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Androgen Excess as a Mechanism for Adipogenic Dysfunction in PCOS Women


Phase 2
18 Years
35 Years
Open (Enrolling)
Female
Polycystic Ovary Syndrome (PCOS)

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Trial Information

Androgen Excess as a Mechanism for Adipogenic Dysfunction in PCOS Women


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 assessment of basal insulin sensitivity and beta-cell
function using fasting glucose and insulin levels. All subjects also will undergo a 75 gm
3-hr oral glucose tolerance test (oGTT) to exclude diabetes. After consuming a standard 75 g
glucose solution, 0.5 mL aliquots for plasma glucose and insulin levels will be obtained at
15 and 30 minutes prior to drinking the glucose and again at 30, 60, 90, 120, 150 and 180
minutes after drinking the glucose.

Adipocytes isolation and culture: Approximately 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:

1. . Ovarian morphology: Transvaginal ultrasound will be performed in the follicular phase
in controls and during amenorrhea in PCOS women. Ovarian volume will be calculated.
Antral follicle number, defined as the total follicle number (2-9 mm in diameter) of
both ovaries, will be determined by 1 investigator (D.A.D.). Polycystic ovaries will be
defined by 12 or more follicles in each ovary measuring 2-9 mm in diameter, and/or
increased ovarian volume (> 10 ml), with one such ovary sufficient to define PCO.

2. . Estradiol (E2) response to recombinant human (rh)FSH. Blood samples will be drawn
through an indwelling iv catheter at 0.5-h intervals for 2 h before and at 0.5, 1, 1.5,
2, 3, 4, 6, 8, 10, 12, 16, 20, and 24 h after 150 U rhFSH injection. The E2 response to
rhFSH will be assessed before and after adjusting for numbers of TVUS-detected ovarian
antral follicles.

Aim 2. Examine effect of flutamide in lean PCOS women on SC abdominal adipogenesis, visceral
adipose content and ovarian folliculogenesis.

Adipogenic studies: 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.


Inclusion Criteria:



- Non-Hispanic Caucasian women between the ages of 18 to 35 years.

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.

Exclusion Criteria:

- Exclusion criteria for study participation are: present or 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; recent (within 3 months)
use of androgens, anabolic steroids or hormonal agents (including birth control pills
or insulin sensitizers). These exclusion criteria are chosen to avoid effects from
medical conditions, environmental factors or exogenous agents. Women taking the drug
warfarin, CYP active medications, or herbs will be excluded.

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.

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Outcome Measure:

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.

Outcome Description:

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 oral glucose tolerance testing and reduce subcutaneous (SC) abdominal adipocyte size, as determined by SC abdominal fat biopsy.

Outcome Time Frame:

6 months

Safety Issue:

No

Authority:

United States: Institutional Review Board

Study ID:

UCLA IRB #12-001780

NCT ID:

NCT01889199

Start Date:

April 2013

Completion Date:

March 2018

Related Keywords:

  • Polycystic Ovary Syndrome (PCOS)
  • polycystic ovary syndrome
  • hirsutism
  • anovulation
  • oligomenorrhea
  • amenorrhea
  • hyperandrogenism
  • antiandrogen effect
  • Polycystic Ovary Syndrome

Name

Location

UCaliforniaLALos Angeles, California  90095-1740