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Evaluation of: Legro RS, Barnhart HX, Schlaff WD et al.: Ovulatory response to treatment of polycystic ovary syndrome is associated with a polymorphism in the STK11 gene. J. Clin. Endocrinol. Metab. 93(3), 792-800 (2008). The current study by Legro et al. is a substudy of the recent multicenter, double-blinded, prospective study Pregnancy in Polycystic Ovary Syndrome. Legro et al. randomly assigned 626 infertile women with polycystic ovary syndrome to receive 50 mg clomiphene citrate plus placebo (n = 209), 2 g extended-release metformin plus placebo (n = 208), or a combination of metformin and clomiphene (n = 209) for up to six cycles. Of 626 patients in the original study, 312 women participated in the pharmacogenetic substudy; 98 received metformin XR (2 g/day), 102 clomiphene and 112 combined clomiphene-metformin XR treatment. This study was designed "to identify predictive genetic polymorphism and other determinants of ovulatory response" in prospective fashion. Candidate genes tested included estrogen receptor 1 (ESR1), CYP genes (CYP2C9 and CYP2D6) and STK11. STK11, formerly known as LKB1, is a serine-threonine kinase gene expressed in the liver, which phosphorylates and activates AMP-activated protein kinase. It was shown to be a site of metformin action. The C allele of a SNP in the STK11 gene was associated with a significantly decreased chance of ovulation in polycystic ovary syndrome women treated with metformin. In analysis of ovulation per cycle, the adjusted odds ratio for CC versus GG (wild-type normal) was 0.30 (95% CI: 0.14-0.66) and the odds ratio for CG versus GG was 0.30 (95% CI: 0.14-0.66). This elegant study is of great importance because despite treatment, many women with polycystic ovary syndrome fail to ovulate, 24.9% in the clomiphene group, 44.7% in the metformin group and 16.7% in the clomiphene-metformin group.
Oral administration of clomiphene at 2, 4, or 8 mg/kg to 4-day-old rats caused multiple histopathological abnormalities of the reproductive tract in both male and female animals. No histopathological abnormalities were observed in 30-day-old male rats at any dose examined. In contrast, 30-day-old females showed hypertrophy of the myometrium at all doses examined, and hypertrophy of the luminal or glandular epithelium, and dilatation of the uterine lumen were observed in the highest dose group. In post-pubertal rats, histopathologically marked changes were observed in the testes and epididymides in males, and in the ovaries and uterus in females in the highest dose group. In addition, relative weight of male reproductive organs in the highest dose group was decreased as compared with that in the controls. These results suggested that early neonatal exposure to clomiphene induced marked reproductive tract abnormalities in males after puberty, as well as in females.
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We treated two patients with male infertility due to 21-hydroxylase deficiency. Endocrinologic examinations disclosed low levels of LH and FSH, with elevated ACTH and 17-OH-progesterone in both. In addition, a small testicular tumor was found in Case 1, which disappeared after adrenal replacement. Suppressed gonadotropin levels caused by increased androgen seemed to underlie the sperm dysfunction in these patients. Dexamethasone and then clomiphene were administered in Case 1, and dexamethasone in Case 2. Spermatogenesis was somewhat improved in both patients and pregnancy achieved in Case 2, though spontaneous abortion later occurred.
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Controlled ovarian hyperstimulation was accomplished by clomiphene citrate and gonadotropins.
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Polycystic ovary syndrome (PCOS) is characterised by infrequent or absent ovulation (anovulation), high levels of male hormones (hyperandrogenaemia) and high levels of insulin (hyperinsulinaemia secondary to increased insulin resistance). Hyperinsulinaemia is associated with an increase in cardiovascular risk and the development of diabetes mellitus. Insulin-sensitising agents such as metformin may be effective in treating the features of PCOS, including anovulation.
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Growing interest in preimplantation genetic diagnosis has indicated uterine flushing as one method for obtaining human preimplantation embryos. To date, our institution has performed non-surgical uterine flushing to donate the recovered embryos to infertile recipients. We performed 127 flushings in 127 cycles using a modified urinary bladder catheter. Using the donors' natural cycles, a single ovum was recuperated in 37 out of 88 flushings. In 17 flushings, clomiphene citrate was given to the donors and 14 ova were found in nine positive recoveries. Human menopausal gonadotrophins were administered to the donors in 22 flushings and 22 ova were located in 14 positive recoveries. In total, 22 blastocysts, 11 morulae and 13 pre-embryos at the 2- to 16-cell stages were found. When transferred, these embryos gave rise to 18 clinical pregnancies in the recipients (40.9% of the transfers; 14.1% of the flushings). In comparison with natural cycles, superovulation of donors did not significantly increase the recipients' pregnancy rate. At present, non-surgical recovery of uterine pre-embryos does not seem to carry much potential as a tool for infertility treatment, or for genetic diagnosis. This is because currently available alternative methods are more successful.
After the procedure, serum T, LH, homocysteine levels and LH-FSH ratio were significantly lower than at baseline (0.93 +/- 0.15 vs 0.67 +/- 0.11 ng/ml, p < 0.001; 12.72 +/- 1.13 vs 7.36 +/- 0.57 mlU/ml, p < 0.001; 9.77 +/- 1.06 vs 7.13 +/- 0.99 micromol/L, p < 0.001; 2.16 +/- 0.22 vs 1.29 +/- 0.13, p < 0.001, respectively). In addition, SHBG levels were higher than at baseline (370.7 +/- 19.08 vs 404.7 +/- 16.71 nmol/L, p < 0.001) No reduction in high-density lipoprotein cholesterol was observed after the procedure. Similarly, no differences were observed between treating women with LOD and their baseline measurements in E2, FSH, DHEAS, and PRL concentrations (p = 0.255, p = 0.140, p = 0.250, p = 0.137, respectively). Ovulation occurred spontaneously in 77% of women after the procedure. The chance of conception at 12 months after surgery was 54%.
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16 patients aged 23-38 suffering from primary or secondary sterility due to oligomenorrhea or amenorrhea had ovarian biopsies performed by surgical culdoscopy using Clyman's method. The technique was useful in diagnosing 8 cases of premature menopause. In the other patients the surgical culdoscopy approach was superior to ordinary culdoscopy for evaluating ovarian structure and changes due to the ovulation stimulants chlomiphene and Pergonal.
Report of 39 patients suffering from functional sterility, having been treated with Clostylbegyt. Under analysis were the age of the patients, complications during therapy, time of ovulation and the effect of the drug on several ovarian caused difficulties of conception. Controlling examinations as well as the pregnancies obtained and their progress were discussed.
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To test whether the reduced fecundity in women who smoke cigarettes may be attributed to the accelerated development of diminished ovarian reserve.
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To investigate the association of non-cavity-distorting uterine fibroids and pregnancy outcomes after ovarian stimulation-intrauterine insemination (OS-IUI) in couples with unexplained infertility.
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A systematic review and meta-analysis.
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The authors report on gonadotropin treatment of 91 women who were infertile due to luteal dysfunction. As an effect of treatment there was an improvement of the corpus luteum function in 77 patients (84.6%), and 30 of them (33.0%) became pregnant. Application of HCG is recommended in cases if clomiphene treatment proved ineffective previously. Application of FSH and HCG is recommended at low level of estrogen.
Ninety infertile women were randomized to receive either sequential CC/hMG regimen (45 women) or low-dose step-up protocol of hMG (45 women). All participants had received at least six consecutive cycles of clomiphene citrate for ovulation induction within the last year before inclusion in this study, but they did not conceive. The CC/hMG regimen group received clomiphene citrate 100 mg/day for 5 days, followed by hMG 75 IU for 4 days. The hMG group received low-dose step-up protocol for 10-14 days. To detect the number and size of the follicles, TVS was done on cycle day 8 and repeated daily or every other day according to follicular development. When one to three follicles reached a diameter ≥18 mm, hCG injection was scheduled. Before hCG injection, the E2 level and endometrial thickness were evaluated. β-hCG levels were measured on cycle day 22.
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Race, ethnicity, body mass index (BMI), insurance coverage, history of smoking, and history of alcohol use were significantly associated with retention whether they were considered in bivariate analyses or a multivariable logistic model. Specifically, white race, higher income, having graduate degrees, normal weight, better insurance coverage, nonsmokers, and those who reported current use of alcohol at the start of the trial, had higher retention rates.
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A total of 442 SREI and/or SRS members.
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Metformin is not an effective addition to clomifene citrate as the primary method of inducing ovulation in women with polycystic ovary syndrome.
Induction of ovulation by adding DEX (high dose, short course) to CC in CC-resistant PCOS with normal DHEAS is associated with no adverse anti-estrogenic effect on the endometrium and higher ovulation and pregnancy rates in a significant number of patients. Induction with DEX appears to be independent on age, period of infertility, BMI or WHR.
In the present prospective randomized trial, 140 women with clomiphene-citrate-resistant PCOS were randomly allocated to receive 5mg letrozole from day 3 to day 7 of menses for 6 consecutive cycles, or to undergo LOD. When a leading follicle of at least 18 mm was present, ovulation was triggered with human chorionic gonadotropin (hCG). The 6-month rates of ovulation, pregnancy, abortion, and live births were evaluated.
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Prospective quasi-randomized trial.