Acupuncture or Metformin for Insulin Resistance in Women With PCOS
Acupuncture or Metformin for Insulin Resistance in Women With PCOS
The hypothesis is that acupuncture is equally effective as metformin (both treatments
 combined with lifestyle management) in improving whole body glucose homeostasis in insulin
 resistant women with polycystic ovary syndrome (PCOS), and that both are superior to
 lifestyle management alone. The investigators hypothesize that acupuncture and metformin
 induce ovulation and improve hyperandrogenism, as well as health related quality of life
 (HRQoL) and symptoms of anxiety and depression. Although equally effective (acupuncture and
 metformin), the investigators hypothesize that acupuncture is associated with less negative
 side-effects. The investigators also hypothesize that these treatments have the potential to
 restore epigenetic and molecular alterations in target tissues (endometrial-, adipose-, and
 skeletal muscle tissue) and thus have the potential to prevent the development of type 2
 diabetes (T2D).
Specific Aims The purpose of the study is to perform a randomized controlled trial of women
 with PCOS, comparing the effectiveness of lifestyle management alone, and in combination with
 acupuncture or metformin treatment on whole body glucose homeostasis, with the ultimate goal
 to prevent the development of type 2 diabetes.

 Primary aim

 1. To determine the clinical effectiveness of 4 months of 1) electroacupuncture + lifestyle
 management and 2) metformin + lifestyle management, compared to 3) lifestyle management only,
 for improvement of insulin sensitivity as measured by HOMA-IR, by the insulin response to
 glucose assessed by calculating the area under the curve (AUCinsulin) during the oral glucose
 tolerance test (OGTT), and by glucose regulation (assessed by analyzing Hba1c levels).

 Secondary aims

 1. To evaluate changes in secondary metabolic measures, including fasting insulin,
 c-peptide, glucose, and adipokines, calculation of HOMA-B (i.e. the Islet β-cell
 function) and the c-peptide index, assessment of the adipokines and lipid profile, body
 size and proportions and body fat distribution.

 2. To determine changes in genome-wide gene expression and DNA methylation profiles related
 to insulin sensitivity in fat, muscle and endometrial tissue biopsies, and biomarkers in
 whole blood.

 3. To evaluate endocrine measures including menstrual pattern and ovulation frequency,
 circulating hormones (sex steroids, AMH, gonadotropins), and excretion of metabolites of
 sex steroids in urine.

 4. To determine changes in women's HRQoL, symptoms of anxiety and depression, dieting and
 eating patterns, and negative side-effects.

 5. To evaluate the cost-effectiveness of the different treatments.
Inclusion criteria - women with PCOS:

 1. Age 18 to 40 years

 2. Body mass index (BMI) ≥25 to ≤40 given that 95% of all women with PCOS with a BMI ≥25
 are insulin resistant (71,72).

 3. PCOS diagnosis according to Rotterdam criteria 2003 (73), with at least two of the
 following three symptoms: Clinical signs of hyperandrogenism (hirsutism or acne);
 oligo/amenorrhea; and/or polycystic ovaries (PCOS). Hirsutism is defined as a
 self-reported Ferriman-Gallwey (FG) score ≥8 (≥5 Asian) (74,75). Acne is defined by a
 positive response to the question Do you have acne? Oligomenorrhea is defined as an
 intermenstrual interval >35 days and <8 menstrual bleedings in the past year.
 Amenorrhea as <3 cycles per year. PCO is defined by transvaginal ultrasound with ≥12
 follicles 2-9 mm and/or ovarian volume ≥10 ml in one or both ovaries.

 4. Willing to sign the consent form.

 Inclusion criteria - controls:

 Controls should have BMI >25 to <40, regular cycles with 28 days ± 2 days, and no signs of
 hyperandrogenism. They are excluded if they have menstrual irregularities, signs of
 hyperandrogenism (FG >4), or evidence of PCO morphology on ultrasound.

 Exclusion criteria for all women

 1. Age >40

 2. Exclusion of other endocrine disorders such as non-classic congenital adrenal
 hyperplasia (17-hydroxyprogesterone < 3nmol/L), androgen secreting tumors or suspected
 Cushing's syndrome.

 3. Having known renal disease (creatinine clearance < 60 mL/min), hepatic insufficiency,
 autoimmune disorders or cancer.

 4. Any acute condition with potential to alter renal function or cause tissue hypoxia.

 5. Type I diabetes.

 6. Pharmacological treatment (cortizon, antidepressant, other antidiabetic treatment such
 as insulin and acarbose, hormonal contraceptives, hormonal ovulation induction or
 other drugs judged by discretion of investigator) within 12 weeks. Depo Provera or
 similar within 6 months.

 7. Hypersensitivity to metformin hydrochloride or to any of the excipients.

 8. Blood pressure >160 / 100 mmHg

 9. Pregnancy or breastfeeding the last 6 months

 10. Acupuncture the last 2 months

 11. Daily smoking and alcoholic intake

 12. Language barrier or disabled person with reduced ability to understand the information
 given.

 In total 50 controls will be matched at baseline (age, weight and BMI) to women with PCOS.
 Controls will undergo screening and baseline visit, but will not be randomized to any
 treatment.