Progesterone is produced by the corpus luteum in the ovary after ovulation and by the placenta during pregnancy. After ovulation (approximately day 14), the corpus luteum starts producing progesterone. The corpus luteum is the remainder of the egg left behind in the ovary. The second half of the cycle is thus called the luteal phase; it is the progesterone dominant phase of the menstrual cycle. Progesterone peaks approximately 6-8 days prior to the next menses, which occurs around day 21-22 of the cycle.

Progesterone is responsible for stabilizing the thickened endometrial lining in the uterus.

If conception occurs, the corpus luteum continues to produce progesterone until 6 weeks after conception. The placenta then takes over the production of progesterone. If conception does not occur, the corpus luteum regresses, causing the progesterone level to fall. When the progesterone level gets back to its initial baseline, menstruation sets in and a new cycle is started. If ovulation fails to occur, progesterone is not produced. In perimenopause, ovulation is sporadic, so progesterone levels begin to decline. In menopause, progesterone is completely absent.

Rarely do menopausal women take progesterone; instead they are prescribed a synthetic progestin. There are many different synthetic progestins invented and patented by pharmaceutical companies. Hormones act on receptors and that receptor is looking for a specific molecule. The molecular structure of progesterone is not exactly the same as that of a synthetic progestin. The synthetic hormone can bind to the receptor but it does not fit exactly right, causing a different effect. Progestins also have been accused of tying up the receptor, not giving a pure progesterone response, causing estrogen dominance in tissues throughout the body. Synthetic progestins have a different effect on breast tissue, the cardiovascular system, and the brain when compared with progesterone.

Provera is a synthetic progestin, not progesterone or even close to it. Provera attenuates the benefits of estrogen. Provera raises LDL and total cholesterol, and lowers HDL cholesterol. As a result, it is damaging to the vascular system. A study published in the Journal of Reproductive Medicine showed that progesterone did not negatively affect estrogen’s positive effect on the heart, whereas Provera did. In another study progesterone, but not Provera, enhanced the beneficial effect of estrogen on exercise induced myocardial ischemia (lack of oxygen to the heart). In several other studies, Provera was shown to constrict coronary arteries, causing vasospasm and myocardial infarction (heart attack), whereas progesterone dilated coronary vessels in primates. It is felt that natural progesterone has a direct impact on reducing platelet aggregation through its ability to enhance endothelium-derived nitric oxide. Progesterone also increases HDL cholesterol, making it even more protective to the heart. The data from these studies demonstrate that progesterone has a different effect on the body compared to Provera.

Provera also increases the risk of breast cancer. Studies looking at estrogen versus estrogen and Provera show an increase incidence of breast caner in the latter. Studies have shown no increased risk when natural progesterone is added to estrogen. It is believed that progesterone is cancer protective by counterbalancing the aggressive effects of estrogen.

Critics of this philosophy state that both progesterone and Provera act on the same receptors, thus they should elicit the same response. These molecules are completely different from one another and thus elicit different responses. Provera has been shown to cause bloating, breast tenderness, mood disturbances, somatic complaints, and lowers core body temperature. One reason why women stop taking HRT is because of the side effects of Provera. In contrast, women enjoy the way they feel on natural progesterone. Instead of causing bloating, it is a natural diuretic. It also reduces irritability, anxiety, depression, and raises core body temperature. With such different effects on the same receptor, it is readily apparent that these two hormones are not interchangeable. Additionally it is felt that Provera may provide insufficient balance for estrogen, making a woman estrogen dominate causing the diseases above.

After the WHI study, progesterone is now thought of as a dangerous hormone because of the increase in disease seen with Prempro. If progesterone is so dangerous, we should see disastrous events during pregnancy because this is when progesterone is at its highest. We should also see complications in younger women when they are naturally producing progesterone. We do not see either of these.
Initially when women were started on HRT, they were only given estrogen. Physicians started to see an increase in endometrial cancer (cancer of the uterus) secondary to the unopposed estrogen in the uterus. Instead of prescribing progesterone, they started prescribing synthetic progestins. If a woman has had a hysterectomy, only an estrogen is prescribed. The philosophy behind this is that if a woman no longer has a uterus she cannot develop endometrial cancer and thus does not need progesterone or a progestin. Progesterone has many positive effects in the body besides protecting the uterus. Progesterone is responsible for counterbalancing estrogen in all organ systems.

Progesterone is cancer protective. Progesterone reduces the mitotic change in endometrial and breast tissue. It reduces cell proliferation; it enhances natural killer cells, interleukin-2, and the p53 molecule. Natural killer cells and interleukin-3 are important components of the immune system. Molecule p53 coordinates the actions of more than 60 genes that prevent damaged cells from turning cancerous. Progesterone increases apoptosis, cell destruction before damaged cells are converted to malignant cells. Several studies have shown that the higher a woman’s progesterone level, the less likely she is of developing cancer cells.
Additionally, progesterone is a calming hormone. It reduces anxiety, irritability, and depression. This is why progesterone should be the first line treatment for PMS. Progesterone is helpful for insomnia as well. It prevents osteoporosis by aiding in bone formation. Adequate progesterone helps prevent uterine fibroids, ovarian cysts, and fibrocystic breast disease.

It is usually recommended to take progesterone for two weeks a month, replicating the natural menstrual cycle. I often prescribe progesterone daily because it is less confusing this way and women generally feel better when on progesterone. If women are still menstruating, I recommend using it for two weeks starting on day 14 of the menstrual cycle so their menses stays regular.

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