Prevalence and possible mechanisms of reactive hypoglycemia in polycystic ovary syndrome.

STUDY QUESTION: What is the prevalence of reactive hypoglycemia (RH) in polycystic ovary syndrome (PCOS) versus age- and body mass index (BMI)-matched healthy controls. SUMMARY ANSWER: The prevalence of RH was increased in PCOS versus controls. WHAT IS KNOWN ALREADY: Previous studies suggested an increased prevalence of RH in PCOS. STUDY DESIGN, SIZE, DURATION: Cross-sectional study of 88 women with PCOS and 34 healthy age- and BMI-matched controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: Eighty-eight women with PCOS and 34 age- and BMI-matched controls were included. The study was conducted at Odense University Hospital, Denmark. Participants underwent 5 h oral glucose tolerance test (5 h OGTT). Indices of insulin resistance, ß-cell function, and area under the curve (AUC) for glucose, insulin and C-peptide were calculated. Insulin clearance was estimated as 5 h AUC C-peptide/insulin. RH was defined as blood glucose ≤3.3 mmol/l during 5 h OGTT. MAIN RESULTS AND THE ROLE OF CHANCE: RH occurred in 15/88 (17%) women with PCOS versus 0/34 controls ( ITALIC! P = 0.01). Nine out of 15 women with RH were obese and 6 were lean ( ITALIC! P = 0.42). Obese patients with RH had significantly higher 5 h AUCs insulin and C-peptide compared with lean patients with RH ( ITALIC! P = 0.02 and 0.04, respectively). Obese patients with RH had significantly lower 5 h AUC C-peptide/insulin versus obese patients without RH ( ITALIC! P = 0.02). In lean patients with RH, 5 h AUCs insulin and C-peptide were similar to lean controls. LIMITATIONS, REASONS FOR CAUTION: The 5 h OGTT was used to diagnose RH and may be a limitation of the study. Although the 5 h OGTT is the most widely accepted method, no gold standard exists in terms of diagnosing RH. The 5 h OGTT was suggested to over-estimate the incidence of RH compared with meal test. WIDER IMPLICATIONS OF THE FINDINGS: The study supports previous suggestions of increased prevalence of RH in women with PCOS compared with controls. STUDY FUNDING/COMPETING INTERESTS: This study was funded by Jacob Madsen's and Olga Madsen's Foundation, Institute of Clinical Research, Odense University Hospital, Kolding Hospital, AP Møller's Foundation, Bernhard and Marie Kleins Foundation, The Novo Nordisk Foundation, and The Danish Medical Association. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: The trial was registered at www.clinicaltrials.gov (registration numbers NCT00451568 (patients) and NCT01995773 (controls)).

Hyperandrogenism and phenotypes of polycystic ovary syndrome are not associated with differences in obstetric outcomes.

OBJECTIVES: To investigate obstetric outcomes in Danish women with different phenotypes of polycystic ovary syndrome (PCOS) and isolated hyperandrogenism (HA) and describe the risk of adverse obstetric outcomes in women with PCOS and HA compared to controls. DESIGN: Cohort study. SETTING: Odense University Hospital, Denmark. POPULATION: Women with PCOS were identified prospectively starting in 1997. Singleton pregnancies in women with PCOS and HA during 2003-2011 were included (n = 199). A control group was matched to the patient cohort according to date of childbirth (n = 995). METHODS: Data on clinical characteristics and obstetric outcomes were collected in patients with PCOS and HA and controls. In PCOS and HA, total and free testosterone, sex hormone binding globulin, and hemoglobin A1c were measured outside pregnancy. During pregnancy, oral glucose tolerance tests were performed in 39 patients and 123 controls according to Danish national guidelines. PCOS phenotypes were based on the Rotterdam criteria. MAIN OUTCOME MEASURES: Gestational diabetes mellitus, pregnancy-induced hypertension, preeclampsia, delivery by emergency cesarean section, preterm delivery and anthropometric measures in the newborn. RESULTS: The incidence of adverse obstetric outcomes and anthropometric measures among the newborns were comparable between different phenotypes of PCOS and patients with HA. In the oral glucose tolerance test, patients had a higher risk of gestational diabetes mellitus compared with controls; the odds ratio (95% confidence interval) was 3.3 (1.5-6.9) after adjustment for age, parity, and body mass index (p = 0.002). The incidence of other adverse obstetric outcomes was similar in patients and controls. CONCLUSIONS: Obstetric outcomes were comparable in women with different PCOS phenotypes.

Prolactin is associated with metabolic risk and cortisol in 1007 women with polycystic ovary syndrome.

STUDY QUESTION: Is there an association between prolactin and markers of metabolic risk in polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Low serum prolactin was a metabolic risk marker in PCOS. WHAT IS KNOWN ALREADY: Prolactin is routinely measured to exclude endocrine diseases in PCOS. Recent studies have suggested that prolactin can be used as a marker for metabolic and cardiovascular risk. STUDY DESIGN, SIZE, DURATION: Retrospective cross-sectional study in an academic tertiary-care medical center. Data were collected during 1997-2012. Premenopausal women (n = 1007) with hirsutism and/or PCOS and 116 healthy, age-matched controls were included. Prolactin levels were measured in blood samples taken in the morning after a minimum of 2 h awakening time. Macroprolactinemia was excluded by the precipitation of serum with polyethylene glycol in patients with increased prolactin levels. PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum prolactin levels were measured along with a clinical evaluation (Ferriman-Gallwey score, BMI, waist circumference, blood pressure) plus hormone analyses (sex hormones, fasting lipids, insulin, glucose), transvaginal ultrasound, and oral glucose tolerance (n = 234) and adrenocorticotrophic hormone tests (n = 201). All patients had prolactin levels below the upper reference limit (23 µg/l). MAIN RESULTS AND THE ROLE OF CHANCE: Prolactin levels were significantly lower in patients versus controls; median (quartiles) prolactin levels 7 (5-10) versus 9 (7-13) µg/l (P < 0.001). In the patient population prolactin levels were inversely associated with age, smoking status, waist circumference, total cholesterol, triglyceride and low-density lipoprotein (LDL) and positively associated with high-density lipoprotein, estradiol, total testosterone, dehydroepiandrosterone sulfate, 17-hydroxyprogesterone and cortisol levels. In multiple regression analyses, prolactin was inversely associated with LDL and positively associated with estradiol, 17-hydroxyprogesterone and cortisol after correcting for age, BMI and smoking status in patients with PCOS. LIMITATIONS, REASONS FOR CAUTION: The study design was cross-sectional and prospective studies are needed to further determine the impact of prolactin levels on cardiovascular outcomes. Patients included in the study were relatively lean and only 20 had diabetes, which could have affected our findings. In addition, the collection of blood samples when estrogen levels were low (follicular phase) could be related to the lower levels of prolactin. Furthermore, as prolactin is secreted in a pulsatile manner, several measures of prolactin may be needed to further investigate associations between prolactin and metabolic risk. WIDER IMPLICATIONS OF THE FINDINGS: Our findings of inverse associations between prolactin levels and metabolic risk markers are supported by studies in populations of women without PCOS. The association between prolactin and adrenal activity should be evaluated in future studies. STUDY FUNDING/COMPETING INTERESTS: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector. There are no conflicts of interest to declare.

Adiponectin, interleukin-6, monocyte chemoattractant protein-1, and regional fat mass during 12-month randomized treatment with metformin and/or oral contraceptives in polycystic ovary syndrome.

CONTEXT: Central obesity in polycystic ovary syndrome (PCOS) is associated with increased inflammatory markers and increased risk for type 2 diabetes. OBJECTIVE: To evaluate if improved body composition during treatment with metformin (M) vs. oral contraceptive pills (OCP) was associated with changes in circulating adiponectin, interleukin (IL)-6, and monocyte chemoattractant protein (MCP)-1. PATIENTS AND INTERVENTIONS: Ninety patients with PCOS were randomized to 12-month treatment with M (2 g/day), M + OCP (150 mg desogestrel + 30 microgram ethinylestradiol) or OCP. Adiponectin, IL-6, MCP-1, whole body DXA scans, and clinical evaluations were performed before and after the intervention period in the 65 study completers. MAIN OUTCOME MEASURES: Changes in inflammatory markers and changes in total and regional fat mass estimates. RESULTS: Adiponectin, IL-6, and MCP-1 levels were unchanged during the three types of medical intervention. Treatment with M and M + OCP was superior to OCP regarding decreased regional fat mass. Baseline adiponectin and IL-6 were associated with BMI, waist, and trunk fat mass. Changes in trunk fat were significantly associated with changes in IL-6 and MCP-1 during M + OCP. CONCLUSIONS: Long-term treatment with M alone or in combination with OCP was associated with improved body composition compared to OCP, whereas inflammatory markers were unchanged. OCP was not associated with increased inflammatory markers despite a small but significant weight gain.

Maternal cortisol levels in third trimester and early language development: A study of 1093 mother-child pairs from the Odense Child Cohort.

Language development during early childhood is considered an important marker of fetal neurodevelopment. Prenatal cortisol exposure plays a critical role in maturation of the fetal brain; however, the effect on offspring language development needs further investigation. In this prospective observational study we aimed to evaluate the association between maternal third trimester cortisol and early longitudinal offspring language development in the Odense Child Cohort (OCC) and to test whether there were sex differences in the association. The study cohort included 1093 mother-child dyads (570 boys and 523 girls). Fasting morning serum (s-) cortisol was collected from third trimester (gestational week 26-28) pregnant women and measured by liquid chromatography-tandem mass spectrometry. Offspring receptive and productive vocabulary assessments by MacArthur-Bates Communicative Development Inventories parent reports were completed every third month from children age 12-37 months. Levels of cortisol were higher in women carrying a girl (858 ± 214 nmol/L) than in women carrying a boy (820 ± 222 nmol/L). Higher third trimester maternal cortisol levels showed a positive association with development of productive vocabulary in boys at age 12-21 months (OR = 1.23, SE = 0.07, p = .005) and age 22-37 months (OR = 1.09, SE = 0.06, p = .967). Higher maternal cortisol levels in the third trimester were positively associated with receptive vocabulary in girls at 12-21 months of age (OR = 1.16, SE = 0.05, p = .002). Maternal third trimester s-cortisol levels were positively associated with early language development in children at age 12-37 months.

Smoking is associated with increased adrenal responsiveness, decreased prolactin levels and a more adverse lipid profile in 650 white patients with polycystic ovary syndrome.

We investigated the associations between smoking status and metabolic risk factors and sex hormones in polycystic ovary syndrome (PCOS). The study was designed as a retrospective trans-sectional study including 650 white premenopausal women with the diagnoses hirsutism or PCOS divided according to smoking status: non-smokers (NS-PCOS = 390) and smokers (S-PCOS = 260). One hundred and nineteen healthy women were studied as controls (NS-Control = 105, S-Control = 14). Patients and controls underwent clinical evaluation, hormone analyses, transvaginal ultrasound, oral glucose tolerance tests (OGTT) and adrenocorticotropic hormone (ACTH) tests. S-PCOS has significantly higher fasting lipid profile and 17-hydroxyprogesterone levels (basal and ACTH-stimulated) than NS-PCOS patients, whereas prolactin levels were decreased. No significant differences were found in body composition and measures of insulin resistance between NS-PCOS and S-PCOS. PCO was more prevalent in NS-PCOS patients. During multiple regression analyses, smoking was positively associated with 17-hydroxyprogesterone (17OHP) and cholesterol, triglycerides and low-density lipoprotein and inversely associated with prolactin and high-density lipoprotein. We concluded that smoking was associated with increased adrenal responsiveness, decreased prolactin levels and a more adverse lipid profile in PCOS patients, whereas smoking was unassociated with body composition and insulin resistance. Smoking may be associated with the prevalence of individual Rotterdam criteria.

Ethnic differences in Rotterdam criteria and metabolic risk factors in a multiethnic group of women with PCOS studied in Denmark.

OBJECTIVE: Clinical manifestations and metabolic risk factors may differ in ethnic subgroups of patients with polycystic ovary syndrome (PCOS). DESIGN: Retrospective trans-sectional study. PATIENTS: One thousand and two premenopausal women with the diagnoses hirsutism or PCOS were divided according to ethnicity: Caucasian (CA, n = 784), Middle East (ME, n = 190), Asian (n = 14) and others (n = 14). MEASUREMENTS: Clinical evaluation (hirsutism, BMI, waist, blood pressure), hormone analyses (testosterone, sex hormone-binding globulin, prolactin, lipids, insulin, glucose) and transvaginal ultrasound were performed. Oral glucose tolerance tests (OGTT) (n = 499) and ACTH tests (n = 434) were performed in a subgroup of patients. RESULTS: (CA vs ME women) CA women were older [32(25-37) vs 25(18-32) years, median (quartiles)] and had increased BMI compared to ME women. After correcting for age and BMI, CA women were less hirsute, but had increased testosterone levels compared to ME women. The Rotterdam criteria were fulfilled in 56% of both populations, but PCO was diagnosed in 47% CA vs 29% ME women, P < 0·01. CA women had increased blood pressure and smoked at a higher frequency (40 vs 23%), whereas area under the curve for insulin during OGTT was decreased, all P < 0·001. Prolactin levels were significantly lower in CA women compared to ME women [7(5-10) vs 9(6-12) µg/l] and were inversely associated with smoking status. CONCLUSION: CA women had a more adverse cardiovascular profile than ME women, whereas insulin sensitivity was higher. The prevalence of the individual Rotterdam criteria differed significantly in the two study populations.

Effect of oral contraceptives and/or metformin on GLP-1 secretion and reactive hypoglycaemia in polycystic ovary syndrome.

CONTEXT: Insulin resistance in polycystic ovary syndrome (PCOS) may increase the risk of reactive hypoglycaemia (RH) and decrease glucagon-like peptide-1 (GLP-1) secretion. The possible effects of treatment with oral contraceptives (OCP) and/or metformin on GLP-1 secretion and risk of RH in PCOS is undetermined. SETTING: Outpatient clinic. PATIENTS AND INTERVENTIONS: Randomized, controlled clinical trial. Ninety women with PCOS were randomized to 12-month treatment with OCP (150 mg desogestrel + 30 mg ethinylestradiol), metformin (2 g/day) or metformin + OCP. Five-hour oral glucose tolerance tests (5-h OGTT) measuring fasting and area under the curve (AUC) for GLP-1, glucose, insulin and C-peptide were performed before and after the intervention period. Sixty-five women completed the study and 34 weight-matched healthy women were included as controls. MAIN OUTCOME MEASURES: Changes in GLP-1, glucose, insulin and C-peptide during 5-h OGTT. RESULTS: Fasting GLP-1 levels increased during metformin + OCP vs OCP treatment, whereas AUC GLP-1 levels were unchanged during medical treatment. The prevalence of reactive hypoglycemia increased from 9/65 to 14/65 after intervention (P < 0.01) and was more common after treatment with metformin + OCP (increase from 3/23 to 6/23, P = 0.01). Reactive hypoglycaemia was associated with higher insulin and C-peptide levels during 5-h OGTT, but was unassociated with BMI and AUC GLP-1. GLP-1 levels were comparable in PCOS vs controls. AUC GLP-1 levels were significantly lower in obese vs lean patients and were inversely associated with BMI. CONCLUSIONS: AUC GLP-1 levels were unchanged during treatment. Increased risk of hypoglycemia during metformin + OCP could be associated with increased insulin secretion.

Increased thrombin generation in women with polycystic ovary syndrome: A pilot study on the effect of metformin and oral contraceptives.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is associated with risk factors for cardiovascular disease (CVD) which may be modified by the use of metformin and oral contraceptives (OC). Thrombin generation (TG) measures are risk markers of CVD and address the composite of multiple factors that influence blood coagulation. This prospective, randomized, intervention study evaluated the potential influence of PCOS on TG measures and the effect of OC and/or metformin on TG measures in women with PCOS. MATERIAL AND METHODS: Ninety patients with PCOS and 35 controls were included. Patients were randomized to 12 months of treatment with metformin, metformin+OC or OC alone. C-reactive protein (CRP), fibrinogen, total cholesterol, trunk fat mass, body mass index, estradiol, testosterone, sex hormone binding globulin (SHBG) as well as TG measures, i.e. the lag time for formation of thrombin, the endogenous thrombin potential (ETP), peak thrombin concentration (peak) and time to peak were determined at baseline and after 12 months of treatment. RESULTS: CRP and total testosterone were significantly higher and SHBG significantly lower in PCOS women than in controls (P=0.012, P<0.001 and P=0.008, respectively). The TG measures ETP, peak and lag time were increased in women with PCOS compared to controls (P<0.01). Significant correlations were observed between TG measures and fibrinogen, CRP, SHBG and fat trunk mass (P>0.01). ETP (P=0.006), peak (P=0.003) and lag time (P=0.023) remained increased after adjustment for these potential confounders. Treatment with OC and metformin+OC further increased ETP (P<0.001) and peak (P<0.005) and reduced time to peak (P<0.04). The increase in ETP was significantly lower in the metformin+OC group than in the OC group (P<0.05). Metformin alone did not affect TG significantly. CONCLUSIONS: PCOS is associated with increase in TG measures independent of other risk factors of CVD. OC increase TG measures further and may thus add to the increased risk of CVD already present in women with PCOS.

Body composition is improved during 12 months' treatment with metformin alone or combined with oral contraceptives compared with treatment with oral contraceptives in polycystic ovary syndrome.

CONTEXT: Central obesity in polycystic ovary syndrome (PCOS) is associated with increased inflammatory markers and increased risk for type 2 diabetes. OBJECTIVE: The objective of the study was to evaluate whether treatment with metformin (M) or M combined with oral contraceptive pills (OCPs) resulted in a more advantageous body composition than treatment with OCP alone. SETTING: The study was conducted at an outpatient clinic. PATIENTS AND INTERVENTIONS: This was a randomized, controlled clinical trial. Ninety patients with PCOS were randomized to 12 months' treatment with M (2 g/d), M + OCP (150 mg desogestrel+30 µg ethinylestradiol), or OCP. Whole-body dual-energy x-ray absorptiometry scans and clinical and hormonal evaluations were performed before and after the intervention period. A total of 65 of 90 patients completed the study. MAIN OUTCOME MEASURES: Changes in weight at 6 and 12 months and changes in regional fat mass estimates at 12 months were measured. RESULTS: Dropout rates between intervention groups were not significantly different. Treatment with M and M+OCP were superior to OCP regarding weight and regional fat mass. The median (quartiles) weight changes during 12 months of M, M+OCP, and OCP treatment were -3.0 (-10.3; 0.6), -1.9 (-4.9; 0.1), and 1.2 (-0.8; 3.0) kg, respectively, P < .05. Upper to lower fat mass ratio was unchanged. Changes in body composition were predicted by the type of medical intervention (M, M+OCP, or OCP) and not by body mass index at study inclusion. OCP and M+OCP were superior to M regarding reduction in free T levels. CONCLUSIONS: M treatment alone or in combination with OCP was associated with weight loss and improved body composition compared with OCP, whereas free T levels decreased during M+OCP or OCP. Combined treatment with M+OCP should be considered as an alternative to treatment with OCP alone to avoid weight gain in PCOS.

Birth weight and polycystic ovary syndrome in adult life: a register-based study on 523,757 Danish women born 1973-1991.

OBJECTIVE: To study the association between birth weight and polycystic ovary syndrome (PCOS) in adult life in Danish women born 1973-1991. DESIGN: Register study. SETTING: Data were extracted from the Danish Medical Birth Register and the Danish National Patient Register (NPR). PATIENT(S): All female children born of Danish mothers in Denmark between 1973 and 1991 were included (n = 523,757) and followed for a total of 4,739,547 person-years at risk. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Information on birth weight was extracted from the Danish Medical Birth Register. The cohort was followed up in the NPR for PCOS diagnoses from age 15 years until the end of 2006. Furthermore, information on maternal diabetes diagnoses was extracted from the NPR. RESULT(S): The risk of PCOS was significantly increased in women with birth weight ≥4,500 g (incidence rate ratio, 1.57; 95% confidence interval 1.21-2.03) compared to women with birth weight 3,000-3,499 g. All women with birth weight ≥4,500 g were born large for gestational age and a birth weight of 4,500 g represented the 98.5th percentile of the birth weights. Women born of mothers diagnosed with diabetes were at increased risk of PCOS. In these women the risk of PCOS increased with decreasing birth weight. CONCLUSION(S): The risk of PCOS was increased in women born with birth weight ≥4,500 g. In women of diabetic mothers we found an increased risk of PCOS, which was inversely related to birth weight.

Hemoglobin A1c as a tool for the diagnosis of type 2 diabetes in 208 premenopausal women with polycystic ovary syndrome.

OBJECTIVE: To study hemoglobin A1c (HbA1c) as a tool for diagnosing diabetes and to study HbA1c as a cardiovascular risk marker in patients with polycystic ovary syndrome (PCOS). DESIGN: Retrospective observational study. SETTING: Academic tertiary-care medical center. PATIENT(S): Two hundred eight premenopausal women with PCOS. INTERVENTION(S): Patients underwent clinical evaluation (Ferriman-Gallwey score, body mass index, waist, blood pressure), hormone analyses (T, sex hormone-binding globulin, fasting lipids, insulin, glucose, HbA1c), transvaginal ultrasound, and 2-hour oral glucose tolerance tests (OGTT) measuring capillary blood glucose (BG) at 0 (BG 0) and 120 (BG 120) minutes, insulin, and C-peptide. MAIN OUTCOME MEASURE(S): Results of OGTT, HbA1c values. RESULT(S): Twenty patients were diagnosed with type 2 diabetes during OGTT. The sensitivity and specificity of HbA1c ≥6.5% for the diagnosis of diabetes were 35% and 99%, respectively, compared with the diagnosis established by OGTT. Hemoglobin A1c showed closer correlation with waist, body mass index, and lipid profile than BG 120, suggesting that HbA1c could be a cardiovascular risk marker. CONCLUSION(S): The clinical utility of HbA1c for diagnosing impaired glucose tolerance and type 2 diabetes in PCOS in daily practice is low. Long-term prospective studies are needed to determine whether HbA1c is superior to glucose levels as a cardiovascular risk marker in patients with PCOS.