Effect on ovarian activity and ovulation inhibition of different oral dosages of levonorgestrel.

OBJECTIVES: To investigate the effect of different oral dosages of levonorgestrel (LNG) on ovarian activity and to identify the lowest dosage at which no ovulation occurred. Secondary objectives were to assess return of ovulation after stopping treatment, bleeding pattern, pharmacokinetic (PK) parameters and safety and tolerability. STUDY DESIGN: A parallel-group study with adaptive design was performed in 90 healthy women with proven ovulatory cycles. Investigated dosages were LNG 0.095, 0.115 and 0.135 mg per day. Measurements of follicular growth and estradiol (E2) and progesterone concentrations were performed every 3 (±1) days during a 56-day treatment and a post-treatment period. Follicle-stimulating hormone and luteinizing hormone concentrations and multiple-dose PK parameters were determined during treatment. RESULTS: Two normal ovulations occurred in the LNG 0.095 mg group, none in the higher dose groups. Most subjects had active follicle-like structures without ovulation (Hoogland-Skouby scores 4). Ovarian activity was more suppressed in the highest dose group than in the other groups. Mean E2 concentrations were 241, 219 and 180 pmol/L during treatment with 0.095, 0.115 and 0.135 mg per day, respectively. PK results showed dose-proportionality. Most subjects ovulated during the post-treatment period. CONCLUSION: LNG 0.115 mg per day was the lowest effective dosage for consistent ovulation inhibition. All investigated dosages were safe and well-tolerated, and mean E2 concentrations were sufficient for prevention of hypoestrogenic side effects. IMPLICATIONS: Marketed progestogen-only pills (POP) containing 0.03 mg LNG do not consistently inhibit ovulation. Increasing the dosage to 0.115 mg or 0.135 mg per day, resulting in consistent ovulation inhibition, may improve the contraceptive efficacy of the LNG-POP.

The effects on ovarian activity of delaying versus immediately restarting combined oral contraception after missing three pills and taking ulipristal acetate 30 mg.

OBJECTIVE: Among combined oral contraception (COC) users, to determine the effect on ovarian activity and ovulation of waiting five days before restarting COC, versus restarting immediately, having taken ulipristal acetate 30 mg (UPA, the dose used for emergency contraception) after missing three consecutive COC pills. STUDY DESIGN: Women already using COC were enrolled for two cycles of COC use (21/7 regimen). In cycle 2, all women omitted COC pills for three consecutive days (days 5,6,7), and on day 8 took UPA 30 mg. They were randomized either to restart their COC pills that same day (immediate restart) or to wait five days (delayed restart). Transvaginal ultrasound, and blood sampling for estradiol and progesterone were undertaken on days 4,8,11,13,15,18,22 and 26. A modified Hoogland score was used to quantify ovarian activity/ovulation and to assess whether luteal phase progesterone concentrations were sufficiently 'adequate' to have conferred a theoretical risk of pregnancy. RESULTS: No one ovulated with risk of pregnancy during the five days following UPA. Among 26 women with immediate restart, none ovulated with a theoretical risk of pregnancy at any time in the cycle. Four of 23 women (17.4% CI [5.0; 38.8]) with delayed restart ovulated with theoretical risk of pregnancy before the end of the cycle. This difference was statistically significant (p = 0.042). CONCLUSION: Women who delay restarting COC for five days after taking UPA 30 mg are at much greater risk of ovulation, and therefore theoretically of pregnancy, than if they restart their COC on the same day as taking UPA. Current recommendations should be revisited. IMPLICATIONS: Women who take UPA-EC after having missed combined oral contraceptive pills are advised to wait five days before restarting the COC. This delay puts them at risk of ovulation and, if intercourse occurs, theoretically therefore of pregnancy. Women who restart their COC pills immediately are much less likely to ovulate. The label for UPA-EC and clinical guidelines on using EC after missed pills should be revisited.

A field study into the appropriateness of transcutaneous ultrasonography in the diagnoses of uterine disorders in reproductively failed pigs.

This study was conducted to define the characteristics of the uterus of reproductively failed pigs by transcutaneous ultrasonography (SONO) in order to investigate the appropriateness of SONO to diagnose presumptive uterine disorders. Zearalenone (ZEA) is known to affect uterine function and causes endometrial liquid accumulation and was also determined. In 33 sows and 14 gilts, of unknown reproductive stages and culled for failing to conceive, the uterus was scanned transcutaneously and the females slaughtered on the same day or the day after scanning. Parameters determined by SONO were uterine echotexture (UET; graded 1 for homogeneous to 4 for highly heterogeneous), uterine size (US; expressed as the mean sectional area of two to three cross-sections of the uterine horns given in cm2) and intrauterine content. Post mortem, the ovarian structures were assessed and females grouped accordingly into those in estrus (n=2), early diestrus (n=14), diestrus (n=15), late diestrus (n=1), anestrus (n=10) and having polycystic ovarian degeneration (n=5). The uterine weight (UW) was recorded and uterine specimens microscopically evaluated for an endometrial oedema (EO; grades 1 for none, to 4, if an oedema was clearly evident) and for immune cells to assess endometritis. Total ZEA was analysed in bile and females with >or=50 ng/ml judged as positive. The uterus could be examined in all animals. UET, US, UW and EO was found to be different between groups, and a positive correlation (P<0.001) established for US and UET (r=0.71), US and EO (r=0.51), UET and EO (r=0.57), US and UW (UW=357.6 x US(0.801); r=0.88). One female had intrauterine fluid and an acute-chronic endometritis diagnosed. Almost all females had a chronic endometritis and a majority found ZEA positive. No differences were observed between groups and a relationship between ZEA or chronic endometritis and UET, US, UW and EO were not established. In conclusion, transcutaneous SONO is appropriate to examine the uterus in reproductively failed pigs on farms, and the estimation of UET and US gives information on EO and UW. Intrauterine fluid is indicative for a severe uterine inflammation. Since groups differed in UET and US, but were equally ZEA positive and the uteri chronically inflamed, an UET and US specifically associated with ZEA or chronic endometritis is questioned.

Ultrasonographic characterization of the ovaries and the uterus in prepubertal and pubertal gilts.

In two experiments (EXP), 44 and 52 crossbred gilts (mean age+/-S.D. and weight+/-S.D.: 204+/-22 and 203+/-9 days, 114+/-13 and 127+/-12 kg, respectively, in EXP 1 and 2) from four farms were examined by means of transcutaneous ultrasonography (US) to define the characteristics of the ovaries and the uterus (echotexture, size) and to investigate the appropriateness of US to determine sexual maturity. Gilts were judged as prepubertal [PRE; follicles 2-5 mm (F2-5) only] or pubertal [PUB; F7-8, corpora lutea (CL), corpora haemorrhagica (CH)] at the first (PUB-1; EXP 1) or a subsequent estrous cycle [PUB-2; additionally corpora albicantia (CA); EXP 1] by US, and results were verified by postmortem examination (EXP 1), or progesterone analysis and detection of estrous signs (EXP 2). Accuracy of US was 100% for PRE and PUB (both EXP) and 77.3% for PUB-1 and PUB-2 (EXP 1). PRE and PUB with CL/CH had uteri of homogeneous, PUB with F7-8 of heterogeneous echotexture. The size was expressed as the mean sectional area (SAsono) of 2-5 cross-sections of the uterine horns (calculated by multiplication of 1/2 the maximum x the minimum dimension of the cross-sections x pi). SAsono corresponded with the sectional area of postmortem dissected transverse uterine segments relatively with r=0.92 (P<0.0001; EXP 1). Mean SAsono (both EXP) and mean uterine weight (EXP 1) were PRE

Ultrasonographic characterization of the ovaries in non-pregnant first served sows and gilts.

This study was aimed firstly, to examine the ovaries in non-pregnant first served sows and gilts by transcutaneous ultrasonography and secondly, to evaluate the suitability for this procedure to be performed routinely on farms. Two thousand five hundred and twenty-three females on a 1250-sow unit, synchronized with Regumate (gilts only) and/or gonadotropins (sows and gilts) not detected as returned to estrus by daily boar contact prior to scanning were ultrasonographically tested for pregnancy between days 20 and 114 postinsemination (p.i.). Of 256 sows (S) and 130 gilts (G) found to be non-pregnant the ovaries were visualized in 87.1 and 80.0% of them, respectively. Ovarian findings were: corpora lutea (CL); follicles of 2-6mm (F(2-6)); peri-ovulatory ovarian structures (POS; comprising follicles of 7-8mm and corpora haemorrhagica); single cysts (SC); oligocystic ovarian degeneration (OOD) and polycystic ovarian degeneration (POD). Their incidence was: CL>F2-6>POS>POD ( P<0.05 ) in both S and G. POD and SC plus OOD were more frequently in S ( P<0.05 ). The ovarian findings were related to the intervals of regular (days 18-25 p.i. (R1), 38-46 p.i. (R2)) and irregular service returns (days 26-37 p.i. (IR1), 47-114 p.i. (IR2)). Comparison within intervals: CL tended to be more frequently with P<0.05 only at IR2 in S. Comparison among intervals (R1 to IR2): The percentage of females (1) with CL tended to increase (S and G) and (2) with F2-6 plus POS decreased significantly (S; P<0.05 ) or tendentiously (G). SC plus OOD was higher before R2, POD after IR1 (S and G; P<0.05 ). In conclusion, the results indicate a high heterogeneity of ovarian structures in non-pregnant first served sows and gilts up to day 114 after service and suggest CL as an important cause for a delayed and, rather than POD, a failed service return. The results further demonstrate that transcutaneous ultrasonography is an appropriate and recommended method for examining the ovaries on farm in female pigs with reproductive failures.