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Open access

Sam68 mediates leptin signaling and action in human granulosa cells: possible role in leptin resistance in PCOS

Teresa Vilariño-García, Antonio Pérez-Pérez, Esther Santamaría-López, Nicolás Prados, Manuel Fernández-Sánchez, and Víctor Sánchez-Margalet

Introduction

Polycystic ovary syndrome (PCOS) is a complex metabolic disorder associated with ovulatory dysfunction, hyperandrogenism, obesity, and insulin resistance, that leads to subfertility. Sam68 is an RNA-binding protein with signaling functions that is ubiquitously expressed, including gonads. Sam68 is recruited to leptin signaling, mediating different leptin actions.

Objective

We aimed to investigate the role of Sam68 in leptin signaling, mediating the effect on aromatase expression in granulosa cells and the posible implication of Sam68 in the leptin resistance in PCOS.

Materials and methods

Granulosa cells were from healthy donors (n = 25) and women with PCOS (n = 25), within the age range of 20 to 40 years, from Valencian Infertility Institute (IVI), Seville, Spain. Sam68 expression was inhibited by siRNA method and overexpressed by expression vector. Expression level was analysed by qPCR and immunoblot. Statistical significance was assessed by ANOVA followed by different post-hoc tests. A P value of <0.05 was considered statistically significant.

Results

We have found that leptin stimulation increases phosphorylation and expression level of Sam68 and aromatase in granulosa cells from normal donors. Downregulation of Sam68 expression resulted in a lower activation of MAPK and PI3K pathways in response to leptin, whereas overexpression of Sam68 increased leptin stimulation of signaling, enhancing aromatase expression. Granulosa cells from women with PCOS presented lower expression of Sam68 and were resistant to the leptin effect on aromatase expression.

Conclusions

These results suggest the participation of Sam68 in leptin receptor signaling, mediating the leptin effect on aromatase expression in granulosa cells, and point to a new target in leptin resistance in PCOS.

DOI:
https://doi.org/10.1530/EC-20-0062
Volume 9: Issue 6,
Pages:
479–488 (10 total)
Open access

Questions concerning fertility preservation during transition in girls with Turner syndrome: review of the literature

Małgorzata Więcek, Jakub Gawlik, Zuzanna Nowak, and Aneta Gawlik

Loss of fertility is one of the most important concerns facing Turner syndrome (TS) patients as they transition into adult health care. Due to the limited and rapidly decreasing ovarian reserve, many TS patients require fertility preservation (FP) techniques to preserve their reproductive potential until they are ready to pursue procreation. One has to also remember about the additional risks connected with pregnancy in TS patients. In order to determine the optimal time for introducing FP techniques and decrease the chance of an unnecessary intervention, markers and procedures assessing ovarian reserve have been developed. The exposure to potential cardiovascular complications should be determined before FP to avoid unnecessary procedures in patients with potential contraindications to pregnancy. The aim of the present review is to answer the following three questions important for successful preservation of fertility and safe pregnancy in TS: which markers of ovarian reserve should be used as selection criteria for FP? Which methods of FP are the safest and most effective? Are there any cardiovascular contraindications to FP? For each of those questions, separate literature searches have been conducted. A total of 86 articles have been included in this review: 34 for the first question, 35 for the second, and 17 for the third. Ovarian reserve markers and cardiovascular contraindications to pregnancy should be established before FP; hoverer, there are no unambiguous indicators as to which patients should be disqualified from the FP and more evidence is needed in this subject.

DOI:
https://doi.org/10.1530/EC-22-0344
Volume 11: Issue 12
Open access

Structured education programme for women with polycystic ovary syndrome: a randomised controlled trial

Hamidreza Mani, Yogini Chudasama, Michelle Hadjiconstantinou, Danielle H Bodicoat, Charlotte Edwardson, Miles J Levy, Laura J Gray, Janette Barnett, Heather Daly, Trevor A Howlett, Kamlesh Khunti, and Melanie J Davies

Objective

To evaluate the effectiveness of a structured education programmes in women with polycystic ovary syndrome (PCOS).

Methods

Single-centre, randomised controlled trial, testing a single exposure to a group-based, face-to-face, structured education programme. Inclusion criteria were women with PCOS, aged 18–49 years inclusive and body mass index ≥23 kg/m2 for black and minority ethnicities or ≥25 kg/m2 for white Europeans. Primary outcome was step-count/day at 12 months. Secondary outcomes included indices of physical activity, cardiovascular risk factors, quality of life (QoL) and illness perception (IP).

Results

161 women were included (78 control, 83 intervention); 69% white; mean age 33.4 (s.d. 7.6) years, of whom 100 (48 intervention; 52 control) attended their 12-month visit (38% attrition). 77% of the intervention arm attended the education programme. No significant change in step-count was observed at 12 months (mean difference: +351 steps/day (95% confidence interval −481, +1183); P = 0.40). No differences were found in biochemical or anthropometric outcomes. The education programme improved participants’ IP in 2 dimensions: understanding their PCOS (P < 0.001) and sense of control (P < 0.01) and improved QoL in 3 dimensions: emotions (P < 0.05), fertility (P < 0.05), weight (P < 0.01) and general mental well-being (P < 0.01).

Discussion

A single exposure to structured education programme did not increase physical activity or improve biochemical markers in overweight and obese women with PCOS. However, providing a structured education in parallel to routine medical treatment can be beneficial for participants’ understanding of their condition, reducing their anxiety and improving their QoL.

DOI:
https://doi.org/10.1530/EC-17-0274
Volume 7: Issue 1,
Pages:
26–35 (10 total)
Open access

Long-term health of women with genetic POI due to FSH-resistant ovaries

Kaisu Luiro, Kristiina Aittomäki, Pekka Jousilahti, and Juha S Tapanainen

Objective

To study the use of hormone therapy (HT), morbidity and reproductive outcomes of women with primary ovarian insufficiency (POI) due to FSH-resistant ovaries (FSHRO).

Design

A prospective follow-up study in a university-based tertiary clinic setting.

Methods

Twenty-six women with an inactivating A189V FSH receptor mutation were investigated by means of a health questionnaire and clinical examination. Twenty-two returned the health questionnaire and 14 were clinically examined. Main outcome measures in the health questionnaire were reported as HT, morbidity, medication and infertility treatment outcomes. In the clinical study, risk factors for cardiovascular disease (CVD) and metabolic syndrome (MetS) were compared to age-matched controls from a national population survey (FINRISK). Average number of controls was 326 per FSHRO subject (range 178–430). Bone mineral density and whole-body composition were analyzed with DXA. Psychological and sexual well-being was assessed with Beck Depression Inventory (BDI21), Generalized Anxiety Disorder 7 (GAD-7) and Female Sexual Function Index (FSFI) questionnaires.

Results

HT was initiated late (median 18 years of age) compared with normal puberty and the median time of use was shorter (20–22 years) than the normal fertile period. Osteopenia was detected in 9/14 of the FSHRO women despite HT. No major risk factors for CVD or diabetes were found.

Conclusions

HT of 20 years seems to be associated with a similar cardiovascular and metabolic risk factor profile as in the population control group. However, optimal bone health may require an early-onset and longer period of HT, which would better correspond to the natural fertile period.

DOI:
https://doi.org/10.1530/EC-19-0244
Volume 8: Issue 10,
Pages:
1354–1362 (9 total)
Open access

Vitamin D, PCOS and androgens in men: a systematic review

Christian Trummer, Stefan Pilz, Verena Schwetz, Barbara Obermayer-Pietsch, and Elisabeth Lerchbaum

Background

Accumulating evidence from animal and human studies suggests that vitamin D is involved in many functions of the reproductive system in both genders.

Aim

The aim of this review was to provide an overview on the effects of vitamin D on polycystic ovary syndrome (PCOS) in women and androgen metabolism in men.

Methods

We performed a systematic literature search in PubMed for relevant English language publications published from January 2012 until September 2017.

Results and discussion

The vitamin D receptor and vitamin D-metabolizing enzymes are found in reproductive tissues of women and men. In women, vitamin D status has been associated with several features of PCOS. In detail, cross-sectional data suggest a regulatory role of vitamin D in PCOS-related aspects such as ovulatory dysfunction, insulin resistance as well as hyperandrogenism. Moreover, results from randomized controlled trials (RCTs) suggest that vitamin D supplementation may be beneficial for metabolic, endocrine and fertility aspects in PCOS. In men, vitamin D status has been associated with androgen levels and hypogonadism. Further, there is some evidence for a favorable effect of vitamin D supplementation on testosterone concentrations, although others failed to show a significant effect on testosterone levels.

Conclusion

In summary, vitamin D deficiency is associated with adverse fertility outcomes including PCOS and hypogonadism, but the evidence is insufficient to establish causality. High-quality RCTs are needed to further evaluate the effects of vitamin D supplementation in PCOS women as well as on androgen levels in men.

DOI:
https://doi.org/10.1530/EC-18-0009
Volume 7: Issue 3,
Pages:
R95–R113
Open access

Afamin predicts gestational diabetes in polycystic ovary syndrome patients preconceptionally

Angela Köninger, Antonella Iannaccone, Ensar Hajder, Mirjam Frank, Boerge Schmidt, Ekkehard Schleussner, Rainer Kimmig, Alexandra Gellhaus, and Hans Dieplinger

Background

Patients suffering from polycystic ovary syndrome (PCOS) are often insulin resistant and at elevated risk for developing gestational diabetes mellitus (GDM). The aim of this study was to explore afamin, which can be determined preconceptionally to indicate patients who will subsequently develop GDM. Serum concentrations of afamin are altered in conditions of oxidative stress like insulin resistance (IR) and correlate with the gold standard of IR determination, the HOMA index.

Methods

Afamin serum concentrations and the HOMA index were analyzed post hoc in 63 PCOS patients with live births. Patients were treated at Essen University Hospital, Germany, between 2009 and 2018. Mann–Whitney U test, T test, Spearman’s correlation, linear regression models and receiver-operating characteristic (ROC) analyses were performed for statistical analysis.

Results

Patients who developed GDM showed significantly higher HOMA and serum afamin values before their pregnancy (P < 0.001, respectively). ROCs for afamin concentrations showed an area under the curve of 0.78 (95% confidence interval (CI) 0.65–0.90) and of 0.77 (95% CI 0.64–0.89) for the HOMA index. An afamin threshold of 88.6 mg/L distinguished between women who will develop GDM and those who will not with a sensitivity of 79.3% and a specificity of 79.4%. A HOMA index of 2.5 showed a sensitivity of 65.5% and a specificity of 88.2%.

Conclusion

The HOMA index and its surrogate parameter afamin are able to identify pre-pregnant PCOS patients who are at risk to develop GDM. Serum afamin concentrations are independent of fasting status and therefore an easily determinable biomarker.

DOI:
https://doi.org/10.1530/EC-19-0064
Volume 8: Issue 5,
Pages:
616–624 (9 total)
Open access

Association between FGF19, FGF21 and lipocalin-2, and diabetes progression in PCOS

Feifei Cheng, Noel Yat Hey Ng, Claudia Ha Ting Tam, Yuying Zhang, Cadmon King Poo Lim, Guozhi Jiang, Alex Chi Wai Ng, Tiffany Tse Ling Yau, Lai Ping Cheung, Aimin Xu, Juliana C N Chan, and Ronald C W Ma

Women with polycystic ovary syndrome (PCOS) have an increased risk of developing type 2 diabetes. FGF19, FGF21 and lipocalin-2 have emerged as important markers of metabolic risk. This study aims to compare the levels of FGF19, FGF21 and lipocalin-2 between subjects with or without PCOS, and to investigate the relationship between proteins and diabetes progression. In this nested case–control cohort study, 128 Chinese PCOS women and 128 controls were recruited and followed-up. All subjects underwent the oral glucose tolerance test for the evaluation of glycaemic status. Baseline serum protein levels were measured using ELISA. Compared with controls, PCOS subjects had higher levels of FGF19 (P < 0.001) and FGF21 (P = 0.022), but had lower lipocalin-2 (P < 0.001). In total, 20.8% of PCOS and 9.2% of controls developed diabetes over a mean duration of 10.4 ± 1.2 and 11.3 ± 0.5 years, respectively. Logistic regression analyses suggested FGF19 was positively associated with diabetes progression in controls, after adjusting for age, follow-up duration, waist and fasting glucose (P = 0.026, odds ratio (OR) (95% CI): 7.4 (1.3–43.6)), and the positive relationship between FGF21 and diabetes progression in controls was attenuated by adjusting for age and follow-up duration (P = 0.183). Lipocalin-2 was positively correlated with diabetes progression in PCOS group (P = 0.026, OR (95% CI)): 2.5 (1.1–5.6)); however, this became attenuated after adjusting for waist and fasting glucose (P = 0.081). In conclusion, there is differential expression of FGF19, FGF21, and lipocalin-2 in PCOS. The serum level of FGF19, and FGF21 is associated with diabetes progression in women without PCOS, while lipocalin-2 was related to diabetes progression in PCOS women.

DOI:
https://doi.org/10.1530/EC-21-0082
Volume 10: Issue 10,
Pages:
1243–1252 (10 total)
Open access

Can dysglycemia in OGTT be predicted by baseline parameters in patients with PCOS?

Sarantis Livadas, Christina Bothou, Justyna Kuliczkowska-Płaksej, Ralitsa Robeva, Andromahi Vryonidou, Jelica Bjekic Macut, Ioannis Androulakis, Milica Opalic, Zadalla Mouslech, Andrej Milewicz, Alessandra Gambineri, Dimitrios Panidis, and Djuro Macut

Background

Polycystic ovary syndrome (PCOS) is considered a risk factor for the development of type 2 diabetes mellitus (T2DM). However, which is the most appropriate way to evaluate dysglycemia in women with PCOS and who are at increased risk are as yet unclear.

Aim of the study

To determine the prevalence of T2DM, impaired glucose tolerance (IGT), and impaired fasting glucose (IFG) in PCOS women and potential factors to identify those at risk.

Subjects and methods

The oral glucose tolerance test (OGTT), biochemical/hormonal profile, and ovarian ultrasound data from 1614 Caucasian women with PCOS and 362 controls were analyzed in this cross-sectional multicenter study. The data were categorized according to age and BMI.

Results

Dysglycemia (T2DM, IGT, and IFG according to World Health Organization criteria) was more frequent in the PCOS group compared to controls: 2.2% vs 0.8%, P = 0.04; 9.5% vs 7.4%, P = 0.038; 14.2% vs 9.1%, P = 0.002, respectively. OGTT was essential for T2DM diagnosis, since in 88% of them basal glucose values were inconclusive for diagnosis. The presence of either T2DM or IFG was irrespective of age (P = 0.54) and BMI (P = 0.32), although the latter was associated with IGT (P = 0.021). There was no impact of age and BMI status on the prevalence of T2DM or IFG. Regression analysis revealed a role for age, BMI, fat deposition, androgens, and insulin resistance for dysglycemia. However, none of the factors prevailed as a useful marker employed in clinical practice.

Conclusions

One-third of our cohort of PCOS women with either T2DM or IGT displayed normal fasting glucose values but without confirming any specific predictor for dysglycemic condition. Hence, the evaluation of glycemic status using OGTT in all women with PCOS is strongly supported.

DOI:
https://doi.org/10.1530/EC-21-0358
Volume 11: Issue 4
Open access

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

Dorte Glintborg, Hanne Mumm, Jens Juul Holst, and Marianne Andersen

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.

DOI:
https://doi.org/10.1530/EC-17-0034
Volume 6: Issue 4,
Pages:
267–277 (11 total)
Open access

Liraglutide in polycystic ovary syndrome: a randomized trial, investigating effects on thrombogenic potential

Malin Nylander, Signe Frøssing, Caroline Kistorp, Jens Faber, and Sven O Skouby

Polycystic ovary syndrome (PCOS) is associated with increased risk of venous thromboembolism (VTE) and cardiovascular disease (CVD) in later life. We aimed to study the effect of liraglutide intervention on markers of VTE and CVD risk, in PCOS. In a double-blind, placebo-controlled, randomized trial, 72 overweight and/or insulin-resistant women with PCOS were randomized, in a 2:1 ratio, to liraglutide or placebo 1.8 mg/day. Endpoints included between-group difference in change (baseline to follow-up) in plasminogen activator inhibitor-1 levels and in thrombin generation test parameters: endogenous thrombin potential, peak thrombin concentration, lag time and time to peak. Mean weight loss was 5.2 kg (95% CI 3.0–7.5 kg, P < 0.001) in the liraglutide group compared with placebo. We detected no effect on endogenous thrombin potential in either group. In the liraglutide group, peak thrombin concentration decreased by 16.71 nmol/L (95% CI 2.32–31.11, P < 0.05) and lag time and time to peak increased by 0.13 min (95% CI 0.01–0.25, P < 0.05) and 0.38 min (95% CI 0.09–0.68, P < 0.05), respectively, but there were no between-group differences. There was a trend toward 12% (95% CI 0–23, P = 0.05) decreased plasminogen activator inhibitor-1 in the liraglutide group, and there was a trend toward 16% (95% CI −4 to 32, P = 0.10) reduction, compared with placebo. In overweight women with PCOS, liraglutide intervention caused an approximate 5% weight loss. In addition, liraglutide affected thrombin generation, although not significantly differently from placebo. A concomitant trend toward improved fibrinolysis indicates a possible reduction of the baseline thrombogenic potential. The findings point toward beneficial effects of liraglutide on markers of VTE and CVD risk, which should be further pursued in larger studies.

DOI:
https://doi.org/10.1530/EC-16-0113
Volume 6: Issue 2,
Pages:
89–99 (11 total)