Bone mass density in lean and overweight women with polycystic ovary syndrome.

INTRODUCTION: Polycystic ovary syndrome is a condition characterized by hormonal and metabolic disturbances that may affect bone health. The purpose of this study was to investigate the effect of polycystic ovary syndrome on bone mineral density and to examine which clinical characteristics of the syndrome could influence bone mineral density. MATERIALS AND METHODS: We examined 183 premenopausal women: 158 women with polycystic ovary syndrome and 25 healthy age- and body mass index matched controls. Bone mineral density and body composition were investigated by whole-body dual energy X-ray absorption. Total and free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, estradiol, fasting insulin and glucose, parathyroid hormone, calcium and 25-OH-cholecalciferol were measured. The effect of polycystic ovary syndrome on bone mineral density was analyzed by statistical two-way analysis of variance tests and multiple linear regressions for investigating the connection between bone mineral density and selected clinical parameters. RESULTS: Women with polycystic ovary syndrome had significantly lower bone density in the lumbar vertebrae L1-L4 compared to healthy controls, independently of body mass index. We found that total lean body mass was the most important associating factor for bone mineral density and these were strongly correlated throughout all regression analyzes. We found no connection between lumbar bone density and androgen status, hyperinsulinemia, estradiol or calcium homeostasis. CONCLUSIONS: Premenopausal women with polycystic ovary syndrome have lower bone mineral density in the lumbar vertebrae L1-L4 compared to healthy controls. Total lean body mass and polycystic ovary syndrome are significantly associated to this finding.

[Intrauterine insemination with or without ovarian stimulation is often a first-choice treatment for infertility].

In Denmark, intrauterine insemination (IUI) with or without ovarian stimulation is a common treatment for infertility. If strict cancellation criteria are met to reduce the risk of multiple pregnancies in ovarian stimulation cycles, IUI can be considered safe, less invasive and less costly compared to in vitro fertilisation. In 2019, a total of 9,322 homologous IUIs and 8,433 IUIs using donor sperm were performed in Denmark, and 2,000 children were expected to be born after the use of IUI. Thus, in this review we conclude that IUI is an effective treatment for infertility in selected patients.

RUBIC (ReproUnion Biobank and Infertility Cohort): A binational clinical foundation to study risk factors, life course, and treatment of infertility and infertility-related morbidity.

BACKGROUND: Infertility affects 15%-25% of all couples during their reproductive life span. It is a significant societal and public health problem with potential psychological, social, and economic consequences. Furthermore, infertility has been linked to adverse long-term health outcomes. Despite the advanced diagnostic and therapeutic techniques available, approximately 30% of infertile couples do not obtain a live birth after fertility treatment. For these couples, there are no further options to increase their chances of a successful pregnancy and live birth. OBJECTIVES: Three overall questions will be studied: (1) What are the risk factors and natural life courses of infertility, early embryonic loss, and adverse pregnancy outcomes? (2) Can we develop new diagnostic and prognostic biomarkers for fecundity and treatment success? And (3) what are the health characteristics of women and men in infertile couples at the time of fertility treatment and during long-term follow-up? MATERIAL AND METHODS: ReproUnion Biobank and Infertility Cohort (RUBIC) is established as an add-on to the routine fertility management at Copenhagen University Hospital Departments in the Capital Region of Denmark and Reproductive Medicine Centre at Skåne University Hospital in Sweden. The aim is to include a total of 5000 couples equally distributed between Denmark and Sweden. The first patients were enrolled in June 2020. All eligible infertile couples are prospectively asked to participate in the project. Participants complete an extensive questionnaire and undergo a physical examination and collection of biospecimens (blood, urine, hair, saliva, rectal swabs, feces, semen, endometrial biopsies, and vaginal swabs). After the cohort is established, the couples will be linked to the Danish and Swedish national registers to obtain information on parental, perinatal, childhood, and adult life histories, including disease and medication history. This will enable us to understand the causes of infertility and identify novel therapeutic options for this important societal problem.

[Diagnostic criteria for polycystic ovary syndrome].

Since 2004, the Rotterdam criteria have been used in the diagnosis of polycystic ovary syndrome (PCOS), requiring the presence of two of the following three criteria: oligo-/anovulation, hyperandrogenism or polycystic ovaries. Reports of high prevalences of polycystic ovaries in younger women have caused concerns about overdiagnosis. Recently, the international guideline for PCOS has recommended raising the follicle threshold for polycystic ovaries and avoiding ultrasound in adolescents. Anti-Müllerian hormone has been proposed as a substitute marker for polycystic ovaries but is not yet considered adequate for diagnosis.

Expression Patterns and Correlations with Metabolic Markers of Zinc Transporters ZIP14 and ZNT1 in Obesity and Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is associated with infertility, increased androgen levels, and insulin resistance. In adipose tissue, zinc facilitates insulin signaling. Circulating zinc levels are altered in obesity, diabetes, and PCOS; and zinc supplementation can ameliorate metabolic disturbances in PCOS. In adipose tissue, expression of zinc influx transporter ZIP14 varies with body mass index (BMI), clinical markers of metabolic syndrome, and peroxisome proliferator-activated receptor gamma (PPARG). In this study, we investigated expression levels of ZIP14 and PPARG in subcutaneous adipose tissue of 36 PCOS women (17 lean and 19 obese women) compared with 23 healthy controls (7 lean and 16 obese women). Further, expression levels of zinc transporter ZIP9, a recently identified androgen receptor, and zinc efflux transporter ZNT1 were investigated, alongside lipid profile and markers of glucose metabolism [insulin degrading enzyme, retinol-binding protein 4 (RBP4), and glucose transporter 4 (GLUT4)]. We find that ZIP14 expression is reduced in obesity and positively correlates with PPARG expression, which is downregulated with increasing BMI. ZNT1 is upregulated in obesity, and both ZIP14 and ZNT1 expression significantly correlates with clinical markers of altered glucose metabolism. In addition, RBP4 and GLUT4 associate with obesity, but an association with PCOS as such was present only for PPARG and RBP4. ZIP14 and ZNT1 does not relate to clinical androgen status and ZIP9 is unaffected by all parameters investigated. In conclusion, our findings support the existence of a zinc dyshomeostasis in adipose tissue in metabolic disturbances including PCOS-related obesity.

Adipose expression of adipocytokines in women with polycystic ovary syndrome.

OBJECTIVE: To investigate the role of adipocytokines in the pathophysiology of polycystic ovary syndrome (PCOS) by analyzing the messenger RNA (mRNA) expression and plasma levels of adipocytokines. DESIGN: Cross sectional study. SETTING: Hospital. PATIENT(S): Thirty-six women with PCOS, 17 lean (LP) and 19 obese (OP), and 24 age- and weight-matched controls, 8 lean (LC) and 16 obese (OC). INTERVENTION(S): Subcutaneous adipose tissue and fasting plasma samples collected from 60 women, and insulin sensitivity evaluated by euglycemic hyperinsulinemic clamp and homeostatic model assessment insulin resistance index (HOMA-IR). MAIN OUTCOME MEASURE(S): mRNA expression of adiponectin, leptin, and interleukin-6 (IL-6) in adipose tissue, and plasma levels of leptin, adiponectin, resistin, visfatin, and tumor necrosis factor α (TNF-α). RESULT(S): The baseline data on body mass index (BMI), age, androgen levels, and insulin sensitivity was published previously. We found no independent effect of PCOS on the adipose expression of leptin, adiponectin, or IL-6 or on the plasma levels of adiponectin, leptin, resistin, visfatin, and TNF-α. Obesity was associated with increased mRNA expression of leptin, lower expression of adiponectin, and increased plasma levels of leptin. CONCLUSION(S): Obesity is per se associated with increased adipose expression and plasma levels of leptin, lower expression of adiponectin, and marginally elevated expression of IL-6, but PCOS does not appear to have an independent effect on the adipose expression of leptin, adiponectin, and IL-6 or the circulating adipocytokines. CLINICAL TRIAL REGISTRATION NUMBER: NCT00975832.

The insulin-resistant phenotype of polycystic ovary syndrome.

OBJECTIVE: To investigate the individual parameters included in the diagnosis of polycystic ovary syndrome (PCOS), and their impact on insulin sensitivity. DESIGN: Cross-sectional study. SETTING: Department of Obstetrics and Gynaecology, Copenhagen University Hospital, Hvidovre, Denmark. PATIENT(S): Sixty-one women; 36 women with PCOS and 25 age- and weight-matched control women were investigated. INTERVENTION(S): Peripheral insulin sensitivity was evaluated by the hyperinsulinemic euglycemic clamp, glucose tolerance by an oral glucose tolerance test (OGTT), and ovarian morphology by transvaginal ultrasonography (TVS). MAIN OUTCOME MEASURE(S): The Rotterdam criteria were used for diagnosing PCOS, and hirsutism was evaluated by the Ferriman Gallwey score. Insulin sensitivity was calculated as the insulin sensitivity index, and whole body insulin sensitivity was assessed by the homeostatic model assessment insulin resistance (IR) index. RESULT(S): Multiple regression analysis showed that body mass index (BMI) and hirsutism were independent predictors of IR evaluated by insulin sensitivity index, whereas BMI, total T, and hirsutism were independent predictors of IR evaluated by the homeostatic model assessment IR index. We found no significant association between ovarian morphology and insulin sensitivity or between menstrual frequency and insulin sensitivity. CONCLUSION(S): The PCOS is associated with IR. Body mass index, hyperandrogenemia, and hyperandrogenism are independent predictors of low insulin sensitivity.

Incretin hormone secretion in women with polycystic ovary syndrome: roles of obesity, insulin sensitivity, and treatment with metformin.

In normal subjects, the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are responsible for 70% of the insulin response during a meal; but in diabetic subjects and other insulin-resistant conditions, the incretin effect is impaired. Polycystic ovary syndrome (PCOS) is associated with insulin resistance, and the pathophysiologic mechanisms behind PCOS resemble those of type 2 diabetes mellitus; therefore, women with PCOS may have alterations in the incretin hormone response. Metformin is widely used in the treatment of both type 2 diabetes mellitus and PCOS. Metformin may exert some of its effect on glucose metabolism by increasing GLP-1 biosynthesis and secretion and thereby increasing the incretin effect. The objective of the study was to measure incretin hormone secretion in women with PCOS and to evaluate the effect of metformin treatment. Cross-sectional comparison of 40 women with PCOS (19 lean and 21 obese) and 26 healthy control women (9 lean and 17 obese) and longitudinal evaluation of the effects of 8 months of metformin 1000 mg twice daily in women with PCOS were performed. Plasma concentrations of GIP and GLP-1 were determined frequently during a 75-g glucose tolerance test, and insulin sensitivity was evaluated by the euglycemic hyperinsulinemic clamp. The incretin hormone response did not differ between subjects with and without PCOS. Subgroup analysis showed lower GIP (area under the curve [AUC]) levels in obese women with PCOS compared with obese control women (P < .05) and compared with lean women with PCOS (P < .05). Metformin increased GIP (AUC) and GLP-1 (AUC) in lean women with PCOS (P < .05), and a similar trend was seen in the obese women (P = .07). The GIP secretion is attenuated in obese women with PCOS, whereas treatment with metformin increases the levels of both GIP and GLP-1 in women with PCOS.

Obesity, body composition and metabolic disturbances in polycystic ovary syndrome.

BACKGROUND: We determined the impact of polycystic ovary syndrome (PCOS) and obesity on glucose and lipid metabolism and beta-cell function in women with PCOS. METHODS: In 35 women with PCOS (17 lean, lean PCOS and 18 obese, obese PCOS) and 25 control women (9 lean, lean controls and 16 obese, obese controls), beta-cell function was evaluated by the first-phase insulin response after intravenous glucose, acute insulin response to glucose (AIRg); insulin sensitivity, determined as insulin sensitivity index (ISI), was evaluated by the euglycemic hyperinsulinemic clamp. Indirect calorimetry was used for the assessment of glucose and lipid oxidation. Body composition was estimated by dual X-ray absorptiometry scan. RESULTS: When adjusted for obesity, PCOS was associated with higher 2-h glucose levels (P < 0.05), higher trunk/periphery fat ratio (P < 0.001), lower ISI (P < 0.001), lower insulin-stimulated glucose oxidation (GOX 2) (P < 0.05) and lower non-oxidative glucose metabolism (P < 0.05), but a normal AIRg compared with control women. Lean women with PCOS had lower ISI (P < 0.001), GOX-2 (P < 0.05) and higher trunk/periphery fat ratio (P < 0.05) than lean control women. In obese women with PCOS, ISI was reduced with 25% compared with obese control women, whereas trunk/peripheral fat ratio did not differ. AIRg was increased in obese groups compared with lean groups (P < 0.05), but was, in all groups, appropriate for the ambient action of insulin. CONCLUSIONS: PCOS is associated with a low ISI, which in lean women with PCOS may partly be explained by higher trunk/peripheral fat ratio. AIRg was amplified by obesity, but was, in all groups, appropriate for prevailing insulin sensitivity, suggesting a normal beta-cell adaptation.

[Polycystic ovary syndrome. New pathophysiological discoveries--therapeutic consequences]. / Polycystisk ovariesyndrom. Nyere patofysiologiske iagttagelser--behandlingsmaessige konsekvenser.

Polycystic ovary syndrome (PCOS) is characterised by anovulation, infertility and hyperandrogenism. The condition affects about 5-10% of women in the reproductive age group. Insulin resistance has proven to be a key factor in the pathogenesis of PCOS. There are several similarities between PCOS and the metabolic syndrome, and PCOS may be a risk factor for development of type 2 diabetes and cardiovascular disease. The treatment of PCOS has, so far, been focussed on treatment of the clinical signs and symptoms. Oral contraceptives have been the standard treatment. There is now a greater focus on the management of the metabolic consequences of PCOS, primarily through lifestyle intervention to achieve weight loss and increase physical activity. Metformin has proven to be effective in the management of the metabolic disturbances, anovulation and hirsutism and is now a widely accepted therapy. The thiazolidinediones (pio- and rosiglitazone), a novel class of insulin-sensitising agents, also seem to ameliorate the metabolic disturbances and clinical symptoms characterizing PCOS, but more randomised, controlled trials are needed before clinical guidelines can be determined.

Comparison of gemeprost and vaginal misoprostol in first trimester mifepristone-induced abortion.

BACKGROUND: The aim of this study was to compare efficacy and side effects of gemeprost and vaginal misoprostol in mifepristone-induced abortions in women up to 63 days of gestation. METHODS: A retrospective study of 833 consecutive patients admitted for medical termination of first trimester pregnancy was conducted. Four-hundred ten patients received mifepristone 600 mg, followed 48 h later by gemeprost 1 mg (regimen I), and 423 patients received mifepristone 200 mg followed by vaginal misoprostol 800 microg (regimen II). Success rates were evaluated after 2 weeks and after 3 months. The severity of bleeding and side effects (pain, nausea, vomiting and diarrhea) was scored by the patients, and requests for supplementary analgesic treatment were recorded by the attending nurse. RESULTS: Success rates were 99% in both groups after 2 weeks of follow-up. At 3 months of follow-up, success rates had declined to 94% for regimen I and 96% for regimen II. The frequency of severe pain was higher in regimen I compared to regimen II (72% vs. 60%, p < .001), but the severity of bleeding and gastrointestinal side effects was similar in the two regimens. CONCLUSION: When combined with mifepristone, gemeprost and vaginal misoprostol are equally effective for termination of first trimester abortion, but may be associated with varying intensity of side effects.