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Effect of Increased Circulating Androgens on Granulosa Cell Responses to FSH.

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ClinicalTrials.gov Identifier: NCT02389088
Recruitment Status : Completed
First Posted : March 17, 2015
Results First Posted : September 28, 2015
Last Update Posted : March 10, 2016
Sponsor:
Information provided by (Responsible Party):
Jeffrey Chang, MD, University of California, San Diego

Tracking Information
First Submitted Date  ICMJE March 9, 2015
First Posted Date  ICMJE March 17, 2015
Results First Submitted Date  ICMJE May 26, 2015
Results First Posted Date  ICMJE September 28, 2015
Last Update Posted Date March 10, 2016
Study Start Date  ICMJE April 2006
Actual Primary Completion Date January 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 26, 2015)
  • Estradiol During Phase I and Phase II [ Time Frame: At time 24 hours during Week 0 and times 0 and 24 hours during Weeks 5 and 6 after FSH stimulation for both Phase I and Phase II ]
    Estradiol (pmol/L) measured during Phase I (without Letrozole) and during Phase II (with Letrozole) at time 24 hours during Week 0 and times 0 and 24 hours during Weeks 5 and 6 after FSH stimulation.
  • Inhibin B During Phase I and Phase II [ Time Frame: At time 24 hours during Week 0 and times 0 and 24 hours during Weeks 5 and 6 after FSH stimulation for both Phase I and Phase II ]
    Inhibin B (ng/L) measured during Phase I (without Letrozole) and during Phase II (with Letrozole) at time 24 hours during Week 0 and times 0 and 24 hours during Weeks 5 and 6 after FSH stimulation.
  • LH and FSH During Phase I and Phase II [ Time Frame: At time 24 hours during Week 0 and times 0 and 24 hours during Weeks 5 and 6 after FSH stimulation for both Phase I and Phase II ]
    LH and FSH (IU/L) measured during Phase I (without Letrozole) and during Phase II (with Letrozole) at time 24 hours during Week 0 and times 0 and 24 hours during Weeks 5 and 6 after FSH stimulation.
  • Testosterone, Androstenedione and 17-OH Progesterone During Phase I and Phase II [ Time Frame: At time 24 hours during Week 0 and times 0 and 24 hours during Weeks 5 and 6 after FSH stimulation for both Phase I and Phase II ]
    Testosterone, Androstenedione and 17-OH Progesterone (nmol/L) measured during Phase I (without Letrozole) and during Phase II (with Letrozole) at time 24 hours during Week 0 and times 0 and 24 hours during Weeks 5 and 6 after FSH stimulation.
Original Primary Outcome Measures  ICMJE
 (submitted: March 16, 2015)
Granulosa Cell Response as Measured by Inhibin B [ Time Frame: 6 weeks ]
Change History Complete list of historical versions of study NCT02389088 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effect of Increased Circulating Androgens on Granulosa Cell Responses to FSH.
Official Title  ICMJE Effect of Increased Circulating Androgens on Granulosa Cell Responses to FSH
Brief Summary The purpose of this study is to evaluate the effect of increased circulating androgens on estradiol production by the granulosa cells in response to FSH stimulus.
Detailed Description

Various previous studies have demonstrated that androgens enhance granulosa cell function in a variety of animal species including rodents and non-human primates. In vitro studies have shown that granulosa cells exposed to either testosterone or dihydrotestosterone exhibit increased production of estrogen, progesterone and inhibin in response to FSH. Studies done in non-human primates have also shown that androgen increases the numbers of preantral and antral follicles as well as increases FSH receptor mRNA expression in granulosa cells. This suggests that granulosa cell hyperresponsiveness to FSH in polycystic ovary syndrome (PCOS) may be related to androgen excess. The investigators plan to address this possibility by performing a series of in vivo studies. In one of the investigator's prior studies androgen blockade was done by administration of flutamide and E2 responses to FSH assessed. This study has been completed and the manuscript is being prepared for publication. In the present protocol, the investigators propose to further study the role of androgens with a 2 phase study. In the first phase the investigators plan to suppress endogenous steroid hormone production by the ovaries via treatment with the GnRH analog Lupron for 4 weeks beyond which a gradual resumption of ovarian activity will occur. Granulosa cell (inhibin B) responses to FSH will be examined before and after ovarian suppression as well as during early and moderate recovery of ovarian steroidogenesis. These results will provide control data to which comparisons can be made from results of the next phase.

In the second phase, after a 2 month washout interval, the same subjects will again receive Lupron to suppress endogenous steroid production. After 4 weeks, at the beginning of ovarian activity resumption, the investigators will administer Letrozole 5mg for 14 days and again examine granulosa cell responses to FSH during recovery. Letrozole is a 3rd generation aromatase inhibitor which results in suppression of E2 production and increase in circulating serum androgen levels to about 40% greater than pre-treatment values. It is now also being used for ovulation induction. It has minimal side effects and is in general very well tolerated. By using Letrozole for 2 weeks after GnRH suppression of the ovaries, the investigators will more effectively increase the amount of circulating androgen while keeping estrogen at low levels, thereby allowing the investigators to more completely study the effects of isolated and elevated androgen levels on granulosa cell responses to FSH. By comparing results obtained in phase 1, the investigators will be able to determine if there is an androgen mediated response by granulosa cells to FSH stimulation in the absence of other ovarian steroids. Also, the addition of a control group will allow investigators to determine if the granulosa cell response is different between PCOS and normals.

It is hypothesized that there will be a significant rise in inhibin B production by the granulosa cells in PCOS women in response to FSH after treatment with Letrozole as compared to both the control group and to responses observed in the control phase of study. This would confirm that androgens are indeed responsible at least in part for the hyperresponsiveness to FSH seen in women with PCOS.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Health Services Research
Condition  ICMJE Polycystic Ovary Syndrome
Intervention  ICMJE Drug: Letrozole
In Phase II, letrozole, 5 mg/day, will be given for 14 days
Other Name: Femora
Study Arms  ICMJE
  • No Intervention: Phase I

    9 PCOS women will be studied. On study day one, r-FSH will be administered I.V. at a dose of 150 IU (FSH stimulation test). Blood samples will be obtained before and after FSH administration. After the FSH stimulation test, each subject will receive an I.M. injection of Lupron 3.75 mg. This dose has a duration effect of one month.

    The FSH stimulation test will be repeated, as described above, at 5 weeks (early resumption of ovarian function) and 6 weeks (moderate resumption of ovarian function).

  • Active Comparator: Phase II

    Women that participated in Phase I will be studied again after a washout of 2 months. On study day one, an FSH stimulation test will be performed as described above.

    After the FSH stimulation test, each subject will receive an I.M. injection of Lupron 3.75 mg. This dose has a duration effect of one month. Four weeks after administration of Lupron, each subject will receive Letrozole 5mg for 14 days. The FSH stimulation test will be repeated at 5 weeks (early resumption of ovarian function) and 6 weeks (moderate resumption of ovarian function).

    Intervention: Drug: Letrozole
Publications * Homer MV, Rosencrantz MA, Shayya RF, Chang RJ. The effect of estradiol on granulosa cell responses to FSH in women with polycystic ovary syndrome. Reprod Biol Endocrinol. 2017 Feb 10;15(1):13. doi: 10.1186/s12958-017-0230-0.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 16, 2015)
9
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE January 2013
Actual Primary Completion Date January 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Subjects will be determined to have PCOS based on clinical criteria such as history of irregular menses and clinical or laboratory evidence of hyperandrogenism.
  • Subjects should not have been on any hormonal therapy or metformin for at least 2 months prior to study start.

Exclusion Criteria:

  • Women with hemoglobin less than 11gm/dl at screening evaluation.
  • Women with untreated thyroid abnormalities
  • Pregnant women
  • Women with BMI>37
  • Women with known sensitivity to the agent being used.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years to 40 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02389088
Other Study ID Numbers  ICMJE UCSD-2016
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Jeffrey Chang, MD, University of California, San Diego
Study Sponsor  ICMJE University of California, San Diego
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: R. Jeffrey Chang, M.D. University of California, San Diego
PRS Account University of California, San Diego
Verification Date February 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP