Hormones and Research

The topic of Hormone Replacement Therapy has been the focus of debate both within professional circles as well as among the lay population since its inception. Over time, this debate has received varying degrees of public attention. At times the coverage has been wide enough to create some controversy is was the case in the aftermath of Oprah Winfrey’s first program in the series of bio-identical hormones in January 2009; I received many calls and e-mails from people interested in more details as well as a professional assessment of what was presented. A sound interpretation of the genuine benefits and risks of hormone replacement therapy (HRT) requires an indepth review of a large and quite complex body of data. It is for this reason that I decided to dedicate a section to this topic, where I would devote my knowledge and experience as well as my best effort at objectivity to dissect the issue from a strictly research-based angle in an attempt to facilitate a better understanding of HRT among my patients. Walking you through the history of research in the field of HRT from the 90′s to the present requires an explanatory format which I have done my best to condense in these pages. If you are concerned and genuinely interested in improving your understanding of this issue, I greatly recommend that you take time and read this important information.

The Women’s Health Initiative (WHI) has thus far been the most far reaching program of research on women’s health that has ever been undertaken in the United States and therefore, its findings stand at present as the most definitive. The WHI has generated a vast amount of practical information for women and their health care professionals and it should be noted that besides HRT, this information covers other topics such as dietary patterns as well as calcium and vitamin D supplementation and their role in the prevention of heart disease, cancer and osteoporotic fractures. Because of the pivotal nature of the WHI, it will serve as the primary focus of my discussion of research into hormones. I should also add that the focus of this article will be on the data related to HRT, topics pertaining to other aspects of the study will be covered in other articles on this site.

Women’s Health Initiative, a History

The NIH (National Institute of Health) along with the National Heart, Lung, and Blood Institute (NHLBI) initiated the WHI in the early 90′s as a series of clinical trials followed up with observational studies. The original program, designed as a 15 year effort involving over 160,000 generally healthy postmenopausal women, was launched in an effort to better understand and ultimately address the diseases that are the major causes of death, disability, and frailty (such as heart disease, breast and colorectal cancer and osteoporosis) among postmenopausal women of all races and socioeconomic backgrounds. WHI was conducted as multiple and sometimes concurrent branches, each focusing on a specific aspect of disease. One of these branches focused on the effects of E (Premarin)+P (Progestin) on heart disease and hip fractures as well as associated change in risk of breast and colorectal cancer (Important Note: Progestin is a synthetic progestogen with progestinic effects that are similar to those of progesterone however it is not the same thing as Progesterone; a closer look at this difference will be presented later on in this article). The E+P trial was included in WHI mainly in light of previous large observational studies whose findings suggested HRT provided benefits against heart disease. An additional key impetus for the inclusion of the E+P branch was WHI was to see whether or not HRT increased the risk of breast cancer.

How was the Study Designed?

The particular branch focusing on Estrogen + P was a type of study employing a design called a “Randomized , Double blind, Placebo” study whereby subjects were randomly assigned to one of two groups; one group receiving Estrogen (Premarin) plus Progestin, and the other group receiving a placebo. Furthermore, during the trial, neither the women nor the medical staff were aware of which type of pill the participants were taking thus both side were blind to any expectations. The 16,608 participants in this part of the study were healthy, active postmenopausal women ages 50 to 79 who had an intact uterus.

E[strogen]+P[rogestin], 2002 Findings

One of the key initial findings of the study, published in 2002, conluded in a positive correlation between HRT and breast cancer among other diseases. While the original plan called for a long duration of clinical study, the effort was halted after a few years of follow-ups based on results which indicated an increase in the incidence of breast cancer, heart attack, stroke, as well as blood clots among the women who were given the hormones as compared to the placebo groups – after a period of almost 5 years, some 245 of the 8,506 women on E+P developed breast cancer, compared to 185 of the 8,102 women on placebo. This difference was statistically significant enough to warrant the abrupt halt of that branch of the study in July 2002. Ultimately, these findings had a large impact on public opinion regarding HRT, causing many women and their health care providers to opt away from the usage of HRT.

After 2002…

Subsequent to the 2002 findings, questions and controversy began to surface with regard to the applicability of the WHI data to women of the age when just entering menopause. While the study included women whose ages ranged 50-79 years old, the participants’ average age was 63, and only a relatively small portion, 3.5% of the participants, were between the ages of 50 and 54 years old, the typical age range during which the decision to initiate HRT is taken. Additionally, a major indication for HRT use, relief of symptoms, was not addressed by the WHI.

The sharp drop in the use of HRT among American women following the 2002 release of the WHI findings was accompanied by a decrease in rates of breast cancer. Naturally, this suggested a relationship between HRT and breast cancer. Some researchers wondered whether the drop in breast cancer was too rapid to be explained by decrease in hormone use while others pondered a link with the recent drop in mammography rates during the same time frame. In any case, following the termination of the E+P arm of WHI, observational studies pertaining to this arm of the study have continued. For several years, information gleaned from preliminary data (such as data for the 3 year post-study follow up available on 95% of the original participaant) obtained from these observational studies was published in the news media. Quite often, this data indicated that women who took HRT during the study continue to be exposed to a higher risk, as compared to those who took placebo, of developing breast cancer many years after the trial was stopped. At the same time, the same data indicated that higher risks of cardiovascular events (heart disease, stroke, and blood clots) seen in those taking HRT abated in the follow-up period, as did the beneficial effects of HRT on bone strength and colon cancer.

As controversy continued in the various public professional and lay forums, the WHI investigators remained engaged in recompiling and reexamining data from WHI participants. In February 2009, the WHI investigators published their updated findings in the New England Journal of Medicine. The three main February 2009 findings are:

  • The use of Estrogen+Progestin for a period longer than 5-years nearly doubles the subsequent annual risk of breast cancer.
  • The decline in breast cancer observed in the years following the termination of the E+P study is unrelated to changes in mammography use.
  • Together, these findings reinforce the hypothesis that the recent reduction in breast cancer rates is primarily related to a decrease in Estrogen+Progestin use.

A New Paradigm

The public discussions that have ensued in the aftrmath of the WHI data analysis have largely excluded the specific nature of the specific hormones at the center of the E+P findings. Yet, for the many women who continue to enter their menopausal years questions remain.

Question: Might there be clinical differences resulting from exposure to a single hormones (i.e.; estrogen) versus to the combined (i.e.; estrogen plus progestin) use of hormones?

Answer: Differences in effect on tissue do indeed exist. An example of the complexity of multi-hormone interactions is that while progestin appears to counter estrogen’s effects on certain tissue such as the uterus, it may enhance the effects in other tissues such as the breast and bone. Thus, there is no uniform effect throughout the body. Is the estrogen+progestin combination the only hormone combination in use in HRT? if not, what are the alternatives? This information brings us to the next few questions:

Question: Are there any differences between “progesterone” and “progestin”?
Answer: Yes, while both belong to the same family of hormones called progestogens, there is at least one key difference between the two which has been shown to be detrimental to the nature of their affect on the body; progesterone is bio-identical -is the exact form as the natural progesterone produced by the human ovaries and adrenal glands- while progestin is non bio-identical. A review of data available from the many studies comparing the effects of these two hormones on both human and animal subjects shows that their effects differ in some quite important ways. For example, as mentioned earlier, progestin appears to counter estrogen’s effects in certain tissue such as the uterus, but may enhance the effects in other tissue such as the breast and bone. Since impact on the breast tissue is a significant area of difference between these two hormones, it would be logical to ask whether there is a corresponding difference in risk for breast cancer. Had the WHI reseach included an estrogen+progesterone wing, would such fundamental differences have led to alternate results?

How different is the effect of Progesterone vs Progestin on breast tissue?

Breast cells are subject to ongoing cell division due to constant exposure to Estrogen. During the process of cell division, DNA inside the breast cell can become damaged. Damaged cells have the capacity to become precancerous and eventually cancerous. But nature has its own tried and true solution for this problem, it is called Apoptosis. Apoptosis or “programmed cell death” is the key mechanism by which the body is rid of cells with damaged DNA thus preventing the process of precancerous/ cancerous cell development.

Progestin has been found to prevent apoptosis in some unhealthy breast cells while the opposite has been found to be the case with Progesterone which appears to even promote programmed cell death thus allowing the elimination of cells with the likelihood of becoming cancerous. Progestins also promote the conversion of weaker Estrogens into more potent Estrogens, thereby contributing to their cancer producing potential. Progesterone on the other hand appears to have an opposite influence, creating Estrogens with much reduced potency.

A number of studies have been conducted with the specific aim of identifying the difference in quality, character as well as mechanism of action between Progesterone and Progestin. The following are a sampling of such studies with specific focus on the risk of breast cancer with non bio-identical Progestin:

  1. Colditz et al from one of the Nurses’ Health Study’s data, concluded that compared with women who never used hormones, those who used Estrogen alone during their 50’s, increased the risk of breast cancer by over 20%. The same study also found that the addition of Progestin to Estrogen resulted in almost tripling of the risk for breast cancer to over 60%.
  2. Newcomb et al studied the risk for breast cancer in large groups of postmenopausal women aged 50-79 years. They found a statistically significant increase in breast cancer of 2% per year for an Estrogen only group, and a 4% per year increase if a synthetic Progestin was used in addition to Estrogen. Use of Progestin only preparation doubled the risk for breast cancer.

Risk of breast cancer with bioidentical Progesterone:

  1. Although no randomized, controlled trials were identified that compared the risks for breast cancer between Progesterone and synthetic Progestin, large scale observation studies in humans do show significant differences. In one such observational study in 2007, Fournier et al reported an association between various forms of HRT and the incidence of breast cancer in large number of postmenopausal women who were followed for more than 8 post menopausal years. Compared with women who had never used any HRT, women who used Estrogen only had a non significant increase of 1.29 times the risk for breast cancer. If a synthetic Progestin was used in combination with Estrogen, the risk for breast cancer increased significantly to 1.69 times that for control.
  2. In another study done by Fournier, analysis of another group of postmenopausal women indicated the risk for breast cancer was increased significantly when synthetic Progestin was used, but was reduced if Progesterone was used instead.

Putting it all Together

I have cited several studies in this article and there are many more studies providing data that support the same conclusion – adding Progestin, the non-bio-identical form of Progesterone, seems to be a key factor in the rising risk of breast cancer. However, much more data is still needed . Until we can have large scale randomized controlled study like what was done in WHI, the above statement is just an justified educated hypothesis.

“To take advantage of these benefits (bone health, symptom relief etc), you first have to give up the notion that there is an easy, “one size fits all” solution. There isn’t. Some women need or want HRT, some don’t. Some need to use it for only a year or two some will want to stay on it longer. When it comes to hormone replacement, the science we look to for answers is inconsistent at best, influenced by market forces, and confusing to researchers, doctors, and patients alike. The blessing is that this dilemma forces us to tune in more fully to our inner wisdom and to make our choices in full partnership with our intuition and intellect. This approach is the essence of feminine wisdom.”

Christiane Northrup, M.D. – “wisdom of menopause” (http://www.drnorthrup.com/)
© Copy Right 2009 Natural Solutions for Women’s Health

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