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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00930228
Recruitment Status : Active, not recruiting
First Posted : June 30, 2009
Last Update Posted : May 18, 2022
Information provided by (Responsible Party):
Chris McCartney, University of Virginia

Brief Summary:
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 or disease Intervention/treatment Phase
Polycystic Ovary Syndrome Drug: Flutamide Drug: Placebo Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Randomized, placebo-controlled, crossover study
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Other
Official Title: Influence of Hyperandrogenemia on the Sleep-associated Slowing of Follicular LH Frequency in Adult Polycystic Ovary Syndrome
Study Start Date : January 2009
Estimated Primary Completion Date : May 2023
Estimated Study Completion Date : August 2023

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Flutamide
Flutamide 250 mg taken by mouth twice a day for 4 weeks. Flutamide is an androgen-receptor blocker.
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

Placebo Comparator: Placebo
Placebo contains only inert ingredients and is not expected to exert any direct physiological effects.
Drug: Placebo
Placebo, for oral administration, twice a day for 4 weeks (or menstrual cycle length in normally-cycling controls)

Primary Outcome Measures :
  1. Luteinizing hormone pulse frequency [ Time Frame: One and two months ]

Secondary Outcome Measures :
  1. Luteinizing hormone pulse amplitude [ Time Frame: One and two months ]
  2. Mean luteinizing hormone level [ Time Frame: One and two months ]
  3. Mean follicle stimulating hormone level [ Time Frame: One and two months ]
  4. Sleep study parameters [ Time Frame: One and two months ]
    Sleep study parameters (sleep stage, overnight ventilatory variables) will be assessed when available

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 35 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00930228

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United States, Virginia
University of Virginia
Charlottesville, Virginia, United States, 22908
Sponsors and Collaborators
University of Virginia
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Principal Investigator: Christopher R McCartney, MD University of Virginia
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Responsible Party: Chris McCartney, Associate Professor of Medicine, University of Virginia Identifier: NCT00930228    
Other Study ID Numbers: 14067
First Posted: June 30, 2009    Key Record Dates
Last Update Posted: May 18, 2022
Last Verified: May 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: We do not have current plans to share IPD

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Chris McCartney, University of Virginia:
Luteinizing hormone
Additional relevant MeSH terms:
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Polycystic Ovary Syndrome
Pathologic Processes
Ovarian Cysts
Ovarian Diseases
Adnexal Diseases
Gonadal Disorders
Endocrine System Diseases
Androgen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents