Potential Influence of the Microbiome on Infertility and Assisted Reproductive Technology

Ido Sirota; Shvetha M. Zarek; James H. Segars


Semin Reprod Med. 2014;32(1):35-42. 

In This Article

Progesterone Resistance

Recent evidence from a study of normal fertile women in an artificial hormonally controlled cycle demonstrated that the minimum P4 concentration needed for endometrial maturation was as low as 4 ng/mL and might be even lower than that seen in ovulatory women.[92] Despite that, supplementation of P4 during IVF cycles has proven to increase the clinical pregnancy rate of infertility patients.[92 93 94] Because P4 concentrations approaching the lowest of those observed in ovulatory women support normal endometrial structural and functional maturation in normal individuals, while infertility patients appear to benefit from higher P4 concentrations, it is possible that it is the resistance of the endometrium to P4, rather than a reduced concentration of P4, that may contribute to infertility.

It has been hypothesized that resistance to P4 is caused by altered P4-receptor expression or activity.[95] Supporting data come from endometriosis studies, which demonstrate local changes in the responsiveness of the tissue to P4 and lower expression of "P4-regulated" genes such as IGFBP-1 and PRL.[83] Resistance to cyclic adenosine monophosphate, an intracellular signaling molecule that enhances P4-receptor activity and supports decidualization, has been found to contribute to P4 resistance in women with endometriosis as well.[96] Savaris et al demonstrated P4-resistant endometria in women with polycystic ovary syndrome (PCOS) and hyperandrogenemia.[97] On the basis of the role of inflammation in the induction of a progesterone-resistant endometrium, we hypothesize that failure of implantation might be explained, perhaps in part, by alteration in the uterine microbiome in response to inflammation.

This hypothesis finds support in the ability of environmental factors to alter progesterone sensitivity. As noted before, environmental factors play an important role in the success of implantation. Bruner-Tran and Osteen showed that exposure to in utero environmental toxins, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in mice led to a progesterone-resistant phenotype in adult animals that can persist for several generations.[98] Maternal exposure to TCDD promoted a progesterone-resistant endometrium, similar to the endometrium of women with endometriosis, which manifested as infertility or PTB,[99,100,101] likely due in part to loss of P4-receptor expression.

A very important finding derived from this study demonstrated that TCDD-mediated P4 resistance might increase sensitivity to inflammation, even in subsequent generations not exposed to the toxicants, resulting in PTB.[98] By means of extrapolation, these data support the hypothesis that a combination of environmental factors, taken together, are a risk for recurrent pregnancy loss and PTB in humans; the mechanism being creation of a P4-resistant endometrium and the presence of inflammation.

Therefore, we conclude that the association between the microbiome of the reproductive tract and circulating serum E2 concentrations may reflect the environment and availability of glycogen. However, progesterone resistance, albeit an unproven relationship to the microbiome, might contribute to implantation failure and infertility. This putative role of undetected endometrial colonization and progesterone resistance requires further investigation.