Hormone Replacement (R)evolution Part 2: Timing

In the last post we discussed the results of the WHI Trials (http://www.nhlbi.nih.gov/whi/), the most commonly quoted studies regarding hormone replacement therapy (HRT) risk for menopausal symptoms. We defined the hormones used in those trials (estrogens from horse urine (CEE), and progestin) and briefly talked about the importance of placing this information in context. To be clear, we have learned a great deal from the WHI, and subsequently HRT has evolved.  However, women remain confused about what, exactly, has evolved and how this relates to them. Particular to any patient’s mind are issues of safety. Despite the reassurance that new options exist, women remain unclear about the key ways in which they are new options.

In specific, strides have been made to determine:

§  Safer candidates for therapy.

§  Safer ways to take HRT.

§  Safer dosing that still helps with symptoms.

§  Safer specific hormone combinations (bioidentical vs non-bioidentical, single vs combination therapy).

Today we discuss what we have learned about who is a safer candidate for therapy and who should not start therapy.

Smoking Risks:

Studies show women who smoke and take HRT are at increased risk of both lung cancer and blood clots. The progestin, medroxyprogesterone acetate, used in the WHI is responsible for a large percentage of the clotting risk seen in these women. However, estrogen also carries clotting risk and smoking increases this risk.

Personal History of Breast Cancer:

Early, early, research and observation suggested estrogens were protective for breast cancer and possibly helpful in breast cancer survival.  The non-bioidentical hormones used in the WHI were shown contribute to breast cancer risk. This was one reason for ending the trial, and taking women off of HRT. Ultimately the culprit was primarily the types of hormones used and the types of breast cancer the patients had. The progestin used in the WHI certainly increased the risk of breast cancer in women with no personal history of this issue. This would make progestin’s use in both survivors and healthy menopausal women unfavorable. Many people debate natural progesterone’s place here. Some say it is beneficial, others say it is risky. Estrogen whether bioidentical or otherwise does cause breast cells to grow and can lead to cancer recurrence in survivors. This may be more so with specific types of breast cancer. In healthy women with no risk factors it does seem to carry breast protective benefits if used correctly with the right estrogen.  Data is limited on this issue. Given that risk is possible here, one would be hard-pressed to find a provider who would prescribe HRT to a woman with history of breast cancer. Current thought is that HRT results in increased risk of cancer recurrence in this population. This recommendation may change in the future. It may depend on the type of hormone given and the method of delivery. For example, some providers may feel comfortable with low dose vaginal estrogen therapy for vaginal symptoms in certain groups within this population.


Hormones are not advised with clotting disorders.

Cardiovascular Disease:

Initially thought to be protective against cardiovascular disease, the hormones used in WHI were found to contribute to cardiovascular risk. This is another reason the trial was abruptly stopped. Since that study, the cardiovascular benefits have been clarified. There is significant cardiovascular benefit to HRT, but it all comes down to when hormones are started and making sure that medroxyprogesterone acetate is not used as the progesterone component. Bioidentical hormones are key to providing benefit. The most important factor is age (please see below). The longer the body has gone without exposure to natural hormones (time since menopause), the less the benefit in starting them. This is followed closely in risk by the choice of progestogen (progesterone component) used. While studies are still slow to evaluate the use of natural progesterone here (there isn’t really a financial incentive to do so), there is some basic science evidence that suggests the cardiovascular benefits of estrogen would be preserved and perhaps enhanced with the use of natural progesterone. Estrogen itself carries the bulk of the cardiovascular benefit. These benefits are completely negated by medroxyprogesterone acetate, making it a dangerous choice of progestogen.


Similar to the cardiovascular story, WHI showed increased risk of dementia with use of HRT. Again, it appears to all come down to the age at which a woman first starts HRT. The longer one waits, the more risk.

Age, The Biggie:

Women, on average, enter menopause in their early 50’s. Many of the body’s natural hormones decrease rapidly around this time.  These decreased hormone concentrations are the cause of menopausal symptoms like night sweats, hot flashes, mood changes, etc., which motivate a woman to make an appointment to talk to their doctor. Let’s contrast this to the WHI. The average age of women given high doses of non-bioidentical HRT medications in the WHI, was 63. These women were receiving relatively high doses of oral hormones for the first time. That is about 12 years beyond the time when most women usually begin HRTWhy is this significant?

§  Some suggest that hormone receptors may change, or decrease in number during the healthy menopausal time. It is unclear exactly what combination of things is happening here, but we do see more risks with starting HRT the longer one has been menopausal, and many have suggested it is due to hormone receptor activity.

§  The WHI was studying women who, on average, were starting HRT 12 years after they would have entered menopause and normally requested hormones. This is not representative.

§  When follow-up trials assessed benefits of HRT in women who started therapy at a younger age, similar risks existed, but were much less significant.

Bottom Line:

In healthy, menopausal women, assuming no other risk factors, the most benefit for HRT is seen when it is started as close to onset of menopause as possible. Many providers consider the risks to outweigh the benefits of HRT after about 5-10 years of treatment (in women who started therapy close to menopause.) However, how long to take HRT is still being debated. In fact, the North American Menopause Society (NAMS) describes when to wean women off HRT to be the biggest challenge in HRT prescribing. Some conventional providers have become outspoken advocates for starting some form of HRT at any age if there is a specific reason to do so and leaving women on therapy past the 10 year mark. The profound benefits for a woman’s bones as she ages should be considered in older women, especially in light of the emerging side effects of osteoporosis medications. Low dose estrogen may be a great fit in older women who are low risk candidates for HRT. As well, quality of life is huge. HRT can have a enormous impact on sense of wellbeing while aging.


 In addition to timing HRT appropriately, we must also consider other factors such as:

§  How the hormones are taken.

§  Dose of hormones taken.

§  What specific hormones are used.

Next week we will talk about how hormones are taken. Conventional and compounded HRT have moved beyond pills, and it has been an important step


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Shannon Hirst