch, can help alleviate vasomotor symptoms and GSM, as well as offer the advantage of providing contraception. The IUD is often used during the menopausal transition and women often share that they arrived into menopause without ever having experienced a perimenopausal symptom. The literature seems to suggest that while it can help prevent unwanted pregnancy and even treat heavy menstrual bleeding, it will not relieve vasomotor symptoms or GSM. It also seems to offer endometrial protection.

The decision to continue hormonal therapy should be reevaluated annually. If hormone therapy really does seem to be the best approach for managing the client's current symptoms, then discussing options and preferred routes of administration is most appropriate. Certainly for my clients, we seek to address any underlying imbalance, evaluate lifestyle choices, and consider a plethora of botanical medicines, but progesterone may be most appropriate for some.

After the publication of the initial WHI results, due to significant media input and interpretation, a great deal of misinterpretation resulted, even by clinicians. Women were abruptly discontinued from their therapy and suffered needlessly. An overestimation of the risks for women less than 60 years of age and for those at low risk for cardiovascular disease and breast cancer occurred. Since this publication, clinicians, researchers, and even women have reevaluated the data, looked at long-term outcomes from this study, and reconsidered the risks and benefits.

This fairly straight-forward study addressed a complex issue within women's health. When the age group of women from 50 to 59 years was evaluated specifically, it was shown that therapy for them reduced their overall mortality, but they did have increased venous thrombotic events, breast cancer, and cardiovascular disease. We can't really extrapolate results from data that wasn't provided though, as only two hormone formulations were studied. In other studies, #depression, anxiety, and even atherosclerosis have reduced with low doses immediately after menopause. Women taking higher doses or hormones for more than five years, did show some increased risk for coronary vascular disease and breast cancer.

Newer Options for Menopausal Management

Pharmaceutical companies have invested in identifying new ways to meet the needs of women following the published researching implicating breast cancer and cardiovascular disease as risks with ongoing therapy. Bazedoxifene is a SERM with agonist-antagonist properties which works to prevent endometrial hyperplasia in place of the progestin. Ospemifene is an oral SERM approved by the FDA for treatment of moderate to severe dyspareunia. This medication is especially appealing to women at risk for breast cancer, as it has neutral effects in this tissue. It does however, carry a blackbox warning regarding deep vein thrombosis and increased risk of endometrial cancer. A small number of women experience vasomotor symptoms while using this product.

Dehydroepiandroesterone is now available as a 6.5-mg vaginal capsule and has been shown to improve vaginal dryness, and even moderate to severe discomfort with sexual intercourse. Desire, arousal, orgasm, and satisfaction were all improved in addition to dyspareunia and lubrication.

Estrogen is available as a pill one takes by mouth, as a transdermal patch, a spray or a gel. It can also be taken vaginally as a cream, tablet, ring, or in some countries, as a pessary. Progesterone is also available orally or in combination patches with estrogen, via injectables, vaginal gels, or tablets. Non-oral routes of administration may offer potential advantages because non-oral routes bypass the first-pass hepatic effect, but there are no head-to-head random control trials to validate this theory but overall, there is significant research.

Bioidentical & Custom-Compounded Hormones

Following publication of the risks of conventional hormone therapy, more and more women began treatment utilizing bioidentical hormones. Sales were in excess of $800 million dollars within a year of the 2002 WHI publication. In fact, management of #bioidentical hormones has become a very popular boutique type of service that many women's health practitioners now offer.

These are typically prescribed in response to serum or saliva testing, and one study estimated these types of scripts account for 28% to 68% of all hormonal prescriptions, although there is no evidence that compounding is more appropriate or has fewer risks than standard pharmaceutical-grade products.

The thought though is that this salivary testing can allow for a more specific dosing, better individualizing one's treatment plan, but here too, there is no scientific evidence to support this is safer or more effective. Keep in mind, much of disease management is offered without supporting evidence but this should be part of the informed consent process when discussing options with women.

The term #bioidentical implies that the product comes from a plant source and is identical to the human hormone. Consumers are rarely cognizant that plants do not make human hormones, and the process of conversion of plant products in a laboratory is an entirely synthetic derivation. Bioidentical is compared directly to synthetic, however, it may be a bit of a stretch to believe this product is more natural or safer than current pharmaceutical options. Even some medications can be classified as bioidentical based on current definition.

However, because we are what we eat and so many women feel security in botanical healing, there is peace for many in understanding that bioidentical hormones are derived, even if synthetically processed, from yams and soy beans whereas synthetically-derived hormones are the product of a pregnant mare's urine. There are FDA-approved bioidentical hormones as well.

Interestingly, while you can get 17B-estradiol (rather inexpensively) in both a patch and oral form, many experts will argue that if the hormone is oral, then it is not considered bioidentical, because once these move through the first pass in the liver, they are converted to estrone (E1), hit different receptors, which may increase risk for a cardiovascular events. The patches available are bioidentical, and the transdermal patch, Vivelle-Dot is FDA-approved as a bioidentical hormone replacement therapy. The micronized progesterone oral or vaginal are also bioidentical which would include your Prometrium, which is generic. Keep in mind, this is micronized in oil to make it better bioavailable, and this is typically a peanut oil. If a peanut-allergy is present, a compounding pharmacy can create this using a different oil. The patches and gels are oftentimes covered by third party payers.

Consider then that troche also bypasses the digestion through the mucous membranes, via saliva, which is thought to be about 50 percent of its absorption. Sublingual drops would be similar. Subdermal pellets are really quite the rage currently, but there are many practitioners who are giving really high doses. When a client is seen who is already utilizing this therapy, I like to evaluate their hormones and specifically look at their estradiol, which should not be higher than 600 and that's when ovulating. A post-menopausal woman should not be measuring at a 2000 level for example. These are quite expensive, and not well understood with regards to dosing.

Testosterone

Sexual interest does decline with age, although this could be related to aging as well as hormonal decline. Testosterone supplementation has been utilized to address sexual dysfunction, and off-label use of reduced amounts of transdermal products developed for men appears to be more effective than older oral formulations. One fairly good sized study did demonstrate that testosterone supplementation can significant improve sexual satisfaction, and no adverse events resulted, although women did report acne, hair growth, and site reactions.

Symptoms of lower testosterone in clients can often look like anxiety, fatigue, loss of pubic hair, mild depression, weight gain, and decreased sex drive as mentioned previously. Elevated testosterone, such as those with polycystic ovarian syndrome, often demonstrate anger, agitation, clitoromeagaly, hair loss, facial hair/hirsutism, acne, and voice changes. Pellet therapy is another way clients will experience high levels of testosterone, which may also cause rage. Unfortunately, these can't really be taken out, so one has to just sort-of wait for it to wear off.

The North American Menopause Society (NAMS) does not really address testosterone therapy. There is a synthetic testosterone available, which is FDA-approved for vasomotor symptoms in those who haven't found success with other options or estrogens alone. This is not bioidentical, as it is a cream. There are no testosterone creams available which are FDA-approved, so these must be compounded.

Non-hormonal Treatments for Menopausal Symptoms

When women are at high risk for #cardiovascular disease or breast cancer, or have a preference for avoiding hormonal therapy, low-dose paroxetine or other SSRIs can be utilized for the treatment of vasomotor symptoms. When the SSRIs are contraindicated, gabapentin, pregabaline, or a clonidine patch may prove helpful. Black cohosh, isoflavones, and #ginseng are additional options.

Prevention of #osteoporosis is an important long-term goal; however, although hormonal treatment is beneficial in preventative, it is not currently recommended after the age of 60 years. Bisphosphonates are first-line medications for the prevention and treatment of osteoporosis. SERMs, calcitonin, RANKL inhibitors, or teriparatide may also be appropriate alternatives if there are no contraindications. Adequate calcium (1200 mg/day) and vitamin D are essential for bone health.-ll

Contraindications for Hormone Replacement Therapy

Certainly the WHI publication created a great deal of fear among practitioners and healthcare consumers. We do need to be cautious and respectful, but there are certainly benefits to women who utilize these supportive therapies. The contraindications are: unexplained vaginal bleeding, severe active liver disease, prior estrogen-sensitive breast or endometrial cancer (rarely this does occur but in consultation with a specialist), coronary heart disease, stroke, dementia, thromboembolic disease, porphyria cutanea tarda, hypertriglyceridemia, and concerns that endometriosis (already a high estrogen state) might reactivate. Migraine headaches may worsen (sometimes it can help) and leiomyomas (estrogen dependent) may grow with hormone therapy.

Potential risks may occur for those younger than 60 years that may be different if they are over 60. For example, if a woman enters menopause at the age of 45 years and desires hormone replacement therapy at 55 years, this would potentially be appropriate because the cardioprotective benefit is significant, and she's closer to ten years post-menopausal, but if this woman is 65 years and now wants hormonal therapy, at twenty years post-menopause, then as a practitioner, it would be important to understand her coronary-artery risk. Women only suffer menopausal symptoms about 7.5 years though, so at this point, she is unlikely to be suffering twenty years post-menopausal. Other risks with bioidentical hormones include endometrial hyperplasia and #cancer if estrogen is unopposed or inadequately opposed. Venous thromboembolism, biliary issues, heart attack, stroke, and dementia are additional risks.

FDA-Approved Indications for HRT

Hormone replacement therapy is approved for vasomotor symptoms, prevention of bone loss, premature hypoestrogenism, and genitourinary symptoms. When a woman endures premature hypoestrogenism, or early menopause, they will have less risk for breast cancer but increased risk for cardiovascular disease. Therefore, under the age of thirty-five years, these women should be offered hormone replacement therapy until they are 52 years of age for cardiovascular disease.

Regarding genitourinary symptoms, hormones are really utilized sufficiently for this purpose. If a woman is experiencing frequent urinary tract infections, then replacement can be significant for them in reducing this risk. Even with a history of estrogen-dependent breast cancers, this treatment is being utilized because as a vaginal cream, there is very, very little exposure. Of course, use with caution. Endometrial hyperplasia is a potential.

Evolving Recommendations

Hormone therapy has demonstrated a safe option for women within ten years of menopause who are at low risk of cardiovascular disease and breast cancer. As long as women remain at low risk of cardiovascular disease and breast cancer, hormone therapy does not need to be discontinued based on age alone.

Local low-dose estrogen without the addition of progestogen can be used to relieve symptoms of GSM. This can be initiated at any age and used indefinitely. There are also new SERM products for both systemic treatment and vasomotor symptoms and dyspareunia associated with GSM.

Ward, K., & Deneris, A. (2018). An update on menopause management. Journal of Midwifery & Women's Health, 63, 168-177.