For women with PCOS, the stair-step clomiphene protocol is associated with decreased time to ovulation and increased ovulation rates at higher doses when compared with the traditional protocol.

PurposeTo compare ovulation rates between Letrozole and Clomiphene Citrate (CC) using a stair-step protocol to achieve ovulation induction in women with Polycystic Ovarian Syndrome (PCOS).MethodsThis is a retrospective cohort of predominantly Hispanic PCOS women of reproductive age who completed ovulation induction (OI) comparing women who underwent Letrozole stair-step protocol to those who underwent OI with CC stair-step. All women had a diagnosis of PCOS based on the 2003 Rotterdam criteria. For both protocols, sequentially higher doses of Letrozole or CC were given 7 days after the last dose if no dominant follicles were seen on ultrasonography. The primary outcome was ovulation rate (determined by presence of a dominant follicle) between the two treatment groups. Secondary outcomes included time to ovulation, clinical pregnancy rates and side effects.Results49 PCOS patients completed a Letrozole stair-step cycle and 43 completed a CC stair-step cycle for OI. Overall, demographics were comparable between both groups. Ovulation rates with the Letrozole stair-step protocol were equivalent to CC stair-step protocol (96% vs 88%, p = 0.17). Although the mean time (days) to ovulation was shorter in the Letrozole group (19.5 vs 23.1, p = 0.027), the pregnancy rates were similar for both groups.ConclusionsThis is the first study to date that has compared the efficacy of the stair-step protocol in PCOS patients using Letrozole and CC. Both Letrozole and CC can be prescribed in a stair-step fashion. Letrozole stair-step was as efficacious as CC stair-step; patients achieved comparable rates of ovulation and clinical pregnancy. Time to ovulation was shorter in the Letrozole protocol.

Progressive scarring is ubiquitous postoperatively and in an array of chronic systemic diseases. Recent studies indicate that such scarring has a high female propensity; females are also almost exclusively affected by endometriosis, a common sex steroid-dependent fibrotic disease. Endometriosis-related fibrosis is regulated epigenetically through transcription factor Krüppel-like factor 11 (KLF11). In response to surgical induction of endometriosis, Klf11-/- female mice develop significant fibrosis in contrast to wild-type mice. We therefore hypothesized that female fibrotic predilection was mediated by differential sex steroid regulation of KLF11/collagen 1a1 signaling and investigated the fibrotic response in wild-type and Klf11-/- male and female animals using a sterile peritonitis model. Fibrosis selectively developed in Klf11-/- females. Fibrosis in these animals was almost completely abrogated by ovariectomy. Ovariectomized animals were selectively supplemented with estradiol, medroxyprogesterone acetate (MPA), or dihydrotestosterone; fibrosis was only observed in mice exposed to MPA. Fibrosis therefore selectively developed in Klf11-/- female mice in response to physiological or pharmacological progesterone. The fibrotic response in these animals was also mitigated in response to antiprogestin therapy. Profibrotic gene expression was activated in a primary human peritoneal cell line in response to KLF11 short hairpin RNA and MPA but not estradiol. KLF11/collagen 1a1 signaling previously shown to be linked to fibrosis was thus selectively dysregulated in MPA-treated cells. Our in vivo and in vitro findings in an animal model and human cells, respectively, suggest that progressive fibrotic scarring is a sexually dimorphic response irrespective of etiology; moreover, it is responsive to novel, individualized therapeutic intervention.

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