Hormone therapy for uterine and endometrial development in women with premature ovarian insufficiency

Background Premature ovarian insufficiency (POI) is a clinical syndrome resulting from loss of ovarian function before the age of 40. It is a state of hypergonadotropic hypogonadism, characterised by amenorrhoea or oligomenorrhoea, with low ovarian sex hormones (oestrogen deficiency) and elevated pituitary gonadotrophins. POI with primary amenorrhoea may occur as a result of chromosomal and genetic abnormalities, such as Turner syndrome, Fragile X, or autosomal gene defects; secondary amenorrhoea may be iatrogenic after the surgical removal of the ovaries, radiotherapy, or chemotherapy. Other causes include autoimmune diseases, viral infections, and environmental factors; in most cases, POI is idiopathic. Appropriate replacement of sex hormones in women with POI may facilitate the achievement of near normal uterine development. However, the optimal effective hormone therapy (HT) regimen to maximise the reproductive potential for women with POI remains unclear. Objectives To investigate the effectiveness and safety of different hormonal regimens on uterine and endometrial development in women with POI. Search methods We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and two trials registers in September 2021. We also checked references of included studies, and contacted study authors to identify additional studies. Selection criteria We included randomised controlled trials (RCTs) investigating the effect of various hormonal preparations on the uterine development of women diagnosed with POI. Data collection and analysis We used standard methodological procedures recommended by Cochrane. The primary review outcome was uterine volume; secondary outcomes were endometrial thickness, endometrial histology, uterine perfusion, reproductive outcomes, and any reported adverse events. Main results We included three studies (52 participants analysed in total) investigating the role of various hormonal preparations in three different contexts, which deemed meta‐analysis unfeasible. We found very low‐certainty evidence; the main limitation was very serious imprecision due to small sample size. Conjugated oral oestrogens versus transdermal 17ß‐oestradiol We are uncertain of the effect of conjugated oral oestrogens compared to transdermal 17ß‐oestradiol (mean difference (MD) ‐18.2 (mL), 95% confidence interval (CI) ‐23.18 to ‐13.22; 1 RCT, N = 12; very low‐certainty evidence) on uterine volume, measured after 12 months of treatment. The study reported no other relevant outcomes (including adverse events). Low versus high 17ß‐oestradiol dose We are uncertain of the effect of a lower dose of 17ß‐oestradiol compared to a higher dose of 17ß‐oestradiol on uterine volume after three or five years of treatment, or adverse events (1 RCT, N = 20; very low‐certainty evidence). The study reported no other relevant outcomes. Oral versus vaginal administration of oestradiol and dydrogesterone We are uncertain of the effect of an oral or vaginal administration route on uterine volume and endometrial thickness after 14 or 21 days of administration (1 RCT, N = 20; very low‐certainty evidence). The study reported no other relevant outcomes (including adverse events). Authors' conclusions No clear conclusions can be drawn in this systematic review, due to the very low‐certainty of the evidence. There is a need for pragmatic, well designed, randomised controlled trials, with adequate power to detect differences between various HT regimens on uterine growth, endometrial development, and pregnancy outcomes following the transfer of donated gametes or embryos in women diagnosed with POI.