Objective: To evaluate whether a combination of letrozole and clomiphene citrate (CC) results in higher ovulation rates than letrozole alone in infertile women with polycystic ovary syndrome (PCOS). Design: Open-label randomized controlled trial. Setting: Academic medical center using two clinic sites. Patient(s): Women 18-40 years of age with a diagnosis of infertility and PCOS as defined by the Rotterdam criteria and no other known cause of infertility. Interventions(s): Participants were randomized in a 1:1 ratio, stratified by age and body mass index, to either 2.5 mg letrozole alone or the combination of 2.5 mg letrozole and 50 mg CC daily on cycle days 3-7 for one treatment cycle. Main Outcome Measure(s): Ovulation defined as mid-luteal serum progesterone concentration R3 ng/mL. Result(s): Seventy patients were randomized: 35 to letrozole alone and 35 to letrozole and CC. Results were analyzed according to the intention-to-treat principle. Women who received the combination of letrozole and CC had a statistically higher ovulation rate compared with those who received letrozole alone (27 of 35 women [77%] vs. 15 of 35 women [43%]). There were no serious adverse events or multiple-gestation pregnancies in either group. The side-effects profile was similar in the two treatment groups. Conclusion(s): The combination of letrozole and CC was associated with a higher ovulation rate compared with letrozole alone in women with infertility and PCOS. Further studies are needed to evaluate the effect on live birth rate.

The mechanisms that control the timing of labor have yet to be fully characterized. In a previous study, the overexpression of small conductance calcium-activated K(+) channel isoform 3 in transgenic mice, Kcnn3(tm1Jpad)/Kcnn3(tm1Jpad) (also known as SK3(T/T)), led to compromised parturition, which indicates that KCNN3 (also known as SK3) plays an important role in the delivery process. Based on these findings, we hypothesized that SK3 channel expression must be downregulated late in pregnancy to enable the uterus to produce the forceful contractions required for parturition. Thus, we investigated the effects of SK3 channel expression on gestation and parturition, comparing SK3(T/T) mice to wild type (WT) mice. Here, we show in WT mice that SK3 transcript and protein are significantly reduced during pregnancy. We also found the force produced by uterine strips from Pregnancy Day 19 (P19) SK3(T/T) mice was significantly less than that measured in WT or SK3 knockout control (SK3(DOX)) uterine strips, and this effect was reversed by application of the SK3 channel inhibitor apamin. Moreover, two treatments that induce labor in mice failed to result in complete delivery in SK3(T/T) mice within 48 h after injection. Thus, stimuli that initiate parturition under normal circumstances are insufficient to coordinate the uterine contractions needed for the completion of delivery when SK3 channel activity is in excess. Our data indicate that SK3 channels must be downregulated for the gravid uterus to generate labor contractions sufficient for delivery in both term and preterm mice.

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The window of implantation of human embryos into the endometrium spans Cycle Days 20-24 of the 28-day menstrual cycle. However, uterine receptivity may not be reliably replicated in infertile patients throughout this span. Thus, it is of importance to be able to determine optimal receptivity through a minimally invasive measure. We screened expression of a number of candidate micro-RNAs (miRNAs) in endometrial tissues and serum collected from a panel of fertile women during both the proliferative phase and the secretory phase of a normal menstrual cycle. We found that several miRNAs were significantly elevated in endometrial tissues in the secretory phase versus the proliferative phase. One of these, miR-31, was found to be not only detectable in serum samples but also significantly elevated in the secretory phase versus the proliferative phase. MiR-31 is known to target several immunomodulatory factors, such as FOXP3 and CXCL12. We find that both of these factors are significantly downregulated in endometrial tissues during the secretory phase. Our data suggest that miR-31 is a potential biomarker for optimal endometrial receptivity, possibly operating through an immunosuppressive mechanism.

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Objectives

Although there is a need for uterine-sparing treatment for atypical endometrial hyperplasia and early adenocarcinoma, especially in the setting of desired fertility, caution should be exercised. We do not recommend using the levonorgestrel-releasing intrauterine system as a treatment for atypical hyperplasia or adenocarcinoma until further studies demonstrate the efficacy of this treatment.

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