Women utilizing estrogen hormone therapy with an intact uterus are at risk for endometrial proliferation and hyperplasia, a potential forerunner to endometrial cancer, unless a progestogen is given alongside estrogen. However, the type of progestogen, the route of administration, dosage, and timing of therapy are controversial due to incongruent research findings. This article will highlight the challenges in the determination of best practices and describe why research findings are so varied.
Progestogens:
First and foremost, care must be taken when reviewing the research. Progesterone and progestins are often lumped into the category of progestogens, and not differentiating between them will lead to conflicting results and differing interpretations.
Orally administered progesterone has limited biological effects because it’s poorly absorbed, even in micronized form, and is extensively metabolized during first pass hepatic detoxification. For this reason, and because more potent progestational compounds were needed for effective antifertility treatment, progestins were developed. A variety of progestins are now available for contraception and for hormone therapy to prevent endometrial hyperplasia and endometrial cancer in estrogen-treated postmenopausal women.
While progestins do provide endometrial protection in the face of estrogen, they do not outperform progesterone (when used in adequate dosages and the through the correct route of administration) and they increase the risk of breast cancer, Alzheimer’s, birth defects, heart disease, and mood disorders, making long term therapy unwarranted.
Because breast cancer rates are far greater than endometrial cancer rates, using a therapy meant to protect the endometrium that subsequently increases breast health risk is short sighted; the preferred therapy is progesterone.
Paracrine Signaling:
Part of what makes hormonal impact on the endometrium so challenging to study is that estrogen and progesterone action is vastly paracrine in nature. In paracrine signaling, hormones act on nearby cells. In contrast, autocrine signals include extracellular matrix molecules and various factors that stimulate cell growth.
As a paracrine signaler, studies that show estradiol alone is not sufficient to induce mammary gland cellular proliferation in pregnant animals. Similarly, progesterone is not sufficient to stimulate cellular proliferation in the absence of estrogen. The paracrine nature of estradiol and progesterone make them dependent on one another, therefore, studying their action in isolation is fruitless.
It is now well accepted that pharmacologic and physiologic concentrations of estradiol increase the mitogenic activity of epithelial cells, while the influence of progesterone continues to be debated. Inconsistent evidence suggests that progesterone can increase, decrease, or have no effect on mitotic activity and proliferation in breast epithelial cells.
In contrast, a relative consensus has been reached that long-duration exposure to pharmacologic progestin levels of a specific type combined with estrogen, via contraceptives (transient, albeit small elevation in risk with current use) or menopausal hormone therapy (primarily with estrogen+progestin formulations, but not estrogen+progesterone or dydrogesterone), increases breast cancer risk.
Because of this risk, caution must also be taken when considering the endometrium, since body organs exist within a whole. Though it has long been common practice in medicine to separate body components into distinct systems and stand-alone organs, overlooking the cohesiveness within the whole is unsound.
Oral Progesterone:
When utilizing salivary testing, oral progesterone supplementation will yield in lower than ideal ranges. This is because 80-90% of orally delivered progesterone metabolizes through phase 1 detoxification in the liver, leaving only a small amount of progesterone available to the breast, uterus and other body tissues.
This is confirmed by literature from Adlercreutz, Nahoul and Levine, where oral progesterone consistently shows quick conversion to metabolites so that blood and tissue levels never reach significant levels.
Transdermal Progesterone:
Many research studies have drawn the conclusion that because transdermal progesterone fails to significantly increase serum levels, it is therefore not well absorbed nor effective. However, these studies overlook the unique transport of transdermal progesterone.
Transdermal progesterone, due to its strong non-polar and hydrophobic nature, travels by means of a weak bond to capillary red blood cell membranes and lymph. Though serum levels do not rise after physiologic doses of topically administered progesterone, tissue levels (as represented in the saliva) significantly increase. This represents the hormone’s movement by way of free diffusion as non-polar molecules easily move from capillary red blood cell membranes and lymph into the tissue’s cells, though almost entirely avoiding arterial and venous circulation.
Within standard venous blood processing, whole blood is spun down to separate out serum and red blood cells are discarded, along with any topically administered progesterone molecules that made it into circulation, therefore entirely missing the transdermally delivered progesterone. Only when the dose of transdermal progesterone exceeds the carrying capacity of red blood cells and lymph does the serum level rise, as excess hormone backs up into the venous blood stream. This is true especially of progesterone as it is closest to its parent cholesterol and therefore the most non-polar and hydrophobic in nature, though the same is true of testosterone and to a lesser degree, estradiol.
Chang showed that when radiolabeled progesterone was given topically and then measured in breast tissue biopsy that high levels had indeed been found despite little to none being seen in the blood stream. This is likely also what is happening in the endometrial tissue as well.
The study by Levine and Watson used either 90 mg of vaginal progesterone or 100 mg of oral and then measured blood values by LC-MS (liquid chromatography-mass spectrometry). The vaginal progesterone gel dramatically outperformed the oral, generating a C-max reading of 10.51 ng/ml compared to the oral progesterone’s mere 2.2 ng/ml. Not only was the gel greater in peak concentration, but it also produced a long-term effect lasting many more hours than the oral dose. The area under the curve was 133 ng-h/ml for the vaginal gel and only 3.46 ng-h/ml for the oral dose.
Based upon these findings, aggressive metabolism of orally administered progesterone could leave the uterus and breast tissue unprotected.
