Ovarian stimulation under the effect of isotretinoin.

Isotretinoin (13-cis-retinoic acid) is a pharmaceutical vitamin A analog that is frequently used in the treatment of severe cystic acne, many women at reproductive age being exposed to this substance. This drug has a clearly documented teratogenicity and data from rodents and humans indicate that a direct aggression to ovarian follicles also occurs. Here we report the case of a 29-year-old woman with breast cancer referred for emergency preservation of reproductive potential that used isotretinoin up to the day before the initiation of ovarian stimulation. Ultrasound scan showed an antral follicle count of 17 and 13 follicles on the right and the left ovary, respectively, and her antimüllerian hormone levels were 4.03 ng/ml. Standard ovarian stimulation for oocyte vitrification in oncological patients was initiated during the luteal phase and final estradiol levels were 49 pg/ml. Three mature oocytes were obtained. Other four oocytes were retrieved in the germinal vesicle and metaphase I developmental stage, all of which matured in vitro in the following 30 h and were also vitrified. Response to ovarian stimulation, both in terms of the number of mature oocytes obtained and serum sex steroids production were in the lower range of what is observed in patients with a similar clinical profile. These findings suggest that isotretinoin impairs follicular-oocyte maturation.

Effect of estradiol valerate on endometrium thickness during clomiphene citrate-stimulated ovulation.

AIM: The aim of this study was to examine the effects of estradiol valerate (EV) on the thickness of clomiphene citrate (CC)-stimulated endometrium. MATERIAL AND METHODS: Thirty-four normal ovulatory women were randomized double-blindly into two groups to receive CC 100 mg/day on day 2-6 of the treatment cycle, and either vitamin B (placebo) or EV 6 mg/day on day 10-14 of the cycle. The endometrial thickness, endometrial pattern, numbers of mature follicles, and maximal diameters of preovulatory follicles were evaluated by transvaginal sonographic examination. RESULTS: Thirty women completed both treatment cycles. Two other participants dropped out during the treatment due to side-effects (headache). The average endometrial thickness of the group treated with CC + placebo became slightly thinner when compared to the thickness at the baseline (9.04 vs 9.52 mm; P = 0.24). The CC + placebo and the CC + EV resulted in similar endometrial pattern, ovulation day, numbers of mature follicles, and sizes of the leading follicles before ovulation. However, an addition of EV into the CC cycle significantly increased the average endometrial thickness (10.7 mm vs 9.04 mm; P < 0.001). CONCLUSIONS: We concluded that the addition of 6 mg/day EV following the CC treatment can prevent the endometrial thinning without perturbing folliculogenesis and ovulation.

Effects of cortisol on pregnancy rate and corpus luteum function in heifers: an in vivo study.

To determine whether glucocorticoids affect the function of the bovine corpus luteum (CL) during the estrous cycle and early pregnancy, we examined the effects of exogenous cortisol or reduced endogenous cortisol on the secretion of progesterone (P4) and on pregnancy rate. In preliminary experiments, doses of cortisol and metyrapone (an inhibitor of cortisol synthesis) were established (n=33). Cortisol in effective doses of 10 mg blocked tumor necrosis factor-induced prostaglandin F(2α) secretion as measured by its metabolite (PGFM) concentrations in the blood. Metyrapone in effective doses of 500 mg increased the P4 concentration. Thus, both reagents were then intravaginally applied in the chosen doses daily from Day 15 to 18 after estrus (Day 0) in noninseminated heifers (n=18) or after artificial insemination (n=36). Pregnancy was confirmed by transrectal ultrasonography between Days 28-30 after insemination. Plasma concentrations of P4 were lower in cortisol-treated heifers than in control heifers on Days 17 and 18 of the estrous cycle (P<0.05). However, the interestrus intervals were not different between control and cortisol-treated animals (P>0.05). Moreover, metyrapone increased P4 and prolonged the CL lifespan in comparison to control animals (P<0.05). Interestingly, in inseminated heifers, cortisol increased the pregnancy rate (75%) compared with control animals (58%), whereas metyrapone reduced the pregnancy rate to 16.7% (P<0.05). The overall results suggest that cortisol, depending on the physiological status of heifers (pregnant vs. nonpregnant), modulates CL function by influencing P4 secretion. Cortisol may have a positive influence on CL function during early pregnancy, leading to support of embryo implantation and resulting in higher rates of pregnancy in heifers.

The age-related recurrence of endometrioma after conservative surgery.

OBJECTIVE: As endometrioma frequently recurs after conservative surgery, long-term postoperative medical treatment for the prevention of recurrence is necessary. However, it has not been elucidated whether long-term postoperative medical treatment is crucial to all patients until menopause. Thereupon, this study was conducted to evaluate the age-related recurrence patterns after conservative surgery for endometrioma. STUDY DESIGN: A retrospective cohort study was performed on a total of 420 reproductive-aged women who underwent conservative surgery for endometrioma between January 2000 and December 2010. Ultrasonography was used during the follow-up period to detect endometrioma recurrence. Patients were classified into two groups according to the use of postoperative medications. The first group was observation only, while the second received gonadotropin releasing hormone agonists followed by cyclic oral contraceptives. The cumulative recurrence rate of endometrioma was compared according to the age at surgery (20-29 years, 30-39 years, 40-45 years) within each group. Subgroup analysis was performed according to the age between the two groups. RESULTS: The median follow-up duration after surgery was 29.0 months (range 6-159 months) for all patients. After adjusting for parity, size and bilaterality of cyst, and stage with American Society for Reproductive Medicine classification of endometriosis which was statistically different, within the group of no treatment, the cumulative recurrence rate in 40-45 years (10.2%) was significantly lower compared with those in 20-29 years (43.3%; hazard ratio (HR)=0.04; 95% confidence interval (CI)=0.01-0.52) and 30-39 years (22.5%; HR=0.19; 95% CI=0.04-0.92). However, there were no differences within the group of postoperative medical treatment. When we compared between the two groups, the cumulative recurrence rate was significantly different in 20-29 years (8.1 vs 43.3%; p<0.001) and 30-39 years (5.4 vs 22.5%; p=0.007), but there was no difference in 40-45 years (4.5 vs 10.2%; p=0.901). CONCLUSIONS: Our preliminary results demonstrate that the risk of endometrioma recurrence decreases with age. After the age of forty, the recurrence rate does not differ according to the use of postoperative medication. Based on our results, postoperative medical treatment may be individualized according to the patient's age at the time of surgery. Further studies are needed to identify patients who may benefit from postoperative medication.

Short-term delay of puberty causes a transient reduction in bone strength in growing female rats.

Multiple factors affect the structural development of the skeleton; in particular, estrogen levels during growth are an important factor in the pathogenesis of bone fragility. The delay of menarche and infrequent menstrual cycles decrease estrogen levels during adolescence and decrease peak bone mass. The aim of this study was to determine if delayed puberty through administration of a GnRH antagonist initiated prior to the onset of the first estrus cycle would delay the increase in estrogen levels and impede bone strength development in female rats. Twenty-three-day-old female Sprague-Dawley rats were randomly assigned to one of four groups; 1) short-term control group (C-ST) (n = 12), 2) long-term control (C-LT) (n = 12), 3) short-term GnRH antagonist group (G-ST) (n = 12) and 4) long-term GnRH antagonist group (G-LT) (n = 12). Injections (0.2 ml) of either saline or GnRH antagonist (100 microg/day) (Cetrotide, Serono, Inc) were given intraperitoneally for a duration of 18 days. Pubertal and gonadal development was retarded as indicated by a delay in vaginal opening (an indicator of pubertal onset), lower ovarian and uterine weights and lower estradiol levels in the short-term experimental animals (G-ST). However, at maturity (G-LT), there were no significant differences found in these measures. A delay in the timing of puberty significantly attenuated the development of femoral bone strength at 6 weeks of age. Peak moment, yield moment and stiffness in the G-ST group were all significantly less than the C-ST group. Cortical width was significantly attenuated due to the increased percentage of marrow area per total bone area in the G-ST group. However, femoral bone strength was recovered at maturity (G-LT). In summary, a transient delay in pubertal timing has short-term effects on bone strength development. In the current animal model of delaying puberty through GnRH antagonist injections, there appears to be no long-term effects on bone strength.

Pharmacological options in resistent ovary syndrome and premature ovarian failure.

PURPOSE: To present methods of treating women in apparent ovarian failure to allow them to ovulate and conceive. METHODS: Ethinyl estradiol was used to lower elevated serum follicle stimulating hormone (FSH) levels to restore down-regulated FSH receptors on the follicle. Ovulation and pregnancy rates were then determined. Aggressive progesterone (P) therapy in the luteal phase was also used. Lowering elevated serum FSH with gonadotropin releasing hormone agonists was also successful in inducing ovulation in these patients. RESULTS: Several anecdotal studies have demonstrated that ethinyl estradiol therapy can induce ovulation in women in apparent menopause and achieve live births. CONCLUSIONS: The advantage of ethinyl estradiol over other estrogens to induce ovulation in hypergonadotropic women is that it does not cross-react in the assay for serum estradiol and can allow detection of estradiol secretion by the follicle. Thus estrogen therapy is by far the most effective treatment.

[Decreased quality of cervix mucus under the influence of clomiphene: a meta-analysis]. / Verminderde kwaliteit van cervixslijm onder invloed van clomifeen: een meta-analyse.

OBJECTIVE: To determine whether clomiphene (citrate) has a negative influence on cervical mucus qualities and whether administration of exogenous oestrogens has a favourable influence in that case. DESIGN: Meta-analysis. SETTING: Stichting Gezondheidszorg Oostelijk Zuid-Limburg, Midwifery School, Kerkrade, the Netherlands. METHOD: Relevant articles were searched using the Medline database for the years 1980-1996 and the Knowledge Finder search system. The reference lists of these articles were studied. All prospective, randomized and controlled clinical trials mentioning detailed figures were selected and analysed. RESULTS: Six articles met all criteria for analysis of the effect of clomiphene on cervical mucus. Clomiphene 50 mg/day had an unfavourable influence on cervical mucus (not significant), but clomiphene 100 and clomiphene 150 mg/day did have a significant effect, the relative risk of unfavourable cervical mucus being more than seven in comparison with women not using clomiphene (respective odds ratios 7.90 (95% confidence interval: 4.15-15.00) and 7.50 (1.97-28.60)). Four articles met all criteria for analysis of the effect of exogenous oestrogens on cervical mucus of women being treated with clomiphene. Exogenous oestrogens resulted in improvement of the cervical mucus qualities in these women (odds ratio: 2.87 (1.76-4.69)). CONCLUSION: The influence of clomiphene 50 mg/day on cervical mucus is not significantly unfavourable, unlike the influence of clomiphene 100 and 150 mg/day. Exogenous oestrogen administration improves this cervical mucus. In all patients being treated with clomiphene the cervical mucus qualities should be investigated.

2-Arylindoles as gonadotropin releasing hormone (GnRH) antagonists: optimization of the tryptamine side chain.

A series of 2-arylindoles containing novel heteroaromatic substituents on the tryptamine tether, based on compound 1, was prepared and evaluated for their ability to act as gonadotropin releasing hormone (GnRH) antagonists. Successful modifications of 1 included chain length variation (reduction) and replacement of the pyridine with heteroaromatic groups. These alterations culminated in the discovery of compound 27kk which had excellent in vitro potency and oral efficacy in rodents.