Biomedical subjects

R S Legro

Publications and source records attributed to R S Legro.

At least 37 records · Page 2Linked to original sources

PubMed2000

Is there a male phenotype in polycystic ovary syndrome families?

The male phenotype in PCOS is still uncertain. Multiple possible phenotypes have been proposed including such abnormalities in male hair distribution as premature balding and metabolic abnormalities such as insulin resistance. Problems with phenotyping to date are reviewed and potential new paths for familial phenotyping are discussed. Identifying a male phenotype would increase the sample size for genetic analyses of the causative gene. It may also improve the phenotyping of female family members by identifying familial traits that are gender independent.

Alopecia↗

PubMed2000

Searching for the polycystic ovary syndrome genes.

PCOS is a common disorder of unknown etiology. Studies of first-degree relatives of women diagnosed with PCOS suggest familial clustering of the disease. A prospective study of first-degree female relatives of women with PCOS conducted by NCPIR found that 46% of ascertainable sisters of women with PCOS were hyperandrogenemic. NCPIR has conducted linkage and association studies using affected sibling-pair analysis and the transmission/disequilibrium test to explore candidate PCOS genes. These studies point a finger at a region 1 MB centromeric to the insulin receptor gene on chromosome 19.

Female↗

PubMed1999

Thirty-seven candidate genes for polycystic ovary syndrome: strongest evidence for linkage is with follistatin.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder of women, characterized by hyperandrogenism and chronic anovulation. It is a leading cause of female infertility and is associated with polycystic ovaries, hirsutism, obesity, and insulin resistance. We tested a carefully chosen collection of 37 candidate genes for linkage and association with PCOS or hyperandrogenemia in data from 150 families. The strongest evidence for linkage was with the follistatin gene, for which affected sisters showed increased identity by descent (72%; chi(2) = 12.97; nominal P = 3.2 x 10(-4)). After correction for multiple testing (33 tests), the follistatin findings were still highly significant (P(c) = 0.01). Although the linkage results for CYP11A were also nominally significant (P = 0.02), they were no longer significant after correction. In 11 candidate gene regions, at least one allele showed nominally significant evidence for population association with PCOS in the transmission/disequilibrium test (chi(2) >/= 3.84; nominal P < 0.05). The strongest effect in the transmission/disequilibrium test was observed in the INSR region (D19S884; allele 5; chi(2) = 8.53) but was not significant after correction. Our study shows how a systematic screen of candidate genes can provide strong evidence for genetic linkage in complex diseases and can identify those genes that should have high (or low) priority for further study.

Chromosome Mapping↗

PubMed1999

The proenkephalin gene (PENK) and opioid dependence.

We tested the hypothesis that the alleles at the (CA)n repeat of the proenkephalin gene (PENK) might be associated with opioid addiction in 31 non-Hispanic Caucasian subjects with opioid dependence (heroin), 89 ethnically matched subjects with substance dependence other than opioid dependence and 132 controls. Among the subjects with opioid dependence, 66% carried the > or = 81 bp allele compared with 40% of subjects with other types of substance abuse (chi2 = 11.31, p < 0.004) and 49% of controls (chi2 = 6.0, p < 0.015). These results are consistent with a role of the PENK gene in opioid dependence.

Adult↗

PubMed1999

Bone mineral density and body composition in lean women with polycystic ovary syndrome.

OBJECTIVE: To examine bone mineral density (BMD) and fat distribution in lean women with polycystic ovary syndrome (PCOS) compared with matched control women. DESIGN: Controlled clinical study. SETTING: An academic clinical research center. PATIENT(S): Twelve non-Hispanic white women with PCOS and a body mass index of <26 and 10 healthy control women matched for age, ethnicity, and weight. INTERVENTION(S): Biometric measures, blood sample collection, and total body/regional bone density and fat analysis were performed. MAIN OUTCOME MEASURE(S): Serum levels of androgens, glucose, and insulin were measured. Bone density and fat distribution were measured by total body dual-energy x-ray absorptiometry. RESULT(S): Androgen levels were elevated significantly in the lean women with PCOS compared with the controls. There was no statistically significant difference in total body BMD between the two groups. A significant increase in BMD was noted in the left arm, right arm, and left ribs of the lean PCOS group. Evaluation of upper body BMD showed a significant correlation between testosterone levels and BMD. No statistically significant differences were noted in body fat distribution, although the lean PCOS group tended to have lower mean percentages of body fat. CONCLUSION(S): Lean women with PCOS have regional differences in BMD, with significantly increased BMD in the upper skeleton compared with control women.

Absorptiometry, Photon↗

PubMed1999

Alterations in low-density lipoprotein and high-density lipoprotein subclasses among Hispanic women with polycystic ovary syndrome: influence of insulin and genetic factors.

OBJECTIVE: To examine the influence of hyperandrogenism on low-density lipoprotein (LDL) and high-density lipoprotein (HDL) subclass levels as well as lipoprotein (a) levels in hyperandrogenic women compared with a control group. DESIGN: Case-control study. SETTING: University-based outpatient clinic. PATIENT(S): Sixteen Hispanic women with polycystic ovary syndrome were compared with 21 controls matched for age, weight, and ethnicity. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Fasting serum levels of testosterone, insulin, and lipoproteins. RESULT(S): Compared with controls, women with polycystic ovary syndrome had significantly lower levels of apolipoprotein A-I (95+/-28 mg/dL versus 144+/-42 mg/dL) and HDL2a (30.9%+/-4.4% versus 36.6%+/-5.4%) but significantly higher levels of HDL3c (5.1%+/-2.2% versus 2.4%+/-1.5%). There were no statistically significant differences in LDL subclasses between groups, but there was a high incidence (54%) of the atherogenic lipoprotein phenotype B in this Hispanic population. As a group, Hispanic women with the abnormal B phenotype had significantly higher levels of insulin, HDL, HDL2b, and triglycerides. CONCLUSION(S): Hyperandrogenemia may have an adverse effect on serum lipoproteins through effects on HDL subclasses. Hispanic women may have a higher incidence of the atherogenic lipoprotein phenotype B, which may increase their risk for atherosclerosis.

Adult↗

PubMed1999

Oocyte donors as gynecologic teaching associates.

OBJECTIVE: To fulfill the need for gynecologic teaching associates for an expanded pelvic examination module for third-year medical students, we sought women who were able to provide feedback to medical students. Oocyte donors were hypothesized as a useful potential pool of gynecologic teaching associates. METHODS: Gynecologic teaching associates were recruited from a pool of women who were involved in our oocyte donor program. Students were evaluated on a scale of 1 (best) to 5 (worst) on their performance on the pelvic examination by themselves (n = 91), by the gynecologic teaching associate (n = 10), and by the supervising faculty (n = 6). Students were shown their evaluations, and these were reviewed at the end of the session to provide students with immediate feedback. RESULTS: Students consistently ranked their skills lower than either the gynecologic teaching associate or supervising faculty member for all four categories evaluated (communication skills, technical skills, professional demeanor, and overall performance) (P < .001). Students gave their communications skills the highest mean rankings, whereas gynecologic teaching associates gave them the lowest. The highest correlation and agreement between pairs of evaluators were between the gynecologic teaching associate and the supervising faculty member. Gynecologic teaching associates and faculty members also were more likely to praise the students' performance in written comments (chi2 58.2, P < .001), whereas no student found anything praiseworthy in his or her performance. CONCLUSION: Oocyte donors represent a useful pool of potential gynecologic teaching associates. They provide important feedback to students. Their evaluation of the proficiency of the student correlates well with that of the supervising faculty member.

Female↗

PubMed1999

Polycystic ovary syndrome. Phenotype to genotype.

Available studies suggest there is a strong familial component to PCOS regardless of the diagnostic criteria used to ascertain probands and to assign affected status in kindreds. Investigation of all kindred members using the same systematic screen for metabolic and reproductive abnormalities strengthens the validity of conclusions. There is no substitute for direct biometric or biochemical proof of the phenotype. Initial studies by the author and his colleagues suggest that hyperandrogenemia in sisters is a valid phenotype characteristic. Further study is necessary to establish other phenotypes in the families. Large family clusterings of PCOS offer the best opportunity for identifying unique strains of PCOS. These families may represent a homogeneous etiology of the syndrome despite significant phenotypic heterogeneity within a given pedigree. Linkage analysis should be performed between polymorphic markers spaced at regular genetic intervals, and these familial traits may identify critical regions for further investigation.

Female↗

PubMed1999

Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women.

Women with polycystic ovary syndrome (PCOS) are insulin resistant, have insulin secretory defects, and are at high risk for glucose intolerance. We performed this study to determine the prevalence of glucose intolerance and parameters associated with risk for this in PCOS women. Two-hundred and fifty-four PCOS women, aged 14-44 yr, were prospectively evaluated at 2 centers, 1 urban and ethnically diverse (n = 110) and 1 rural and ethnically homogeneous (n = 144). The rural PCOS women were compared to 80 control women of similar weight, ethnicity, and age. A 75-g oral glucose challenge was administered after a 3-day 300-g carbohydrate diet and an overnight fast with 0 and 2 h blood samples for glucose levels. Diabetes was categorized according to WHO criteria. The prevalence of glucose intolerance was 31.1% impaired glucose intolerance (IGT) and 7.5% diabetes. In nonobese PCOS women (body mass index, <27 kg/m2), 10.3% IGT and 1.5% diabetes were found. The prevalence of glucose intolerance was significantly higher in PCOS vs. control women (chi2 = 7.0; P = 0.01; odds ratio = 2.76; 95% confidence interval = 1.23-6.57). Variables most associated with postchallenge glucose levels were fasting glucose levels (P < 0.0001), PCOS status (P = 0.002), waist/hip ratio (P = 0.01), and body mass index (P = 0.021). The American Diabetes Association criteria applied to fasting glucose significantly underdiagnosed diabetes compared to the WHO criteria (3.2% vs. 7.5%; chi2 = 4.7; P = 0.046; odds ratio = 2.48; 95% confidence interval = 1.01-6.69). We conclude that 1) PCOS women are at significantly increased risk for IGT and type 2 diabetes mellitus at all weights and at a young age; 2) these prevalence rates are similar in 2 different populations of PCOS women, suggesting that PCOS may be a more important risk factor than ethnicity or race for glucose intolerance in young women; and 3) the American Diabetes Association diabetes diagnostic criteria failed to detect a significant number of PCOS women with diabetes by postchallenge glucose values.

Adolescent↗

PubMed1999

Augmented androgen production is a stable steroidogenic phenotype of propagated theca cells from polycystic ovaries.

To test the hypothesis that the hyperandrogenemia associated with polycystic ovary syndrome (PCOS) results from an intrinsic abnormality in ovarian theca cell steroidogenesis, we examined steroid hormone production, steroidogenic enzyme activity, and mRNA expression in normal and PCOS theca cells propagated in long-term culture. Progesterone (P4), 17alpha-hydroxyprogesterone (17OHP4), and testosterone (T) production per cell were markedly increased in PCOS theca cell cultures. Moreover, basal and forskolin-stimulated pregnenolone, P4, and dehydroepiandrosterone metabolism were increased dramatically in PCOS theca cells. PCOS theca cells were capable of substantial metabolism of precursors into T, reflecting expression of an androgenic 17beta-hydroxysteroid dehydrogenase. Forskolin-stimulated cholesterol side chain cleavage enzyme (CYP11A) and 17alpha-hydroxylase/17,20-desmolase (CYP17) expression were augmented in PCOS theca cells compared with normal cells, whereas no differences were found in steroidogenic acute regulatory protein mRNA expression. Collectively, these observations establish that increased CYP11A and CYP17 mRNA expression, as well as increased CYP17, 3beta-hydroxysteroid dehydrogenase, and 17beta-hydroxysteroid dehydrogenase enzyme activity per theca cell, and consequently increased production of P4, 17OHP4, and T, are stable properties of PCOS theca cells. These findings are consistent with the notion that there is an intrinsic alteration in the steroidogenic activity of PCOS thecal cells that encompasses multiple steps in the biosynthetic pathway.

17-Hydroxysteroid Dehydrogenases↗

PubMed1998

Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome.

Our preliminary family studies have suggested that some female first-degree relatives of women with polycystic ovary syndrome (PCOS) have hyperandrogenemia per se. It was our hypothesis that this may be a genetic trait and thus could represent a phenotype suitable for linkage analysis. To investigate this hypothesis, we examined 115 sisters of 80 probands with PCOS from unrelated families. PCOS was diagnosed by the combination of elevated serum androgen levels and </=6 menses per year with the exclusion of secondary causes. The sisters were compared with 70 healthy age- and weight-comparable control women with regular menses, no clinical evidence of hyperandrogenemia, and normal glucose tolerance. Twenty-two percent of the sisters fulfilled diagnostic criteria for PCOS. In addition, 24% of the sisters had hyperandrogenemia and regular menstrual cycles. Circulating testosterone (T) and nonsex hormone-binding globulin-bound testosterone (uT) levels in both of these groups of sisters were significantly increased compared with unaffected sisters and control women (P < 0.0001 for both T and uT). Probands, sisters with PCOS, and hyperandrogenemic sisters had elevated serum luteinizing hormone levels compared with control women. We conclude that there is familial aggregation of hyperandrogenemia (with or without oligomenorrhea) in PCOS kindreds. In affected sisters, only one-half have oligomenorrhea and hyperandrogenemia characteristic of PCOS, whereas the remaining one-half have hyperandrogenemia per se. This familial aggregation of hyperandrogenemia in PCOS kindreds suggests that it is a genetic trait. We propose that hyperandrogenemia be used to assign affected status in linkage studies designed to identify PCOS genes.

Adolescent↗

PubMed1998

Insulin resistance in polycystic ovary syndrome: treating a phenotype without a genotype.

PCOS women are uniquely insulin resistant. The underlying genetic defect in insulin action is unknown. Obesity aggravates the underlying predisposition to insulin resistance. Diagnostic criteria which focus on menstrual irregularity are more likely to identify insulin resistant women. About 40% of PCOS women display glucose intolerance (either impaired glucose tolerance or type 2 diabetes) in response to an oral glucose challenge. The lack of a clear etiologic mechanism to the syndrome has led to a multitude of symptom-oriented treatments with few therapies improving all aspects of the endocrine syndrome of PCOS. Empirical studies of interventions improving insulin sensitivity in PCOS, either weight loss/diet programs or pharmaceutical agents, have been shown to improve the endocrine abnormalities in the syndrome. These initial results with anti-diabetic agents, though promising, need to be confirmed in larger, randomized studies.

Female↗

PubMed1998

Polycystic ovary syndrome: current and future treatment paradigms.

Polycystic ovary syndrome is characterized by excess levels of circulating androgens and by chronic anovulation. Although the fundamental pathophysiologic defect has not been determined, women with polycystic ovary syndrome are known to be uniquely insulin resistant. Obesity in polycystic ovary syndrome aggravates the underlying predisposition towards insulin resistance. Diagnostic criteria that focus on menstrual irregularity are more likely to discriminate insulin-resistant women than are such criteria as abnormal gonadotropin secretion or ovarian morphologic characteristics. About 40% of patients with polycystic ovary syndrome demonstrate glucose intolerance (either impaired glucose tolerance or type 2 diabetes) in response to an oral glucose challenge. The lack of a clear causal mechanism in the syndrome has led to a multitude of symptom-oriented treatments, with few therapies improving all aspects of the endocrine abnormalities associated with polycystic ovary syndrome. Many of these therapies-such as ovulation induction with medical agents-hold increased risks for women with polycystic ovary syndrome, including ovarian hyperstimulation syndrome and multiple gestation. Empirical studies of interventions that improve insulin sensitivity in polycystic ovary syndrome (either weight loss and diet programs or pharmaceutical agents) have been shown to improve the endocrine abnormalities in the syndrome. Initial results with antidiabetic agents (specifically insulin-sensitizing agents) are promising but need to be confirmed with larger, randomized studies.

Androgens↗

PubMed1998

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.

Centrifugation↗

PubMed1998

A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome.

Women with polycystic ovary syndrome (PCOS) are profoundly insulin resistant, and the resultant hyperinsulinemia exacerbates the reproductive abnormalities of the syndrome. Agents that ameliorate insulin resistance and reduce circulating insulin levels could provide a new therapeutic modality for PCOS. Identifying the subset of PCOS women who are most insulin resistant may therefore be useful for selecting women who will respond to this therapy. We examined the correlation of basal and oral glucose-stimulated glucose and insulin levels and fasting and stimulated glucose/insulin (G:I) ratios with parameters of insulin sensitivity obtained by frequently sampled i.v. glucose tolerance test (FSIGT) to assess whether there is a simple screening test for insulin resistance in PCOS. Forty PCOS women (aged 18-40 yr; body mass index, >26 kg/m2) and 15 control women matched for age, weight, and ethnicity underwent both a 75-g oral glucose tolerance test (OGTT) and a FSIGT. The insulin sensitivity index (S(I)) was calculated by application of the minimal model of glucose kinetics to the dynamics of plasma glucose and insulin levels during the FSIGT. The best correlation in PCOS between S(I) and a fasting level was found with fasting G:I ratios (r = 0.73; P < 0.0001). A less substantial, but significant, correlation was found with fasting insulin levels (r = 0.50; P < 0.001), and no significant correlation was found with fasting glucose levels (r = 0.24; P = NS). The fasting G:I was more strongly correlated with S(I) than with integrated glucose and insulin responses during the OGTT. The only stronger correlation was with the OGTT 2 h G:I ratio (r = 0.74; P < 0.001). Stepwise regression analysis with S(I) as the dependent variable and fasting glucose and insulin levels, area under the curve for glucose and insulin, and a fasting G:I ratio showed that only the fasting G:I ratio was significantly predictive of S(I) in the model (F to remove value = 38.1; P < 0.001). When viewed as a screening test for insulin resistance in PCOS, setting a value of the fasting G:I ratio of less than 4.5 as abnormal (using an S(I) value below the 10th percentile of our control population as evidence for insulin resistance), the sensitivity of a fasting G:I ratio was 95%, the specificity was 84%, the positive predictive value was 87%, and the negative predictive value was 94%. Receiver operator curve analysis showed that this fasting G:I ratio was the single best screening measure for detecting insulin resistance. We conclude that a fasting G:I ratio may be useful as a screening test for insulin resistance in obese non-Hispanic white PCOS women. This may be a clinically useful parameter for selecting PCOS women most likely to respond to therapeutic interventions that improve insulin sensitivity.

Adolescent↗

PubMed1998

Phenotype and genotype in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common disorder in premenopausal women and is characterized by hyperandrogenic chronic anovulation. The cause is unknown. PCOS is associated with significant insulin resistance as well as with defects in insulin secretion. These abnormalities place these women at substantial risk for developing type 2 diabetes mellitus. A defect in insulin-mediated receptor autophosphorylation has been found in a substantial proportion of PCOS women. Both PCOS and the insulin resistance that accompanies it appear to have major genetic components. Family studies of PCOS have supported this, although they suffer from incomplete phenotyping of probands and first-degree relatives. The phenotype in males and nonreproductive age females is uncertain. Despite the shortcomings of the family studies of PCOS, they have consistently indicated familial clustering and suggested that the mode of inheritance is dominant. Our initial studies of 50 families of PCOS probands indicate that 24% of sisters are affected with PCOS. There also appears to be an intermediate phenotype of sisters with regular menstrual cycles who are hyperandrogenic per se (22% of sisters). Additionally, there appears to be a major familial defect, with 50% of first-degree relatives having glucose intolerance (impaired glucose tolerance by oral glucose tolerance test or type 2 diabetes mellitus). These findings suggest that hyperandrogenism in females and glucose intolerance may be genetic traits in PCOS kindreds. Systematic phenotyping will allow assignment of affected status for eventual linkage analysis.

Female↗

PubMed1997

ART in women 40 and over. Is the cost worth it?

OBJECTIVE: To determine the efficacy and cost of assisted reproductive techniques in older women (40 years or older) in comparison to younger women (less than 30 years old). STUDY DESIGN: Retrospective review of records from one university-based infertility practice. RESULTS: Women 40 years or older were significantly less likely to achieve pregnancy with human menopausal gonadotropin (hMG)/intrauterine insemination as compared to women under age 30. The older women were also significantly less likely to achieve pregnancy with in vitro fertilization (IVF). The use of donor oocytes resulted in the highest pregnancy rates in older women. Costs per cycle were similar, however, for both groups. CONCLUSION: Older women will consume an equal amount of medical resources per cycle in infertility treatment as compared to younger women (aged < 30 years). However, older women utilizing assisted reproductive techniques are four to five times less likely to achieve pregnancy than the younger group. This poor prognosis for success in older women adds significantly to the mean cost per pregnancy as compared to younger women. Donor oocytes may be the most cost-effective option for achieving pregnancy in older women.

Adult↗

PubMed1996

Efficacy of oocytes donated by older women in an oocyte donation programme.

Population and insemination studies indicate that women experience declining fertility with ageing. The question therefore arises whether older women are suitable oocyte donors. This study addresses this issue by examining the relationship between oocyte donor age and clinical outcome in a large oocyte donation programme. We retrospectively reviewed data from 458 consecutive oocyte donation cycles completed by 164 different designated oocyte donors. Data were divided into two groups: group A, cycles with donors aged 21-30 years at the time of follicular aspiration (193 cycles, 88 donors); and group B, cycles with donors aged 31-40 years at the time of follicular aspiration (265 cycles, 86 donors). Five donors, because of ageing during repetitive donations, contributed data to groups A and B. In a given cycle, all oocytes for a recipient came from only one designated donor. Comparing the two donor groups, there was no difference in the amount of gonadotrophin used to achieve optimal stimulation; however, more oocytes were obtained from group A than group B donors (16.8 +/- 6.9 and 15.1 +/- 8.1 respectively, P < 0.05). Similar percentages of oocytes were fertilized in each group, resulting in the transfer of comparable numbers of embryos (4.5 +/- 1.1 and 4.4 +/- 1.3 respectively). Comparable clinical pregnancy rates were achieved (group A, 36%; group B, 37%). The spontaneous abortion rates were also similar (group A, 20%; group B, 12%), resulting in comparable ongoing and delivered pregnancy rates per cycle (group A, 29%; group B, 32%) and per embryo transferred (group A, 6.4%; group B, 7.3%). In conclusion, women of proven fertility should not be excluded from donating oocytes simply because of their age. There exists a cohort of fertile women who resist the decreasing fecundity and increasing spontaneous abortion rates associated with ageing. With careful screening, many women of proven fertility can donate oocytes until the age of 40 years with an efficacy equal to that of younger women. Given the relative shortage of suitable oocyte donors, and increasing requests from recipients with previous donor oocyte babies to obtain oocytes from the same, now older, donor, the findings of this study are of practical clinical importance.

Adult↗