Androgen Excess as a Mechanism for Adipogenic Dysfunction in PCOS Women
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|ClinicalTrials.gov Identifier: NCT01889199|
Recruitment Status : Recruiting
First Posted : June 28, 2013
Last Update Posted : April 26, 2018
|First Submitted Date ICMJE||June 20, 2013|
|First Posted Date ICMJE||June 28, 2013|
|Last Update Posted Date||April 26, 2018|
|Study Start Date ICMJE||April 2013|
|Estimated Primary Completion Date||March 2019 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Six-month flutamide (antiandrogen) administration to lean women with polycystic ovary syndrome (PCOS) will improve impaired glucose tolerance by glucose tolerance testing and normalize the size of enlarged subcutaneous (SC) fat cells by fat biopsy. [ Time Frame: 6 months ]
Women with PCOS exhibit impaired glucose tolerance that correlates with enlarged subcutaneous (SC) abdominal adipocytes. Since a common denominator to these abnormalities is hyperandrogenism, we hypothesize that 6-month flutamide (antiandrogen) administration to lean PCOS women will improve glucose tolerance by glucose tolerance testing and reduce subcutaneous (SC) abdominal adipocyte size, as determined by SC abdominal fat biopsy.
|Original Primary Outcome Measures ICMJE
|Change History||Complete list of historical versions of study NCT01889199 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||Quality of Life Questionnaires [ Time Frame: 6 months ]|
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Outcome Measures ICMJE
||Liver transaminases (serum glutamic oxaloacetic transaminase [SGOT]; serum glutamic-pyruvic transaminase [SGPT]) [ Time Frame: 6 months ]
This study carefully considers the safety of low-dose flutamide in examining how hyperandrogenism in PCOS affects ovarian function, subcutaneous fat storage and glucose metabolism. The 125 mg oral dose of flutamide has been specifically chosen because it has not been associated with liver enzyme abnormalities (0%, 62.5-125 mg/day), while being as effective as high dose flutamide in improving androgenic symptoms. Furthermore, in the rare event mild elevation of hepatic enzymes occurs with low-dose flutamide despite its dose-dependency, it is easily detected and reversible.
|Original Other Outcome Measures ICMJE||Same as current|
|Brief Title ICMJE||Androgen Excess as a Mechanism for Adipogenic Dysfunction in PCOS Women|
|Official Title ICMJE||Androgen Excess as a Mechanism for Adipogenic Dysfunction in PCOS Women|
The purpose of this research study is to collect specimen samples and study medical information from women with Polycystic Ovary Syndrome (PCOS) and women without PCOS. The goal is to learn more about the changes that take place in the body that result in PCOS.
We anticipate that 59 women will take part in this study (15 without PCOS and 44 with PCOS). All patients will undergo a physical exam, blood tests, and ultrasound of their ovaries. If they meet the criteria for this study, they will then undergo additional blood tests, removal of a small amount of subcutaneous abdominal fat, measurement of regional body fat (i.e., MRI, DXA scan), a modified frequently-sampled intravenous glucose tolerance test (FSIGTT), and determination of ovarian function (via a follicle stimulating hormone [FSH] test). The women without PCOS will be complete the study at this point.
The women with PCOS will be randomized to receive the drug flutamide 125 mg/day or placebo. They will take the drug every day for six 28-day cycles. They will be asked to collect and store a urine sample once a week. They will also be asked to complete a pill diary and menstrual diary. Once a month while they are taking the flutamide/placebo, they will return to the clinic and bring their frozen urine samples. At that time they will undergo a physical exam, toxicity assessment, and blood draw.
Quality of Life assessments will be done at the beginning of the study for all participants. Women with PCOS who are taking the flutamide or placebo will be asked to repeat the Quality of Life assessments during the study and at the end of the study.
Six months following the completion of protocol procedures, participants who received flutamide/placebo will be contacted by phone to check on the status of their health. They will be asked if they have experienced any health problems or have become pregnant since they completed the study procedures.
After the six 28-day cycles are completed they will then undergo additional blood tests, removal of a small amount of subcutaneous abdominal fat, measurement of regional body fat (i.e., MRI, DXA scan), a modified frequently-sampled intravenous glucose tolerance test (FSIGTT), and determination of ovarian function (via a FSH test).
Aim 1. Compare differences in SC abdominal adipogenesis of lean PCOS women vs. age- and BMI-matched controls Subjects and clinical assessment: We will recruit 36 lean (18.5-25 kg/M2) PCOS subjects and 12 age- and BMI-matched controls. Subjects will complete a standardized questionnaire emphasizing menstrual dating, abnormal hair growth and acne. The questionnaire also will annotate age, smoking status, medications, surgical history and family histories of excess hair growth in female relatives and of diabetes in parents or siblings for exclusion criteria and for inclusion of some basic traits as covariates. Subjects also will undergo a physical examination; hirsutism will be scored by the modified Ferriman-Gallwey (mFG) method. Transvaginal sonography (TVUS) will be performed to determine the presence or absence of polycystic ovaries. A screening blood sample will be obtained for determinations of steroid hormones, SHBG, TSH, and prolactin.
Non-Hispanic Caucasian women between the ages of 18 and 35 years will be recruited to avoid confounding differences as a function of race. PCOS patients will be diagnosed by 1990 NIH criteria. Controls will have regular menstrual cycles at 21 to 35 day intervals, a luteal phase progesterone (P4) level > 3 ng/mL, and no evidence of hirsutism, acne, alopecia, polycystic ovaries or endocrine dysfunction. Exclusion criteria are: present/past history (<5 years) of smoking, cancer, alcohol abuse, drug addiction, severe depression, or post traumatic stress; diabetes; uncontrolled hypertension (≥ 165/100); clinically significant hepatic or renal disease, or other major medical illness; signs or symptoms of infection; recent (within 30 days) use of an experimental device; recent (within 6 months) use of androgens, anabolic steroids or non-steroidal anti-inflammatory drugs; recent (within 3 months) use of hormonal agents (including birth control pills or insulin sensitizers); use of the drug warfarin.
Studies will be conducted in the follicular phase in controls and during amenorrhea in PCOS women. All subjects will undergo a modified frequently-sampled intravenous glucose tolerance test (FSIGTT). Glucose in the form of a 50% solution (0.3 g/kg) and regular human insulin (0.03 units/kg) will be injected through an intravenous line at 0 and 20 min, respectively. Blood will be collected at -20, -15, −5, 0, 2, 4, 8, 19, 22, 30, 40, 50, 70, 90, and 180 min for glucose and insulin determinations. Mathematical modeling of serial glucose and insulin determinations will calculate: insulin sensitivity index (SI, i.e. the action of insulin to accelerate glucose uptake and suppress glucose production), glucose effectiveness index (SG, i.e. the combined effect of glucose to enhance glucose uptake and suppress endogenous glucose production at basal insulin levels) and the acute response to glucose (AIRG).
Adipocytes isolation and culture: Approximately 1-3 gm of fat will be obtained from the lower SC abdomen using standard procedures under local anesthesia. Adipocytes (fat cells) and surrounding fat tissue will be isolated to measure adipocyte cell number and diameter, lipid accumulation and function, adiponectin, and stem cell development.
Procedures: All procedures will be performed in normal and PCOS women at the start of study.
i). Venipuncture: Fasting blood will be collected for blood count, chemistry panel, LH, FSH, total/free T, DHT, A4, DHEAS, E1, E2, anti-mullerian hormone (AMH), SHBG, adiponectin, IL-6, lipid profile and free fatty acids (FFAs).
ii ). Body composition: Body composition will be assessed by BMI, waist-to-hip circumference and DEXA scanning. Girths will be measured at the waist (narrowest section of the torso between ribs and umbilicus) and hips (largest protrusion of the hip region, above the gluteal fold). For total body fat and regional fat distribution, whole body scans will be performed, utilizing DEXA imaging.
iii). Body fat distribution: Total body DEXA will measure abdominal fat (i.e., the area between the dome of the diaphragm and the top of the hip. Total body DEXA images also will determine % body fat; fat-free body mass; total body, abdominal, and leg fat; and abdomen/leg fat mass ratio. The leg region is that area below the top of the hip bone (greater trochanter).
Multiple axial abdominal MRI slices from the diaphragm to the pelvis will assess cross-sectional areas of SC abdominal and visceral fat.
iv). Ovarian testing:
Aim 2. Examine effect of flutamide in lean PCOS women on SC abdominal adipogenesis, visceral adipose content and ovarian folliculogenesis.
Modified FSIGTT and Adipogenic studies: The modified FSIGTT and all adipogenic studies performed at study initiation will be repeated at the end of the 6-month flutamide vs. placebo intervention in PCOS women.
Procedures: All procedures performed at study initiation also will be repeated at the end of the six 28-day cycles of flutamide vs. placebo intervention in PCOS women. In addition, monthly liver function studies will be performed to detect possible elevations of serum transaminase levels above the normal range during flutamide vs. placebo therapy.
Menstrual records and urinary pregnanediol glucuronide (UPDG): Ovulatory frequency will be determined by having subjects keep a daily menstrual record and collect weekly first morning urine samples for UPDG and creatinine assay. Urine samples will be frozen for later analysis to determine evidence of ovulation.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 2|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Condition ICMJE||Polycystic Ovary Syndrome (PCOS)|
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE
|Original Estimated Enrollment ICMJE||Same as current|
|Estimated Study Completion Date||March 2019|
|Estimated Primary Completion Date||March 2019 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
Groups will be: 12 lean controls (Aim 1); 36 age- and BMI-matched PCOS women randomized to flutamide vs. placebo for 6 months (Aims 1 and 2).
i) Lean patients with PCOS: 36 subjects with PCOS (defined by 1990 NIH criteria [all Aims]), BMI 18.5-25 kg/m2. This BMI range is defined as normal and has been chosen to examine underlying mechanisms of PCOS-related androgen excess in the genesis of adipogenic and ovarian dysfunction, independent of obesity.
ii) Lean control women: 12 healthy subjects, BMI 18.5-25 kg/m2. Controls will have regular menstrual cycles, and no evidence of hirsutism, acne, alopecia, polycystic ovaries, and/or endocrine dysfunction. This BMI range has been chosen to match that of the PCOS group.
Up to 44 lean PCOS patients and 15 lean controls will be recruited, for a total of 59 study participants over a 5-year interval, accounting for a 20% rate of patient drop-out or insufficient adipose procurement.
Since this study involves MRI testing, women with pacemakers, metal implants, or claustrophobia will be excluded.
The screener will assess the participants response to establish if depression or drug use exclude participation in this study.
Women taking beta blockers will be excluded.
Women who have taken birth control pills or had a Mirena IUD or used Plan B contraception during the previous 3 months will be excluded.
|Ages||18 Years to 35 Years (Adult)|
|Accepts Healthy Volunteers||Yes|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT01889199|
|Other Study ID Numbers ICMJE||UCLA IRB #12-001780|
|Has Data Monitoring Committee||No|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||Not Provided|
|Responsible Party||Daniel A. Dumesic, MD, University of California, Los Angeles|
|Study Sponsor ICMJE||University of California, Los Angeles|
|PRS Account||University of California, Los Angeles|
|Verification Date||February 2018|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP