Progestins Related to Progesterone and Testosterone Elicit Divergent Human Endometrial Transcriptomes and Biofunctions

Abstract

Progestins are widely used for the treatment of gynecologic disorders and alone, or combined with an estrogen, are used as contraceptives. While their potencies, efficacies and side effects vary due to differences in structures, doses and routes of administration, little is known about their effects on the endometrial transcriptome in the presence or absence of estrogen. Herein, we assessed the transcriptome and pathways induced by progesterone (P 4 ) and the three most commonly used synthetic progestins, medroxyprogesterone acetate (MPA), levonorgestrel (LNG), and norethindrone acetate (NETA), on human endometrial stromal fibroblasts (eSF), key players in endometrial physiology and reproductive success. While there were similar transcriptional responses, each progestin induced unique genes and biofunctions, consistent with their structural similarities to progesterone (P 4 and MPA) or testosterone (LNG and NETA), involving cellular proliferation, migration and invasion. Addition of estradiol (E 2 ) to each progestin influenced the number of differentially expressed genes and biofunctions in P 4 and MPA, while LNG and NETA signatures were more independent of E 2 . Together, these data suggest different mechanisms of action for different progestins, with progestin-specific altered signatures when combined with E 2 . Further investigation is warranted for a personalized approach in different gynecologic disorders, for contraception, and minimizing side effects associated with their use.

HIV-Exposed Seronegative Sex Workers Express Low T-Cell Activation and an Intact Ectocervical Tissue Microenvironment

“…The strengths of this study were that it was performed ex vivo using genital mucosal samples from a well-defined group of HESN participants. To control for the influence of sex hormones, only women who were not using hormonal contraceptives were included since sex hormone levels and use of hormonal contraceptives can significantly affect the apical (E-cadherin − ) epithelial layer, as well as the genital proteome and transcriptome [ 22 , 23 , 25 , 54 , 55 , 56 , 57 ]. As the study was controlled for menstrual cycle stage, our study groups had comparable progesterone levels.…”

Solving the Puzzle: What Is the Role of Progestogens in Neovascularization?

“…Furthermore, the pharmacological effect of PR modulators and P4 antagonists has been reported to work in a cell-specific manner [ 149 ]. A study confirmed that P4 and progestins activate or repress unique genomic and proteomic profiles [ 168 ], which explains some puzzling findings in previous studies, such as that P4 uniquely affects angiogenesis while MPA affects cell migration [ 86 ]. Therefore, some conflicting outcomes are likely due to the use of different progestogen types.…”

“…In addition, E2 priming and its combination with E2 bring changes to original regulatory patterns. Certainly, some amount of the changes come from E2-mediated signaling, which activates cognate nuclear receptor and non-genomic pathways, leading to altered proangiogenic profiles [ 86 ]. Further, more than 80% of genes regulated by E2 are regulated by progestogens, while progestogen treatment can alter more than half of E2-induced transcriptomes [ 14 ], suggesting that PR dominantly conveys an antagonist to E2-related gene expression and signaling.…”

“…A later study confirmed that blocking the glucocorticoid receptor can attenuate the inhibitory effect of MPA [ 85 ]. Therefore, progestins might activate nongenomic regulation or crosstalk with other steroid hormone receptors, and thus alter downstream signaling and gene transcription [ 86 , 87 ]. A more recent study confirmed this activation of nongenomic regulation; P4-mediated membrane progestin receptors (mPRs), which can mediate a rapid nongenomic signaling, were found to significantly increase endothelial NOS activity and phosphorylation in HUVECs, accompanied by an activation of the PI3K/Akt and MAPK pathways, ultimately influencing the vascular status and function [ 88 ].…”

Depot Medroxyprogesterone Acetate Use and the Development and Progression of Uterine Leiomyoma

“…28 Also, in endometrial stromal fibroblasts, treatment with medroxyprogesterone acetate resulted in differential expression of almost 150 genes compared with progesterone. 29 Given these important biological differences, mechanistic studies of myometrial and leiomyoma tissue obtained from women with different exposures to DMPA are needed to investigate the biological pathways at play. Our study has limitations.…”