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.

Immediate pre-ovulatory administration of 30 mg ulipristal acetate significantly delays follicular rupture.

BACKGROUND: Current methods of hormonal emergency contraception (EC) are ineffective in preventing follicular rupture when administered in the advanced pre-ovulatory phase. This study was designed to determine the capacity of ulipristal acetate (UPA), a selective progesterone receptor modulator developed for EC, to block follicular rupture when administered with a follicle of >or=18 mm. METHODS: This was a double-blind, crossover, randomized, placebo-controlled study. Thirty-five women contributed with UPA (30 mg. oral) and a placebo cycle. Serial blood sampling for luteinizing hormone (LH), estradiol and progesterone measurements and follicular monitoring by ultrasound were performed before and for 5 days following treatment. Follicular rupture inhibition was assessed in the overall study population and in subgroups of women stratified by when treatment was administered in relation to LH levels (before the onset of the LH surge, after the onset of the surge but before the LH peak or after the LH peak). RESULTS: Follicular rupture failed to occur for at least 5 days following UPA administration in 20/34 cycles [59%; 95% confidence interval (CI) (40.7-75.4%)], whereas rupture took place in all cycles within 5 days of placebo intake. When UPA was administered before the onset of the LH surge, or after the onset but before the LH peak, follicle rupture had not occurred within 5 days in 8/8 (100%) and 11/14 [78.6%; 95% CI (49.2-95.3)] cycles, respectively. In contrast, when UPA was given after the LH peak, follicle rupture inhibition was only observed in 1/12 [8.3%; 95% CI (0.2-38.5)] cycles. CONCLUSIONS: This study demonstrates that UPA can significantly delay follicular rupture when given immediately before ovulation. This new generation EC compound could possibly prevent pregnancy when administered in the advanced follicular phase, even if LH levels have already begun to rise, a time when levonorgestrel EC is no longer effective in inhibiting ovulation.

[Adnexal defect identified with hysterosalpingogram and laparoscopy during infertility evaluation]. / Anomalie annexielle physiologique découverte lors d'une hystérosalpingographie et laparoscopie pour bilan d'infertilité.

OBJECTIVE: To describe a previously unreported adnexal defect as a cause of an abnormal hysterosalpingogram (HSG), identified during infertility evaluation. MATERIAL AND METHOD: An abnormal hysterosalpingogram (HSG) consistent with partial left tubal obstruction or hydrosalpynx was identified during the evaluation of a 33 year-old nulligravida with no prior surgical history. At laparoscopy, the diagnosis was revised when a approximately 3x4cm regular, ovoid, physiologic aperture was noted in the central aspect of the left broad ligament in the region corresponding to the HSG defect. The lesion was explored but not repaired. Bilateral tubal patency was confirmed via indigo carmine chromopertubation. RESULTS: Ovulation induction and intrauterine insemination were undertaken based on findings at surgery and careful discussion of same with the couple. The patient successfully conceived and had a normal term delivery. CONCLUSION: While HSG abnormalities discovered during infertility assessment are not unusual, intrinsic or de novo peritoneal defects have not been described previously. Abnormal radiographic findings may be explained by this lesion in selected cases.

The role of LH in ovarian stimulation: exogenous LH: let's design the future.

Historically, follicular stimulation protocols have included both FSH and LH in an attempt to mimic the physiology of normal human folliculogenesis. However, many recent gonadotrophin administration regimens have completely eliminated LH bioactivity. The importance and the amount of LH necessary for optimal follicular stimulation has been a topic of debate. Several recent studies have added to our understanding of the actions of androgens, oestrogens, gonadotrophins, and insulin on the follicle-oocyte unit, allowing a less speculative approach. Moreover, the availability of human gonadotrophins synthesized by recombinant DNA technology and gonadotrophin-releasing hormone (GnRH) antagonists, should soon permit a precise in-vivo assessment and re-evaluation of the historical 2-cell, two-gonadotrophin hypothesis. These pharmacological tools may also provide essential insights into the physiological roles of FSH and LH in human follicular development and oocyte maturation. The recombinant gonadotrophins give clinicians the unique opportunity to tailor ovarian stimulation regimens according to the patient's medical history, in an effort both to maximize oocyte yield and to improve oocyte quality.

Strategies for ascertaining ovarian reserve among women suspected of subfertility.

"Ovarian reserve" describes the native oocyte endowment and is closely associated with reproductive potential. As a diagnostic entity, ovarian reserve screening developed from clinical experience with the advanced reproductive technologies--particularly in vitro fertilization. Diminished ovarian reserve generally presages a poor response to any fertility treatment, and sharply limits the possibility of successful pregnancy. Screening for ovarian reserve is a fundamental component of the initial infertility evaluation, since it is a key determinant of what, if any, treatment should be offered. Methods of clinical ascertainment of ovarian reserve may be classified in two groups: passive and provocative testing. Both approaches seek to provide information regarding oocyte quality and quantity, which then may be used to direct specific therapeutic interventions. This monograph presents basic elements of ovarian reserve testing as currently practiced, and provides insights into the interpretation and limitations of these assessments.

A prospective, randomized comparison of ovulation induction using highly purified follicle-stimulating hormone alone and with recombinant human luteinizing hormone in in-vitro fertilization.

The commercial availability of highly purified, s.c. administered urinary follicle stimulating hormone (FSH) preparations for ovarian stimulation marked the beginning of a new era in the treatment of infertility. As these new formulations contain essentially no luteinizing hormone (LH), supplemental LH may be needed for optimal folliculogenesis. It was the aim of this pilot study to compare fertilization rates, embryo morphology, implantation rates and pregnancy outcomes prospectively in two age-matched patient groups: women who received highly purified FSH (FSH-HP) (n = 17), and women who received FSH-HP plus recombinant human LH (rhLH, n = 14) throughout ovarian stimulation. All patients received mid-luteal pituitary down-regulation with s.c. gonadotrophin-releasing hormone agonist (GnRHa) (leuprolide). Mean implantation rates were 26.9 and 11.9% in the FSH-HP only and FSH-HP + rhLH groups respectively. The mean clinical pregnancy/initiated cycle rate was 64.7 and 35.7% for the FSH-HP only and FSH-HP + rhLH patients respectively. FSH-HP patients and FSH-HP + rhLH patients achieved clinical pregnancy/transfer rates of 68.8 and 45.5% respectively. One patient in the FSH-HP + rhLH group had a spontaneous abortion; no pregnancy losses occurred in the FSH-HP only group. There were more cancellations for poor ovarian response among FSH-HP + rhLH patients (n = 3) than among FSH-HP patients (n = 1). The trend toward better pregnancy outcomes among patients who received FSH-HP without supplemental rhLH did not reach statistical significance. It is postulated that appropriate endogenous LH concentrations exist despite luteal GnRHa pituitary suppression, thereby obviating the need for supplemental LH administration.

[Average length of spontaneous labor in Chinese primigravidas]. / Durée moyenne du travail spontané chez les primipares chinoises.

OBJECTIVE: To determine if labor duration is affected by ethnicity, we measured the average length of normal spontaneous labor in recently immigrated Chinese primigravidas and compared our findings to reference primigravida populations of differing ethnicity. MATERIALS AND METHODS: In this descriptive, retrospective study of 1,006 recently immigrated low-risk Chinese primigravidas delivering singleton, vertex, term infants (37-42 weeks gestation, inclusively) without conduction anesthesia or oxytocin, the length of first-, second-, and third-stage labor, maternal age, gestational age, and infant weight was measured and compared to labor lengths previously reported for women of differing ethnicity. RESULTS: Mean first stage labor duration was 326 minutes (SD +/- 185 min, range 25-1640 min), mean second stage labor duration was 52 minutes (SD +/- 42 min, range 2-450 min), and a mean third stage labor duration was 4.6 min (SD +/- 4.5 min, range 1-62 min). Interquartile range (IQR)/median for first-, second-, and third-stage labor was 225 min/300 min, 50 min/40 min, and 3 min/3 min respectively. Weak correlations were observed between first- and second-stage labor lengths, and second- and third-stage labor lengths. Average birth weight was 3250 g (SD +/- 376 g, range 2280-4660 g). Chinese parturients showed a significantly shorter duration of first-stage (P < 0.0001) when compared to parity-matched patients of differing ethnicity. Second-stage labor in Chinese parturients was also shorter, but did not differ significantly (P = 0.185) from previously reported non-Asian controls. CONCLUSION: When compared to previously collected data from non-Chinese women, clinically significant differences in first-stage labor lengths were measured in our study population. While second-stage labor durations were also shorter, the difference was not significant. Labor management should be individualized to account for these differences, and previous reports attempting to show equivalency of labor progress regardless of ethnicity warrant reinterpretation given these findings.

Enzymatic cleavage of disaccharide side groups in insoluble synthetic polymers: a new method for specific delivery of drugs to the colon.

A series of water-insoluble acrylic polymers containing disaccharide side groups were synthesized and evaluated in vitro. A cellobiose-derived monomer, 4-O-beta-D-glucopyranosyl-1-methacrylamido-1-deoxy-D-glucitol, was prepared and copolymerized with methacrylic acid. Two different modes of polymerization were used to give two products, P-1 and P-2. A homopolymer, P-3, was also synthesized using the same method as P-2. The degradation of the disaccharide side groups in these polymers and the monomer was evaluated by incubation with beta-glucosidase and measurement of the amount of glucose cleaved. It was found that the degradation rate increased in those polymers possessing lower contents of the disaccharide side groups (i.e. higher content of methacrylic acid). Scanning electron microscopy (SEM) observations of cross-sectioned slabs of P-1 visualized the degradation of the polymer. The enzymatic reaction caused a porous structure to be formed. The increased porosity may be used for the specific release of drugs into organs that contain large amounts of beta-glucosidases, such as the human colon.

Sperm in "parhenogenetic" freshwater gastrotrichs.

Freshwater members of the phylum Gastrotricha have been considered obligate parthenogens. In Lepidodermelia squammata, the species for which there is most evidence for parthenogenesis, sperm have been discovered. This finding will necessitate reexamination of the nature of sexuality and life cycles and of the concept of "species" in freshwater gastrotrichs.