Abnormalities of the endometrium persist despite adequate progesterone supplementation in the Polycystic Ovary Syndrome

Abstract Objective: To study the influence of metabolic factors on the action of progesterone on the endometrium of women with PCOS. Methods: A prospective open-label clinical trial. Participants were recruited from an outpatient reproductive endocrinology clinic at an academic tertiary medical care center from 2014 to 2020. To assess the sole effect of progesterone (P4) on the endometrium we studied amenorrheic (cycles> 90 days) women with PCOS (n=23), comparing them to healthy eumenorrheic control women ( n=13). All subjects underwent an endometrial biopsy (EB) in the follicular phase of the first study cycle. They were then treated with micronized P4 (400 mg/day x 10 days intravaginally) from days 14-28 of the cycle, and a second EB was performed between days 20-24 of the cycle (second phase). EB samples were analyzed under light microscopy for histomorphometric analysis.Results: The surface and glandular epithelia were thicker in PCOS subjects than one in controls (p<0.023) in first phase. The endometrium of PCOS women in second phase demonstrated an uniform surface epithelium with less leukocyte infiltration and absence of apoptotic figures compared to control group. The The thickness of the surface epithelium in the second phase of PCOS group correlated positively with the percentage of free testosterone and bioavailable testosterone. The thicknesses of glandular epithelium of the same group correlated negatively with BMI. The number of stromal cells increased with insulin levels. Conclusion: Histomorphometric abnormalities of the endometrium persisted despite what appears to be adequate P4 supplementation in PCOS. The clinical impact of these abnormalities, what factors (hormonal, metabolic, genetic) may underlie this persistent abnormality. Whether higher doses or different routes of P4 administration required, remains to be determined.Clinical Trials: NCT05062135