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

Materials and Methods

Participants

The data in the study were from a large randomized controlled trial (Polycystic Ovary Syndrome Acupuncture and Clomiphene Trial, PCOSAct) conducted at 21 sites (27 hospitals) from 2012 to 2015. PCOSAct[10] was registered with Clinical Trials.gov (NCT01573858) and chictr.org.cn (ChiCTR-TRC-12002081). The protocol was approved by the local ethics committees at all sites, and all women signed a consent form before being enrolled in the trial. The study design, methods, and inclusion and exclusion criteria have been described in detail else where,[11] and the main results were published in details in JAMA.[10]

A total of 1000 women with PCOS ranging in age from 20 to 40 years fulfilled the diagnostic criteria according to the modified Rotterdam criteria,[12,13] including oligomenorrhoea or amenorrhoea together with clinical or biochemical hyperandrogenism and/or polycystic ovaries. Oligomenorrhoea is defined as an intermenstrual interval >35 days or <8 menstrual bleedings in the past year. Amenorrhoea is defined as an intermenstrual interval >90 days. Clinical hyperandrogenism in China is defined as a Ferriman-Gallwey (FG) score ≥5.[14] Polycystic ovaries are present when there are ≥12 antral follicles (2-9 mm) or ovarian volume >10 mL on transvaginal scanning.[15] Exclusion criteria included other endocrine disorders, use of hormones or other medication (including Chinese herbal prescriptions) in the past 2 months, miscarriage, having given birth within the past 6 weeks and breastfeeding within the past 6 months. For the present study, husbands with poor sperm quality (sperm concentrations <15 × 106/mL, total motility <40%, semen volume ≤1.5 mL and total motile sperm count ≤9 million) were excluded. A total of 957 patients had baseline measurements of fasting insulin (FIN), 926 PCOS patients completed the trial.

Anthropometric Measurements and Phenotypes

Anthropometric parameters included height, weight, waist circumference, hip circumference, blood pressure, pulse, acne, hirsutism and acanthosis nigricans. Hirsutism was graded according to the modified FG method.[14] Acne lesions were assessed by trained study personnel by evaluating the patient's face.[16] Oligomenorrhoea was defined as an intermenstrual interval >35 days and <8 menstrual bleedings in a year. All subjects underwent transvaginal scanning of the pelvis at the baseline visit. Polycystic ovaries were diagnosed by transvaginal ultrasound when at least one ovary had a volume of >10 mL or there were 12 or more follicles measuring 2-9 mm in diameter.

Biochemical Assessment

Biochemical assays of reproduction and metabolism were tested at baseline. Fasting blood was drawn at day 3 of menstruation, and all blood samples were transported on dry ice and batched and analysed in the core laboratory, which is accredited by ISO 15189. Sex steroids and gonadotrophins included follicle-stimulating hormone (FSH), LH, progesterone (P), oestradiol (E2), total testosterone (TT), free testosterone (FT) and sex hormone–binding globulin (SHBG). The free androgen index (FAI) was calculated from measurable values of TT and SHBG using the following equation: (FAI = TT [nmol/L]/SHBG [nmol/L] × 100). Metabolism measurements included FIN, fasting glucose, cholesterol, triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), lipoprotein A, apoprotein A1 (Apo A1) and apoprotein B (Apo B). The homeostasis model assessment-insulin resistance (HOMA-IR) was obtained from the following calculation: (HOMA-IR = fasting plasma insulin [mIU/L] × fasting plasma glucose [mmol/L]/22.5). All sex hormones were analysed by electrochemiluminescence immunoassays using a Roche Cobas 6000-E601, except for FT, which was measured by radioimmunoassay. Glucose and lipid profiles were assayed by enzymatic methods using a Hitachi Biochemical Analyzer (LABOSPE CT008). Metabolic syndrome was diagnosed using waist circumference, TG, HDL, blood pressure, and fasting glucose and was defined by meeting any three of the following five criteria: waist circumference >88 cm, triglycerides ≥150 mg/dL, HDL <50 mg/dL, blood pressure ≥135/85 mm Hg and fasting glucose ≥110 mg/D.

Interventions

The PCOS patients were randomized into four groups—clomiphene plus active acupuncture, placebo plus active acupuncture, clomiphene plus control acupuncture, or placebo and control acupuncture—for four menstrual cycles. Pregnancy outcomes were assessed after each cycle. Once conception was achieved, the intervention was stopped and the pregnancy was followed up until miscarriage or delivery. For the fertility outcomes, ovulation was defined as a serum progesterone level above 5 ng/mL during a cycle. Ovulation rates were calculated from patients who achieved one or more ovulations in four cycles. Conception was defined as any positive serum hCG test, that is biochemical pregnancy. Clinical pregnancy was defined as an intrauterine pregnancy with foetal heart pulsation as detected by transvaginal ultrasound. Pregnancy losses included miscarriage or foetal death or still births before or after 20 weeks. Live birth was defined as delivery at 20 weeks' or later gestation during the study period.

Statistical Analysis

The chi-square test was used for the comparison of categorical variables, and the Kruskal-Wallis omnibus test was used for the comparison of continuous variables among groups as appropriate. In the latter case, variations in statistical significance were further subjected to post hoc pairwise analysis by applying the Mann-Whitney U test and Bonferroni correction. For correlation analysis, partial correlation was used with the correlation coefficient by adjusting for age and body mass index (BMI). A P-value <0.05 was considered statistically significant. The STATA 13.0 software (StataCorp) was used for all calculations.

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