Multiple failures in the lutenising hormone surge generating system in GABAB1KO female mice.

Female mice lacking GABAB receptors, GABAB1KO, show disrupted oestrous cycles, reduced pregnancies and increased hypothalamic Gnrh1 mRNA expression, whereas anteroventral periventricular/periventricular preoptic nucleus (AVPV/PeN) Kiss1 mRNA was not affected. In the present study, we characterise the important components of the gonadotrophic preovulatory surge, aiming to unravel the origin of this reproductive impairment. In GABAB1KO and wild-type (WT) females, we determined: (i) hypothalamic oestrogen receptor (ER)α and ß and aromatase mRNA and protein expression; (ii) ovulation index and oestrus serum follicle-stimulating hormone (FSH) and pituitary Gnrh1r expression; (iii) in ovariectomised-oestradiol valerate-treated mice, we evaluated ex vivo hypothalamic gonadotrophin-releasing hormone (GnRH) pulsatility in the presence/absence of kisspeptin (Kiss-10, constant or pulsatile) and oestradiol (constant); and (iv) in ovariectomised-oestradiol silastic capsule-treated mice (proestrous-like environment), we evaluated morning and evening kisspeptin neurone activation (c-Fos+) and serum luteinising homrone (LH). In the medial basal hypothalamus of oestrus GABAB1KOs, aromatase and ERα mRNA and protein were increased, whereas ERß was decreased. In GABAB1KOs, the ovulation index was decreased together with decreased first oestrus serum FSH and increased pituitary Gnrh1r mRNA. Under constant Kiss-10 stimulation, hypothalamic GnRH pulse frequency did not vary, although GnRH mass/pulse was increased in GABAB1KOs. In WTs, pulsatile Kiss-10 together with constant oestradiol significantly increased GnRH pulsatility, whereas, in GABAB1KOs, oestradiol alone increased GnRH pulsatility and this was reversed by pulsatile Kiss-10 addition. In GABAB1KOs AVPV/PeN kisspeptin neurones were similarly activated (c-Fos+) in the morning and evening, whereas WTs showed the expected, marked evening stimulation. LH correlated with activated kisspeptin cells in WT mice, whereas GABAB1KO mice showed high, similar LH levels both in the morning and evening. Taken together, all of these alterations point to impairment in the trigger of the preovulatory GnRH surge that entails the reproductive alterations described.

Ovulatory effects of three oral contraceptive regimens: a randomized, open-label, descriptive trial.

OBJECTIVE: This study describes ovarian activity suppression of a 21/7-active low-dose combined oral contraceptive (COC) regimen that included only ethinyl estradiol (EE) during the traditional hormone-free interval (HFI) and two commercially available 28-day regimens, a 24/4 and a 21/7 regimen. STUDY DESIGN: The randomized, open-label, parallel-group descriptive study was conducted at two US sites. Healthy, reproductive-aged women (n=146) were randomized to one of three groups for three consecutive 28-day cycles, as follows: treatment 1 (n=39 completed): 21/7-active COC [21 days of 150 mcg desogestrel (DSG)/20 mcg EE, followed by 7 days of 10 mcg EE (DSG/EE+7 days EE)], treatment 2 (n=39 completed): 24 days of 3mg drospirenone (DRSP)/20 mcg EE, followed by 4 placebo (PBO)-pill days (DRSP/EE+4 days PBO) and treatment 3 (n=42 completed): 21 days of 100 mcg levonorgestrel (LNG)/20 mcg EE, followed by 7 PBO-pill days (LNG/EE+7 days PBO). The primary outcome was ovarian activity suppression assessed by transvaginal ultrasound and serum hormone concentrations and classified using the Hoogland and Skouby (H/S) method. RESULTS: Ovarian activity rate (H/S grade 4 or 5) was low for all three treatments: 0% [95% confidence interval (CI) 0-2.8] for DSG/EE+7 days EE, 1% (95% CI 0.2-5.2) for DRSP/EE+4days PBO and 1% (95% CI 0-3.9) for LNG/EE+7 days PBO. All three treatments showed similar suppression of serum progesterone, 17ß-estradiol, follicle-stimulating hormone and luteinizing hormone levels. CONCLUSIONS: The 21/7-active low-dose COC regimen (DSG/EE+7 days EE) showed ovarian activity suppression that was similar to the 24/4 (DRSP/EE+4 days PBO) and 21/7 (LNG/EE+7days PBO) regimens. IMPLICATIONS: The 21/7-active low-dose COC regimen (DSG/EE+7 days EE) that included only EE during the traditional HFI showed suppression of ovarian follicular activity that was similar to the 24/4 (DRSP/EE+4days PBO) and the 21/7 (LNG/EE+7 days PBO) comparator regimens.

A randomized study of the effect of mifepristone alone or in conjunction with ethinyl estradiol on ovarian function in women using the etonogestrel-releasing subdermal implant, Implanon®.

BACKGROUND: Mifepristone alone or in combination with ethinyl estradiol (EE) can effectively stop an episode of uterine bleeding in women using the etonogestrel-releasing contraceptive implant, Implanon® but could impair contraceptive efficacy. AIM: To examine the effects of administration of mifepristone alone or with EE on ovarian function and cervical mucus consistency in women using Implanon. STUDY DESIGN: Women using Implanon were randomized to mifepristone 25 mg twice daily on day 1 plus placebo 1 daily for 4 days or plus EE 20 mcg daily for days 2-5. Measurements of serum estradiol (E(2)), progesterone (P(4)), luteinizing hormone (LH), follicle-stimulating hormone (FSH), cervical mucus examination and maximal follicle size (by vaginal ultrasound) were carried out at various times. RESULTS: Following mifepristone intake, there was a dramatic increase in E(2) levels ranging from 543 to 1183 pmol/L (p=.000), which was not correlated with maximal follicle size or preceded by LH or FSH increase. The increase in E(2) triggered an LH increase resulting in development of a luteinized follicle in four women with no evidence of ovulation. One of these women had estradiol and progesterone levels suggestive of ovulation, but no corpus luteum was seen. Almost all women had very low mucus scores, which did not correlate with E(2) levels. DISCUSSION: Despite a transient increase in E(2) levels after mifepristone, there was no evidence of subsequent ovulation irrespective of whether they also received EE. The mechanism by which mifepristone in the presence of etonogestrel results in a rapid increase in E(2) levels remains unclear and could not be related to any significant changes in FSH, LH, ovarian follicle dynamics or subsequent possible ovulation. CONCLUSION: Pregnancy is very unlikely to occur if mifepristone and EE are given during use of Implanon to stop an episode of bleeding.

Pharmacokinetics of a combined oral contraceptive in obese and normal-weight women.

BACKGROUND: This study was conducted to compare oral contraceptive (OC) pharmacokinetics (PK) in normal-weight [body mass index (BMI) 19.0-24.9] and obese (BMI 30.0-39.9) women. STUDY DESIGN: During the third week of the third cycle of OC use, we admitted 15 normal-weight and 15 obese women for collection of 12 venous specimens over 24 h. Using radioimmunoassay techniques, we measured levels of ethinyl estradiol (EE) and levonorgestrel (LNG). During the same cycle, women underwent twice-weekly sonography to assess ovarian follicular development and blood draws to measure endogenous estradiol (E2) and progesterone levels. RESULTS: Obese women had a lower area under the curve (AUC; 1077.2 vs. 1413.7 pg*h/mL) and lower maximum values (85.7 vs. 129.5 pg/mL) for EE than normal-weight women (p=.04 and <0.01, respectively); EE trough levels were similar between BMI groups. The similar, but smaller, differences in their LNG levels for AUC and maximum values (C(max)) were not statistically significant. While peak values differed somewhat, the LNG trough levels were similar for obese and normal-weight women (2.6 and 2.5 ng/mL, respectively). Women with greater EE AUC had smaller follicular diameters (p=.05) and lower E2 levels (p=.04). While follicular diameters tended to be larger among obese women, these differences were not statistically significant. CONCLUSION: OC hormone peak levels are lower among obese women compared to normal-weight women, but their trough levels are similar. In this small study, the observed PK differences did not translate into more ovarian follicular activity among obese OC users.

Follicular development and ovulation in extremely obese women receiving depo-medroxyprogesterone acetate subcutaneously.

BACKGROUND: Subcutaneous depo-medroxyprogesterone acetate (DMPA-SC) has not been studied in the extremely obese population (BMI >or=40 kg/m(2)). The purpose of this 26-week prospective experimental study was to determine incidence of ovulation and follicular development among women with Class 1, 2 and 3 obesity after receiving DMPA-SC. METHODS: Five normal-weight, five Class 1-2 obese, and five Class 3 obese women received subcutaneous injections of 104 mg DMPA-SC at baseline and 12 weeks later. Weekly progesterone levels, bimonthly estradiol (E(2)), and monthly medroxyprogesterone acetate (MPA) levels were measured by immunoassay methods for a total of 26 weeks in each subject. RESULTS: Ovulation did not occur in any subject more than 1 week after the first injection. There was large intersubject and intrasubject variability in E(2) levels, and fluctuating E(2) levels were more frequent among obese women than normal-weight women. Median MPA levels remained above the level needed to prevent ovulation but, compared with normal-weight subjects, were lower among Class 1-2 obese and lowest among Class 3 obese subjects. CONCLUSION: Fluctuating E(2) levels reflective of follicular development occurred more often among Class 1, 2 and 3 obese women than normal-weight women after DMPA-SC injections. Median MPA levels were consistently lowest among Class 3 obese women but remained above the level needed to inhibit ovulation. Further studies should more fully address the pharmacokinetics of DMPA-SC in extremely obese women.

Suppression of ovulation by a synthetic progestin in the capuchin monkey.

BACKGROUND: From the limited research in New World monkeys it is not clear whether they are as sensitive to the antiovulatory effects of synthetic progestins as noted in human beings. We examined whether levonorgestrel prevented ovulation in the capuchin monkey. METHODS: Cebus apella monkeys were treated orally with two doses of 2 mg of levonorgestrel, 8-9 hours apart, in four periovulatory stages assessed by laparoscopy. RESULTS: Levonorgestrel-induced luteinization of the follicle prevented oocyte release up to 8 hours before ovulation. Unhealthy oocytes were recovered from 46% of unruptured follicles. Luteal progesterone was reduced by 55%, 35%, and 25% according to when levonorgestrel was given -2, -1, and 0 day from estradiol peak respectively. CONCLUSION: The capuchin monkey, a neotropical primate in which progesterone circulates at levels much higher than in Old World primates and human beings, is sensitive to the antiovulatory effects of synthetic progestins.

Pituitary desensitization for eight weeks after the administration of two distinct gonadotrophin-releasing hormone agonists.

OBJECTIVE(S): The objective was to evaluate the duration of pituitary desensitization after the administration of 3.5 mg of triptorelin (T) and leuprolin (L) depot preparations in patients with endometriosis. STUDY DESIGN: Two groups of 30 patients received, on 21st day of the cycle, 3.75 mg i.m. of triptorelin (T group), and of leuprolin acetate (L group). From the first to the eighth week following gonadotrophin-releasing hormone agonists (GnRH-a) administration both groups underwent pelvic ultrasound and serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E2) evaluation. Statistical analysis was performed using the ANOVA test and the median test. A p-value < 0.05 was considered significant. RESULTS: Pituitary suppression was achieved from two to six and from two to seven weeks after the administration of 3.75 mg of leuprolin and triptorelin, respectively. FSH and LH serum levels were significantly higher in the L group than in the T group after the fourth week. CONCLUSIONS: Leuprolin and triptorelin depots (3.75 mg) promote satisfactory ovarian suppression lasting for six and seven weeks, respectively, after administration, with significantly different ambient levels of endogenous LH.