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1.  Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations 
Nature Communications  2015;6:7502.
Polycystic ovary syndrome (PCOS) is a common, highly heritable complex disorder of unknown aetiology characterized by hyperandrogenism, chronic anovulation and defects in glucose homeostasis. Increased luteinizing hormone relative to follicle-stimulating hormone secretion, insulin resistance and developmental exposure to androgens are hypothesized to play a causal role in PCOS. Here we map common genetic susceptibility loci in European ancestry women for the National Institutes of Health PCOS phenotype, which confers the highest risk for metabolic morbidities, as well as reproductive hormone levels. Three loci reach genome-wide significance in the case–control meta-analysis, two novel loci mapping to chr 8p32.1 and chr 11p14.1, and a chr 9q22.32 locus previously found in Chinese PCOS. The same chr 11p14.1 SNP, rs11031006, in the region of the follicle-stimulating hormone B polypeptide (FSHB) gene strongly associates with PCOS diagnosis and luteinizing hormone levels. These findings implicate neuroendocrine changes in disease pathogenesis.
Polycystic Ovary Sydrome is a highly heritable, complex reproductive disorder with unknown underlying genetic factors. Here Hayes and Urbanek et al. identify three loci in European women strongly associated with neuroendocrine changes and disease susceptibility.
PMCID: PMC4557132  PMID: 26284813
2.  Impaired Insulin Signaling in Human Adipocytes After Experimental Sleep Restriction 
Annals of internal medicine  2012;157(8):549-557.
Insufficient sleep increases the risk for insulin resistance, type 2 diabetes, and obesity, suggesting that sleep restriction may impair peripheral metabolic pathways. Yet, a direct link between sleep restriction and alterations in molecular metabolic pathways in any peripheral human tissue has not been shown.
To determine whether sleep restriction results in reduced insulin sensitivity in subcutaneous fat, a peripheral tissue that plays a pivotal role in energy metabolism and balance.
Randomized, 2-period, 2-condition, crossover clinical study.
University of Chicago Clinical Resource Center.
Seven healthy adults (1 woman, 6 men) with a mean age of 23.7 years (SD, 3.8) and mean body mass index of 22.8 kg/m2 (SD, 1.6).
Four days of 4.5 hours in bed or 8.5 hours in bed under controlled conditions of caloric intake and physical activity.
Adipocytes collected from subcutaneous fat biopsy samples after normal and restricted sleep conditions were exposed to incremental insulin concentrations. The ability of insulin to increase levels of phosphorylated Akt (pAkt), a crucial step in the insulin-signaling pathway, was assessed. Total Akt (tAkt) served as a loading control. The insulin concentration for the half-maximal stimulation of the pAkt–tAkt ratio was used as a measure of cellular insulin sensitivity. Total body insulin sensitivity was assessed using a frequently sampled intravenous glucose tolerance test.
The insulin concentration for the half-maximal pAkt–tAkt response was nearly 3-fold higher (mean, 0.71 nM [SD, 0.27] vs. 0.24 nM [SD, 0.24]; P = 0.01; mean difference, 0.47 nM [SD, 0.33]; P = 0.01), and the total area under the receiver-operating characteristic curve of the pAkt–tAkt response was 30% lower (P = 0.01) during sleep restriction than during normal sleep. A reduction in total body insulin sensitivity (P = 0.02) paralleled this impaired cellular insulin sensitivity.
This was a single-center study with a small sample size.
Sleep restriction results in an insulin-resistant state in human adipocytes. Sleep may be an important regulator of energy metabolism in peripheral tissues.
Primary Funding Source
National Institutes of Health.
PMCID: PMC4435718  PMID: 23070488
3.  Antimüllerian hormone levels are independently related to ovarian hyperandrogenism and polycystic ovaries 
Fertility and sterility  2012;98(1):242-249.
To determine the relationship of antimüllerian hormone (AMH) levels to polycystic ovaries and ovarian androgenic function.
Prospective case-control study.
General clinical research center.
Eumenorrheic asymptomatic volunteers without (V-NO; n = 19; reference population) or with (V-PCO; n = 28) a polycystic ovary and hyperandrogenemic anovulatory subjects grouped according to ovarian function into typical PCOS (PCOS-T; n = 37) and atypical PCOS (PCOS-A; n = 18).
Pelvic ultrasonography, short dexamethasone androgen-suppression test (SDAST), and GnRH agonist (GnRHag) test.
Main Outcome Measure(s)
Baseline AMH levels were related to polycystic ovary status, testosterone response to SDAST, and 17-hydroxyprogesterone response to GnRHag test.
AMH levels correlated with SDAST and GnRHag test outcomes. AMH was elevated (>6.2 ng/mL) in 32% of V-PCO versus 5% V-NO. The 21% of V-PCO who met Rotterdam PCOS criteria all had functional ovarian hyperandrogenism, but AMH levels were similar to nonhyperandrogenic V-PCO. AMH >10.7 ng/mL discriminated V-PCO from PCOS with 96% specificity and 41% sensitivity for PCOS-T, and insignificantly for PCOS-A.
AMH levels are independently related to ovarian androgenic function and polycystic ovaries. Very high AMH levels are specific but insensitive for PCOS. In the absence of hyperandrogenism, moderate AMH elevation in women with normal-variant polycystic ovaries seems to indicate an enlarged oocyte pool.
PMCID: PMC3597099  PMID: 22541936
Antimüllerian hormone; dexamethasone suppression test; functional ovarian hyperandrogenism; GnRH agonist test; obesity; ovarian reserve; polycystic ovary
4.  Determination of the source of androgen excess in functionally atypical polycystic ovary syndrome by a short dexamethasone androgen-suppression test and a low-dose ACTH test 
Human Reproduction (Oxford, England)  2011;26(11):3138-3146.
Polycystic ovary syndrome (PCOS) patients typically have 17-hydroxyprogesterone (17OHP) hyperresponsiveness to GnRH agonist (GnRHa) (PCOS-T). The objective of this study was to determine the source of androgen excess in the one-third of PCOS patients who atypically lack this type of ovarian dysfunction (PCOS-A).
Aged-matched PCOS-T (n= 40), PCOS-A (n= 20) and controls (n= 39) were studied prospectively in a General Clinical Research Center. Short (4 h) and long (4–7 day) dexamethasone androgen-suppression tests (SDAST and LDAST, respectively) were compared in subsets of subjects. Responses to SDAST and low-dose adrenocorticotropic hormone (ACTH) were then evaluated in all.
Testosterone post-SDAST correlated significantly with testosterone post-LDAST and 17OHP post-GnRHa (r = 0.671–0.672), indicating that all detect related aspects of ovarian dysfunction. An elevated dehydroepiandrosterone peak in response to ACTH, which defined functional adrenal hyperandrogenism, was similarly prevalent in PCOS-T (27.5%) and PCOS-A (30%) and correlated significantly with baseline dehydroepiandrosterone sulfate (DHEAS) (r = 0.708). Functional ovarian hyperandrogenism was detected by subnormal testosterone suppression by SDAST in most (92.5%) PCOS-T, but significantly fewer PCOS-A (60%, P< 0.01). Glucose intolerance was absent in PCOS-A, but present in 30% of PCOS-T (P < 0.001). Most of the PCOS-A cases with normal testosterone suppression in response to SDAST (5/8) lacked evidence of adrenal hyperandrogenism and were obese.
Functional ovarian hyperandrogenism was not demonstrable by SDAST in 40% of PCOS-A. Most of these cases had no evidence of adrenal hyperandrogenism. Obesity may account for most hyperandrogenemic anovulation that lacks a glandular source of excess androgen, and the SDAST seems useful in making this distinction.
PMCID: PMC3196876  PMID: 21908468
glucose intolerance; functional adrenal hyperandrogenism; functional ovarian hyperandrogenism; obesity
5.  Sleep Disturbances and Their Relationship to Glucose Tolerance in Pregnancy 
Diabetes Care  2011;34(11):2454-2457.
To explore relationships among sleep disturbances, glucose tolerance, and pregnancy outcomes.
Four validated sleep questionnaires were administered to 169 pregnant women at the time of 50-g oral glucose tolerance testing (OGTT) during the second trimester. Pregnancy outcomes were analyzed in 108 women with normal glucose tolerance (NGT).
Of the participants, 41% had excessive daytime sleepiness (Epworth Sleepiness Scale [ESS] >8); 64% had poor sleep quality; 25% snored frequently; 29% had increased risk of sleep-disordered breathing (SDB); 52% experienced short sleep (SS); 19% had both increased SDB risk and SS (SDB/SS); and 14% had daytime dysfunction. Reported sleep duration inversely correlated with glucose values from 50-g OGTT (r = −0.21, P < 0.01). Each hour of reduced sleep time was associated with a 4% increase in glucose levels. Increased likelihood of gestational diabetes mellitus (GDM) was found in subjects with increased SDB risk (odds ratio 3.0 [95% CI 1.2–7.4]), SS (2.4 [1.0–5.9]), SDB/SS (3.4 [1.3–8.7]), and frequent snoring (3.4 [1.3–8.8], after adjustment for BMI). Among NGT subjects, preterm delivery was more frequent in those with increased ESS (P = 0.02), poor sleep quality (P = 0.02), and SS (P = 0.03). Neonatal intensive care unit admissions were associated with increased ESS (P = 0.03), SDB/SS (P = 0.03), and daytime dysfunction (P < 0.01) in mothers.
Pregnant women experience significant sleep disturbances that are associated with increased risk of GDM and unfavorable pregnancy outcomes. Pregnant women with increased SDB risk, frequent snoring, and sleep duration of <7 h/night have increased risk of developing GDM.
PMCID: PMC3198297  PMID: 21926292
6.  Potential Diagnostic Utility of Intermittent Short-Acting GnRH Agonist Administration in Gonadotropin Deficiency 
Fertility and sterility  2010;94(7):2697-2702.
The objective was to determine if intermittent, low-dose, short-acting GnRH agonist (GnRHag) administration up-regulates pituitary-gonadal function in gonadotropin deficiency (GnD) sufficiently to be of diagnostic or therapeutic value.
Low-dose leuprolide acetate was administered SC at 4–5 d intervals up to one year.
Adult volunteers and GnD patients were studied.
The studies were performed in a General Clinical Research Center.
Main Outcome Measures
LH, FSH, and sex steroid responses were determined.
In normal men and women, low-dose GnRHag repetitively transiently stimulated gonadotropins in a gender-dimorphic manner. In congenitally GnD deficient men (n=6) and women (n=1), none of whom had a normal LH response to an initial GnRHag test dose, this regimen consistently stimulated LH to the normal baseline range within two weeks. Long-term GnRHag administration to a partially GnD man did not alleviate hypogonadism, however. Women with hypothalamic amenorrhea (n=2) responded normally to a single GnRHag injection; however, repeated dosing did not seem to induce the normal priming effect.
The subnormal LH response to GnRHag of congenital GnD normalized in response to repetitive intermittent GnRHag, but not sufficiently to improve hypogonadism. Hypothalamic amenorrhea patients lacked the priming response to repeated GnRHag, but otherwise had normal hormonal responses to GnRHag. We conclude that intermittent administration of a short-acting GnRHag is of potential diagnostic value in distinguishing hypothalamic from pituitary causes of GnD.
PMCID: PMC2944005  PMID: 20553679
gonadotropin deficiency; gonadotropin-releasing hormone agonist; repetitive administration; gonadotropin sexual dimorphism
Obstructive sleep apnea (OSA) is an underrecognized, yet significant factor in the pathogenesis of metabolic derangements in polycystic ovary syndrome (PCOS). Recent findings suggest that there may be two “subtypes” of PCOS, i.e. PCOS with or without OSA, and these two subtypes may be associated with distinct metabolic and endocrine alterations. PCOS women with OSA may be at much higher risk for diabetes and cardiovascular disease than PCOS women without OSA and may benefit from therapeutic interventions targeted to decrease the severity of OSA. The present chapter will review what is currently known about the roles of sex steroids and adiposity in the pathogenesis of OSA, briefly review the metabolic consequences of OSA as well as the metabolic abnormalities associated with PCOS, review the prevalence of OSA in PCOS and finally present early findings regarding the impact of treatment of OSA on metabolic measures in PCOS.
PMCID: PMC3030192  PMID: 21112021
Cardiometabolic; Impaired glucose tolerance (IGT); Insulin resistance; Metabolic syndrome; Obstructive sleep apnea (OSA); Polycystic ovary syndrome (PCOS); Type 2 diabetes
8.  Variation in the Perilipin Gene (PLIN) Affects Glucose and Lipid Metabolism in Non-Hispanic White Women With and Without Polycystic Ovary Syndrome 
Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women. It is characterized by chronic anovulation, hyperandrogenism, obesity and a predisposition to type 2 diabetes mellitus (T2DM). Since obesity plays an important role in the etiology of PCOS, we sought to determine if variants in the perilipin gene (PLIN), a gene previously implicated in the development of obesity, were also associated with PCOS. We typed six single nucleotide polymorphisms (haplotype tagging and/or previously associated with obesity or related metabolic traits) in PLIN in 305 unrelated non-Hispanic white women (185 with PCOS and 120 without PCOS). None of the variants was associated with PCOS (P < 0.05). However, the variant rs1052700*A was associated with increased risk for glucose intolerance (impaired glucose tolerance or T2DM) in both non-PCOS (OR = 1.75 [1.02-3.01], P = 0.044) and PCOS subjects (OR = 1.67 [1.08-2.59], P = 0.022). It was also associated with increased LDL (P = 0.007) and total cholesterol levels (P = 0.042). These results suggest that genetic variation in PLIN may affect glucose and lipid metabolism in women both with and without PCOS.
PMCID: PMC2794304  PMID: 19782423
Perilipin; polycystic ovary syndrome (PCOS); type 2 diabetes mellitus; glucose; lipid
9.  Polycystic Ovary Syndrome and Obstructive Sleep Apnea 
Sleep medicine clinics  2008;3(1):37-46.
Polycystic ovary syndrome (PCOS), the most common endocrine disorder of pre-menopausal women, is characterized by chronic hyperandrogenism, oligoanovulation, obesity and insulin resistance. Importantly, PCOS women are at increased risk for glucose intolerance, type 2 diabetes and cardiovascular disorders. Recent reports indicate an unexpectedly high prevalence of obstructive sleep apnea (OSA) in PCOS. Alterations in sex steroids (i.e. high androgen and low estrogen levels) and increased visceral adiposity in PCOS could potentially contribute to the increased prevalence of OSA in this disorder. There is some evidence to suggest that there may be strong associations between the presence and severity of OSA and the metabolic disturbances that characterize PCOS. Causal mechanisms in the link between PCOS and OSA remain to be elucidated. Clinicians who manage PCOS patients should be aware of the high prevalence of OSA in these patients and systematically evaluate these women for sleep disturbances.
PMCID: PMC2390828  PMID: 19255602
PCOS; visceral adiposity; obesity; insulin resistance; OSA
10.  Factors Associated With Diabetes Onset During Metformin Versus Placebo Therapy in the Diabetes Prevention Program 
Diabetes  2007;56(4):1153-1159.
In the Diabetes Prevention Program, treatment of subjects with impaired glucose tolerance with metformin >3.2 years reduced the risk of developing type 2 diabetes by 30% compared with placebo. This study describes the mechanisms of this effect. In proportional hazards regression models with 2,155 subjects, changes in weight, the insulinogenic index (IGR), fasting insulin, and proinsulin were predictive of diabetes, though to different degrees within each group. The mean change in weight, fasting insulin, and proinsulin, but not IGR, differed between groups during the study. The 1.7-kg weight loss with metformin versus a 0.3-kg gain with placebo alone explained 64% of the beneficial metformin effect on diabetes risk. Adjustment for weight, fasting insulin, proinsulin, and other metabolic factors combined explained 81% of the beneficial met-formin effect, but it remained nominally significant (P = 0.034). After the addition of changes in fasting glucose, 99% of the group effect was explained and is no longer significant. Treatment of high-risk subjects with metformin results in modest weight loss and favorable changes in insulin sensitivity and proinsulin, which contribute to a reduction in the risk of diabetes apart from the associated reductions in fasting glucose.
PMCID: PMC2533728  PMID: 17395752
11.  Identification of a Functional Polymorphism of the Human Type 5 17β-Hydroxysteroid Dehydrogenase Gene Associated with Polycystic Ovary Syndrome. 
Polycystic ovary syndrome (PCOS) is characterized by chronic hyperandrogenic anovulation and is associated with insulin resistance. Its pathogenesis is believed to be multifactorial, and abnormal gene regulation could be one contributing factor. Type 5 17 beta-hydroxysteroid dehydrogenase (17β-HSD5) appears to be the major testosterone-forming 17β-HSD isoenzyme in females.
To investigate the role of a potentially activating 17β-HSD5 gene (HSD17B5) variant in hyperandrogenism.
Case report and case-control cohort study.
General Clinical Research Center.
Study subjects
A case of PCOS who had hyperthecosis associated with profound type B insulin resistance and an unusual, frankly male, testosterone response to a gonadotropin releasing hormone agonist test, 121 PCOS, and 128 population controls.
Main outcome measures
Sequencing of HSD17B5 5′-flanking region and 9 exons, genotype/phenotype studies, and in vitro functional studies.
Our case had a previously undescribed homozygous HSD17B5 variant (G-to-A substitution) -71 bp in the promoter region. Genotyping controls showed this to be a single nucleotide polymorphism (SNP-71G). Luciferase activity of a SNP-71G promoter construct was significantly higher than that of the wild-type, and electrophoretic mobility shift assays revealed that SNP-71G possessed significantly increased affinity to nuclear transcription factors. SNP-71G allele frequency (32.2% vs. 22.3%) and SNP-71G allele presence (53.7% vs. 38.3%) were significantly increased in PCOS (p=0.01). SNP-71G homozygosity tended to contribute about 20% to the plasma testosterone level.
SNP-71G is a functional polymorphism that may contribute to testosterone excess in a subset of PCOS patients.
PMCID: PMC1522092  PMID: 16263811
17 beta-hydroxysteroid dehydrogenase (17β-HSD); Type 5 17β-HSD gene (HSD17B5); electrophoretic mobility shift assays (EMSA); polycystic ovary syndrome (PCOS); Sp1/Sp3; Single nucleotide polymorphism (SNP)

Results 1-12 (12)