Effect of Hyperinsulinaemia and Insulin Resistance on Endocrine, Metabolic and Fertility Outcomes in Women With Polycystic Ovary Syndrome Undergoing Ovulation Induction

Duojia Zhang; Xinming Yang; Jian Li; Jiarui Yu; Xiaoke Wu

Disclosures

Clin Endocrinol. 2019;91(3):440-448. 

In This Article

Abstract and Introduction

Abstract

Objective: The aim of this study was to evaluate the effects of hyperinsulinaemia and insulin resistance (IR) on reproductive and metabolic disorders and fertility in women with polycystic ovary syndrome (PCOS).

Design, Setting, Participants and Measurements: This was a multicenter, randomized controlled trial involving a total of 1000 women diagnosed with PCOS according to the modified Rotterdam criteria at 21 sites (27 hospitals). We evaluated the effects of serum insulin levels and HOMA-IR on parameters and outcomes. The main outcome measures were anthropometric, biometric and ultrasound parameters at baseline and the clinical outcomes of ovulation, conception, pregnancy, live birth and pregnancy loss.

Results: The relevant analysis between hyperinsulinaemia and IR and clinical characteristics showed that weight, waist and hip circumference, BMI, waist-to-hip ratio, acanthosis nigricans score and menstrual period were significantly correlated with fasting insulin (FIN) and HOMA-IR. There was no significant correlation between the hirsutism score or acne score with FIN or HOMA-IR. The relevant analysis between hyperinsulinaemia and IR and circulating sex steroids and gonadotrophins showed that FAI was significantly correlated with FIN and HOMA-IR (r = 0.240, P < 0.001 and r = 0.191, P < 0.001, respectively). Free testosterone was significantly correlated with FIN after adjusting for the influence of age. LH and LH/FSH were not related to FIN or HOMA-IR after statistical correction for differences in BMI. The relevant analysis between hyperinsulinaemia and IR and metabolic profile showed that FIN and HOMA-IR were positively associated with fasting glucose, cholesterol, triglycerides, low-density lipoprotein, Apo B, and the incidence of metabolic syndrome and were negatively associated with high-density lipoprotein. The predictive analysis between hyperinsulinaemia and IR with fertility showed that the levels of FIN and HOMA-IR were related to the fertility outcome (ovulation, pregnancy, conception or live birth) in patients with PCOS. After adjustments for age, total testosterone and free testosterone, increasing serum insulin levels and HOMA-IR were significantly associated with decreased cycle ovulation, conception, pregnancy and live birth rates.

Conclusions: Hyperinsulinaemia and IR are associated with reproductive and metabolic disorders and can predict the fertility outcomes in PCOS patients.

Introduction

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women, and it affects 5%-10% of women of reproductive age and is characterized by the three main phenotypes of ovulatory dysfunction, hyperandrogenism and polycystic ovaries on ultrasonography. PCOS is frequently associated with insulin resistance (IR) and obesity, and approximately 50%-70% of all cases demonstrate IR and hyperinsulinaemia. Both lean and obese women with PCOS have evidence of decreased insulin sensitivity,[1] although obesity is an important stimulative factor for IR. There is still much controversy about the origin and mechanism of IR. However, it is generally believed that the mechanism of IR in PCOS involves many factors such as polygenic inheritance and endocrine, metabolic and immune factors that interact with environmental factors.

Most scholars believe that IR and hyperinsulinaemia play important roles in the pathogenesis of PCOS,[2] and the hypersensitivity of the androgen synthesis pathway in the ovary to insulin stimulation is responsible for the development of PCOS in some polycystic ovarian women. This defect is inherent in PCOS and does not result from chronic luteinizing hormone (LH) stimulation.[3] The ovaries of many women with PCOS and without systemic IR or hyperinsulinaemia are also more sensitive to insulin stimulation.[4] In this case, any improvement in IR in PCOS patients can reduce testosterone levels and recover ovulation, and the amplification of the steroid hormone response to LH can also be abated.[5] Research shows that decreasing serum insulin concentrations with metformin reduces ovarian cytochrome P450c17 alpha activity and ameliorates hyperandrogenism.[6]

In the long run, PCOS patients have a significantly increased risk of type 2 diabetes mellitus, hypertension and coronary heart disease due to the persistent effect of IR on metabolism.[7] Studies have found the incidence of dyslipidaemia in PCOS patients with IR to be significantly higher than in women with PCOS and normal insulin sensitivity.[8]

Based on the process of insulin-regulating glucose metabolism, IR is divided into prereceptor IR, receptor IR and postreceptor IR. Receptor and prereceptor IR are often caused by mutations in genes that cause structural abnormalities[9] and insulin-secretion abnormalities. Postreceptor IR includes a series of metabolic abnormalities caused by abnormal signal transduction or abnormal function of signalling molecules involved in signal transduction after binding to insulin receptor.[9]

The understanding of the pathogenic characteristics of IR in women with PCOS is important for revealing the specificity of the PCOS phenotype and for finding more effective treatments. The purpose of this study was to investigate the relationship between hyperinsulinaemia and IR with reproductive hormones, metabolic indices, clinical phenotypes and fertility outcomes in order to determine the effect of IR on the reproductive and metabolic dysfunction of PCOS.

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