An interventional study of Letrozole in Polycystic Ovary Syndrome, sponsored by University of California, San Diego. Completed. Open to female participants aged 18 Years to 40 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2016-03-10.
Sponsored by University of California, San Diego · Not applicable, Interventional, and Health services research
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.
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.
944 studies on the registry are indexed under Polycystic Ovary Syndrome; 174 are open to participants now.
This study's enrollment of 9 is below the median of 70 across 685 interventional studies indexed under Polycystic Ovary Syndrome.
Browse Polycystic Ovary Syndrome studies →University of California, San Diego is the lead sponsor of 958 studies on the registry; 191 are open to participants now.
Of its 110 completed or terminated interventional studies of FDA-regulated products, 70 (64%) have results posted.
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Exclusion Criteria:
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).
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).
Drug: Letrozole
In Phase II, letrozole, 5 mg/day, will be given for 14 days
Also known as: Femora
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.
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 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.
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 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.
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 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.
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
| Milestone | Phase I - All Study Participants |
|---|---|
| Started | 9 |
| Completed | 9 |
| Not completed | 0 |
| Milestone | Phase I - All Study Participants |
|---|---|
| Started | 9 |
| Completed | 9 |
| Not completed | 0 |
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.
| pmol/L | Phase I - Week 0 - 24 Hours | Phase I - Week 5 - 0 Hour | Phase I - Week 5 - 24 Hour | Phase I - Week 6 - 0 Hour | Phase I - Week 6 - 24 Hour | Phase II - Week 0 - 24 Hours | Phase II - Week 5 - 0 Hours | Phase II - Week 5 - 24 Hours | Phase II - Week 6 - 0 Hours | Phase II - Week 6 - 24 Hours |
|---|---|---|---|---|---|---|---|---|---|---|
| Estradiol During Phase I and Phase II | 451.7 ± 131 | 116 ± 27.8 | 247.2 ± 105.5 | 131.4 ± 20.2 | 347.5 ± 83.9 | 401.4 ± 103.4 | 57.9 ± 27 | 91.3 ± 80.8 | 66.5 ± 36.6 | 126.6 ± 117.7 |
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.
| ng/L | Phase I - Week 0 - 24 Hours | Phase I - Week 5 - 0 Hour | Phase I - Week 5 - 24 Hour | Phase I - Week 6 - 0 Hour | Phase I - Week 6 - 24 Hour | Phase II - Week 0 - 24 Hours | Phase II - Week 5 - 0 Hours | Phase II - Week 5 - 24 Hours | Phase II - Week 6 - 0 Hours | Phase II - Week 6 - 24 Hours |
|---|---|---|---|---|---|---|---|---|---|---|
| Inhibin B During Phase I and Phase II | 420.6 ± 120 | 87.9 ± 76.5 | 395.1 ± 186.5 | 85.2 ± 40.2 | 445.5 ± 169 | 390 ± 142.4 | 165.2 ± 202.7 | 340 ± 309 | 184.3 ± 192.1 | 427.3 ± 260 |
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.
| IU/L | Phase I - Week 0 - 24 Hours | Phase I - Week 5 - 0 Hour | Phase I - Week 5 - 24 Hour | Phase I - Week 6 - 0 Hour | Phase I - Week 6 - 24 Hour | Phase II - Week 0 - 24 Hours | Phase II - Week 5 - 0 Hours | Phase II - Week 5 - 24 Hours | Phase II - Week 6 - 0 Hours | Phase II - Week 6 - 24 Hours |
|---|---|---|---|---|---|---|---|---|---|---|
| LH | NA ± NA | 0.6 ± 0.8 | NA ± NA | 2.0 ± 2.0 | NA ± NA | NA ± NA | 1.22 ± 1.8 | NA ± NA | 3.6 ± 3.9 | NA ± NA |
| FSH | NA ± NA | 3.5 ± 1.2 | NA ± NA | 4.3 ± 0.9 | NA ± NA | NA ± NA | 8.0 ± 2.6 | NA ± NA | 9.3 ± 3.1 | NA ± NA |
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.
| nmol/L | Phase I - Week 0 - 24 Hours | Phase I - Week 5 - 0 Hour | Phase I - Week 5 - 24 Hour | Phase I - Week 6 - 0 Hour | Phase I - Week 6 - 24 Hour | Phase II - Week 0 - 24 Hours | Phase II - Week 5 - 0 Hours | Phase II - Week 5 - 24 Hours | Phase II - Week 6 - 0 Hours | Phase II - Week 6 - 24 Hours |
|---|---|---|---|---|---|---|---|---|---|---|
| Testosterone | NA ± NA | 0.6 ± 0.2 | NA ± NA | 0.8 ± 0.4 | NA ± NA | NA ± NA | 0.6 ± 0.2 | NA ± NA | 0.01 ± 0.44 | NA ± NA |
| Androstenedione | NA ± NA | 2.8 ± 0.9 | NA ± NA | 3.6 ± 1.0 | NA ± NA | NA ± NA | 2.9 ± 0.8 | NA ± NA | 4.3 ± 1.9 | NA ± NA |
| 17OH-Progesterone | NA ± NA | 32.1 ± 17.5 | NA ± NA | 31.1 ± 9.8 | NA ± NA | NA ± NA | 24.0 ± 16.1 | NA ± NA | 37.4 ± 22.1 | NA ± NA |
Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Phase I | — | 0/9 (0%) | 0/9 (0%) |
| Phase II | — | 0/9 (0%) | 0/9 (0%) |
9 PCOS women
| Age, Continuous(years) | Phase I |
|---|---|
| Mean | 26 ± 1.2 |
| Sex: Female, Male(Participants) | Phase I |
|---|---|
| Female | 9 |
| Male | 0 |
| Race (NIH/OMB)(Participants) | Phase I |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 0 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 1 |
| White | 7 |
| More than one race | 1 |
| Unknown or Not Reported | 0 |
| Region of Enrollment(participants) | Phase I |
|---|---|
| United States | 9 |
| Phase I - LH, FSH(IU/L) | Phase I |
|---|---|
| LH | 9.5 ± 4.04 |
| FSH | 5.1 ± 1.03 |
| Phase I - Testosterone, Androstenedione, 17-OH Progesterone(nmol/L) | Phase I |
|---|---|
| Testosterone | 1.34 ± 0.3 |
| Androstenedione | 5.29 ± 1.3 |
| 17-OH Progesterone | 47.3 ± 24.6 |
| Phase I - Estradiol(pmol/L) | Phase I |
|---|---|
| Mean | 180.4 ± 25.5 |
| Phase II - LH, FSH(IU/L) | Phase I |
|---|---|
| LH | 8.6 ± 4.4 |
| FSH | 4.7 ± 1.3 |
2 further baseline measures are reported on the registry.
No study locations are listed for this record.
Plan to share: No
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University of California, San Diego