Valerie S. Ratts

Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone

OBJECTIVE To determine whether metformin treatment increases the ovulation and pregnancy rates in response to clomiphene citrate (CC) in women who are resistant to CC alone. DESIGN Randomized, double-blind, placebo-controlled trial. SETTING Multicenter environment. PATIENT(S) Anovulatory women with the polycystic ovary syndrome (PCOS) who were resistant to CC. INTERVENTION(S) Participants received placebo or metformin, 500 mg three times daily, for 7 weeks. Information on reproductive steroids, gonadotropins, and oral glucose tolerance testing was obtained at baseline and after treatment. Metformin or placebo was continued and CC treatment was begun at 50 mg daily for 5 days. Serum P level > or =4 ng/mL was considered to indicate ovulation. With ovulation, the daily CC dose was not changed, but with anovulation it was increased by 50 mg for the next cycle. Patients completed the study when they had had six ovulatory cycles, became pregnant, or experienced anovulation while receiving 150 mg of CC. MAIN OUTCOME MEASURE(S) Ovulation and pregnancy rates. RESULT(S) In the metformin and placebo groups, 9 of 12 participants (75%) and 4 of 15 participants (27%) ovulated, and 6 of 11 participants (55%) and 1 of 14 participants (7%) conceived, respectively. Comparisons between the groups were significant. CONCLUSION(S) In anovulatory women with PCOS who are resistant to CC, metformin use significantly increased the ovulation rate and pregnancy rate from CC treatment.

Analysis of apoptosis and expression of bcl-2 gene family members in the human and baboon ovary

Recent data support a role for apoptosis, under tight regulatory control by bcl-2, oxidative stress response, tumor suppressor, and CASP gene family members, in mediating granulosa cell demise during follicular atresia in the rodent and avian ovary. Herein we evaluated the occurrence of apoptosis in the human and baboon ovary relative to follicular health status, and analyzed expression of several cell death genes in these tissues. In situlocalization of DNA strand breaks in fixed human and baboon ovarian tissue sections indicated that apoptosis was essentially restricted to granulosa cells of atretic antral follicles. Biochemical analysis of DNA oligonucleosomes in individual follicles isolated from baboon ovaries during the ovulatory phase revealed the presence of apoptotic DNA fragments in subordinate but not dominant follicles, thus substantiating the in situ labeling studies. Messenger RNA transcripts encoded by the bax death susceptibility gene, the bcl-xlong survival gene, the bcl-xshort pro-apoptosis gene, the p53 tumor suppressor gene, and two members of the CASP gene family (CASP-2/Ich-1, CASP-3/CPP32), were detected by Northern blot analysis of total RNA prepared either from human ovaries or from Percoll-purified granulosa-lutein cells obtained from patients undergoing assisted reproductive technologies. Lastly, immunohistochemical localization of the BAX death-susceptibility protein in the human ovary revealed abundant expression in granulosa cells of early atretic follicles, whereas BAX protein was extremely low or non-detectable in healthy or grossly-atretic follicles. We conclude that apoptosis occurs during, and is probably responsible for, folicular atresia in the human and baboon ovary. Moreover, apoptosis in the human ovary is likely controlled by altered expression of the same cohort of cell death regulatory factors recently implicated as primary determinants of apoptosis induction or suppression in the rodent ovary.

Associations between free fatty acids, cumulus oocyte complex morphology and ovarian function during in vitro fertilization

OBJECTIVE To determine if follicular free fatty acid (FFA) levels are associated with cumulus oocyte complex (COC) morphology. DESIGN Prospective cohort study. SETTING University in vitro fertilization (IVF) practice. PATIENT(S) A total of 102 women undergoing IVF. INTERVENTION(S) Measurement of FFAs in serum and ovarian follicular fluid. MAIN OUTCOME MEASURE(S) Total and specific follicular and serum FFA levels, correlations between follicular and serum FFAs, and associations between follicular FFA levels and markers of oocyte quality, including COC morphology. RESULT(S) Predominant follicular fluid and serum FFAs were oleic, palmitic, linoleic, and stearic acids. Correlations between follicular and serum FFA concentrations were weak (r=0.252, 0.288, 0.236, 0.309, respectively for specific FFAs; r=0.212 for total FFAs). A receiver operating characteristic curve determined total follicular FFAs≥0.232 μmol/mL distinguished women with a lower versus higher percentage of COCs with favorable morphology. Women with elevated follicular FFAs (n=31) were more likely to have COCs with poor morphology than others (n=71; OR 3.3, 95% CI1.2-9.2). This relationship held after adjusting for potential confounders, including age, body mass index, endometriosis, and amount of gonadotropin administered (β=1.2; OR 3.4, 95% CI 1.1-10.4). CONCLUSION(S) Elevated follicular FFA levels are associated with poor COC morphology. Further work is needed to determine what factors influence follicular FFA levels and if these factors impact fertility.

Morbid obesity is associated with lower clinical pregnancy rates after in vitro fertilization in women with polycystic ovary syndrome

OBJECTIVE To determine whether morbid obesity is associated with decreased pregnancy and live birth rates after IVF in women with polycystic ovary syndrome (PCOS). DESIGN Retrospective cohort study. SETTING University-based fertility center. PATIENT(S) Seventy-two women with PCOS who completed their first IVF cycle between 2001 and 2006. INTERVENTION(S) Outcomes of IVF were compared between women with a body mass index (BMI) of <40 kg/m(2) vs. those with a BMI of > or =40 kg/m(2). MAIN OUTCOME MEASURE(S) Clinical pregnancy rate, live birth rate. RESULT(S) Morbidly obese women with PCOS (n = 19) had significantly lower clinical pregnancy rates after IVF than patients with PCOS who were not morbidly obese (n = 53) (32% vs. 72%, relative risk 0.44, 95% confidence interval 0.22-0.87). Their live birth rates were lower too, although this difference was not statistically significant (32% vs. 60%, relative risk 0.52, 95% confidence interval 0.26-1.05). CONCLUSION(S) Morbid obesity is associated with lower pregnancy rates in women with PCOS after IVF, raising the question of whether weight loss may improve IVF success rates for morbidly obese PCOS patients.

Polycystic ovary syndrome and maternal obesity affect oocyte size in in vitro fertilization/intracytoplasmic sperm injection cycles

To determine the impact of maternal metabolic state on oocyte development in women undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI), we retrospectively analyzed a cohort of women with PCOS undergoing IVF/ICSI from 2008-2009 in a university-based fertility center. We determined that women with PCOS and obesity have smaller oocytes than control subjects, and that when further subdivided by body mass index, both PCOS and obesity independently influence oocyte size.

Risk of surgery after use of potassium chloride for treatment of tubal heterotopic pregnancy.

BACKGROUND: Spontaneous heterotopic pregnancies are rare, but with assisted reproductive techniques the incidence may approach 1:100. With the widespread use of transvaginal ultrasonography, physicians have attempted treatment of heterotopic pregnancies with minimally invasive procedures such as transvaginal guided potassium chloride (KCl) injection. However, there are few data on the success of this treatment. CASE: A 30-year-old primigravida presented with a desired pregnancy and was found to have a tubal pregnancy in addition to an intrauterine pregnancy. Ultrasound-guided KCl injection into the heterotopic pregnancy was complicated by abdominal pain, surgical abdomen, and hemoperitoneum requiring salpingectomy. CONCLUSION: A review of the literature revealed that 55% of tubal heterotopic pregnancies treated by KCl injection required subsequent salpingectomy. This raises concerns about the advisability of this treatment.

A prospective comparison of the impact of uterine artery embolization, myomectomy, and hysterectomy on ovarian function

PURPOSE To prospectively compare uterine artery embolization (UAE) versus myomectomy and hysterectomy with regard to ovarian function as measured by postprocedure follicle-stimulating hormone (FSH) levels and symptoms. MATERIALS AND METHODS Fifty-five patients were prospectively enrolled in the study: 33 patients who underwent UAE, seven who underwent myomectomy, and 15 who underwent hysterectomy. Patients had serum FSH and estradiol levels measured on the third day of the menstrual cycle before their procedure and at regular follow-up visits for as long as 6 months. At these intervals, patients were also surveyed regarding menopausal symptoms. RESULTS Although a mild transient increase in mean FSH level after UAE was noted at 3 months, there were no statistically significant differences among the three groups in mean FSH levels at 1 month, 3 months, or 6 months of follow-up. Menopausal symptoms arose in the UAE and hysterectomy groups, but there was no statistically significant difference or permanent effect in either group. CONCLUSION There is no significant difference in impact on ovarian function after UAE, hysterectomy, or myomectomy at follow-up for a maximum of 6 months.

A prospective, randomized, double-blinded study of assisted hatching in women younger than 38 years undergoing in vitro fertilization

OBJECTIVE To determine whether assisted hatching is beneficial to IVF patients younger than 38 years whose embryos have a thickened zona pellucida (ZP). DESIGN Prospective, randomized, double-blinded, crossover study. SETTING University-based infertility center. PATIENT(S) One hundred twenty-one women less than 38 years of age, undergoing IVF at Washington University between April 2004 and February 2007, with ZP thickness > or =13 microm for any embryos. INTERVENTION(S) Measurement of ZP thickness in embryos undergoing IVF; randomization of women with embryos with ZP thickness > or =13 microm to no procedure or assisted hatching performed by acidic Tyrodes solution. MAIN OUTCOME MEASURE(S) Clinical intrauterine pregnancy rate, implantation rate, spontaneous pregnancy loss, and live birth rate. RESULT(S) Baseline characteristics and ZP thickness were not significantly different between the two study arms (hatched and unhatched). No significant differences were observed between hatched and unhatched patients in the rates of clinical pregnancy (47% vs. 50% respectively) or live birth (46% vs. 45% respectively). Further, no significant differences were noted between hatched and unhatched groups in rates of spontaneous abortions, monozygotic twinning, dizygotic twinning, chromosomal abnormalities, or ectopic gestations. In addition, mean ZP thickness did not have a significant effect on pregnancy. CONCLUSION(S) In patients younger than 38 years with embryos with ZP thickness of > or =13 microm, assisted hatching does not improve the rates of implantation, clinical pregnancy, or live birth, and thus does not appear to offer any benefit to patients in this age group undergoing IVF.

Sperm banking for fertility preservation: a 20-year experience.

OBJECTIVE Sperm banking is an effective method to preserve fertility, but is not universally offered to males facing gonadotoxic treatment in the United States. We compared the disposition and semen parameters of cryopreserved sperm from individuals referred for sperm banking secondary to a cancer diagnosis to those of sperm from men banking for infertility reasons. STUDY DESIGN We performed a retrospective cohort study that reviewed 1118 records from males who presented to bank sperm at Washington University between 1991 and 2010. We collected and analyzed demographics, semen parameters, and disposition of banked sperm. RESULTS Four hundred and twenty-three men with cancer and 348 banking for infertility reasons attempted sperm cryopreservation in our unit during the specified time period. The most prevalent cancers in our cohort were testicular (32%), lymphoma (25%), and leukemia (11%). Patients with leukemia had the lowest pre-thaw counts and motility. Most cancer patients (57%) who banked elected to use, transfer to another facility, or keep their specimens in storage. The remaining samples were discarded electively (34%) or following death (8%). Overall semen parameters were similar between the cancer and infertility groups, but demographics, ability to bank a sample, azoospermia rates, length of storage, current banking status, and use of banked sperm differed significantly between the two groups. CONCLUSIONS The majority of cancer patients who banked survived their cancer and chose to continue storage of banked samples. Cancer patients were more likely than infertility patients to use or continue storage of banked samples. Our study provides evidence that sperm banking is a utilized modality of fertility preservation in patients with a myriad of cancer diagnoses and should be offered to all men facing gonadotoxic therapies. Further work is needed to determine where disparities in access to sperm banking exist to improve the potential for future fertility in these males.

Reduction of ovarian torsion 1 week after embryo transfer in a patient with bilateral hyperstimulated ovaries

OBJECTIVE To report a rare case of unilateral ovarian torsion 1 week after embryo transfer in a patient with bilateral hyperstimulated ovaries. DESIGN Case report and literature review. SETTING Reproductive Endocrine division in a university teaching hospital. PATIENT(S) Infertility patients undergoing IVF-ET. INTERVENTION(S) Laparoscopic reduction of adnexa 1 week after ET. MAIN OUTCOME MEASURE(S) Successful preservation of the affected adnexa. RESULT(S) Delivery of 3.324 kg male infant with preservation of the affected ovary. CONCLUSION(S) Untwisting of the affected ovary at laparoscopy without aspiration reduction of cystic masses is appropriate. The outcome of the pregnancy (even very early) in patients with torsion of the adnexa may be favorable after a laparoscopic unwinding of the affected adnexa.