• Taking a much lower dose of hormone than in the past.
• Taking a bioidentical hormone medication.
• Using a patch, cream, or spray to deliver this hormone to your system.

Lower doses of HRT have been shown to carry less breast cancer and clotting risks than their original counterparts.  So, how did researchers decide on the dose of hormone to use in the original trials? How much less hormone are you taking now with the newer medications?

How was the original HRT dose determined for the WHI? What did we learn?

Even early doses of HRT were significantly less hormone than could be found in an oral birth control pill. However, these early doses still represent more hormone than is currently used for HRT today.  The original dose of HRT used in the Women’s Health Initiative trials (WHI) was derived to provide the optimal osteoporosis protection. The estrogen used was called Premarin ® This name comes from PREgnant MARes’ urINe. These are non-bioidentical estrogens from horse urine (also known as conjugated equine estrogens [CEE]). They are quite potent estrogens. Originally in HRT prescribing there was no real concern about cardiovascular risk (in fact improved heart health in women taking HRT was anticipated), and while there was  some suspected breast cancer risk, it was not assumed to be as significant as it turned out to be. Therefore when estrogen and progestin doses were established for the WHI:

• Osteoporosis risk was the top priority.
• Menopausal symptom relief also ranked high on the list.
• Suspected cardiovascular benefit was also included in the decision process.

The choice of progestin dose was made only for the purpose of balancing estrogens in the uterus to avoid cancer of the endometrium.  At that time there were no distinctions made between different sources of progestogens (the class of hormones that includes progesterone and synthetic progestins) and it was thought that variants in this class should be relatively similar. Therefore, the widely available medroxyprogesterone acetate (MPA) was chosen. The actual dosage used in the WHI trials was 0.625mg of CEE and 2.5mg of MPA. Since that time it has been noted that breast cancer risk and clotting risk of HRT are reduced with lower doses of HRT used transdermally. Additionally, the cardiovascular risk of the higher dose oral hormones used in the WHI actually transforms into cardiovascular BENEFITS with lower dose, transdermal HRT in younger women taking a better progestogen.

What has changed?

Since the poor results from the WHI on the hormones listed above, bioidentical estradiol has become preferred by most providers, both conventional and alternative.  The oral dose of estradiol in newer HRT prescriptions is about half of the equivalent dose of estrogens used in the WHI. More exciting, however, the dosing of transdermal estradiol preparations is just a small fraction of the oral dose of the original estrogens used in the WHI. They even have a name for these new low doses. They are called “ultra low dose estrogen replacement therapy.”  If 0.625mg of CEE was used in the WHI, current transdermal estradiol systems can deliver as little as 0.025mg a day. Vaginal preparations deliver even less hormone with excellent symptom relief. All of it bypasses the liver. This is a huge difference. In terms of progestogens, the quality of these hormones has improved so drastically, no real dose equivalents can even be made. The now routine use of bioidentical progesterone here is a significant step forward regardless of dose. If there is one thing that can’t be stressed enough it is this: medroxyprogesterone acetate should be avoided in routine HRT prescribing. It carries substantial risk. Natural progesterone, if available and tolerated well, performs so differently it is not a fair comparison.

Summary of HRT dose:

• While WHI doses of hormones are now considered high, they were still lower doses of hormones than could be found in birth control pills
• Bioidentical estradiol tends to be the estrogen of choice in current HRT. This is used most preferably in a transdermal patch or cream at a fraction of the dose used in the WHI. These decreased doses do not compromise symptom relief and provide significant reductions in risk from HRT.
• The progesterone component of HRT has changed so drastically it now has nothing to do with dose, but the quality of the hormone used. New generation progestins and, most importantly, natural progesterone have completely changed the face of combination HRT (estrogen + a progestogen).

What happens to hormones taken as oral pills?

When hormones are made in the body, they enter directly into the bloodstream and make their way to tissues where they are utilized and processed. When we take hormones as oral pills, something different happens. They enter the blood leaving the stomach and intestines and go straight to the liver first. This results in a unique ratio of processed hormone forms that is not identical to the ratios seen when we make the hormones ourselves. It is this initial processing by the liver which many feel accounts for a significant amount of the risk seen in the WHI. The mechanisms for this risk are continuously being investigated and revised in search of safer medication options. However, the bottom line is, oral dosing of HRT, particularly estrogen, has become less favorable in both the conventional and alternative medical communities. This has resulted in a plethora of safer, easy to use, and well tolerated options for many women.

What are the options, if not pills?

Both estrogen and progestogens (the name of the class of hormones which contains progesterone) have different options for delivery.

Estrogens:

• Transdermal. This means via the skin. Transdermal methods include: patches, creams, sprays, and gels. Many of the conventional transdermal options are low-dose bioidentical  estradiol. Some bioidentical brand names include (not a complete list): Vivelle-Dot®, Climara®, Menostar®, Estrace®, Divigel®, Evamist®.
• Nasal spray
• Vaginal:  these come as rings, tablets, gels, and creams. Many of the conventional vaginal options are also low-dose bioidentical estradiol, although CEE is still used. Some bioidentical brand names include (again, not complete): Vagifem®, Estrace®, Estring®.

Progestogens:

Progestogens vary greatly. Bioidentical progesterone exists in several forms (including oral), but other conventional options fall on a wide spectrum in their relationship to this hormone. Some of the newer versions of this class are more true to the key characteristics of the natural progesterone. It is safe to say that progestogens are getting much better, but there are still some practitioners using the medroxyprogesterone acetate (MPA) from the original WHI. There are some instances where this makes sense (it is also unbelievably cheap), but for the most part, much safer and well-tolerated options are now available.

• Transdermal: gels and creams primarily. Almost all of these must be compounded. There is some controversy that transdermal progestogens are not as effective at balancing estrogens in the uterus.
• Vaginal: creams, gels, suppositories. Some conventional options here are bioidentical progesterone. One bioidentical brand here is Prometrium®
• Uterine: the Mirena® system is the main example here. While this progestin is not bioidentical, it has very little, if any, effect on the rest of the body.

There is growing significance in how HRT is given to women seeking help with menopausal symptoms. It appears that bypassing the liver processing by placing hormones on the skin, mucous membranes or near the uterus, decreases the risks associated with these medications. Luckily, there are compounded and conventional options widely available to women that offer low-dose, bioidentical relief for their symptoms.

Next week we talk about how dosing of hormones has changed since the WHI.

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

Many women face a challenge when trying to treat menopausal symptoms. On the one hand, some women find their experience at this time to be particularly difficult and are relieved to have prescription hormone options. On the other hand, since the 1990’s, media news reports on hormone therapy have been, at times, schizophrenic, offering little to clarify a patient’s decision process. With all the information out there it is easy to feel confused. Women can often feel torn between concern with the risks of treatment vs. concern with the severity of their symptoms. The purpose of this article is to provide information and history about the evolving practice of using hormone replacement, specifically estrogens and progestogens, to treat menopausal symptoms. Hopefully this helps give you a better grasp of the news out there and sparks a more fulfilling discussion with your doctor.

The Past:

Likely every woman over the age of 40 has followed the unfortunate results of the Women’s Health Initiative Trials (WHI http://www.nhlbi.nih.gov/whi/) in the news over the years. It caused a lot of concern while teaching us a lot. The WHI continues to contribute to our understanding of risks and benefits as they evolve.

• The WHI Trials started in 1991 and studied many things including the risk of breast cancer and cardiovascular disease in healthy postmenopausal women taking hormone replacement therapy (HRT). The HRT used in the trial was estrogens (CEE) from pregnant horse urine paired with or without  progestin (a non-bioidentical substitute for progesterone). It was a big deal and recruited thousands of women from all over the United States.
• Both hormone portions of the trial were stopped early when researchers found that the CEE plus progestin put these women at increased risk of breast cancer, cardiovascular disease, and pulmonary embolism. CEE alone, without progestin, put these women at increased risk mainly for stroke. For a lot of physicians and their healthy menopausal patients, this meant stopping all hormone replacement prescriptions abruptly.  What followed was a great deal of confusion and fear in the female population regarding HRT.
• Even with new options on the market, many patients are still not sure what to make of them. Are they the same? Do they have the same risks? What about bioidentical hormones?

The Present and Future:

The WHI Trials remain instrumental in helping us understand the potential risks of a specific set of hormones at a specific dose (CEE and progestin at relatively high doses). Continued analysis of trial data has brought about a radical change in the prescription options available today. For example, did you know that several of the new pharmaceutical HRT options available to you by your conventional physician are actually bioidentical? Additionally, HRT comes in much lower doses. Does this mean there are risk free hormones now? No, but we are getting smarter about what those risks are, and research is accumulating that helps answer questions such as:

• Who is a safer candidate for therapy?
• Are there safer ways to take HRT (have we evolved beyond pills)?
• Is there safer dosing that still helps with symptoms?
• Are there safer specific hormone combinations (bioidentical vs non-bioidentical, single vs combination therapy)?

Over the next few weeks, in brief installments, we will discuss the evolution of hormone prescribing in menopause. We will touch on each of the questions posed above. Hopefully this helps you have a better discussion with your doctor if the issue of hormone replacement comes up.  Next week we will talk about what the research is teaching us about safer candidates for therapy and length of therapy for menopausal symptoms.

Information in this article is provided for informational purposes only and is not intended as a substitute for the advice provided by your physician or other healthcare professional. You should not use the information on this web site for diagnosing or treating a health problem or disease, or prescribing any medication or other treatment.