Timing is Everything in HRT for Menopause

Estrogen HummingbirdThe current landscape for Hormone Replacement Therapy (HRT) is a confusing one.

Pharmaceutical industry marketing, conflicting study data, variable medical opinions, and confusing social messages about gender and aging have left many modern women completely baffled about what to do when faced with the challenges of menopause.

Physicians today need to sort through a lot of noise to help their patients find the best treatment. Post-menopausal HRT can, indeed, be helpful to some women. But doctors and patients alike need to be realistic about it, says Dr. Joel Evans, Director of The Center for Functional Medicine in Stamford, CT.

HRT is neither the fountain of youth it was touted to be in the 1970s and 80s, nor the wolf in sheep’s clothing as it was made out to be in the early 1990s, said Dr. Evans, speaking at the 2019 Integrative Health Symposium. The pendulum of opinion is swinging back toward a more favorable albeit more nuanced view (see A (Relatively) Short History of HRT)

Evans stressed that the timing of HRT is one of the most important factors in determining whether the potential benefits of treatment will outweigh its risks.

When considering HRT, keep in mind that as women age, their risk increases for a wide range of diseases, but the protective effect of hormones tends to decline over time. In most cases, the greatest benefit of HRT will be obtained early on in the immediate post-menopausal years. Continuation over the long term typically gives diminishing returns.Joel Evans MDJoel Evans, MD, Founder/Director, Center for Functional Medicine, Stamford, CT

Dr. Evans, founder of the Mighty Menopause line of nutraceuticals, outlined the most logical way to discern whether or not a woman needs hormone therapy before and during menopause. To make clear decisions, you need to consider the following:

  • History, history, and history (medical, family, environment)
  • What does the blood say?  
  • Lifestyle factors: diet, stress levels, exercise 
  • Preexisting and ongoing medical issues 

Capturing a detailed family history is crucial. As Dr. Evans put it, familial menopause stories are antecedents. “There is a good correlation between menopausal age in mothers and daughters and between sisters, suggesting genetic factors play an important role in determining menopausal age,” he said.

Pay close attention to family histories of and risk factors for osteoporosis/osteopenia, cognitive decline, and cardiovascular disease.

HRT & Heart Health

With respect to the heart, there’s no question that estrogen is vasoactive, and that it has anti-inflammatory properties. There are data showing that 17β-estradiol inhibits expression of CRP in injured arteries, and reduces oxidative stress in arteries and vascular smooth muscle.

But these effects are not uniform over the course of a woman’s lifetime—and remember that these days, a woman is likely to spend one-third of her full lifespan in menopause.

Estrogen’s effects are different in older women. Where it was once anti-inflammatory and vasoprotective, it can become pro-inflammatory and vasotoxic as a woman ages. From this perspective, HRT may give its greatest cardiovascular benefit early in the menopausal transition.

“Early menopause is associated with adverse cardiovascular outcomes, so starting HRT in perimenopause might reduce these outcomes. The vasoprotective effects of estrogen are age-dependent and disappear with aging and/or estrogen deprivation.”

This age-related shift could explain the highly variable data from interventional studies looking at HRT and CVD. In its 2017 Recommendation Statement on this subject, the US Preventive Services Task Force notes that while observational evidence suggests that HRT is cardioprotective, the data from the Women’s Health Initiative and several other trials have not supported that conclusion. 


“Pooled results of 3 trials reporting on the risk of coronary heart disease in women randomized to combined estrogen and progestin versus placebo (N=18,081) showed a higher risk of coronary events in women who took hormone therapy during a mean follow-up of five years,” wrote the USPSTF authors. They added, however, that this risk elevation was not statistically significant (Grossman DC, et al. JAMA. 2017: 318 (22): 2224-2233).

In its 2013 guidance document on Hormone Therapy and Heart Disease, the American College of Obstetricians & Gynecologists (ACOG) also acknowledged that timing matters. “There is some evidence that lends support to the ‘timing hypothesis,’ which posits that cardiovascular benefit may be derived when estrogen therapy or hormone therapy is used close to the onset of menopause.”

However, ACOG’s general position, reaffirmed in 2015, is that “Menopausal hormone therapy should not be used for the primary or secondary prevention of coronary heart disease.”

With regard to atherosclerosis, timing is again a key factor. Early in the atherosclerotic process, estrogen exerts protective effects on the endothelium and retards plaque formation, while late in the process can lead to plaque erosion or rupture with subsequent thrombosis and acute coronary events, Evans explained.

To complicate matters, the type of estrogen used carries its own risk-benefit profile. The data are most supportive of estradiol for prevention of atherosclerosis and CVD. An analysis of data from more than 489,000 post-menopausal Finnish women indicates that estradiol-based HRT cut CHD-related deaths by 18%, stroke by as much as 39%, and all-cause mortality by 12% (Mikkola TS, et al. Menopause. 2015; 22(9): 976-983).

Dr. Evans said that he takes the timing hypothesis data seriously when working with his patients. For women at high risk for CVD—but at low risk of breast cancerhe encourages initiation of HRT within the first five years of menopause. These patients can safely continue HRT for up to10 years. During that time, he works with them to implement dietary and lifestyle changes to reduce CV risk.

Whenever possible, he prefers to have his patients stop HRT sooner—within 2-5 years.

Bones to Pick

Moving on to bone health, Dr. Evans explained that at menopause, bone turnover is impaired by estrogen deficiency, a situation that might call for HRT.

Estrogen benefits bones in several ways: it lowers sensitivity of bone mass to parathyroid hormone (PTH), thus reducing bone resorption; it increases the production of calcitonin and thereby inhibiting bone resorption; and it reduces calcium excretion from the kidney.

So, it is reasonable to think that post-menopausal HRT would benefit women’s bones.

A 2015 metanalysis of 57 trials (approximately 10,000 women) concluded that hormone therapy (both opposed and unopposed estrogen) does indeed result in higher bone mineral density (BMD).

But one must consider the matter of BMD and fracture risk in the context of each patient’s overall health. For an older woman at high risk of CVD and breast cancer, the potential downsides of HRT may outweigh the bone benefit.

Again, the age at which a woman begins HRT seems to be a critical factor for bone protection.

A 2017 position statement from the North American Menopause Society (NAMS), holds that HRT is beneficial for bone health in younger patients. “For women aged younger than 60 years or who are within 10 years of menopause onset and have no contraindications, the benefit-risk ratio is most favorable for treatment of bothersome VMS and for those at elevated risk for bone loss or fracture.”

For older women (over age 60 or 10 years beyond menopause) the risks of CVD, stroke, and venous thromboembolism begin to overshadow the other benefits, according to NAMS. In these patients, HRT is justified for bone protection only if there is clear evidence of significant bone loss.

That view is supported by a Cochrane Review, also published in 2017, which concludes that although hormone therapy is effective for the prevention of postmenopausal osteoporosis, it is recommended as an option only for women at significant risk for whom non-estrogen osteoporosis therapies are unsuitable.

And ACOG? Well, the organization doesn’t mention HRT at all in its osteoporosis treatment recommendations.

There’s another factor at play in the post-menopausal bone health equation, one that many physicians overlook: celiac disease.

According to Dr. Evans, roughly one-third of all adults with celiac have osteoporosis at time of diagnosis, and another third have osteopenia. On average, people with celiac have lower BMDs than those without the disease. Before jumping to HRT as protection against osteoporosis, check for and address celiac disease or other conditions associated with nutrient malabsorption.

A No-Brainer?

What about HRT to prevent cognitive decline? Evans says current evidence is inconclusive. It is not clear whether estrogen deficiency causes or contributes to age-related learning and/or memory loss.

Estrogen does affect cognition in three ways: 1) through classic genomic mechanisms; 2) intracellular signaling mechanisms; and 3) neurosteroids.

It can also change brain morphology by increasing brain derived neurotrophic factor (BDNF), particularly in the prefrontal cortex and hippocampus. Think of BDNF as the brain’s “fertilizer.” It helps maintain signaling pathways, and protects and maintains the growth of nerves and brain cells.

From this standpoint, Dr. Evans believes estrogen is neuroprotective and that replacing estrogen after menopause can mitigate age-associated changes in cognition.

That said, the literature on the subject is variable, and there’s no clear evidence-based consensus once you delve into the studies. “Whether lack of estrogen is a main contributor to age-related learning and memory loss is, at this time, not fully known,” he told the IHS audience.

There is some evidence to support HRT for cognitive benefits. For example, a double-blind study of 52 peri- and post-menopausal women showed that estrogen replacement increased blood oxygenation in the prefrontal cortex, leading to fewer errors on verbal and spatial working memory tests (Hara Y, et al. Physiol Rev. 2015; 95(3): 785-807).

But overall, the jury’s still out. NAMS holds that in the absence of more definitive evidence, “HT cannot be recommended at any age to prevent or treat a decline in cognitive function or dementia.”

As with CVD, there seems to be a window of opportunity for obtaining the positive neurocognitive effects of estrogen, Dr. Evans says.

In line with the so-called “critical period” hypothesis, there is evidence to suggest that HRT must be given close to the onset of menopause in order to exert its positive brain effects with the lowest overall risk.

“Previous studies of HRT in Alzheimer’s disease, and the WHI study of women aged 65 years and older, and at least 15 years past normal menopausal age, which used conjugated equine estrogens, did not show improved cognitive functioning,” Evans pointed out. However, other trials of 17β-estradiol given shortly after onset of menopausal symptoms do show significant effects on verbal and working memory.

He cited a 2005 study by Bagger and colleagues showing that estrogen replacement for 2 to 3 years immediately following menopause led to a 64% reduced risk of cognitive impairment in 5-15 years (Bagger YZ, et al. Menopause. 2005; 12(1): 12-7).

The Functional Medicine Approach

The functional medicine approach to menopause takes a science-based, patient-centered approach. The symptoms that emerge following the natural depletion of sex hormones are very important to consider, but they are only pieces of the larger puzzle of a woman’s health; they’re not the whole picture.IFM HRT stoplight

The Institute for Functional Medicine promotes a “stoplight” approach to assessing the risks and benefits of HRT:

Red Light (high risk): These are patients for whom HRT is a bad idea because they have one or more of the “classic” contraindications: uncontrolled genital bleeding; history of breast cancer; history of estrogen-dependent endometrial cancer; deep vein thromboses or pulmonary embolism; thromboembolic diseases; or impaired liver function.

Yellow Light (medium/variable risk): These patients might potentially benefit from HRT, and do not have any overt contraindications, but they have indicators suggesting that HRT could be problematic: family histories of breast cancer; mammographically dense breasts; elevated baseline estradiol; genetically based anomalies in estrogen metabolism, methylation, or hepatic detoxification; multiple high-risk lifestyle factors.

Green Light (minimal risk): These women are typically younger, and recently entered menopause. They experience significant vasomotor symptoms, but have no direct contraindications, significant risk factors, or lifestyle variables that raise concern.

For women in the “yellow light” category, breast cancer risk is at the top of the list of considerations.

Assessing Breast Cancer Risk

Obviously, it is important to look at baseline hormone levels, including DHEAS, testosterone, insulin, estrogen and progesterone, and their metabolites. Dr. Evans advises paying close attention to E2 levels, and to work with patients to improve E2 detoxification pathways. Borage and or Evening Primrose oil can be helpful, as can iodine supplementation.

Other lab values like c-reactive protein and leptin are also worth measuring when considering HRT.

Genetic analysis can also provide valuable guidance. Beyond the obvious “breast cancer genes” such as BRCA 1 and 2, there are a number of single nucleotide polymorphisms (SNPs) that are worthy of consideration: CYP 450 1A1, 1B1, 3A 4/5; COMT, MTHFR.

Breast tissue density is another important variable. Women with mammographic breast densities of 75% or greater are at 4-6 times greater risk of developing breast cancer, regardless of family history. This seems to be associated with specific polymorphisms in the COMT Val158 Met gene.

It is equally important to consider lifestyle factors: smoking, overweight, high alcohol consumption, low intake of fruits & vegetables; high intake of dairy, red meat, processed meats, high fat foods, and lack of physical exercise. All of these are modifiable—at least in principle.

In cases where a woman’s risk is largely due to lifestyle variables, diligent effort toward a healthier lifestyle—elimination of high-fat dairy which is strongly associated with breast cancer riskcould ultimately move her from the Yellow Light to the Green Light category for HRT.

HRT does give benefits for menopause symptom relief, CVD, cognition and bones provided that a patient is low-risk and that she starts treatment within the first 2-3 years of menopause.

Once you and your patient reach a decision that HRT is a “go,” you must face host of other questions about the ideal form of HRT: Oral, transdermal, or intravaginal gel? Unopposed estrogen versus estrogen plus progesterone? Custom-compounded “bioidentical” versus standard pharmaceutical products? Dosing?

Based on his extensive review of the HRT literature and his own clinical experience, Evans contends that for many patients, transdermal E2 plus micronized progesterone is the most effective combination with the lowest risk profile. However, this is not a universal rule. The choice of hormones, relative doses, and modes of delivery all need to be individualized.

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