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Effect of High Testosterone on Sleep-associated Slowing of Follicular Luteinizing Hormone (LH) Frequency in Polycystic Ovary Syndrome (CRM004)

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2013 by University of Virginia
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Chris McCartney, University of Virginia
ClinicalTrials.gov Identifier:
NCT00930228
First received: June 24, 2009
Last updated: January 14, 2013
Last verified: January 2013
  Purpose

The purpose of this study is to determine whether a testosterone receptor blocker (flutamide) will normalize sleep-wake luteinizing hormone pulse frequency relationships in women with polycystic ovary syndrome.


Condition Intervention
Polycystic Ovary Syndrome
Drug: Flutamide
Drug: Placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Official Title: Influence of Hyperandrogenemia on the Sleep-associated Slowing of Follicular LH Frequency in Adult Polycystic Ovary Syndrome

Resource links provided by NLM:


Further study details as provided by University of Virginia:

Primary Outcome Measures:
  • Luteinizing hormone pulse frequency [ Time Frame: One and two months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Progesterone concentration [ Time Frame: One and two months ] [ Designated as safety issue: No ]
  • Follicle stimulating hormone [ Time Frame: One and two months ] [ Designated as safety issue: No ]
  • Testosterone concentration [ Time Frame: One and two months ] [ Designated as safety issue: No ]
  • Estradiol concentration [ Time Frame: One and two months ] [ Designated as safety issue: No ]
  • Liver panel (transaminases, bilirubin, alkaline phosphatase) [ Time Frame: 1 day, 14 days, 28 days, 42 days, and 56 days ] [ Designated as safety issue: Yes ]
  • Pregnancy test [ Time Frame: 1 day, 14 days, 28 days, 42 days, and 56 days ] [ Designated as safety issue: Yes ]
  • Red blood cell counts [ Time Frame: 1 day, 28 days, and 56 days ] [ Designated as safety issue: Yes ]
  • Sleep study parameters (sleep stage, overnight ventilatory variables) [ Time Frame: One and two months ] [ Designated as safety issue: No ]

Estimated Enrollment: 72
Study Start Date: January 2009
Estimated Study Completion Date: January 2014
Estimated Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Flutamide/placebo
All study participants will receive both flutamide and placebo, given in randomized order (cross-over study)
Drug: Flutamide
Flutamide, 250 mg capsule for oral administration, twice a day for 4 weeks (or menstrual cycle length in normally-cycling controls)
Other Name: Eulexin
Drug: Placebo
Placebo, for oral administration, twice a day for 4 weeks (or menstrual cycle length in normally-cycling controls)

Detailed Description:

During the follicular phase of the normal menstrual cycle, luteinizing hormone (LH) pulse frequency decreases during sleep. These decreases may be important to support follicle stimulating hormone (FSH) synthesis and secretion. Polycystic ovary syndrome (PCOS) is associated with a persistently rapid gonadotropin hormone-releasing hormone (GnRH) pulse frequency, an abnormality that may account for many of the hormonal manifestations of PCOS. Although one prior study suggests that nocturnal LH frequency decreases slightly in PCOS, methodological issues limit interpretation. Our preliminary data suggest that nocturnal LH frequency does not decrease in untreated PCOS, but that nocturnal decreases of LH frequency are restored with androgen receptor blockade (flutamide) in women with PCOS. We have two hypotheses: (1) Prior to flutamide administration, sleep-associated slowing of LH pulse frequency is less pronounced in women with PCOS compared to that of normally-cycling women in the late follicular phase of the menstrual cycle; (2) After 4 weeks of flutamide administration, sleep-associated LH frequency reduction in women with PCOS is similar to that of normally-cycling women in the late follicular phase of the menstrual cycle. Women with PCOS and normally-cycling women will be studied. For each study participant, LH pulse frequency will be determined (from 1500 to 0700 h) after 4 weeks of flutamide and after 4 weeks of placebo. Flutamide and placebo will be given in random order (i.e., cross-over study). Sleep will be formally evaluated. Flutamide will then be given for 4 weeks prior to reassessment of LH pulse frequency. LH pulse frequency will be analyzed by way of hierarchical mixed effect models. We will use statistical analyses to determine: (a) whether the wake vs. sleep difference in LH frequency is the same for PCOS and normal controls prior to flutamide, and (b) whether the mean wake vs. sleep difference in LH frequency is the same for the two groups after flutamide.

  Eligibility

Ages Eligible for Study:   18 Years to 35 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

Inclusion criteria for all participants:

  • Subjects will be 18-35 years old; we use a cutoff age of 35 y because early menopause at this age is very rare.
  • No significant health problems (other than PCOS and obesity).
  • Subjects will be willing to strictly avoid pregnancy (using non-hormonal methods) during the time of study and must be willing and able to provide informed consent.

Inclusion criteria for normal controls:

  • Controls will be healthy women with regular menstrual cycles and no evidence of hyperandrogenism.

Inclusion criteria for PCOS:

  • PCOS will be defined according to NIH consensus criteria.

    • As such, subjects with PCOS will have hyperandrogenism, whether it is clinical (e.g., hirsutism) or biochemical (i.e., elevated plasma T).
    • Subjects with PCOS will also have oligo- or amenorrhea (i.e., < 7 periods per year) and no evidence for other endocrinopathies (e.g., hyperprolactinemia, Cushing's syndrome, etc.).

Exclusion Criteria:

  • Being a study of GnRH pulse regulation in women with and without PCOS, men are excluded.
  • Obesity associated with a diagnosed (genetic) syndrome, obesity related to medications (e.g., glucocorticoids), etc.
  • Pregnancy or lactation.
  • Virilization.
  • A total testosterone > 150 ng/dl in women with PCOS (which suggests the possibility of a virilizing neoplasm) (confirmed on repeat).
  • Elevated DHEAS (mild elevations may be seen in PCOS, and elevations < 1.5 times the upper limit of normal will be accepted in PCOS)(confirmed on repeat).
  • Follicular 17-hydroxyprogesterone > 300 ng/dl, which suggests the possibility of congenital adrenal hyperplasia (if elevated during the luteal phase and there is a concern about the possibility of congenital adrenal hyperplasia, the 17-hydroxyprogesterone may be collected during the follicular phase, or >60 if oligomenorrheic).

    *NOTE: If a 17-hydroxyprogesterone > 300 ng/dl is confirmed on such repeat testing, an ACTH stimulated 17-hydroxyprogesterone < 1000 ng/dl will be required for study participation.

  • A previous diagnosis of diabetes, a fasting glucose ≥ 126 mg/dl, or a hemoglobin A1c > 6.5%
  • Abnormal TSH (subjects with adequately treated hypothyroidism, reflected by normal TSH values, will not be excluded; or, for a new diagnosis of hypothyroidism, further study will at the least be delayed pending appropriate treatment) (confirmed on repeat).
  • Abnormal prolactin (mild elevations may be seen in PCOS, and elevations < 1.5 times the upper limit of normal will be accepted in this group) (confirmed on repeat).
  • Evidence of Cushing's syndrome by history or physical exam.
  • Hematocrit < 36% or hemoglobin < 12 g/dl (that is not reversed by iron treatment).
  • Significant history of cardiac or pulmonary dysfunction (e.g., known or suspected congestive heart failure; asthma requiring intermittent systemic corticosteroids; etc.)
  • Liver test abnormalities (confirmed on repeat), with the exception that mild bilirubin elevations will be accepted in the setting of known Gilbert's syndrome.
  • Abnormal sodium or potassium (confirmed on repeat); bicarbonate concentration <20 or >30 (confirmed on repeat); or elevated creatinine concentration (confirmed on repeat).
  • Due to the amount of blood being drawn in the study, subjects with body weight < 110 lbs will be excluded from the study.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00930228

Contacts
Contact: Anne Gabel 434-243-6911 am7bd@virginia.edu

Locations
United States, Virginia
University of Virginia Recruiting
Charlottesville, Virginia, United States, 22908
Contact: Anne Gabel    434-243-6911    am7bd@virginia.edu   
Principal Investigator: Christopher R McCartney, MD         
Sub-Investigator: Paul Suratt, MD         
Sponsors and Collaborators
University of Virginia
Investigators
Principal Investigator: Christopher R McCartney, MD University of Virginia
  More Information

No publications provided

Responsible Party: Chris McCartney, Associate Professor of Medicine, University of Virginia
ClinicalTrials.gov Identifier: NCT00930228     History of Changes
Other Study ID Numbers: 14067, R01HD058671
Study First Received: June 24, 2009
Last Updated: January 14, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Virginia:
Luteinizing hormone
Testosterone

Additional relevant MeSH terms:
Polycystic Ovary Syndrome
Syndrome
Adnexal Diseases
Cysts
Disease
Endocrine System Diseases
Genital Diseases, Female
Gonadal Disorders
Neoplasms
Ovarian Cysts
Ovarian Diseases
Pathologic Processes
Flutamide
Testosterone
Androgen Antagonists
Androgens
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Hormone Antagonists
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on November 23, 2014