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.
Progesterone Metabolites:
In normal breast tissue, the conversion of progesterone to pregnene metabolites exceeds or predominates the conversion of progesterone to 5α-pregnane metabolites, whereas the opposite is true in breast cancer tissue. Thus, it has been hypothesized, and laboratory studies have confirmed, that the promotion of breast cancer may be related to relative changes in concentrations of cancer-inhibiting 4-pregnenes (eg, 3α-dihydroprogesterone (3αHP)) and cancer-promoting 5α-pregnanes (eg, 5α-dihydroprogesterone (5αP)).
The enzyme 5-alpha-reductase will rapidly metabolize progesterone to pregnanolone and pregnanediol, the “pregnane” metabolites. These pregnanes are known as neuro-steroids and offer a calming influence to the brain; but when their production outpaces pregnenes this ratio drives breast cancer risk.
Given that topical and vaginal delivery methods bypass the gut and liver metabolism, true progesterone as measured in the blood stream by LC-MS is robustly present. Early studies of progesterone’s movement utilized radio immune assay (RIA) techniques. In recent years, RIA has been shown to be inaccurate as these techniques can’t distinguish metabolites such as pregnenes and pregnanes from true progesterone.
Metabolites can also be measured in urine, which is appropriate for assessing risk and detoxification pattern, but it is not the proper tool for assessing tissue levels or making hormone therapy dose adjustments. When assessing tissue levels, saliva is the most reliable medium. An understanding of progesterone metabolites and various testing mediums now allows for a discussion of endometrial protection.
Endometrial Protection:
Neither progestins nor oral progesterone are 100% capable of endometrial protection. Oral progesterone does provide endometrial protection, but studies indicate that lower doses of 50 to 100 mg still allow for risk of endometrial proliferation and as doses increase to 400 mg, the risk decreases.
However, dosage beyond 200 mg often create excessive pregnane metabolites.
No studies using oral dosages above 200 mg have extended their study to include examination of urinary metabolites. In such dosages, there is strong suspicion of elevated pregnane:pregnene ratios, thus a potential risk to breast tissue.
There is controversy about the beneficial effects of topical progesterone creams for postmenopausal women. A major concern is that serum progesterone levels achieved with progesterone creams are too low to have a secretory effect on the endometrium. However, antiproliferative effects on the endometrium have been demonstrated with progesterone creams when circulating levels of progesterone are low.
Endometrial Cancer Risk
It is important to also consider non-hormonal drivers of endometrial cancer, in addition to excessive estradiol without the protective presence of progesterone and lack of adequate progesterone tissue levels (this can be due to the natural decline of progesterone with age or secondary to anovulation, also the rapid metabolism of orally delivered progesterone or low/brief dosages).
Non hormonal factors which drive hyperplasia and proliferation of the endometrium include:
- Obesity – this creates inflammatory cytokines and more active aromatase, converting testosterone to estrogen, potentiating endometrial proliferation
- Anovulatory cycles – leads to low progesterone levels
- Insulin resistance
- Toxin exposure and endocrine disruptors – i.e. heavy metals, glyphosate, phthalates, BPA, and/or plastics
- Poor lifestyle choices
Missing Data and Misinterpreted Data:
Opposing research findings and the continued controversy of progestogens, as well as oral vs transdermal progesterone in endometrial protection is explained by several factors:
- Not all studies differentiate between progesterone and progestins
- Estrogen and progesterone are challenging to study since they are activated via a paracrine mechanism and thus, action is dependent on the other hormone
- Lack of understanding of the unique transport of transdermal progesterone will lead to misinterpretation of minimally changed serum progesterone levels
- Serum progesterone level is not an adequate way to interpret endometrial protection against estradiol
- Many studies fail to provide adequate days of transdermal progesterone supplementation during the cycle length
- Many studies use excessive estradiol dosing, far exceeding physiologic levels and therefore outpacing the ability of progesterone to counterbalance tissue proliferation (this is often due to dosing transdermal estradiol based on serum levels, which leads to excessive tissue levels)
- Many studies to date used RIA to determine progesterone levels, which has now been determined to be unsatisfactory. Future studies will likely clarify the best means of menopausal hormone therapy for endometrial protection with LC-MS as more accurate depiction of hormone/metabolite levels.
Summary:
Looking at the research as it stands, oral progesterone is generally theorized to be the most protective to the endometrium, as a counterbalance to estrogen. However, reading between the lines, seeing the missing data, the misinterpreted data, the smaller overlooked studies, understanding hormone physiology, the unique movement of transdermal progesterone, and the methodology behind laboratory testing, the possibility of topical progesterone as the most protective version of progesterone emerges.
