Polycystic Ovary SyndromeNCT02389088
Effect of Increased Circulating Androgens on Granulosa Cell Responses to FSH.
A study testing Letrozole in people with Polycystic Ovary Syndrome, run by University of California, San Diego.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 40 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Polycystic Ovary Syndrome
- What is being tested?
- Letrozole
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 9 participants
- Where
- No sites listed yet
- Study dates
- Apr 2006to Jan 2013
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 40 years
- Women only
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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.
Who cannot join
- 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.
About this study
Official title: Effect of Increased Circulating Androgens on Granulosa Cell Responses to FSH
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.
Read the 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.
- Conditions
- Polycystic Ovary Syndrome
- Being tested
- Letrozole
- Keywords
- Granulosa Cell, Androgens, FSH, Ovary
- Medical subject headings
- Polycystic Ovary Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LetrozoleDrug
Also called Femora
In Phase II, letrozole, 5 mg/day, will be given for 14 days
| Study group | Role | What they receive |
|---|---|---|
| Phase I | No intervention | 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). |
| Phase II | Active comparator | 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). Receives: Drug: Letrozole |
What is being measured
The primary outcome is the main question the study is designed to answer.
Estradiol During 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.
Measured: 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 During 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.
Measured: 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 During 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.
Measured: 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 During 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.
Measured: 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
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Mar 2015 (estimated)
- Study startApr 2006
- Primary completionJan 2013
- Study completionJan 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Polycystic Ovary SyndromeStudies of the same condition, open and under way.
- More trials run by University of California, San DiegoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Health services research
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 9 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of California, San Diego
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Jeffrey Chang, MD, University of California, San Diego
- Investigators
- R. Jeffrey Chang, M.D., Principal investigator, University of California, San Diego
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02389088
- Sponsor's protocol ID
- UCSD-2016
- Status last verified
- Feb 2016
- First submitted
- 9 Mar 2015
- Last updated
- 10 Mar 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- Individual data sharing
- No
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.
PubMed 28187771
Study at a glance
From the registry record, last updated by the sponsor on 10 Mar 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of Increased Circulating Androgens on Granulosa Cell Responses to FSH
- ClinicalTrials.gov ID
- NCT02389088
- Acronym / sponsor ID
- UCSD-2016
- Conditions
- Polycystic Ovary Syndrome
- Keywords
- Granulosa Cell, Androgens, FSH, Ovary
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 9 participants (actual)
- Lead sponsor
- University of California, San DiegoUniversity, hospital or other
- Study start
- Apr 2006
- Primary completion
- Jan 2013 (actual)
- Study completion
- Jan 2013 (actual)
- First posted
- 17 Mar 2015 (estimated)
- Results
- Posted 28 Sep 2015
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Health services research
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Phase I | No intervention | –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). |
| Phase II | Active comparator | Drug: LetrozoleWomen 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). |
Who may qualify
- Ages
- 18 to 40 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (2 listed)
- 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.
Key exclusion criteria (5 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LetrozoleAlso: FemoraIn Phase II, letrozole, 5 mg/day, will be given for 14 days | Drug | Phase II |
Primary outcome
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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Mar 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 28187771Homer 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
R. Jeffrey Chang, M.D. principal investigator
University of California, San Diego
Questions about this trial
What is this clinical trial studying?
A study testing Letrozole in people with Polycystic Ovary Syndrome, run by University of California, San Diego.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 10 Mar 2016. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 28 Sep 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02389088, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Mar 2016.