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The Role of Insulin Resistance in PCOS

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ClinicalTrials.gov Identifier: NCT00173043
Recruitment Status : Unknown
Verified October 2004 by National Taiwan University Hospital.
Recruitment status was:  Recruiting
First Posted : September 15, 2005
Last Update Posted : November 24, 2005
Sponsor:
Information provided by:
National Taiwan University Hospital

Tracking Information
First Submitted Date September 12, 2005
First Posted Date September 15, 2005
Last Update Posted Date November 24, 2005
Study Start Date October 2004
Primary Completion Date Not Provided
Current Primary Outcome Measures Not Provided
Original Primary Outcome Measures Not Provided
Change History
Current Secondary Outcome Measures Not Provided
Original Secondary Outcome Measures Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title The Role of Insulin Resistance in PCOS
Official Title The Role of Insulin Resistance and Adiponectin in the Pathogenesis of Polycystic Ovary Syndrome
Brief Summary

Polycystic ovary syndrome (PCOS) phenotype can be structured into three components: anovulation, hyperandrogenism and the metabolic syndrome (of which hyperinsulinemia, secondary to insulin resistance, is the central abnormality)(1). It is the most common endocrinologic disease seen in Gynecologic clinic. The follicular excess in polycystic ovaries and the failure of selection of one dominant follicle contribute to the anovulation of PCOS. The infertile PCOS female usually suffered from difficult ovulation induction and high risk of ovarian hyperstimulation syndrome because of extensive stimulation.

PCOS is the main androgen disorder in women and has been suggested to be associated with a high risk of developing cardiovascular disease and type-2 diabetes. In many PCOS patients, overweight or central obesity is generally associated with increases in fasting insulin levels, insulin resistance, and glucose intolerance, and has been identified as a target for new therapeutic strategy, including early change in lifestyle.

Insulin resistance, defined as decreased insulin-mediated glucose utilization, is commonly (10-25%) found in the normal population. In women with PCOS, insulin resistance appears even more common (up to 50%), in both obese and non-obese women.Hyperinsulinemia appears to play a key pathogenic role in the ovarian androgen overproduction, because of the stimulatory effect of insulin on ovarian steroid production.

Detailed Description

Because of the menstrual irregularity and the hirsutism/acne caused by hyperandrogenism, the treatment of choice for PCOS in young teenagers is to given the oral contraceptive; however, such oral contraceptives fail to correct the endocrinometabolic anomalies and the excess of fat. Therefore, there are some alternative treatments as adding the novel progesterone, which is claimed to have antimineralocorticoid and antiandrogenic activities, or giving an insulin-sensitizing compound such as metformin. These treatments were reported to be effective in changing the endocrinometabolic state and the adiposity of PCOS. Besides, they were also reported to have efficacy in aiding ovulation induction.

PCOS is the main androgen disorder in women and has been suggested to be associated with a high risk of developing cardiovascular disease and type-2 diabetes. In many PCOS patients, overweight or central obesity is generally associated with increases in fasting insulin levels, insulin resistance, and glucose intolerance, and has been identified as a target for new therapeutic strategy, including early change in lifestyle.

The plasma concentrations of adiponectin were lower in men than in women but were not different between pre- and postmenopausal women. It suggests that androgen act to reduce plasma adiponectin concentration. In animal experiment, testosterone supplement reduced plasma adiponectin concentration in male mice. In cultured 3T3-L1 adipocytes, testosterone and 5α-DHT suppressed the secretion of adiponectin, suggesting that androgen decreased plasma adiponectin concentration through its effect on adipocytes.

Clinical and/or biochemical signs of hyperandrogenism are one of the three diagnostic criteria defining the PCOS. Hyperandrogenemia may cause hirsutism, alopecia, acne, and also strongly affect the ovulatory function. Some hormone therapy such as ethinylestradiol cyproterone and ethinlyestradiol drosipirenone were usually used to reduce the serum androgen level and correct the amenorrhea/oligomenorrhea, while its effect in improving the endocrine-metabolic state and the adiposity of PCOS was still undetermined. Obese women with PCOS are known to have high serum concentrations of C-reactive protein (CRP), a marker of inflammation and cardiovascular risk factor; metformin monotherapy reduces the CRP levels, whereas combined treatment with ethinylestradiol and cyproterone-acetate raises CRP further. Therefore, I am interesting about how do the metformin and ethinylestradiol/cyproterone acetate influence the serum adiponectin level.

Insulin resistance, defined as decreased insulin-mediated glucose utilization, is commonly (10-25%) found in the normal population. In women with PCOS, insulin resistance appears even more common (up to 50%), in both obese and non-obese women. Criteria developed for defining a metabolic syndrome in PCOS includes components associated with insulin resistance syndrome including centripetal obesity, hypertension, fasting hyperglycemia and dyslipidemia. Since serum adiponectin concentrations correlate inversely with the severity of insulin resistance was well established, however, the adiponectin levels in women with PCOS is still controversial and need further elucidation. Such as Orio et al. suggested that insulin sensitivity does not play any pivotal role in the control of adiponectin in PCOS women and Ducluzeau et al. mentioned that glucose-to-insulin level is better than adiponectin in predicting insulin resistance in PCOS. Besides, adiponectin level reduced in obese women with PCOS was reported. Currently only a clinical trial suggested that the oral contraceptives plus metformin may reduce the adipocytokine imbalance.

Hyperinsulinemia appears to play a key pathogenic role in the ovarian androgen overproduction, because of the stimulatory effect of insulin on ovarian steroid production. The mechanism that allows the ovary to remain sensitive to insulin when classical target organs for insulin action (liver, fat, and muscle) exhibit insulin resistance was supported by the presence of phosphatidyl inositol 3 (PI-3) kinase independent insulin signaling pathway in human ovarian cells (theca and granulosa cell). Insulin is proposed to directly stimulate activity of cytochrome P450c17α, an enzyme involved in ovarian androgen synthesis that is found in thecal cells.

Study Type Observational
Study Design Observational Model: Case-Control
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Not Provided
Sampling Method Not Provided
Study Population Not Provided
Condition
  • Polycystic Ovary Syndrome
  • Insulin Resistance
  • Obesity
Intervention Not Provided
Study Groups/Cohorts Not Provided
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Unknown status
Enrollment
 (submitted: September¬†12,¬†2005)
500
Original Enrollment Same as current
Study Completion Date August 2005
Primary Completion Date Not Provided
Eligibility Criteria

Inclusion Criteria:

  • Criteria for the definition of PCOS: (2 out of 3 in the following) Oligomenorrhea / chronic anovulation, defined as less than eight cycles of spontaneous menstrual period in one year.

Clinical and /or biochemical signs of hyperandrogenism Polycystic ovaries Exclusion of other aetiologies, such as congenital adrenal hyperplasia, androgen-secreting tumors, Cushing's syndrome

Exclusion Criteria:

  • ever received hormone therapy in the past 6 months, having pregnancy in the past 6 months, having acute illness found in the past 3 months, or having systemic diseases including autoimmune disease, malignancy, hepatic, renal or CVS disease, and ever received chemotherapy or immunosuppressive agents.
Sex/Gender
Sexes Eligible for Study: Female
Ages 12 Years to 50 Years   (Child, Adult)
Accepts Healthy Volunteers Yes
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries Taiwan
Removed Location Countries  
 
Administrative Information
NCT Number NCT00173043
Other Study ID Numbers 9361701208
NSC 94-2314-B-002-195-
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement Not Provided
Responsible Party Not Provided
Study Sponsor National Taiwan University Hospital
Collaborators Not Provided
Investigators
Principal Investigator: Yang Yu-Shih, M.D., PhD Department of Obstetrics and Gynecology, NTUH
PRS Account National Taiwan University Hospital
Verification Date October 2004