Biomedical subjects

R S Legro

Publications and source records attributed to R S Legro.

At least 19 recordsLinked to original sources

PubMed2006

Fine mapping of genetic susceptibility to polycystic ovary syndrome on chromosome 19p13.2 and tests for regulatory activity.

CONTEXT: Little is known about genes that contribute to polycystic ovary syndrome (PCOS). We previously found linkage and association of PCOS with the dinucleotide marker D19S884 in two independent sets of families; allele 8 of D19S884 confers increased risk. OBJECTIVE/DESIGN: The objectives of the study were: 1) use the transmission/disequilibrium test (TDT) to assess linkage and association between PCOS and D19S884 (and nearby markers) in a third set of families; and 2) test D19S884 and surrounding DNA sequence for in vitro regulatory activity in lymphoblastoid cell lines (LCLs) and granulosa cells. SETTING/SUBJECTS: We studied 98 new families with a PCOS proband, father, mother, and other available offspring. We analyzed data from these families separately and in combination with data obtained previously. INTERVENTIONS: Interventions were venipuncture. MAIN OUTCOME MEASURES: Measures were transmission frequencies and in vitro functional studies. RESULTS: The first result we found was that in the 98 new families, the TDT was significant for allele 8 of D19S884 (P = 0.043). In the total collection of 465 families, the TDT evidence is very strong (nominal P < 7 x 10(-5)). Results for all other genetic markers near D19S884 were nonsignificant after correction for multiple testing. The second result was that an approximately 800-bp fragment containing various alleles of D19S884 showed modest but reproducible promoter activity in LCLs. However, no allelic differences were detected. No activity of this fragment was detected in granulosa cells. CONCLUSIONS: This is the second independent confirmation of linkage and association of D19S884 with PCOS. We found in addition that some sequence in the region of D19S884 confers in vitro promoter activity in LCLs.

Chromosome Mapping↗

PubMed2006

Epigenetic modification of the X chromosome influences susceptibility to polycystic ovary syndrome.

CONTEXT: The cause of polycystic ovary syndrome (PCOS) is unknown, although genetic and environmental influences are clearly implicated. Some genetic studies have suggested the involvement of X-linked genes in PCOS, but the influence of X chromosome inactivation (XCI) on manifestation of this disorder has not previously been examined. OBJECTIVE: The objective of the study was to test the null hypothesis that XCI has no influence on clinical presentation of PCOS. DESIGN: We examined patterns of XCI between sister pairs with the same genotype at a polymorphic locus on the X chromosome in families with PCOS. SETTING: The study was conducted at a private practice. PARTICIPANTS: PCOS was defined as hyperandrogenemia with chronic anovulation. Forty families were studied in which DNA was obtained from at least one parent, the proband, and one sister that could be accurately diagnosed as being affected or unaffected. MAIN OUTCOME MEASURE(S): Relative expression of two X-linked alleles was determined, and the ratio of one to the other represented the pattern of XCI. RESULTS: The statistical odds on a different clinical presentation between sisters was approximately 29 times higher in sister pairs with different patterns of XCI, compared with sister pairs with the same pattern of XCI (odds ratio 28.9; 95% confidence interval 4.0-206; P = 0.0008). CONCLUSIONS: This study provides evidence to refute the null hypothesis and propose a closer inspection of X-linked genes in PCOS, one in which both genotype and epigenotype are considered. Environmental determinants of PCOS may alter clinical presentation via epigenetic modifications, which currently remain undetected in traditional genetic analyses.

Chromosomes, Human, X↗

PubMed2005

Candidate gene region for polycystic ovary syndrome on chromosome 19p13.2.

CONTEXT: Polycystic ovary syndrome (PCOS) is a common endocrine disorder that is believed to have a genetic basis. However, no specific susceptibility gene or region has been conclusively identified. OBJECTIVE: The objective of this study was to duplicate a previous study that localized a PCOS susceptibility region to chromosome 19p13.2 and to narrow the susceptibility region. DESIGN: This study was designed to test for genetic linkage and association between PCOS and short tandem repeat polymorphisms in 367 families, by analysis of linkage and family-based association. SETTING: The study was conducted at academic medical centers. PATIENTS OR OTHER PARTICIPANTS: We studied 367 families of predominantly European origin with at least one PCOS patient. Families included 107 affected sibling (sister) pairs (ASPs) in 83 families, and 390 trios with both parents and an affected daughter. The data set comprises two independent groups. Set 1 consists of 44 ASPs and 163 trios. Set 2 consists of 63 ASPs and 227 trios. INTERVENTION(S): The intervention was the drawing of blood for DNA extraction. MAIN OUTCOME MEASURE: We employed measures of evidence for linkage and association between PCOS and 19 STRs. RESULTS: Linkage with PCOS was observed over a broad region of chromosome 19p13.2. The strongest evidence for association was observed with D19S884 (chi2 = 11.85; nominal P < 0.0006; permutation P = 0.034) and duplicated our earlier findings. CONCLUSIONS: The present analysis suggests that a PCOS susceptibility locus maps very close to D19S884. Additional studies that systematically characterize DNA sequence variation in the immediate area of D19S884 are required to identify the PCOS susceptibility variant.

Adult↗

PubMed2002

Polycystic ovary syndrome. Long term sequelae and management.

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies in women and is defined by hyperandrogenic chronic anovulation with the exclusion of secondary causes, such as congenital adrenal hyperplasia or an androgen secreting tumor. PCOS women are uniquely insulin resistant. It is estimated that 5% of the female population is affected. 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. Additionally women display multiple other risk factors for cardiovascular disease including dyslipidemia and elevated circulating inflammatory markers. The lack of a clear etiologic mechanism to the syndrome has led in the past to a multitude of symptom-oriented treatments with few therapies improving all aspects of the endocrine syndrome of PCOS. Recently treatments resulting in improved insulin sensitivity, either through weight loss/exercise programs or pharmaceutical, have been shown to improve both the endocrine and metabolic abnormalities in the syndrome. Anti-diabetic agents in PCOS have been examined in a number of randomized studies which have shown a treatment benefit. Further indications for these agents such as the prevention of pregnancy loss or the conversion to type 2 diabetes still need to be investigated in properly designed studies.

Adult↗

PubMed2001

Prevalence and predictors of dyslipidemia in women with polycystic ovary syndrome.

PURPOSE: Women with polycystic ovary syndrome are hyperandrogenemic and insulin resistant, which are associated with alterations in circulating lipid and lipoprotein levels. We sought to determine the prevalence of, and risk factors for, lipid abnormalities in these women. SUBJECTS AND METHODS: Non-Hispanic white women with polycystic ovary syndrome (n = 195) and ethnically matched control women (n = 62) had fasting blood obtained for hormone and lipid levels. Subjects were categorized by body mass index (nonobese <27 kg/m(2), obese > or =27 kg/m(2)), and analyses were adjusted for age. RESULTS: Total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels increased significantly in obese women with polycystic ovary syndrome (n = 153) compared with obese control women (n = 35; mean difference in total cholesterol level = 29 mg/dL; 95% confidence interval [CI]: 14 to 45 mg/dL; P <0.001; mean difference in LDL-C level = 16 mg/dL; 95% CI: 4 to 30 mg/dL; P = 0.006). Similarly, total cholesterol and LDL-C levels increased significantly in nonobese women with polycystic ovary syndrome (n = 42) compared with nonobese control women (n = 27; mean difference in total cholesterol = 32 mg/dL; 95% CI: 13 to 52 mg/dL; P <0.001; mean difference in LDL-C level = 32 mg/dL; 95% CI: 15 to 52 mg/dL; P <0.001). In obese women, high-density lipoprotein cholesterol (HDL-C) and triglyceride levels increased significantly in women with polycystic ovary syndrome compared with control women (mean difference in HDL-C level = 6 mg/dL; 95% CI: 2 to 12 mg/dL; P = 0.002; mean difference in triglyceride level = 34 mg/dL; 95% CI: 1 to 77 mg/dL; P = 0.04). Differences in LDL-C and HDL-C levels, but not triglyceride levels, remained significant after adjusting for alcohol intake, smoking, and exercise. Although age, body mass index, and polycystic ovary syndrome status were significant predictors of lipid levels, these factors accounted for no more than 25% of the variance. CONCLUSIONS: In this large study of non-Hispanic white women, elevations in LDL-C levels were the predominant lipid abnormality in women with polycystic ovary syndrome, independent of obesity. The characteristic dyslipidemia of insulin resistance was absent. Indeed, obese women with polycystic ovary syndrome had relatively elevated HDL-C levels, which may confer some protection against cardiovascular disease.

Adolescent↗

PubMed2001

Polycystic ovary syndrome: the new millenium.

Our understanding of Polycystic Ovary Syndrome (PCOS) has been hampered by varying diagnostic criteria, and ignorance of the etiology of the syndrome. PCOS women are uniquely insulin resistant and obesity aggravates this underlying predisposition to insulin resistance. Diagnostic criteria which focus on hyperandrogenism and/or menstrual irregularity are more likely to identify insulin resistant women, than such criteria as abnormal gonadotropin secretion or ovarian morphology. 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. Improving insulin sensitivity has become established as a baseline treatment strategy in PCOS. There are, however, few randomized controlled trials of adequate power to provide an evidence based guide to treatment in PCOS.

Cardiovascular Diseases↗

PubMed2001

Spontaneous conception in the presence of stage IIIC endometrioid ovarian cancer.

OBJECTIVE: To describe a rare case of spontaneous conception in a patient with a preexisting metastatic ovarian cancer. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 39-year-old Asian woman who conceived while undergoing an evaluation for primary infertility and newly detected bilateral adnexal masses. INTERVENTION(S): Staging laparotomy and total abdominal hysterectomy and bilateral salpingo-oophorectomy. MAIN OUTCOME MEASURE(S): Anatomic pathology diagnosis. RESULT(S): Blighted ovum and stage IIIC endometrioid adenocarcinoma of ovary. CONCLUSION(S): Metastatic ovarian cancer does not prevent either spontaneous ovulation or spontaneous conception.

Abortion, Missed↗

PubMed2001

Diabetes prevalence and risk factors in polycystic ovary syndrome.

Polycystic ovary syndrome is a reproductive disorder with a significant impact on fertility. It is secondarily, and perhaps for the individual primarily, a disorder with a marked increase risk for diabetes and glucose intolerance. Physicians need to be aware that women who have PCOS are at high risk for impaired glucose tolerance and type 2 diabetes. In the author's opinion, they should be screened for these abnormalities. Minority women with PCOS may have higher prevalence rates of glucose intolerance, and further study of minority groups is indicated. The author's data indicate that fasting glucose levels are inadequate for such screenings. Fasting glucose levels are relatively poor predictors of type 2 diabetes as determined by glucose challenge testing in PCOS. These findings may have substantial clinical relevance. They strongly suggest that all PCOS women should be screened for glucose intolerance, and that basal and 2-hour, glucose-stimulated levels rather than fasting glucose levels alone are required for such screening. Further study is necessary to document conversion rates to worsening glucose tolerance over time, as well as the cardiovascular risk associated with glucose intolerance in PCOS.

Diabetes Mellitus↗

PubMed2001

Role of androgens in the growth of endometrial carcinoma: an in vivo animal model.

OBJECTIVE: We sought to create an animal model for the development of endometrial cancer in women with androgen excess. We examined the effects of estradiol and androgen, both alone and as precursors to estrogen biosynthesis on human endometrial cancers transplanted into a nude mouse model. STUDY DESIGN: We transplanted an estrogen-responsive, well-differentiated, established human endometrial carcinoma, EnCa-101, subcutaneously into athymic male nude mice. We established, first, that aromatase was expressed in this cell line, inducible by estrogen. We measured the growth of the tumor in the various groups weekly with Vernier calipers. We examined the effects of estradiol and androgens, both aromatizable and nonaromatizable, on tumor growth. RESULTS: Estrogen-supplemented tumors showed the greatest rate of growth and were significantly greater than the growth rate in castrate mice. Androgen-supplemented tumors showed a growth rate similar to that of tumors without significant hormonal exposure (castrate mice). Dihydrotestosterone had no effect on tumor growth in comparison with an agonadal state. CONCLUSIONS: Aromatizable and nonaromatizable androgens have little growth-promoting effect on a well-differentiated endometrial carcinoma. Estradiol is the most potent growth stimulus in our model.

Androgens↗

PubMed2001

The biochemical basis for increased testosterone production in theca cells propagated from patients with polycystic ovary syndrome.

Ovarian theca cells propagated from patients with polycystic ovary syndrome (PCOS) convert steroid precursors into T more efficiently than normal theca cells. To identify the basis for increased T production by PCOS theca cells, we examined type I-V 17 beta-hydroxysteroid dehydrogenase (17 beta HSD) isoform expression in long-term cultures of theca and granulosa cells isolated from normal and PCOS ovaries. RT-PCR analysis demonstrated that theca cells express type V 17 beta HSD a member of the aldo-keto reductase (AKR) superfamily (17 beta HSDV, AKR1C3), whereas expression of type I, II, and IV 17 beta HSD, which are members of the short-chain dehydrogenase/reductase superfamily, was limited to granulosa cells. Type III 17 beta HSD, the testicular isoform, was not detected in either granulosa or theca cells. Northern and real-time PCR analyses demonstrated that 17 beta HSDV transcripts were not significantly increased in PCOS theca cells compared with normal theca cells. RT-PCR analysis revealed that theca cells also express another AKR, 20 alpha HSD (AKR1C1). Both basal and forskolin-stimulated 20 alpha HSD mRNA levels were increased in PCOS theca cells compared with normal theca cells. However, 17 beta HSD enzyme activity per theca cell was not significantly increased in PCOS, suggesting that neither AKR1C3 nor AKR1C1 contributes to the formation of T in this condition. In contrast, 17 alpha-hydroxylase/C17,20 lyase and 3 beta HSD enzyme activities were elevated in PCOS theca cells, driving increased production of T precursors. These findings indicate that 1) increased T production in PCOS theca cells does not result from dysregulation of "androgenic" 17 beta HSD activity or altered expression of AKRs that may express 17 beta HSD activity; and 2) increased synthesis of T precursors is the primary factor driving enhanced T secretion in PCOS.

20-Hydroxysteroid Dehydrogenases↗

PubMed2001

Polycystic ovary syndrome is associated with obstructive sleep apnea and daytime sleepiness: role of insulin resistance.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of premenopausal women, characterized by chronic hyperandrogenism, oligoanovulation, and insulin resistance. Obstructive sleep apnea (OSA) and excessive daytime sleepiness (EDS) are strongly associated with insulin resistance and hypercytokinemia, independently of obesity. We hypothesized that women with PCOS are at risk for OSA and EDS. Fifty-three women with PCOS (age range, 16-45 yr) and 452 control premenopausal women (age range, 20-42), from a general randomized sample for the assessment of prevalence of OSA, were evaluated in the sleep laboratory for 1 night. In addition, women with PCOS were tested for plasma free and weakly bound testosterone, total testosterone, and fasting blood glucose and insulin concentrations. In this study, PCOS patients were 30 times more likely to suffer from sleep disordered breathing (SDB) than the controls [odds ratio = 30.6, 95% confidence interval (7.2-139.4)]. Nine of the PCOS patients (17.0%) were recommended treatment for SDB, in contrast with only 3 (0.6%) of the control group (P < 0.001). In addition, PCOS patients reported more frequent daytime sleepiness than the controls (80.4% vs. 27.0%, respectively; P < 0.001). PCOS patients who were recommended treatment for SDB, compared with those who were not, had significantly higher fasting plasma insulin levels (306.48 +/- 52.39 vs. 176.71 +/- 18.13 pmol/L, P < 0.01) and a lower glucose-to-insulin ratio (0.02 +/- 0.00 vs. 0.04 +/- 0.00, P < 0.05). Plasma free and total testosterone and fasting blood glucose concentrations were not different between the two groups of PCOS women. Our data indicate that SDB and EDS are markedly and significantly more frequent in PCOS women than in premenopausal controls. Also, insulin resistance is a stronger risk factor than is body mass index or testosterone for SDB in PCOS women. These data support our proposal that, independently of gender, sleep apnea might be a manifestation of an endocrine/metabolic abnormality in which insulin resistance plays a principal role.

Adolescent↗

PubMed2001

Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial.

We hypothesized that the administration of troglitazone, an insulin-sensitizing agent of the thiazolidinedione class, would improve the ovulatory dysfunction, hirsutism, hyperandrogenemia, and hyperinsulinemia of polycystic ovary syndrome (PCOS) patients. Four hundred and ten premenopausal women with PCOS in a multicenter, double blind trial were randomly assigned to 44 weeks of treatment with placebo (PBO) or troglitazone [150 mg/day (TGZ-150), 300 mg/day (TGZ-300), or 600 mg/day (TGZ-600)]. We compared changes in ovulatory function (by monitoring the urinary level of pregnanediol-3-glucuronide daily), hirsutism (by a modified Ferriman-Gallwey scoring method), hormonal levels (total and free testosterone, androstenedione, sex hormone-binding globulin, LH, FSH, and the LH/FSH ratio), and measures of glycemic parameters (fasting levels of glucose, insulin, hemoglobin A(1c), and the glucose and insulin areas under the curve during an oral glucose challenge) among study groups. Of the 410 patients recruited, 305 (74.4%) met evaluability criteria and were included in the analyses. The patients' baseline characteristics were similar across all treatment arms. Ovulatory rates were significantly greater for patients receiving TGZ-300 and TGZ-600 than for those receiving PBO (0.42 and 0.58 vs. 0.32; P < 0.05 and 0.0001, respectively). Of PCOS patients treated with TGZ-600, 57% ovulated over 50% of the time compared with 12% of placebo-treated patients. There was a significant decrease in the Ferriman-Gallwey score with TGZ-600 compared with PBO (0.22 +/- 0.53 vs. -2.21 +/- 0.49; P < 0.05, respectively). Free testosterone decreased and sex hormone-binding globulin increased in a dose-related fashion with troglitazone treatment, and all three troglitazone treatment groups were significantly different from placebo. Nearly all glycemic parameters showed dose-related decreases with troglitazone treatment. The total number and severity of adverse events (including elevations in liver enzymes) and the proportion of patients withdrawn from the study due to the development of adverse effects were similar between treatment groups. Troglitazone improves the ovulatory dysfunction, hirsutism, hyperandrogenemia, and insulin resistance of PCOS in a dose-related fashion, with a minimum of adverse effects.

Adult↗

PubMed2000

Oral contraceptive use by teenage women does not affect peak bone mass: a longitudinal study.

OBJECTIVE: To determine the effect of oral contraceptive pill (OCP) use during adolescence on peak bone mass. DESIGN: Longitudinal observational study. SETTING: Academic clinical research center. PATIENT(S): Sixty-two non-Hispanic, white females in The Penn State Young Women's Health Study, who were studied for 8 years during ages 12-20. INTERVENTION(S): There were 28 OCP users, who used OCPs for a minimum of 6 months and were still using at age 20, and 34 nonusers who had never used OCPs. MAIN OUTCOME MEASURE(S): Total body bone, dedicated hip bone, and body composition measurements were made by dual-energy roentgenogram absorptiometry. RESULT(S): The OCP users and nonusers did not differ at entry in anthropometric, body composition, or total body bone measurements. By age 20, the average duration of OCP use by the user group was 22 months. At age 20, the groups remained indistinguishable in anthropometric, body composition, total body, and hip bone measures, and in age of menarche and sports exercise scores. CONCLUSION(S): Oral contraceptive pill use by healthy, white, teenage females does not affect acquisition of peak bone mass.

Adolescent↗

PubMed2000

The mentor effect in student evaluation.

OBJECTIVE: To determine if faculty mentors rate their mentored students higher than do nonmentors, and to ascertain if gender is a factor. METHODS: All third-year students (n = 101) from academic years 1996-1998, who performed their obstetrics and gynecology clerkship at the Milton S. Hershey Medical Center in the Penn State Geisinger Health System and were evaluated by full-time faculty (n = 18), were included in the study (total observations = 545). Students were rated by faculty on an ordinal scale in five categories. Generalized estimating equation methodology was used to fit proportional odds models for ordinal data to assess whether there were statistically significant mentor or faculty/student gender effects. RESULTS: Student evaluations from mentors were more likely to have better scores than student evaluations from nonmentoring-faculty for all five categories (all P <.01). The odds ratios (OR) for the mentor effect ranged from 2.1 (95% confidence interval [CI] 1.4, 3.2) for fund of knowledge to 3.2 (95% CI [2.1, 4. 8]) for attitude. For problem-solving and technical skills, male faculty were more likely than female faculty to give male students better scores (problem-solving skills: odds ratio [OR] = 1.7, 95% CI [1.0, 2.7]; technical skills: OR = 2.2, 95% CI [1.1, 4.6]). Mentoring-faculty evaluations were not strongly correlated with the students' objective examination scores. CONCLUSION: Overall, mentors score their mentored students statistically higher than do nonmentors. Gender differences in evaluation, while present, are less consistent and smaller than the mentor effect.

Confidence Intervals↗

PubMed2000

The genetics of obesity. Lessons for polycystic ovary syndrome.

Both polycystic ovary syndrome (PCOS) and obesity are common disorders with a complex phenotype. Both are presumably heterogeneous in etiology. Understanding the genetics of obesity, which has a longer and richer history, may therefore illuminate the genetics of PCOS, where major projects are now underway. Obesity may be the penultimate condition in which the effects of heredity and environment will forever mingle. Most obesity mutations identified to date (with the exception of the Agouti mutation) are inherited in an autosomal recessive manner. Therefore, it is unlikely that such mutations, even when identified in a human population, could explain only a fraction of the cases that make up the high prevalence of both of these disorders. Although the mouse models of single gene defects causing obesity contain many similar aspects of the PCOS phenotype such as obesity and subfecundity, there is no mouse model that mimics all aspects of the syndrome, especially the circulating androgen excess. This elevation in circulating androgens may be the sine qua non of the syndrome as indicated by our findings in sisters of PCOS probands that hyperandrogenemia may be the distintinctive reproductive phenotype. Isolation of PCOS and obesity genes may allow the development of targeted interventions that will lead to effective and safe treatment of both obesity and PCOS.

Adipocytes↗

PubMed2000

Allelic variants of the follistatin gene in polycystic ovary syndrome.

In an earlier study of 37 candidate genes for polycystic ovary syndrome (PCOS), the strongest evidence for genetic linkage was found with the region of the follistatin gene. We have now carried out studies to detect variation in the follistatin gene and assess its relevance to PCOS. By sequencing the gene in 85 members of 19 families of PCOS patients, we found sequence variants at 17 sites. Of these, 16 sites have variants that are too rare to make a major contribution to susceptibility; the only common variant is a single base pair change in the last exon at a site that is not translated. In our sample of 249 families, the evidence for linkage between PCOS and this variant is weak. We also examined the expression of the follistatin gene; messenger RNA levels in cultured fibroblasts from PCOS and control women did not differ appreciably. We conclude that contributions to the etiology of PCOS from the follistatin gene, if any, are likely to be small.

Alleles↗

PubMed2000

Rapid maturation of the reproductive axis during perimenarche independent of body composition.

The development of the reproductive axis is thought to be a gradual process, but our understanding of the complex endocrine changes that accompany the transition from premenarche to reproductive life in women has been hampered by the paucity of longitudinal studies. We studied 112 premenarchal Caucasian females at 6-month intervals over 4 yr and obtained a detailed reproductive and dietary history. We quantified reproductive hormones in 24-h urine collections as a measure of daily output and measured body composition biometrically and with the use of dual energy x-ray absortiometry scans. The percent body fat did not change appreciably in the study period (range, 21-24%) and was unrelated to menarche. Sex steroid and gonadotropin levels changed exponentially in the year approaching menarche. FSH levels peaked at menarche and then progressively declined thereafter. Estradiol output increased rapidly in the year approaching menarche and then plateaued thereafter. The frequency of menstrual bleeding increased rapidly and plateaued at 1 yr postmenarche. At 1 yr, 65% of these adolescent women had established a pattern of 10 or more menstrual episodes/yr, and by 3 yr postmenarche this figure exceeded 90%. There were no significant changes in dietary intake of protein, carbohydrate, or fat in the same period. Menarche occurs as a result of rapid maturation of the reproductive axis and heralds the reestablishment of a negative sex steroid feedback loop that parallels the adult threshold. These events appear to develop independent of changes in body composition and diet, but may reflect the improved nutrition and socioeconomic status of the late 20th century.

Adipose Tissue↗

PubMed2000

Differential activity of the cytochrome P450 17alpha-hydroxylase and steroidogenic acute regulatory protein gene promoters in normal and polycystic ovary syndrome theca cells.

17alpha-Hydroxylase (CYP17) expression in propagated theca cells isolated from the ovaries of women with polycystic ovary syndrome (PCOS) is persistently elevated, compared with theca cells isolated from normal ovaries. To investigate the mechanism for increased CYP17 messenger RNA accumulation in PCOS theca cells, we examined CYP17 and steroidogenic acute regulatory protein (StAR) promoter activities in normal and PCOS theca cells. Conditions were established to transiently transfect human theca cells with reporter gene constructs containing 5' truncations of the human CYP17 and StAR promoters. Cotransfection of a steroidogenic factor-1 expression plasmid was found to be required for detection of basal and forskolin-stimulated CYP17 promoter activity but not for StAR promoter activity. However, cotransfection with a steroidogenic factor-1 expression plasmid augmented both basal and forskolin-stimulated StAR promoter activity. CYP17 reporter activity was compared in theca cells isolated from normal and PCOS patients. Basal and forskolin-stimulated CYP17 promoter activity was 4-fold greater in PCOS cells than in theca cells isolated from normal ovaries. In contrast, StAR promoter activity, and the activity of a reporter construct containing three copies of a cAMP response element (3xCRE), were similar in normal and PCOS theca cells. The results of these studies document: 1) that basal and cAMP-dependent CYP17 gene transcription is increased in PCOS theca cells; 2) that there is differential regulation of promoters of genes required for steroidogenesis in PCOS theca cells; and 3) that passaged normal and PCOS theca cells provide a model system for studying tissue-specific regulation of genes encoding steroidogenic enzymes and identifying the molecular mechanisms involved in increased androgen production in PCOS.

Cells, Cultured↗