Skip to main content
Download PDF

The effect of estradiol on granulosa cell responses to FSH in women with polycystic ovary syndrome

Reproductive Biology and Endocrinology volume 15, Article number: 13 (2017) Cite this article

Abstract

Background

The influence of estradiol (E2) on granulosa cell (GC) function has not been tested clinically in women with polycystic ovary syndrome (PCOS). The objective of this study is to determine if E2 influences GC responses to FSH in women with PCOS.

Methods

This is a two phase, single cohort study conducted over a 2-year period at a single academic center. Nine women with PCOS according to NIH criteria. In Phase 1, FSH stimulation of GC responses as measured by E2 and Inhibin B (Inh B) were assessed before and at 5 and 6 weeks after GnRH agonist administration. In Phase 2, the same protocol was employed with the addition of an aromatase inhibitor (letrozole, LET) administered daily beginning at week 4 for 2 weeks.

Results

In Phase 1, recovery of FSH, E2 and Inh B from ovarian suppression occurred at 5 and 6 weeks after GnRH agonist injection and preceded resumption of LH and androgen secretion. In Phase 2, hormone recovery after GnRH agonist was characterized by elevated FSH and suppressed E2 levels whereas recovery of LH and androgen levels were unchanged. In Phase 1, FSH stimulated E2 and Inh B responses were unaltered during recovery from ovarian suppression. In Phase 2, E2 and Inh B fold changes after FSH were significantly reduced at weeks 5 (p < 0.04) and 6 (p < 0.01), respectively.

Conclusion

In anovulatory women with PCOS, chronic, unopposed E2 secretion may contribute, at least in part, to enhanced ovarian responsiveness to FSH.

Trial registration

NCT02389088

Background

The characteristic features of polycystic ovary syndrome (PCOS) are anovulation, androgen excess, and polycystic ovary morphology. Anovulation is associated with modest estradiol (E2) secretion derived primarily from peripheral extraglandular conversion and minimal progesterone production. However, in vitro and in vivo studies have demonstrated that granulosa cells (GCs) from women with PCOS are hyperresponsive to FSH stimulation compared to responses observed in normal GCs. These findings suggest that the ovary may contribute to circulating E2 in women with this disorder [1,2,3].

Local production of E2 may account, at least in part, for the enhanced CG response to FSH in PCOS. There is considerable evidence that estrogen enhances follicle function including responses to FSH. Diethylstilbestrol treated GCs from immature hypophysectomized rats produced greater E2 release in response to FSH compared to that of untreated cells [4]. In addition, estrogen has been shown to influence GC cytodifferentiation by modulating follicular intracellular gap junctions, estrogen receptor content, and adenylate cyclase activity [5,6,7]. Synergy between E2 and FSH has been demonstrated in GCs with regards to increased FSH receptor binding and increased aromatase activity [8,9,10]. Corresponding in vivo efforts to demonstrate an effect of estrogens on GC E2 production in women has been understandably difficult and not undertaken.

Previously, we and others have shown that in women with PCOS serum E2 and inhibin B (Inh B) exhibit similar temporal responsiveness to FSH [11, 12]. These findings suggest that Inh B may serve as a marker of granulosa cell activity alongside E2. In an effort to determine whether estrogen influences GC function in women with PCOS, we examined Inh B responses to FSH in the presence or absence of an aromatase inhibitor.

Methods

Participants

Nine women with PCOS were recruited for study. All subjects were between 18 and 35 years of age and exhibited clinical and laboratory evidence of hyperandrogenism, were either oligomenorrheic or amenorrheic and had greater than 12 antral follicles per ovary on transvaginal ultrasound that are consistent with criteria established by the NIH, Rotterdam, and Androgen Excess-PCOS Society. Mean age (± SE) was 26 ± 1.2 years and BMI (± SE) was 33.7 ± 2.4 kg/m2. Serum levels of 17-hydroxyprogesterone (17-OHP), TSH, and prolactin were within normal range. All patients were free of medication containing hormones for 3 months or greater prior to study.

The study was approved by the Human Research Protection Program at the University of California, San Diego (UCSD, IRB#100023) and written informed consent was obtained from each participant before study.

Procedures

The study was divided into two phases. For Phase I of the study, participants were admitted on a random day to the Clinical and Translational Research Institute (CTRI) at UC San Diego for testing. Patients all had serum progesterone levels < 1.5 ng/ml and negative hCG tests. After placement of an intravenous line, each subject received an intravenous injection of recombinant human FSH (r-hFSH), 150 IU. Blood samples were obtained prior to and 24 h afterwards. After the last blood sample was obtained, each was given long-acting GnRH agonist (Depot Lupron), 3.75 mg intramuscularly, to maximally suppress ovarian steroid production for one month after which serum E2 levels gradually resume [13]. Ovarian suppression was employed to allow for FSH stimulation studies to be conducted during the recovery phase when the ovary and GCs regain responsiveness, thereby establishing uniform and comparable E2 levels in both phases of study. During this interval, FSH stimulation was repeated at the end of week 5 and week 6.

For Phase II of the study, the same 9 participants were allowed to have a hormone-free washout period of 3 months from administration of GnRH agonist and 2 months from the prior dose of FSH. They were then re-admitted to the CTRI at UC San Diego for study. Similar to Phase I, they underwent a baseline FSH stimulation test after which 3.75 mg of Depot Lupron was administered. At the beginning of week 4, each subject received an aromatase inhibitor, Letrozole (LET), 5 mg daily, for 2 weeks to restrict increases of serum E2 levels that were observed in Phase I. The FSH stimulation test was then repeated at the end of week 5 and week 6.

Assays

Serum concentrations of LH and FSH were measured by radio-immunoassay (RIA) with intra— and inter-assay coefficients of variation (CV) of 5.4 and 8.0%, respectively, for LH and 3.0 and 4.6%, respectively, for FSH (Diagnostic Products Corp., Los Angeles, CA, USA). Serum concentrations of Inh B were measured by ELISA with inter— and intra-assay CV of 6.7 and 4.6% (Diagnostic Systems Laboratories, Inc., Webster, TX, USA). The highly specific two-site ELISA Kit allows for quantitative measurement of dimeric Inh B in human serum. Assay sensitivity for Inh B was 7.0 pg/ml. Serum concentrations of E2, androstenedione (A) and testosterone (T) were measured by well-established RIA with intra-assay CV less than 7%. P4, 17-OHP and dehydroepiandrosterone sulfate (DHEAS) were measured by RIA with intra-assay CV less than 7% (Diagnostic Systems Laboratories, Inc., Webster, TX, USA).

Statistical analysis

Q-Q plot and boxplot were used to check the normality of the data. One-sample t-test and one-sample Wilcoxon signed-rank test were applied as needed to test the differences of hormone measurements at both baseline and after FSH stimulation for Phase I compared to Phase II. We also tested for differences in the log fold change of E2, Inh B and insulin hormone before and after FSH. For all analysis, p values of < 0.05 were considered statistically significant. Statistical analysis were performed using the R statistical computing software (version 2.6.2, http://www.r-project.org, 2009).

Results

Serum hormone levels before and after GnRH agonist ovarian suppression (phase I)

Baseline circulating hormone levels for women with PCOS are shown in Table 1. Mean circulating levels of LH, FSH, A, T, E2 and Inh B before and following pituitary gonadotropin desensitization and ovarian suppression are shown in Fig. 1. As expected, serum E2 levels at the end of week 5 and week 6 after GnRH agonist approximated pretreatment levels that reflected recovery from ovarian suppression. Basal Inh B levels at the end of 5 and 6 weeks after GnRH agonist were not different compared to baseline serum values. Serum FSH levels at the end of week 5 were similar to baseline concentrations indicating complete recovery from pituitary desensitization. By comparison, LH and serum androgens at the end of week 5 remained lower than pre-GnRH agonist treatment levels. Subsequently, there were subtle increases of LH and androgen production by the end of week 6.

Table 1 Baseline circulating steroid hormone and gonadotropin levels in women with PCOS.
Full size table
Fig. 1
figure 1

Serum hormone levels before and during recovery from GnRH agonist. Serum levels of FSH (IU/L), LH (IU/L) T (nmol/L), A (nmol/L), E2 (pmol/L) and Inh B (ng/L)

Full size image

Serum hormone levels before and after GnRH agonist ovarian suppression in the presence of LET (phase II)

In Phase II, corresponding levels of gonadotropins, E2, Inh B and androgens associated with the administration of LET during weeks 4 and 5 after GnRH agonist injection are shown in Fig. 2. Basal E2 levels were significantly lower during daily LET administration (weeks 5 and 6) compared to corresponding values observed in Phase 1. Accordingly, these reduced E2 levels were associated with significantly higher basal serum FSH levels at week 5 and 6 (p < 0.01) as shown in Fig. 2. Notably, these increments of FSH were significantly greater than those observed without LET. In contrast to E2, basal serum Inh B levels exhibited increases during LET treatment compared to the mean baseline value at week 0, although these increments were not statistically significant. In Phase 2 patterns of increasing basal values of LH, A and T levels during recovery were similar to those observed in Phase 1.

Fig. 2
figure 2

Serum hormone levels before and during recovery from GnRH agonist together with LET. Serum levels of FSH (IU/L), LH (IU/L) T (nmol/L), A (nmol/L), E2 (pmol/L) and Inh B (ng/L)

Full size image

E2 and Inh B responses to FSH during recovery from GnRH suppression in the absence and presence of LET

In Phase I, the FSH-stimulated fold-changes of E2 at 5 and 6 weeks during recovery were not significantly different from that observed at baseline, prior to GnRH agonist administration (Table 2). However, in Phase II studies with LET treatment, reduced basal E2 levels were accompanied by a corresponding decline of the fold-change E2 responses to FSH injection at weeks 5 (p < 0.04) and 6 (p < 0.01) compared to baseline. Similarly, Inh B responses to FSH in were not different in Phase I, but significantly decreased fold-changes following FSH were observed at 5 (p < 0.04) and 6 (p < 0.01) weeks.

Table 2 Serum estradiol and Inh B fold-change responses to FSH at week 0 (baseline), week 5 and week 6 during Phase I (without LET) and Phase II (with LET) of study
Full size table

Discussion

The results of this study are consistent with a facilitative role for E2 on GC function in women with PCOS. This is suggested by the reduced fold-change responses of Inh B as well as E2 following FSH administration in the presence of lowered serum E2 levels during LET administration. Decreased responsiveness of Inh B was observed despite corresponding increases of FSH, which is known to enhance Inh B release.

Hyperresponsiveness to FSH administration in women with PCOS is a well-recognized phenomenon that predisposes to hyperstimulation during ovulation induction. This is likely due to the abundance of small antral follicles that exist in women with PCOS as well as an increased number of FSH receptors per granulosa cell in follicles from anovulatory women with this disorder [14, 15]. However, there is a lack of clinical studies in women regarding the role of E2 on GC function and follicle development. As a result, most of our understanding of how E2 impacts follicle health has been inferred from experiments in animal models. It is apparent that E2 does not exert a direct effect on GCs as E2 response elements have not been identified on the CYP19 promoter in the rat model or human GCs [16]. Rather, it is likely synergism between E2 and FSH that promotes GC function and follicle growth. For instance, studies have shown that maximal FSH stimulation of aromatase activation, antrum formation, and LH responsiveness in GCs requires E2 [4,17,18,19,, 16–20]. These findings are underscored by studies conducted in β-estrogen receptor knock out mice that demonstrate the necessity of E2 to achieve maximum FSH action in GCs [21].

There were modest increases of basal serum Inh B during LET treatment in Phase II that were not statistically significant compared to Phase I. The subtle change of Inh B may have been induced by raised levels of circulating FSH as a result of lowered serum E2 levels rather than an inherent increase of GC responsiveness. Nevertheless, corresponding Inh B responses to FSH were not greater than those observed prior to GnRH agonist administration or Inh B responses in Phase I. Thus, the incremental fold-change was significantly less in Phase II in association with diminished E2 levels. Considering that Inh B may serve as a GC marker, this provides indirect evidence that estrogen augments E2 responsiveness to FSH in women with PCOS.

While these results suggest that E2 may contribute to enhanced GC function in women with PCOS, it is less clear as to whether chronic E2 secretion directly impacts GC hyper-responsiveness to FSH as demonstrated in vitro or in women with this disorder. In the hypogonadotropic hypogonadal female, serum E2 levels are low and initial ovarian responses to exogenous FSH are decreased compared to anovulatory women with normal E2 concentrations. Estradiol has also been used in poor ovarian responders to help increase the number of mature follicles retrieved and decrease cycle cancellations [22]. By comparison, anovulatory women with PCOS are distinctive in that efforts to induce ovulation appear to assume varying and, at times, apparent diametrical ovarian responses. In PCOS women initiation of ovulation induction has been characterized by a lack of follicle response that commonly warrants higher therapeutic doses or more intensive treatment modalities. It has been reported that during clomiphene citrate administration significantly smaller increments of E2 were observed compared to those of normal women despite comparable increases of serum FSH [23] As a result, several modified treatment regimens have been proposed that markedly increase the total dose of clomiphene or utilize additional drugs, including gonadotropins, to enhance clomiphene effectiveness. Primary gonadotropin therapy in women with PCOS has also been associated with poor initial ovarian responses to ovulation induction as early E2 responses to daily gonadotropin stimulation were considerably less compared to that found in normal women [24]. The mechanism of ovarian insensitivity in the early stages of ovulation induction has not been examined. In women with PCOS, chronic E2 secretion has been attributed to peripheral extra-glandular conversion and local intra-ovarian production may be insufficient to support early follicular responses to FSH. Alternatively, multiple factors, both intra- and extra-ovarian, may be responsible for or contribute to anovulation in women with this disorder and warrant further investigation. This would include AMH’s possible role in regulation of ovarian function and morphology [25, 26].

Despite the reduction of E2 during LET treatment, circulating levels of T and A were inexplicably not altered. Whether this was the result of LET superimposed on already suppressed ovarian steroidogenesis is uncertain, although it would seem that aromatase inhibition at extra-glandular sites might result in elevated serum androgens. Previously, it was reported that T as well as gonadotropins were unaltered in premenopausal women administered LET, 2.5 mg, daily over 12 weeks [27]. Another consideration may be that our study subjects were comprised of only those with PCOS with an elevated BMI and the results should not be generalized to a non-obese population due to BMI’s influence on insulin resistance and ovarian hormones.

The experimental design of our study was complex, but necessary in an attempt to fully assess the effect of serum E2 reduction on GC function. Our previously studies have demonstrated that GnRH agonist administration may lower, but not eliminate serum E2 levels in normal and PCOS women, particularly those with increased BMI as was the case with our study subjects [12]. To maintain reduced levels of E2 following ovarian suppression LET was employed during the interval of ovarian recovery. Use of an anti-estrogen such as a selective E2 receptor modulator may have been considered, although these compounds may bind to E2 receptors and activate signaling pathways independent of E2. In addition, the degree to which E2 action was reduced would be unclear and measurement of E2 levels would be of questionable value.

Clinical studies to examine the role of estrogen on GC function in PCOS or normal women have not been performed previously. However, the interpretation of our results warrants some caution due to the following limitations. First, there were a limited number of subjects that served as their own controls. Second, non-PCOS women were not included. Third, the stimulatory dose of FSH was relatively high and GC responses may have been maximally stimulated that precluded differential Inh B production. Fourth, in light of ovarian suppression by GnRH agonist, LET administration may have been extended to allow a lengthier recovery prior to FSH stimulation. This is unlikely as our previous studies as well as the current results suggest that adequate steroidogenesis had been reestablished by the time of FSH testing. Lastly, we elected to employ Inh B as a marker of GC responsiveness to FSH as suggested by Dokras, et. al [11]. This assumption was based on the parallelism of Inh B and E2 responses to variable doses of iv FSH in both normal and PCOS women as previously reported [12].

Conclusions

In summary, the results of this study have demonstrated that in women with PCOS Inh B responses to FSH are reduced in the presence of lowered circulating E2 levels. These finding provide indirect evidence that E2 may enhance follicle function in women with this disorder.

Abbreviations

17-OHP:

17-hydroxyprogesterone

A:

Androstenedione

CTRI:

Clinical and translational research institute

CV:

Coefficients of variation

DHEAS:

Dehydroepiandrosterone sulfate

E2 :

Estradiol

GCs:

Granulosa cells

Inhibin B:

Inh B

LET:

Letrozole

PCOS:

Polycystic ovary syndrome

r-hFSH:

Recombinant human FSH

RIA:

Radio-immunoassay

T:

Testosterone

Reference

  1. Coffler MS, Patel K, Dahan MH, Malcom PJ, Kawashima T, Deutsch R, et al. Evidence for abnormal granulosa cell responsiveness to follicle-stimulating hormone in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2003;88:1742–7.

    Article  CAS  PubMed  Google Scholar 

  2. Erickson GF, Magoffin DA, Cragun JR, Chang RJ. The effects of insulin and insulin-like growth factors-I and -II on estradiol production by granulosa cells of polycystic ovaries. J Clin Endocrinol Metab. 1990;70:894–902.

    Article  CAS  PubMed  Google Scholar 

  3. Willis D, Mason H, Gilling-Smith C, Franks S. Modulation by insulin of follicle-stimulating hormone and luteinizing hormone actions in human granulosa cells of normal and polycystic ovaries. J Clin Endocrinol Metab. 1996;81:302–9.

    CAS  PubMed  Google Scholar 

  4. Adashi EY, Hsueh AJ. Estrogens augment the stimulation of ovarian aromatase activity by follicle-stimulating hormone in cultured rat granulosa cells. J Biol Chem. 1982;257:6077–83.

    CAS  PubMed  Google Scholar 

  5. Burghardt RC, Anderson E. Hormonal modulation of gap junctions in rat ovarian follicles. Cell Tissue Res. 1981;214:181–93.

    Article  CAS  PubMed  Google Scholar 

  6. Jonassen JA, Bose K, Richards JS. Enhancement and desensitization of hormone-responsive adenylate cyclase in granulosa cells of preantral and antral ovarian follicles: effects of estradiol and follicle-stimulating hormone. Endocrinology. 1982;111:74–9.

    Article  CAS  PubMed  Google Scholar 

  7. Merk FB, Botticelli CR, Albright JT. An intercellular response to estrogen by granulosa cells in the rat ovary; an electron microscope study. Endocrinology. 1972;90:992–1007.

    Article  CAS  PubMed  Google Scholar 

  8. Daniel SA, Armstrong DT. Involvement of estrogens in the regulation of granulosa cell aromatase activity. Can J Physiol Pharmacol. 1983;61:507–11.

    Article  CAS  PubMed  Google Scholar 

  9. Richards JS, Ireland JJ, Rao MC, Bernath GA, Midgley AR, Reichert LE. Ovarian follicular development in the rat: hormone receptor regulation by estradiol, follicle stimulating hormone and luteinizing hormone. Endocrinology. 1976;99:1562–70.

    Article  CAS  PubMed  Google Scholar 

  10. Richards JS, Jonassen JA, Rolfes AI, Kersey K, Reichert LE. Adenosine 3’,5’-monophosphate, luteinizing hormone receptor, and progesterone during granulosa cell differentiation: effects of estradiol and follicle-stimulating hormone. Endocrinology. 1979;104:765–73.

    Article  CAS  PubMed  Google Scholar 

  11. Dokras A, Habana A, Giraldo J, Jones E. Secretion of inhibin B during ovarian stimulation is decreased in infertile women with endometriosis. Fertil Steril. 2000;74:35–40.

    Article  CAS  PubMed  Google Scholar 

  12. Rosencrantz MA, Wachs DS, Coffler MS, Malcom PJ, Donohue M, Chang RJ. Comparison of inhibin B and estradiol responses to intravenous FSH in women with polycystic ovary syndrome and normal women. Hum Reprod Oxf Engl. 2010;25:198–203.

    Article  CAS  Google Scholar 

  13. de Ziegler D, Steingold K, Cedars M, Lu JK, Meldrum DR, Judd HL, et al. Recovery of hormone secretion after chronic gonadotropin-releasing hormone agonist administration in women with polycystic ovarian disease. J Clin Endocrinol Metab. 1989;68:1111–7.

    Article  PubMed  Google Scholar 

  14. Maciel GA, Baracat EC, Benda JA, Markham SM, Hensinger K, Chang RJ, et al. Stockpiling of transitional and classic primary follicles in ovaries of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2004;89:5321–7.

    Article  CAS  PubMed  Google Scholar 

  15. Almahbobi G, Anderiesz C, Hutchinson P, McFarlane JR, Wood C, Trounson AO. Functional integrity of granulosa cells from polycystic ovaries. Clin Endocrinol (Oxf). 1996;44:571–80.

    Article  CAS  Google Scholar 

  16. Fitzpatrick SL, Richards JS. Regulation of cytochrome P450 aromatase messenger ribonucleic acid and activity by steroids and gonadotropins in rat granulosa cells. Endocrinology. 1991;129:1452–62.

    Article  CAS  PubMed  Google Scholar 

  17. Goldenberg RL, Vaitukaitis JL, Ross GT. Estrogen and follicle stimulation hormone interactions on follicle growth in rats. Endocrinology. 1972;90:1492–8.

    Article  CAS  PubMed  Google Scholar 

  18. Knecht M, Darbon JM, Ranta T, Baukal AJ, Catt KJ. Estrogens enhance the adenosine 3’,5’-monophosphate-mediated induction of follicle-stimulating hormone and luteinizing hormone receptors in rat granulosa cells. Endocrinology. 1984;115:41–9.

    Article  CAS  PubMed  Google Scholar 

  19. Knecht M, Tsai-Morris CH, Catt KJ. Estrogen dependence of luteinizing hormone receptor expression in cultured rat granulosa cells. Inhibition of granulosa cell development by the antiestrogens tamoxifen and keoxifene. Endocrinology. 1985;116:1771–7.

    Article  CAS  PubMed  Google Scholar 

  20. Zhuang LZ, Adashi EY, Hsuch AJ. Direct enhancement of gonadotropin-stimulated ovarian estrogen biosynthesis by estrogen and clomiphene citrate. Endocrinology. 1982;110:2219–21.

    Article  CAS  PubMed  Google Scholar 

  21. Couse JF, Yates MM, Deroo BJ, Korach KS. Estrogen receptor-beta is critical to granulosa cell differentiation and the ovulatory response to gonadotropins. Endocrinology. 2005;146:3247–62.

    Article  CAS  PubMed  Google Scholar 

  22. Chang X, Wu J. Effects of luteal estradiol pre-treatment on the outcome of IVF in poor ovarian responders. Gynecol. Endocrinol. Off. J. Int. Soc. Gynecol. Endocrinol. 2013;29:196–200.

    CAS  Google Scholar 

  23. Rebar R, Judd HL, Yen SS, Rakoff J, Vandenberg G, Naftolin F. Characterization of the inappropriate gonadotropin secretion in polycystic ovary syndrome. J Clin Invest. 1976;57:1320–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. DeFazio J, Meldrum DR, Lu JK, Vale WW, Rivier JE, Judd HL, et al. Acute ovarian responses to a long-acting agonist of gonadotropin-releasing hormone in ovulatory women and women with polycystic ovarian disease. Fertil Steril. 1985;44:453–9.

    Article  CAS  PubMed  Google Scholar 

  25. Durlinger AL, Visser JA, Themmen AP. Regulation of ovarian function: the role of anti-Mullerian hormone. Reproduction. 2002;124:601–9.

    Article  CAS  PubMed  Google Scholar 

  26. Hayes E, Kushnir V, Ma X, Biswas A, Prizant H, Gleicher N, et al. Intra-cellular mechanism of anti-Müllerian hormone (AMH) in regulation of follicular development. Mol Cell Endocrinol. 2016;433:56–65.

    Article  CAS  PubMed  Google Scholar 

  27. Parsanezhad ME, Azmoon M, Alborzi S, Rajaeefard A, Zarei A, Kazerooni T, et al. A randomized, controlled clinical trial comparing the effects of aromatase inhibitor (letrozole) and gonadotropin-releasing hormone agonist (triptorelin) on uterine leiomyoma volume and hormonal status. Fertil Steril. 2010;93:192–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to Mr. Jeff Wong for his technical expertise and to the nurses and staff of the University of California, San Diego, General Clinical Research Center for their dedicated care.

Funding

Eunice Kennedy Shriver NICHD/NIH through cooperative agreement (U54 HD12303-28) as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research, NIH T32 HD007203, and in part by NIH grant MO1 RR00827.

Availability of data and materials

The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.

Authors’ contributions

MVH, MD: Analysis, Manuscript Drafting, Critical Discussion; MAR, MD: Study Design, Execution; RFS, MD: Execution; RJC, MD: Study Design, Analysis, Manuscript Drafting, Critical Discussion. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

Not applicable.

Ethics approval and consent to participate

The study was approved by the Human Research Protection Program at the University of California, San Diego (UCSD, IRB#100023) and written informed consent was obtained from each participant before study.

Author information

Authors and Affiliations

  1. Reproductive Medicine, University of California, 200 West Arbor Drive MC: 8710, San Diego, CA, 92103, USA

    Michael V. Homer & R. Jeffrey Chang

  2. Reproductive Endocrinology and Infertility, Southern California Permanente Medical Group, 6650 Alton Parkway, Irvine, CA, 92618, USA

    Marcus A. Rosencrantz

  3. Obstetrics and Gynecology, Southern California Permanente Medical Group, 250 Travelodge Drive, El Cajon, CA, 92020, USA

    Rana F. Shayya

  4. 9500 Gilman Drive #0633 La Jolla, San Diego, CA, 92093, USA

    R. Jeffrey Chang

Authors
  1. Michael V. Homer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marcus A. Rosencrantz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rana F. Shayya
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. Jeffrey Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R. Jeffrey Chang.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Homer, M.V., Rosencrantz, M.A., Shayya, R.F. et al. The effect of estradiol on granulosa cell responses to FSH in women with polycystic ovary syndrome. Reprod Biol Endocrinol 15, 13 (2017). https://doi.org/10.1186/s12958-017-0230-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12958-017-0230-0

Keywords

Reproductive Biology and Endocrinology

ISSN: 1477-7827

Contact us