Magda Lambaa Altinok

Association of polycystic ovary syndrome susceptibility single nucleotide polymorphism rs2479106 and PCOS in Caucasian patients with PCOS or hirsutism as referral diagnosis

CONTEXT Polycystic ovary syndrome (PCOS) is the most common endocrine disease among premenopausal women. A recent study found association between three single nucleotide polymorphisms (SNPs) and PCOS in a cohort of Han Chinese women. OBJECTIVE To investigate the association between rs13405728 (LHCGR gene), rs13429458 (THADA gene) and rs2479106 (DENND1A gene), PCOS, hirsutism and metabolic and hormonal parameters in a well characterized cohort of Caucasian patients of Danish descendant with PCOS or hirsutism. STUDY DESIGN Patients underwent clinical examination, hormone analyses, oral glucose tolerance test and transvaginal ultrasound. Genetic variation was tested using allelic discrimination by real-time PCR. PATIENTS 268 patients referred to The Department of Endocrinology, Odense University Hospital, Denmark with PCOS or hirsutism between 1997 and 2011. Two hundred and forty-eight healthy females were included as controls. RESULTS Genotype distributions and allele frequencies of rs13405728, rs13429458, and rs2479106 were comparable in patients and controls. The rs2479106 G allele was associated with a decreased PCOS susceptibility. None of the SNPs were associated with hirsutism or increased metabolic parameters. CONCLUSIONS The rs2479106 G allele was associated with decreased PCOS susceptibility, thus confirming previously reported findings of association between rs2479106 and PCOS. Metabolic and hormonal parameters were comparable between genotypes of rs13405728 and rs2479106.

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.

Prescription of antidepressants is increased in Danish patients with polycystic ovary syndrome and is associated with hyperandrogenism. A population-based cohort study

Quality of life is impaired in polycystic ovary syndrome (PCOS). In this study, we compared the time to first prescription of antidepressants (ADM) in PCOS vs two control groups.

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.

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, β-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 Madsens and Olga Madsens Foundation, Institute of Clinical Research, Odense University Hospital, Kolding Hospital, AP Møllers 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)).

Total testosterone levels are often more than three times elevated in patients with androgen-secreting tumours

Hirsutism is present in up to 25% reproductive aged women and is most often caused by polycystic ovary syndrome. Less than 5% of patients with hirsutism are diagnosed with rare endocrine diseases including ovarian or adrenal androgen-producing tumours, but these tumours may be malignant and need surgery. Terminal hair growth on lip and chin gradually increases after menopause, which complicates distinction from normal physiological variation. Precise testosterone assays have just recently become available in the daily clinic. We present three women diagnosed with testosterone-producing tumours. Gold standard techniques were used to measure testosterone levels. All tumours originated from the ovaries. Based on the present cases and the existing literature, we suggest that androgen-producing tumours should be suspected in patients with rapid progression of hyperandrogen symptoms, particularly when total testosterone levels are above three times the upper reference limit.

Effect of 12-month treatment with metformin and/or oral contraceptives on health-related quality of life in polycystic ovary syndrome

Abstract Health-related quality of life (HRQoL) is impaired in polycystic ovary syndrome (PCOS), but the effect of treatment with metformin (M) and/or oral contraceptives (OCP) is undetermined. To assess changes in HRQoL during 12-month randomized treatment with M, OCP or M + OCP in PCOS. Ninety women with PCOS were randomized to treatment with M, OCP or M + OCP. HRQoL was evaluated by a PCOS-specific visual analog scale (PCOS-VAS) regarding 1: Facial hair, 2: Body hair, 3: Acne, 4: Irregular menses, 5: Weight and 6: PCOS in general, and Short Form 36 (SF-36). PCOS-VAS1(facial hair) improved during treatment with OCP (n = 23) compared to M (n = 19), and during M + OCP (n = 23) compared to M treatment, whereas changes in PCOS-VAS2-6 and SF-36 scores were comparable between the three medical intervention groups. Pooled data (n = 65) showed improved PCOS-VAS scores during treatment (all p < .05), but changes in PCOS-VAS were unassociated with changes in BMI or FG-scores despite significant weight-loss during treatment with M (−3.0 kg (−10.3; 0.6)) and M + OCP (−1.9 kg (−4.9; 0.1)) and decreased FG-score during M + OCP treatment (median (quartiles)). PCOS-VAS scores improved significantly and to the same extent during treatment with M, OCP or M + OCP.