Articles

To Cycle or Not to Cycle

By Paul Hueseman, Pharm.D.

One of the most confounding questions for both health care providers and patients alike is whether progesterone should be cycled in a manner that allows for a monthly period, or taken continuously. More attention to this question has been brought about with the recent publishing of Suzanne Sommer's book, Ageless, which presented cyclic dosing of progesterone as the most appropriate method of replacement of progesterone.

One important factor in addressing this question is to clearly distinguish between progesterone, also known as natural or bio-identical progesterone and synthetic progestins such as medroxyprogesterone acetate (MPA), also known as Provera.

There are many well documented benefits of bio-identical progesterone. Progesterone ensures bone health by increasing osteoblast activity. Progesterone has been shown to provide protection against certain types of cancer. It prevents the growth effects of certain breast cancer cell lines through apoptosis or programmed cell death and increases the effects of a gene involved in breast cancer.1 Progesterone offers protection of the brain with evidence demonstrating that it has the potential to enhance nervous system repair after injury, and acts as a neuroprotective agent to reduce some of the health risks associated with hormonal loss in aging and menopause.2 Progesterone presents some protection of the heart compared to MPA which has been associated with increased risks of heart disease in clinical studies. Progesterone has a dilating effect on arteries and reduces platelet aggregation responsible for clotting.1

It has been documented in literature that MPA can cause deterioration of glucose intolerance, or hyperinsulinemia or both. In contrast, bio-identical progesterone reportedly augments the pancreatic response to glucose and increases the release of insulin. However, does this effect of bio-identical progesterone on pancreatic response reverse if dosing is continuous? Diana Schwarzbein, M.D., an endocrinologist, advocates cycling progesterone, because "continuously combining an estrogen with a progestin on a daily basis makes the patient more insulin resistant." Schwarzbein also warns that the negative consequences of continuous dosed progestin therapy do not apply just to synthetic progestins. She believes that bio-identical hormone replacement therapy (HRT) given in a continuous fashion is harmful because it does not mimic normal physiology.3 Of importance, Schwarzbein points out the importance of hormone balance to apply to this equation as well.

During a normal menstrual cycle, estrogen signals the uterus to build up a layer of tissue, known as the endometrium in preparation for the possibility of receiving a fertilized ovum (egg). When the ovum does not appear, this signals progesterone levels to drop, followed by sloughing of the endometrium, hence, a menstrual period. The endometrium contains hormones and other biochemicals that signal growth processes. Shedding the endometrium each month is thus "Mother Nature's" way of protecting a woman’s uterus from uncontrolled growth which may result in fibroids and potentially cancerous cells.

Menopausal women by definition have stopped ovarian production of estradiol, progesterone and testosterone, and have no further ova and are not having cyclic hormone patterns.

However, there does not seem to be a consistent message as it relates to progestin therapy and insulin response. A study published in 2002 in Diabetes Care demonstrated that postmenopausal women in both the group taking HRT in the form of either oral estrogen alone or those taking a combination of estrogen plus progestin in a fixed continuous dose had higher rates of insulin resistance than women not on HRT.4 Another study showed similar results. Postmenopausal women who were on estrogen plus a progestin had reductions in their response to insulin. This reversed when HRT was discontinued.5 However, both of these studies looked at the use of conjugated estrogens, also known as Premarin, and synthetic progestin or MPA, not bio-identical hormone replacement therapy.

Interestingly, a separate study published in Diabetes Care in 2004 that studied patients who were using bio-identical HRT demonstrated significantly fewer cases of type 2 Diabetes. 6 The authors state that proper hormonal balance improves endothelial function. When endothelial function is altered, permeability of blood vessels occurs, reducing peripheral blood flow, limiting insulin delivery and promoting insulin resistance.

There have been animal studies of the effect of progesterone on glucose metabolism. It seems from these studies that progesterone is involved in regulating the steps of glucose metabolism and blocks insulin action in fat cells, thus insulin resistance, the precursor to type 2 diabetes. 7,8 This may explain why in pregnant women, when there are high levels of progesterone for an extended period of time, there is a higher risk of diabetes, known as gestational diabetes. High progesterone levels block the action of insulin.

Some physicians advocate cycling progesterone for other health reasons. Uzzi Reiss, M.D., a board certified physician in obstetrics-gynecology and anti-aging medicine, and author of Natural Hormone Balance for Women, advocates cyclic bio-identical hormone replacement therapy. He believes that an imbalance of estrogen and progesterone creates disease, and that cancer results from a lack of progesterone.

Some physicians disagree wholeheartedly with the proposal that progesterone should always be cycled. Dr. Phillip O. Warner, M.D. is a board certified obstetrician-gynecologist in private practice in Sacramento, California who treats peri-menopausal and menopausal women using bio-identical hormones obtained by prescription from compounding pharmacies. Upon interview, he states, "I recently have great concerns regarding the occurrence of recommendations for giving fixed amounts of estradiol taken daily along with fixed amounts of progesterone taken for 10-14 cycle days in menopausal women." This dosing scheme results in monthly growth of the endometrium that is followed by sloughing of the endometrium, hence, a menstrual period.

According to Dr. Warner, "these patients need bio-identical estradiol, progesterone, and testosterone replacement in the proper dose and delivery form that conforms to the needs of that patient. There is no one dose that fits all. This physiologic treatment gives the woman long term benefits for heart, bones, brain function and emotional stability with no uterine bleeding. It also decreases the risks of breast and colon cancer which is a function of the presence of the hormones."

However, Dr. Warner goes on to state, "It is not necessary to replace the hormones cyclically. The thought of 60, 70, 80 year old women having monthly uterine bleeding is concerning since these women may also have chronic iron deficiency anemia since their bone marrows cannot keep up with the blood loss at their age."

Recent research by Groshong and colleagues presents information that supports cycling progesterone in terms of breast cancer risks. 9 This research involves breast cancer research and progestin's role in preventing the development, growth, and differentiation of breast cancer cells. His work involved in-vitro studies of breast cancer cell line that were exposed to progesterone during different rounds of cell division. He concluded that progestins are neither proliferative (growth producing) nor antiproliferative, but that its effects on growth depend on whether treatment is transient or continuous. He shows that continued exposure to progesterone can cause growth stimulation. Again, this study had the same limitation as the others. The progestins studied were synthetic progestins, not bio-identical progesterone.

However, this research makes sense when one looks at the natural cycle of a female and the biology at a cellular level. Epithelial cells of the breast have the highest mitotic activity which allows for cell division during the luteal phase of the menstrual cycle, when progesterone production peaks.10 So in theory, progesterone peaking during this time would be preventing the differentiation of these cells into cancerous cells. When one looks at the incidence of breast cancer, the incidence is highest in post-menopausal women. During menopause, this progesterone peak no longer occurs, and of course, the ovaries are no longer producing estrogen. Also, more recent research supports that estrogen plus continuous dosed progestin therapy increases risk of breast cancer to a greater extent than does replacement of estrogens alone.10 Note that the therapy in this research, however, was conjugated estrogens or Premarin and MPA.

Is it possible that clinicians have extrapolated the effects of synthetic progestins to bio-identical progesterone? It seems that almost all of the research performed which supports the notion of cycling progestins has involved the study of synthetic progestins, not bio-identical progesterone. It may be simply the inherent differences between synthetic progestins and natural or bio-identical progesterone that determine whether or not progesterone should be cycled. Perhaps, over time, we have used the same lingo, "progesterone", for two very different things, when we should have been clearly differentiating the two. Perhaps, it is required to cycle synthetic progestins, but bio-identical progesterone, which seems to have a different risk profile, may not have these same requirements in dosing. However, looking at the basic physiology in terms of fluctuating progesterone levels in a normal menstruating female, and comparing this to continuous versus cyclical replacement of progesterone, there are certainly several factors presented here in this article that may support the notion of cyclic dosing, so long as a woman is comfortable with having a monthly menstrual cycle.

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