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Effects of Androgen Blockade on Sensitivity of the GnRH Pulse Generator to Suppression by Estradiol and Progesterone

Primary Purpose

Polycystic Ovary Syndrome, Hyperandrogenism

Status

Terminated

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

Flutamide

Progesterone

estrace

About this trial

This is an interventional basic science trial for Polycystic Ovary Syndrome focused on measuring PCOS, hyperandrogenemia

Eligibility Criteria

13 Years - 17 Years (Child)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

Girls ages 13 to 17
Tanner IV or V stage of puberty
Post-menarche
Hyperandrogenemic (total testosterone > 0.4 ng/mL or free testosterone > 35 pmol/L) with or without hirsutism
Normal aspartate aminotransferase/alanine aminotransferase (AST/ALT) (AST < 35 U/L, ALT < 55 U/L)
Hemoglobin > 12 mg/dL or Hematocrit > 36%
Normal screening labs (with exception of the expected hormonal abnormalities inherent in hyperandrogenemia)
Sexually active subjects must agree to abstain or use double barrier contraception during the study
Subjects must agree not to take any other medications during the course of the study without approval by the study investigators

Exclusion Criteria:

Abnormal screening labs (with the exception of the expected hormonal abnormalities inherent in hyperandrogenemia)
Elevated AST/ALT (AST > 35 U/L, ALT > 55 U/L)
Hemoglobin <12 mg/dL or hematocrit < 36%
Weight < 32 kg
History of liver disease, peanut allergy, deep venous thrombosis, breast cancer, endometrial cancer, or cervical cancer
Pregnant or breastfeeding
On medications known to affect the reproductive axis within 3 months of the study (including oral contraceptive pills, metformin, and spironolactone)
On medications known or likely to inhibit or induce CYP1A2 or CYP3A4 (please see "Restrictions on use of other drugs or treatments" section below for common examples of such drugs)
Are currently participating in another study or have been in one in the last 30 days.

Sites / Locations

Center for Research in Reproduction, University of Virginia

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Flutamide, estrace, progesterone

Arm Description

For flutamide, subjects weighing > 50 kg will receive 250 mg orally twice a day, and subjects weighing < 50 kg will receive 125 mg orally twice a day for approximately 3 weeks. Subjects will be given oral estrace, 0.5-1 mg once a day for 7 days following the first overnight study admission. Subjects will be given oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr for seven days following the first overnight study admission.

Outcomes

Primary Outcome Measures

Slope of the Percent Change in Luteinizing Hormone (LH) Pulses as a Function of Day 7 Progesterone Level

The primary outcome variable for the study is the slope of the percent change in LH pulses as a function of day 7 progesterone level.

Secondary Outcome Measures

Full Information

NCT ID

NCT01428193

First Posted

August 29, 2011

Last Updated

May 1, 2018

Sponsor

University of Virginia

Collaborators

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

1. Study Identification

Unique Protocol Identification Number

NCT01428193

Brief Title

Effects of Androgen Blockade on Sensitivity of the GnRH Pulse Generator to Suppression by Estradiol and Progesterone

Official Title

Effect of Androgen Blockade on Sensitivity of the GnRH Pulse Generator to Suppression by Estradiol and Progesterone in Hyperandrogenic Adolescent Girls (JCM021)

Study Type

Interventional

2. Study Status

Record Verification Date

May 2018

Overall Recruitment Status

Terminated

Why Stopped

Haven't enrolled participants since 2010

Study Start Date

September 2006 (Actual)

Primary Completion Date

August 2017 (Actual)

Study Completion Date

August 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Virginia

Collaborators

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

The purpose of this study is to understand the effects of elevated male hormones in adolescent girls and how they effect the development of polycystic ovary syndrome (PCOS). If the investigators understand the effects of elevated male hormones levels in girls, the investigators may be able to better treat girls with elevated male hormone levels and perhaps even learn how to prevent the development of PCOS. Females with elevated levels of male hormones respond differently to estrace (estradiol) and progesterone than females with normal male hormone levels. The investigators will be giving you estrogen and progesterone to see how you respond after the male hormone has been blocked by a medication called flutamide.

Detailed Description

Similar to women with PCOS, girls with hyperandrogenemia have an increased frequency of LH pulses when compared to age matched controls. An ongoing study by our group is investigating whether the progesterone insensitivity of the GnRH pulse generator in adult women with PCOS is also seen in adolescent girls with hyperandrogenemia. Analysis of the data to date suggests that the hyperandrogenic adolescent girls have decreased hypothalamic progesterone sensitivity when compared to adolescent controls, with a subgroup (consisting of approximately half of the hyperandrogenic girls) having marked progesterone insensitivity similar to that seen in adult women with PCOS. These data have recently been published. Given that androgens mediate hypothalamic progesterone insensitivity in adult women with PCOS, we hypothesize that androgens play a similar role in adolescent girls with hyperandrogenemia and that progesterone sensitivity can be restored with the use of the androgen receptor blocker flutamide. Better understanding the effects of hyperandrogenemia in adolescence and its role in the development of PCOS will hopefully lead to improved prevention and treatment strategies for PCOS. This may prove increasingly important if the current epidemic in childhood obesity results in a growing number of girls with elevated androgen levels.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Polycystic Ovary Syndrome, Hyperandrogenism

Keywords

PCOS, hyperandrogenemia

7. Study Design

Primary Purpose

Basic Science

Study Phase

Not Applicable

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

4 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Flutamide, estrace, progesterone

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Flutamide

Intervention Description

Subjects weighing > 50 kg will receive 250 mg orally twice a day, and subjects weighing < 50 kg will receive 125 mg orally twice a day.

Intervention Type

Drug

Intervention Name(s)

Progesterone

Intervention Description

oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr for seven days

Intervention Type

Drug

Intervention Name(s)

estrace

Other Intervention Name(s)

(estradiol)

Intervention Description

0.5-1 mg once a day for seven days

Primary Outcome Measure Information:

Title

Slope of the Percent Change in Luteinizing Hormone (LH) Pulses as a Function of Day 7 Progesterone Level

Description

The primary outcome variable for the study is the slope of the percent change in LH pulses as a function of day 7 progesterone level.

Time Frame

3 weeks after flutamide treatment

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

13 Years

Maximum Age & Unit of Time

17 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Girls ages 13 to 17 Tanner IV or V stage of puberty Post-menarche Hyperandrogenemic (total testosterone > 0.4 ng/mL or free testosterone > 35 pmol/L) with or without hirsutism Normal aspartate aminotransferase/alanine aminotransferase (AST/ALT) (AST < 35 U/L, ALT < 55 U/L) Hemoglobin > 12 mg/dL or Hematocrit > 36% Normal screening labs (with exception of the expected hormonal abnormalities inherent in hyperandrogenemia) Sexually active subjects must agree to abstain or use double barrier contraception during the study Subjects must agree not to take any other medications during the course of the study without approval by the study investigators Exclusion Criteria: Abnormal screening labs (with the exception of the expected hormonal abnormalities inherent in hyperandrogenemia) Elevated AST/ALT (AST > 35 U/L, ALT > 55 U/L) Hemoglobin <12 mg/dL or hematocrit < 36% Weight < 32 kg History of liver disease, peanut allergy, deep venous thrombosis, breast cancer, endometrial cancer, or cervical cancer Pregnant or breastfeeding On medications known to affect the reproductive axis within 3 months of the study (including oral contraceptive pills, metformin, and spironolactone) On medications known or likely to inhibit or induce CYP1A2 or CYP3A4 (please see "Restrictions on use of other drugs or treatments" section below for common examples of such drugs) Are currently participating in another study or have been in one in the last 30 days.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Christopher R. McCartney, MD

Organizational Affiliation

University of Virginia

Official's Role

Principal Investigator

Facility Information:

Facility Name

Center for Research in Reproduction, University of Virginia

City

Charlottesville

State/Province

Virginia

ZIP/Postal Code

22908

Country

United States

12. IPD Sharing Statement

Learn more about this trial

Effects of Androgen Blockade on Sensitivity of the GnRH Pulse Generator to Suppression by Estradiol and Progesterone

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