Raymond W. Ke

Effect of rosiglitazone on spontaneous and clomiphene citrate–induced ovulation in women with polycystic ovary syndrome☆

OBJECTIVE In women suffering from polycystic ovary syndrome (PCOS), correction of hyperinsulinemia results enhances spontaneous ovulation or alternatively, the responsiveness to ovulation induction agents such as clomiphene citrate (CC). We investigated the effect of rosiglitazone maleate on ovulation induction in overweight and obese, CC-resistant women with PCOS. DESIGN Double-blind, randomized, placebo-controlled trial. SETTING Academic reproductive endocrinology clinic. PATIENT(S) Overweight and obese women with clinical and laboratory manifestations of PCOS who desired pregnancy and were resistant to CC. INTERVENTION(S) Twenty-five women were randomized into two treatment groups. Subjects in Group I (n = 12) were randomized to receive rosiglitazone 4 mg b.i.d. with a placebo on cycle days 5-9. Group II (n = 13) was randomized to receive rosiglitazone 4 mg b.i.d. with CC on cycle days 5-9. The duration of the study was 2 months. MAIN OUTCOME MEASURE(S) The primary outcome was ovulation as defined by luteal serum progesterone greater than 5 ng/dL assessed on days 21, 24, and 28 of the cycle. Secondary outcomes were pregnancy and changes in insulin sensitivity, serum lipoproteins, and androgens. RESULT(S) Overall, 14 of 25 (56%) women, who were previously resistant to CC, successfully ovulated. In subjects taking rosiglitazone alone (Group I), 4 of 12 (33%) subjects ovulated compared with 10 of 13 (77%) women randomized to rosiglitazone with CC (Group II) (P=.04, Fishers exact). One subject in Group I became pregnant, resulting in one uncomplicated live birth; two subjects in Group II conceived, with one successful live birth and one first trimester, spontaneous abortion. For all subjects, fasting insulin declined from 29.4 +/- 13.8 microU/mL to 17.3 +/- 7.8 microU/mL after rosiglitazone (P=.003, paired t-test). Although mean levels of total testosterone (T) and dehydroepiandrosterone sulfate (DHEAS) did not decline significantly, sex hormone-binding globulin (SHBG) did increase from 0.7 +/- 0.3 microg/dL to 1.0 +/- 0.3 microg/dL after rosiglitazone therapy (P=.001, paired t test). There was also a decrease in luteinizing hormone (LH) from 9.4 +/- 6.3 mU/mL to 7.2 +/- 3.7 mU/mL (P=.01). Lipoproteins including total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides did not change. CONCLUSIONS Short-term rosiglitazone therapy enhances both spontaneous and clomiphene-induced ovulation in overweight and obese women with PCOS. Rosiglitazone therapy improves insulin sensitivity and decreases hyperandrogenemia primarily through increases in SHBG.

Increased prevalence of insulin resistance in women with a history of recurrent pregnancy loss

OBJECTIVE To determine whether insulin resistance is associated with recurrent pregnancy loss (RPL). DESIGN Single center, case-controlled, prospective study. SETTING University-associated reproductive endocrinology clinical practice. PATIENT(S) Seventy-four nonpregnant, nondiabetic women with RPL. Controls were 74 fertile, nonpregnant, nondiabetic women without RPL who had at least one live infant, and were matched by age, race, and body mass index (BMI). INTERVENTION(S) Both groups consented to obtaining fasting insulin and glucose levels. MAIN OUTCOME MEASURE(S) Insulin resistance was defined as a fasting insulin level >20 microU/mL or a fasting glucose to insulin ratio of <4.5. RESULT(S) Among the 74 women with RPL, 20 (27.0%) demonstrated insulin resistance, whereas only 7 of 74 (9.5%) of the matched controls were insulin resistant (odds ratio 3.55; 95% confidence interval 1.40-9.01). The RPL and control groups were similar with respect to age, ethnicity, and BMI. The RPL and control groups had similar fasting glucose levels and glucose-to-insulin ratios. However, fasting insulin levels > or =20 microU/mL were statistically different between the two groups (odds ratio 3.92). CONCLUSION(S) Women with RPL have a significantly increased prevalence of insulin resistance when compared with matched fertile controls.

A randomized, double-blinded trial of preemptive analgesia in laparoscopy.

Objective We tested the hypothesis that local anesthetic administered before skin incision, an example of preemptive analgesia, reduces postoperative pain for women undergoing laparoscopy, as compared with postincisional local anesthetic or placebo. Methods Patients undergoing diagnostic laparoscopy were randomized to one of three blinded treatment groups. Treatment group A patients received local infiltration of 0.5% bupivacaine at the surgical site before incision and a saline placebo infiltration before incision closure. Treatment group B received the saline placebo before skin incision and bupivacaine after laparoscopy but before closure of the skin incisions. For treatment group C patients, saline was infiltrated as a placebo before and after laparoscopy. All patients underwent a standardized general anesthetic induction and maintenance. Postoperative pain was evaluated using the modified McGill Present Pain Intensity scale. Pain and supplementary analgesic use was compared among the three treatment groups. Results A total of 57 patients completed the study for analysis. Age, weight, height, race, indication, and operating time did not vary significantly between the three groups. By 24 hours after surgery, patients in treatment group A reported significantly lower pain scores (McGill Present Pain Intensity Scale: 0.5 ± 0.9) than either treatment group B (1.6 ± 1.3) or C (1.3 ± 1.2). Group A patients also could tolerate a significantly longer time delay to their first analgesic medication than patients who received postincisional bupivacaine or than control patients who received no bupivacaine. Conclusion The preemptive administration of bupivacaine before laparoscopy results in decreased postoperative pain and should allow a more rapid return to normal activities. The popular practice of infiltrating bupivacaine at time of incision closure does not offer any benefit in the control of pain after laparoscopy.

Cumulative alkylating agent exposure and semen parameters in adult survivors of childhood cancer: a report from the St Jude Lifetime Cohort Study

BACKGROUND Few data define the dose-specific relation between alkylating agent exposure and semen variables in adult survivors of childhood cancer. We undertook this study to test the hypothesis that increased exposure to alkylating agents would be associated with decreased sperm concentration in a cohort of adult male survivors of childhood cancer who were not exposed to radiation therapy for their childhood cancer. METHODS We did semen analysis on 214 adult male survivors of childhood cancer (median age 7·7 years [range 0·01-20·3] at diagnosis, 29·0 years [18·4-56·1] at assessment, and a median of 21·0 years [10·5-41·6] since diagnosis) who had received alkylating agent chemotherapy but no radiation therapy. Alkylating agent exposure was estimated using the cyclophosphamide equivalent dose (CED). Odds ratios (ORs) and 95% CIs for oligospermia (sperm concentration >0 and <15 million per mL) and azoospermia were calculated with logistic regression modelling. FINDINGS Azoospermia was noted in 53 (25%) of 214 participants, oligospermia in 59 (28%), and normospermia (sperm concentration ≥15 million per mL) in 102 (48%) participants. 31 (89%) of 35 participants who received CED less than 4000 mg/m(2) were normospermic. CED was negatively correlated with sperm concentration (correlation coefficient=-0·37, p<0·0001). Mean CED was 10 830 mg/m(2) (SD 7274) in patients with azoospermia, 8480 mg/m(2) (4264) in patients with oligospermia, and 6626 mg/m(2) (3576) in patients with normospermia. In multivariable analysis, CED was significantly associated with an increased risk per 1000 mg/m(2) CED for azoospermia (OR 1·22, 95% CI 1·11-1·34), and for oligospermia (1·14, 1·04-1·25), but age at diagnosis and age at assessment were not. INTERPRETATION Impaired spermatogenesis was unlikely when the CED was less than 4000 mg/m(2). Although sperm concentration decreases with increasing CED, there was substantial overlap of CED associated with normospermia, oligospermia, and azoospermia. These data can inform pretreatment patient counselling and use of fertility preservation services. FUNDING US National Cancer Institute, American Lebanese Syrian Associated Charities.

Effect of short-term hormone therapy on oxidative stress and endothelial function in African American and Caucasian postmenopausal women

In postmenopausal women (PMW), the effect of a short-term course of estrogen/progestin HT on free radical oxidative stress was evaluated. In addition, HTs effect on plasma nitric oxide (NO) activity was determined as a measure of vascular endothelial function. We investigated the relationship of these markers and HT across race and the cardiovascular risk factors of smoking, diabetes and hypertension.A prospective, observational study comparing preintervention and postintervention. Academic research center.Twenty-seven (14 African American and 13 Caucasian) PMW volunteers. Six weeks of continuous, combined estrogen/progestin HT. Plasma concentrations of free 8-epi-prostaglandin F(2alpha) (8-isoprostane) before and after HT were compared as a measure of oxidative stress. Nitrite, the stable oxidation metabolite of NO, was measured by the Greiss reaction after nitrate reduction to nitrite with cadmium. Plasma levels of free 8-isoprostane decreased significantly after 6 weeks of HT. Although almost all subjects benefited from the reduction in free 8-isoprostane, PMW with at least one cardiovascular risk factor (n = 19) demonstrated higher free 8-isoprostane than did subjects with no risk factors. Plasma levels of nitrite increased after 6 weeks of HT, but the difference was not statistically significant. Caucasian PMW demonstrated a greater increase in plasma levels of nitrite after 6 weeks of HT as compared with African American subjects, who exhibited almost no change.Short-term administration of HT significantly reduces oxidative stress in PMW and is consistent across race. However, there was an observed racial difference in endothelial NO response to HT between African American and Caucasian PMW.

Lack of Specificity of Plasma Concentrations of Inhibin B and Follicle-Stimulating Hormone for Identification of Azoospermic Survivors of Childhood Cancer: A Report From the St Jude Lifetime Cohort Study

PURPOSE Many male survivors of childhood cancer are at risk for azoospermia. Although both the levels of follicle-stimulating hormone (FSH) and inhibin B are correlated with sperm concentration, their ability to predict azoospermia in survivors of childhood cancer remains uncertain. PATIENTS AND METHODS Semen analysis was performed and serum levels of FSH and inhibin B were measured in 275 adult male survivors of childhood cancer who had received gonadotoxic therapy. Receiver operating characteristic (ROC) analysis was performed to determine the optimal inhibin B and FSH values for identifying patients with azoospermia. The patient sample was divided into a learning set and a validation set. Sensitivity, specificity, and positive and negative predictive value were calculated. RESULTS Inhibin B was dichotomized as ≤ 31 ng/L or more than 31 ng/L and FSH was dichotomized as ≤ 11.5 mIU/mL or more than 11.5 mIU/mL based on results of the ROC analysis. Using these values, the specificity of the serum level of inhibin B for identifying azoospermic survivors was 45.0%, and the positive predictive value was 52.1%. The specificity for FSH was 74.1%, and the positive predictive value was 65.1%. CONCLUSION Neither serum inhibin B nor FSH is a suitable surrogate for determination of sperm concentration in a semen sample. Young men and their physicians should be aware of the limitations of these measures for assessment of fertility potential.

Endocrine Basis for Recurrent Pregnancy Loss

Common endocrinopathies are a frequent contributor to spontaneous and recurrent miscarriage. Although the diagnostic criteria for luteal phase defect (LPD) is still controversial, treatment of patients with both recurrent pregnancy loss and LPD using progestogen in early pregnancy seems beneficial. For patients who are hypothyroid, thyroid hormone replacement therapy along with careful monitoring in the preconceptual and early pregnancy period is associated with improved outcome. Women with polycystic ovary syndrome (PCOS) have an increased risk of pregnancy loss. Management of PCOS with normalization of weight or metformin seems to reduce the risk of pregnancy loss.

Flow cytometry provides rapid and highly accurate detection of antisperm antibodies

OBJECTIVE Immunobead testing (IBT), the current standard for antisperm antibody detection, is time consuming and somewhat subjective. To overcome these limitations and maintain accuracy, we studied an immunofluorescent assay using flow cytometry. DESIGN A validation study comparing flow cytometry to IBT in the detection of serum antisperm antibodies. SETTING Flow cytometry laboratory. PATIENTS Sera from 37 men after vasectomy (test) and sera from 35 fertile men (control). MAIN OUTCOME MEASURE Test serum with and without immunoglobulin (Ig)G, IgA, and IgM antisperm antibodies as defined by IBT were analyzed by flow cytometry. Sensitivity and specificity of flow cytometry was calculated by defining the IBT as the true result. RESULTS Flow cytometry identified 22 of 22 sera that were IgG positive (100% sensitivity), 12 of 14 sera that were IgA positive (86% sensitivity), and 4 of 4 sera that were IgM positive (100% sensitivity). Overall, 22 of 37 men were positive for antisperm antibodies. The flow cytometry correctly identified 71 of 71 negative sera (100% specificity). Fluorescence intensity values from the 37 study patients significantly correlated with immunobead binding to the head region and to the entire (more than one) region. CONCLUSIONS Detection of IgG, IgA, and IgM antisperm antibodies by flow cytometry is highly sensitive and specific. In addition, flow cytometry is able to assess thousands of sperm rapidly and accurately, reducing sampling error and technical time.

Fertility Preservation in the Age of Assisted Reproductive Technologies

The desire to reproduce is one of the strongest human instincts. Many men and women in our society may experience situations that compromise their future fertility. The past several decades have seen an explosion of technologies that have changed the historical limitations regarding fertility preservation. This review offers an overview of the state of the art within fertility preservation including surgical and medical interventions and therapies that necessitate the need for cryopreservation of eggs, sperm, and embryos. The review also addresses the psychological consequences of banking/not banking materials among patients in need of fertility preservation, particularly in the oncofertility context.

Preimplantation Genetic Screening: A Practical Guide

The past several decades have seen tremendous advances in the field of medical genetics. The application of genetic technologies to the field of reproductive medicine has ushered in a new era of medicine that is likely to greatly expand in the coming years. Concurrent with an in vitro fertilization (IVF) cycle, it is now possible to obtain a cellular biopsy from a developing embryo and genetically evaluate this sample with increasing sophistication and detail. Preimplantation genetic screening (PGS) is the practice of determining the presence of aneuploidy (either too many or too few chromosomes) in a developing embryo. However, how and in whom PGS should be offered is a topic of much debate.