Effect on endometrial histology and pharmacokinetics of different dose regimens of progesterone vaginal pessaries, in comparison with progesterone vaginal gel and placebo.

STUDY QUESTION: Which progesterone vaginal pessary dose regimen induces adequate secretory transformation of the endometrium, in comparison with progesterone vaginal gel and placebo? SUMMARY ANSWER: The best secretory transformation of the endometrium was observed during treatment with 400 mg progesterone vaginal pessaries, administered twice daily. WHAT IS KNOWN ALREADY: Vaginally administered progesterone is widely used for luteal phase support (LPS) in assisted reproductive techniques (ART). Although several vaginal formulations using various doses are available, little is known on the impact of formulation and doses at the endometrial level. STUDY DESIGN, SIZE, DURATION: The study had a randomised, observer-blind design and comprised two parts. The participants used study medication during two or three treatment periods, separated by washout periods. Subjects in Part 1 (n = 61 treated) received 200 mg progesterone vaginal pessaries twice daily (bid), 400 mg pessaries bid and the comparator 90 mg progesterone vaginal gel once daily (od) in a 3-way crossover design. Subjects in Part 2 (n = 64 treated) received 100 mg pessaries bid in one period and 400 mg pessaries od in the other period in a 2-way crossover design. A subgroup of these subjects (n = 22 treated) received placebo vaginal pessaries bid in a third period in a non-randomised manner. The study was performed from May 2012 until April 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was performed at a clinical research centre in healthy female volunteers of reproductive age. The subjects used 2 mg estradiol bid for 24 days in each treatment cycle. Progesterone or placebo was administered vaginally from Day 15 onwards during 10 days. In each treatment period, an endometrial biopsy for histological evaluation was performed on Day 23 and pharmacokinetic parameters were determined after the first progesterone dose on Day 15 and after the last dose on Day 24. MAIN RESULTS AND THE ROLE OF CHANCE: Frequencies of (early and late) secretory transformation of the endometrium, i.e. adequate responses, during treatment with 200 mg and 400 mg vaginal pessaries bid were comparable with those during 90 mg vaginal gel treatment (90-94%), whereas lower secretory transformation rates were observed during treatment with 100 mg bid and 400 mg od (64-75%). At the time of the endometrial biopsy in the cycle the late secretory state of the endometrium, which is characteristic of adequate luteal support, was observed more often with 400 mg pessaries bid (90%) than with vaginal gel (82%) and with lower pessary doses (64-78%). Pharmacokinetic parameters after repeated dosing of vaginal pessaries showed a dose-dependent, but not dose-proportional, increase of plasma progesterone levels. The lowest incidence of bleeding and spotting was reported during treatment with 400 mg pessaries bid. LIMITATIONS REASONS FOR CAUTION: The primary outcome parameter, rate of secretory transformation of the endometrium, is a surrogate for endometrial receptivity and for the actual clinical efficacy. WIDER IMPLICATIONS OF THE FINDINGS: Delivery of progestesterone through 400 mg pessaries bid is an effective alternative method for luteal support in ART. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by Actavis Group PTC ehf., Iceland, part of Teva Pharmaceuticals, and L.D. Collins. I.D. and C.K. are directors of Dinox, a contract research organisation. I.K. is Managing Director of Pharmaplex and M.W. is Managing Director of M.A.R.C.O., service organisations involved in organisation/supervision and evaluation/reporting of clinical trials. All received funding for the conduct of the study from Actavis. S.H. and Th.M. are employees of Actavis. TRIAL REGISTRATION NUMBER: EudraCT number 2012-001726-95.

A prospective, randomized, pharmacodynamic study of quick-starting a desogestrel progestin-only pill following ulipristal acetate for emergency contraception.

STUDY QUESTION: Is there a pharmacodynamic interaction between ulipristal acetate (UPA) 30 mg for emergency contraception and a daily progestin-only contraceptive pill, desogestrel (DSG) 0.75 mg, when initiated the next day? SUMMARY ANSWER: In this study, DSG impaired the ability of UPA to delay ovulation, but UPA had little impact on the onset of contraceptive effects due to DSG. WHAT IS KNOWN ALREADY: UPA is a progesterone receptor modulator used for emergency contraceptive (EC) at the dose of 30 mg. UPA delays ovulation by at least 5 days when administered in the mid to late follicular phase. In theory, potent progestins could reactivate progesterone signaling that leads to follicle rupture, thereby impacting the effectiveness of UPA as EC. In addition, UPA could alter the onset of the contraceptive effect of progestin-containing contraceptives started immediately after UPA. STUDY DESIGN, SIZE, DURATION: A single-blind (for observer), placebo-controlled, partial crossover study was conducted in two sites [Dominican Republic (DR) and the Netherlands (NDL)] over 11 months from October 2012 to September 2013. Healthy female volunteers participated in two of the three treatment cycles separated by a washout cycle. Treatment combinations studied were as follows: (i) a single 30 mg dose of UPA followed by 75 µg per day DSG for 20 days, (ii) a single 30 mg dose of UPA followed by 20 days of placebo matching that of DSG (PLB2) or (iii) one tablet of placebo-matching UPA (PLB1) followed by 75 µg per day DSG for 20 days. Participants were randomized to one of the three treatment sequences (UPA + DSG/UPA + PLB2, PLB1 + DSG/UPA + DSG and UPA + PLB2/PLB1 + DSG) when a lead follicle was ≥ 14 to <16 mm diameter on transvaginal ultrasound imaging (TVU). PARTICIPANTS/MATERIAL, SETTING, METHODS: A total of 71 women were included, and 49 were randomized to a first treatment combination of the three period sequences (20 in the DR and 29 in the NDL); 41 of the 49 continued and completed two treatment combinations (20 in the DR and 21 in the NDL). MAIN RESULTS AND THE ROLE OF CHANCE: Initiating DSG treatment the day after UPA significantly reduced the ovulation delaying effect of UPA (P = 0.0054). While ovulation occurred in only one of the 29 UPA-only cycles (3%) in the first 5 days, it occurred in 13 of the 29 (45%) UPA + DSG cycles. LIMITATIONS, REASONS FOR CAUTION: This was a small, descriptive, pharmacodynamic study in which some findings differed by study site. Distinguishing between a cystic corpus luteum and a luteinized unruptured follicle (LUF) by TVU was difficult in some cases; however, the investigators reached consensus, when the study was still blinded, regarding ovulation based on hormone levels and careful review of daily TVU images. WIDER IMPLICATIONS OF THE FINDINGS: Initiating the use of a DSG progestin-only pill (POP) immediately after UPA reduces the ability of UPA to delay ovulation and thus may decrease its efficacy as EC. If starting a DSG POP after using UPA for EC, and possibly any progestin-only method, consideration should be given to delaying for at least 5 days after UPA intake in order to preserve the ovulation delaying effects of UPA.