Hormone Replacement (R)evolution Part 2: It’s About Timing

Last week 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 these 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 it has changed.

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 or possibly could be helpful in breast cancer survival. More recent data shows that, specifically, estrogen acts to increase breast cell proliferation resulting in potential negative effects on breast cancer survivors. 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 survivors unfavorable. Many people debate natural progesterone’s place here. Some say it is beneficial, others say it is risky. 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.

Clotting:

Hormones are not advised with clotting disorders. Also, similar to oral contraceptives, body mass index of greater than 30 increases the risk of clotting with hormone use of either of these types.

Cardiovascular Disease:

Initially thought to be protective against cardiovascular disease, the hormones used in WHI were found to contribute to cardiovascular risk. Since that study, the cardiovascular benefits have been clarified. There is 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. 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 with the use of natural progesterone. What is certain is the cardiovascular benefits of estrogen are  completely negated by medroxyprogesterone acetate, making it a dangerous choice of progestogen.

Dementia:

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 hormones for the first time. That is about 12 years beyond the time when most women usually begin HRT. Why 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, the duration of therapy is still being debated. In fact, the North American Menopause Society (NAMS) describes the optimal duration of therapy to be the biggest challenge in HRT prescribing. UPDATE: The most recent edition of the journal Menopause confirmed that younger menopausal women have less risk with taking HRT. 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