Carol L. Gnatuk

Effects of Gastric Bypass Surgery on Female Reproductive Function

CONTEXT Reproductive function may improve after bariatric surgery, although the mechanisms and time-related changes are unclear. OBJECTIVE The objective of the study was to determine whether ovulation frequency/quality as well as associated reproductive parameters improve after Roux en Y gastric bypass surgery. DESIGN This was a prospective cohort study that enrolled female subjects from 2005 to 2008 with study visits at baseline and then 1, 3, 6, 12, and up to 24 months after surgery. SETTING The study was conducted at an academic health center. PATIENTS Twenty-nine obese, reproductive-aged women not using confounding medications participated in the study. MAIN OUTCOME MEASURES The primary outcome was integrated levels of urinary progestin (pregnanediol 3-glururonide) from daily urinary collections at 12 months postoperatively. Secondary outcomes were changes in vaginal bleeding, other biometric, hormonal, ultrasound, dual-energy x-ray absorptiometry measures, and Female Sexual Function Index. RESULTS Ninety percent of patients with morbid obesity had ovulatory cycles at baseline, and the ovulatory frequency and luteal phase quality (based on integrated pregnanediol 3-glururonide levels) were not modified by bariatric surgery. The follicular phase was shorter postoperatively [6.5 d shorter at 3 months and 7.9-8.9 d shorter at 6-24 months (P < 0.01)]. Biochemical hyperandrogenism improved, largely due to an immediate postoperative increase in serum SHBG levels (P < 0.01), with no change in clinical hyperandrogenism (sebum production, acne, hirsutism). Bone density was preserved, contrasting with a significant loss of lean muscle mass and fat (P < 0.001), reflecting preferential abdominal fat loss (P < 0.001). Female sexual function improved 28% (P = 0.02) by 12 months. CONCLUSIONS Ovulation persists despite morbid obesity and the changes from bypass surgery. Reproductive function after surgery is characterized by a shortened follicular phase and improved female sexual function.

Hyperandrogenism and Hyperinsulinism in Children of Women with Polycystic Ovary Syndrome: A Controlled Study

OBJECTIVE Hyperandrogenia and insulin resistance are heritable family traits, likely to cluster in children of polycystic ovary syndrome (PCOS) mothers. DESIGN We performed a case control study of PCOS children (n = 32) compared with children from control women (n = 38) for reproductive and metabolic abnormalities, stratifying results by three Tanner stage groupings. The children underwent history and physical examinations, a 3-h timed urine collection, a 2-h oral glucose tolerance test, and abdominal ultrasound examination (females only). Serum was obtained in older children (age > 8 yr) who consented. RESULTS Urine LH levels were significantly lower in the Tanner IV-V PCOS girls compared with controls (P = 0.04). Urine testosterone levels were significantly elevated in Tanner II-III PCOS boys compared with controls (P = 0.007). There were no significant differences in dehydroepiandrosterone levels. We validated the correlation between salivary and serum levels of insulin (insulin areas under the curve) in an adult population [n =30, Pearson correlation coefficient (r) = 0.67; P < 0.0001], which also replicated in the children (2-h insulin r = 0.57; P = 0.0004). Mean area under the curve salivary insulin levels were significantly higher in the Tanner IV-V PCOS girls in the later stages of puberty when compared with controls (3625 +/- 1372 vs. 1766 +/- 621 min x muU/ml, 95% confidence interval 475-3242; P < 0.02). CONCLUSIONS Hyperinsulinism may be a familial characteristic of PCOS children (or at least girls) but does not appear until the later stages of puberty. Other reproductive abnormalities that characterize PCOS may develop later.

A randomized comparison of the methods of sperm preparation for intrauterine insemination

OBJECTIVE To compare the effectiveness of three methods of sperm preparation for IUI during superovulation of infertile women. DESIGN Randomized assignment of one of three sperm preparation methods. SETTING University infertility practice. PATIENT(S) Infertile couples undergoing superovulation and IUI. INTERVENTION(S) The method of preparation of sperm for IUI during superovulation was assigned randomly to double centrifugation, multiple-tube swim-up, or Percoll density gradient. MAIN OUTCOME MEASURE(S) Total number and percent recovery of motile sperm, percent of recovered sperm with normal morphology, and cycle fecundity. RESULT(S) No method of sperm preparation provided better cycle fecundity than the others despite differences in sperm recovery. CONCLUSION(S) Double centrifugation, multiple-tube swim-up, and Percoll density gradient sperm preparation for IUI yield similar cycle fecundity rates.

Benefit of Delayed Fertility Therapy With Preconception Weight Loss Over Immediate Therapy in Obese Women With PCOS

CONTEXT In overweight/obese women with polycystic ovary syndrome (PCOS), the relative benefit of delaying infertility treatment to lose weight vs seeking immediate treatment is unknown. OBJECTIVE We compared the results of two, multicenter, concurrent clinical trials treating infertility in women with PCOS. DESIGN, SETTING, AND PARTICIPANTS This was a secondary analysis of two randomized trials conducted at academic health centers studying women 18-40 years of age who were overweight/obese and infertile with PCOS. INTERVENTION We compared immediate treatment with clomiphene from the Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) trial (N = 187) to delayed treatment with clomiphene after preconception treatment with continuous oral contraceptives, lifestyle modification (Lifestyle: including caloric restriction, antiobesity medication, behavioral modification, and exercise) or the combination of both (combined) from the Treatment of Hyperandrogenism Versus Insulin Resistance in Infertile Polycystic Ovary Syndrome (OWL PCOS) trial (N = 142). MAIN OUTCOME MEASURES Live birth, pregnancy loss, and ovulation were measured. RESULTS In PPCOS II, after four cycles of clomiphene, the cumulative per-cycle ovulation rate was 44.7% (277/619) and the cumulative live birth rate was 10.2% (19/187), nearly identical to that after oral contraceptive pretreatment in the OWL PCOS trial (ovulation 45% [67/149] and live birth: 8.5% [4/47]). In comparison, deferred clomiphene treatment preceded by lifestyle and combined treatment in OWL PCOS offered a significantly better cumulative ovulation rate compared to immediate treatment with clomiphene. (Lifestyle: 62.0% [80/129]; risk ratio compared to PPCOS II = 1.4; 95% confidence interval [CI], 1.1-1.7; P = .003; combined: 64.3% [83/129]; risk ratio compared to PPCOS II = 1.4; 95% CI, 1.2-1.8; P < .001 and a significantly better live birth rate lifestyle: 25.0% [12/48]; risk ratio compared to PPCOS II = 2.5; 95% CI, 1.3-4.7; P = .01 and combined: 25.5% [12/47]; risk ratio compared to PPCOS II = 2.5; 95% CI, 1.3-4.8; P = .01). CONCLUSIONS These data show the benefit of improved ovulation and live birth with delayed infertility treatment with clomiphene citrate when preceded by lifestyle modification with weight loss compared with immediate treatment. Pretreatment with oral contraceptives likely has little effect on the ovulation and live birth rate compared with immediate treatment.

Weight Loss and Lowering Androgens Predict Improvements in Health-Related Quality of Life in Women With PCOS

CONTEXT Polycystic ovary syndrome (PCOS) is associated with reduced health-related quality of life (HRQOL) and increased prevalence of depressive and anxiety disorders. The impact of PCOS-specific treatments on these co-morbidities is unclear. OBJECTIVE To assess the impact of weight loss and decreasing hyperandrogenism on HRQOL and mood and anxiety disorders in women with PCOS. DESIGN/SETTING/PARTICIPANTS A secondary analysis of a randomized controlled trial (OWL-PCOS) of preconception treatment conducted at two academic centers in women (age, 18-40 years; body mass index, 27-42 kg/m(2)) with PCOS defined by Rotterdam criteria. INTERVENTION Continuous oral contraceptive pill (OCP) or intensive lifestyle intervention or the combination (Combined) for 16 weeks. MAIN OUTCOME MEASURE(S) Changes in HRQOL assessed by PCOSQ and SF-36 and prevalence of depression and anxiety disorder assessed by PRIME-MD PHQ. RESULTS The lowest scores were noted on the general health domain of the SF-36 and the weight and infertility domains on the PCOSQ. All three interventions resulted in significant improvement in the general health score on the SF-36. Both the OCP and Combined groups showed improvements in all domains of the PCOSQ (P < .01) compared to baseline scores. The Combined group had significant improvements in the weight, body hair, and infertility domains compared to a single treatment group (P < .05). In a linear regression model, change in weight correlated with improvements in the weight domain (P < .001) and physical well-being (P < .02), change in T correlated with improvements in the hair domain (P < .001), and change in both weight and T correlated with the infertility (P < .001) and menstrual domains (P < .05). CONCLUSIONS Both weight loss and OCP use result in significant improvements in several physical and mental domains related to quality of life, depressive symptoms, and anxiety disorders, and combined therapies offer further benefits in overweight/obese women with PCOS.

Assessment of multiple intrauterine gestations from ovarian stimulation (AMIGOS) trial: baseline characteristics

OBJECTIVE To identify baseline characteristics of women with unexplained infertility to determine whether treatment with an aromatase inhibitor will result in a lower rate of multiple gestations than current standard ovulation induction medications. DESIGN Randomized, prospective clinical trial. SETTING Multicenter university-based clinical practices. PATIENT(S) A total of 900 couples with unexplained infertility. INTERVENTION(S) Collection of baseline demographics, blood samples, and ultrasonographic assessments. MAIN OUTCOME MEASURE(S) Demographic, laboratory, imaging, and survey characteristics. RESULT(S) Demographic characteristics of women receiving clomiphene citrate (CC), letrozole, or gonadotropins for ovarian stimulation were very consistent. Their mean age was 32.2 ± 4.4 years and infertility duration was 34.7 ± 25.7 months, with 59% primary infertility. More than one-third of the women were current or past smokers. The mean body mass index (BMI) was 27 and mean antimüllerian hormone level was 2.6; only 11 women (1.3%) had antral follicle counts of <5. Similar observations were identified for hormonal profiles, ultrasound characterization of the ovaries, semen parameters, and quality of life assessments in both male and female partners. CONCLUSION(S) The cause of infertility in the couples recruited to this treatment trial is elusive, as the women were regularly ovulating and had evidence of good ovarian reserve both by basal FSH, antimüllerian hormone levels, and antral follicle counts; the male partners had normal semen parameters. The three treatment groups have common baseline characteristics, thereby providing comparable patient populations for testing the hypothesis that use of letrozole for ovarian stimulation can reduce the rates of multiples from that observed with gonadotropin and CC treatment. CLINICAL TRIAL REGISTRATION NUMBER NCT 01044862.

Comparison of hormonal and metabolic markers after a high-fat, Western meal versus a low-fat, high-fiber meal in women with polycystic ovary syndrome

OBJECTIVE To determine the effect of meal composition on postprandial T levels in women with polycystic ovary syndrome (PCOS). DESIGN Randomized, crossover design. SETTING Academic research center. PATIENT(S) Fifteen women with PCOS. INTERVENTION(S) We evaluated changes in T, sex hormone binding globulin (SHBG), DHEAS, cortisol, glucose, and insulin for 6 hours after a high-fat, Western meal (HIFAT) (62% fat, 24% carbohydrate, 1 g fiber) and an isocaloric low-fat, high-fiber meal (HIFIB) (6% fat, 81% carbohydrate, 27 g fiber). MAIN OUTCOME MEASURE(S) Change in T levels. RESULT(S) Testosterone decreased 27% within 2 hours after both meals. However, T remained below premeal values for 4 hours after the HIFIB meal and 6 hours after the HIFAT meal. Insulin was twofold higher for 2 hours after the HIFIB meal compared with the HIFAT meal. Glucose was higher for 1 hour after the HIFIB meal compared with the HIFAT meal. DHEAS decreased 8%-10% within 2-3 hours after both meals, then increased during the remainder of the study period. Cortisol decreased during the 6-hour period after both meals. CONCLUSIONS Diet plays a role in the regulation of T levels in women with PCOS. Further studies are needed to determine the role of diet composition in the treatment of PCOS.

Brachial artery conductance during reactive hyperemia is increased in women with polycystic ovary syndrome

OBJECTIVE To examine changes in brachial artery conductance (BAC) during reactive hyperemia in women with polycystic ovary syndrome (PCOS) compared to controls. STUDY DESIGN This is a pilot case-control study performed at a single academic medical center. Changes in BAC during reactive hyperemia were evaluated in 31 women with PCOS and 11 healthy control women. Fasting glucose, insulin, lipids and androgen levels were also determined. A mixed-effects model was used to compare the PCOS curve to the control curve for change in BAC from baseline during reactive hyperemia. RESULTS Body mass index (BMI) and testosterone levels were significantly increased in the PCOS group compared to controls (P<0.05). In addition, the PCOS group had higher total and LDL cholesterol levels (P=0.05 and 0.09, respectively). Change in BAC from baseline during reactive hyperemia was significantly increased in the PCOS group compared to controls even after adjusting for age, BMI and LDL cholesterol levels (P<0.0001). There were no significant differences between the two groups in age, blood pressure, or fasting glucose or insulin levels. CONCLUSIONS Brachial artery conductance during reactive hyperemia is significantly increased in women with PCOS compared to controls and may be a novel early indicator of increased cardiovascular risk in women with PCOS.

Normal Pubertal Development in Daughters of Women with PCOS: A Controlled Study

Context Daughters of women with polycystic ovary syndrome (PCOS) are thought to be at increased risk for developing stigmata of the syndrome, but the ontogeny during puberty is uncertain. Objective We phenotyped daughters (n = 76) of mothers with PCOS and daughters (n = 80) from control mothers for reproductive and metabolic parameters characteristic of PCOS. Design, Setting, and Participants We performed a matched case/control study at Penn State Hershey Medical Center that included non-Hispanic, white girls 4 to 17 years old. Intervention We obtained birth history, biometric, ovarian ultrasounds, whole-body dual-energy X-ray absorptiometry scan for body composition, 2-hour glucose challenged salivary insulin levels, and two timed urinary collections (12 hours overnight and 3 hours in the morning) for gonadotropins and sex steroids. Main Outcome Measures We measured integrated urinary levels of adrenal (dehydroepiandrosterone sulfate) and ovarian [testosterone (TT)] steroids. Other endpoints included integrated salivary insulin levels and urinary luteinizing hormone levels. Results There were no differences in detection rates or mean levels for gonadotropins and sex steroids in timed urinary collections between PCOS daughters and control daughters, nor were there differences in integrated salivary insulin levels. Results showed that 69% of Tanner 4/5 PCOS daughters vs 31% of control daughters had hirsutism defined as a Ferriman-Gallwey score >8 (P = 0.04). There were no differences in body composition as determined by dual-energy X-ray absorptiometry between groups in the three major body contents (i.e., bone, lean body mass, and fat) or in ovarian volume between groups. Conclusions Matched for pubertal stage, PCOS daughters have similar levels of urinary androgens and gonadotropins as well as glucose-challenged salivary insulin levels.

Racial and ethnic differences in the polycystic ovary syndrome metabolic phenotype

BACKGROUND: Women with polycystic ovarian syndrome have a high prevalence of metabolic syndrome and type 2 diabetes mellitus. Blacks and Hispanics have a high morbidity and mortality due to cardiovascular disease and diabetes mellitus in the general population. Since metabolic syndrome is a risk factor for development of type 2 diabetes and cardiovascular disease, understanding any racial and ethnic differences in metabolic syndrome among women with polycystic ovarian syndrome is important for prevention strategies. However, data regarding racial/ethnic differences in metabolic phenotype among women with polycystic ovary syndrome are inconsistent. OBJECTIVE: We sought to determine if there are racial/ethnic differences in insulin resistance, metabolic syndrome, and hyperandrogenemia in women with polycystic ovarian syndrome. STUDY DESIGN: We conducted secondary data analysis of a prospective multicenter, double‐blind controlled clinical trial, the Pregnancy in Polycystic Ovary Syndrome II study, conducted in 11 academic health centers. Data on 702 women with polycystic ovarian syndrome aged 18‐40 years who met modified Rotterdam criteria for the syndrome and wished to conceive were included in the study. Women were grouped into racial/ethnic categories: non‐Hispanic whites, non‐Hispanic blacks, and Hispanic. The main outcomes were the prevalence of insulin resistance, metabolic syndrome, and hyperandrogenemia in the different racial/ethnic groups. RESULTS: Body mass index (35.1 ± 9.8 vs 35.7 ± 7.9 vs 36.4 ± 7.9 kg/m2) and waist circumference (106.5 ± 21.6 vs 104.9 ± 16.4 vs 108.7 ± 7.3 cm) did not differ significantly between non‐Hispanic white, non‐Hispanic black, and Hispanic women. Hispanic women with polycystic ovarian syndrome had a significantly higher prevalence of hirsutism (93.8% vs 86.8%), abnormal free androgen index (75.8% vs 56.5%), abnormal homeostasis model assessment (52.3% vs 38.4%), and hyperglycemia (14.8% vs 6.5%), as well as lower sex hormone binding globulin compared to non‐Hispanic whites. Non‐Hispanic black women had a significantly lower prevalence of metabolic syndrome (24.5% vs 42.2%) compared with Hispanic women, and lower serum triglyceride levels compared to both Hispanics and non‐Hispanic whites (85.7 ± 37.3 vs 130.2 ± 57.0 vs 120.1 ± 60.5 mg/dL, P < .01), with a markedly lower prevalence of hypertriglyceridemia (5.1% vs 28.3% vs 30.5%, P < .01) compared to the other 2 groups. CONCLUSION: Hispanic women with polycystic ovarian syndrome have the most severe phenotype, both in terms of hyperandrogenism and metabolic criteria. Non‐Hispanic black women have an overall milder polycystic ovarian syndrome phenotype than Hispanics and in some respects, than non‐Hispanic white women.