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

Area of Science:

• Endocrinology and Reproductive Biology
• Molecular Biology
• Genomics

Background:

• Progestins are crucial for gynecologic disorder treatment and contraception.
• Their effects on the endometrial transcriptome, especially with estrogen, are not fully understood.
• Human endometrial stromal fibroblasts (eSF) are key to endometrial physiology.

Purpose of the Study:

• To investigate the distinct transcriptomic and pathway responses induced by progesterone (P4) and three synthetic progestins (medroxyprogesterone acetate, levonorgestrel, norethindrone acetate) in eSF.
• To determine how estradiol (E2) modulates these progestin-induced transcriptomic changes.
• To elucidate the mechanisms of action for different progestins in the context of endometrial function.

Main Methods:

• Transcriptomic analysis of human endometrial stromal fibroblasts (eSF) treated with progesterone (P4), medroxyprogesterone acetate (MPA), levonorgestrel (LNG), and norethindrone acetate (NETA).
• Assessment of gene expression and pathway alterations in the presence and absence of estradiol (E2).
• Bioinformatic analysis to identify unique and shared transcriptional responses and functional pathways.

Main Results:

• All progestins induced similar transcriptional responses, yet each uniquely affected gene expression and biofunctions related to proliferation, migration, and invasion.
• Progesterone (P4) and medroxyprogesterone acetate (MPA) showed significant modulation by estradiol (E2), while levonorgestrel (LNG) and norethindrone acetate (NETA) responses were more E2-independent.
• Structural similarities influenced progestin activity, with P4/MPA resembling progesterone and LNG/NETA resembling testosterone.

Conclusions:

• Different progestins exhibit distinct mechanisms of action and alter endometrial signatures uniquely, particularly when combined with estradiol (E2).
• Progestin-specific responses warrant further investigation for personalized gynecologic disorder treatment and contraception.
• Understanding these nuanced effects can help minimize side effects associated with progestin use.