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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 4 1742-1747
Copyright © 2003 by The Endocrine Society

Evidence for Abnormal Granulosa Cell Responsiveness to Follicle-Stimulating Hormone in Women with Polycystic Ovary Syndrome

Mickey S. Coffler, Ketan Patel, Michael H. Dahan, Pamela J. Malcom, Toana Kawashima, Reena Deutsch and R. Jeffrey Chang

Departments of Reproductive Medicine (M.S.C., K.P., M.H.D., P.J.M., R.J.C.) and Family and Preventive Medicine (R.D.), University of California, San Diego, La Jolla, California 92093; and San Diego State University (T.K.), San Diego, California 92182

Address all correspondence and requests for reprints to: R. Jeffrey Chang, M.D., Department of Reproductive Medicine, University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, California 92093-0633. E-mail: rjchang{at}ucsd.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Materials
 Results
 Discussion
 References
 
Women with polycystic ovary syndrome (PCOS) undergoing ovulation induction appear to be extremely sensitive to gonadotropin stimulation and at increased risk for ovarian hyperstimulation syndrome. To determine granulosa cell responsiveness to recombinant human FSH (r-hFSH), dose-response studies were conducted in 16 individual PCOS patients and 7 normal women. Each subject received an iv injection of r-hFSH at doses of 0, 37.5, 75, or 150 IU in a randomized fashion on four separate occasions. Blood samples were obtained at frequent intervals before and for 24 h after r-hFSH administration for measurement of gonadotropins and steroid hormones.

Our results showed that administration of r-hFSH produced instantaneous and equivalent dose-related increases in serum FSH in PCOS and normal women, which were followed by similar exponential decreases to baseline levels within 24 h in both groups. In PCOS subjects, the peak mean incremental response of serum estradiol (E2) to 150 IU of r-hFSH was 1.8-fold greater (P < 0.0001) and considerably accelerated compared with that found in normal women. In contrast, E2 responses to 37.5 IU and 75 IU were similar between groups. Regression analysis of maximal E2 concentrations in response to r-hFSH in each individual subject revealed that the slope of the linear trend line in the group of women with PCOS (r = 0.82) was significantly greater (P < 0.01) than that of normal controls (r = 0.71). The time-course of response revealed that in PCOS women, increases of E2 were not sustained, compared with those of normal controls, because peak concentrations were followed by an estimated 40% decrement in circulating levels, whereas E2 levels in normal women persisted for 24 h after reaching maximal values.

These findings indicate that women with PCOS exhibit a significantly greater capacity for E2 production in response to iv r-hFSH, compared with normal women. In PCOS, E2 production was relatively transient because after peak concentrations a marked decline was detected at each dose, unlike normal women who exhibited persistent elevations of E2 for up to 24 h. That this distinction was dose-dependent supports the concept of an FSH dose-response threshold, beyond which PCOS but not normal women are susceptible to ovarian hyperresponsiveness.


   Introduction
Top
 Abstract
 Introduction
Subjects and Materials
 Results
 Discussion
 References
 
IT HAS BEEN GENERALLY recognized that women with polycystic ovary syndrome (PCOS) undergoing ovulation induction are hypersensitive to the effects of gonadotropin stimulation. Over an entire course of gonadotropin therapy, these individuals are more likely to develop ovarian hyperstimulation syndrome, which is characterized by marked elevation of estradiol (E2) levels and significant ovarian enlargement with the potential for serious clinical consequences (1, 2). However, some PCOS patients have exhibited paradoxical ovarian hyporesponsiveness to clomiphene-mediated gonadotropin release. In an examination of granulosa cell responses to clomiphene administration, it was shown that women with PCOS demonstrated significantly smaller increases in E2 than those of normal women despite comparable increments of FSH (3). This finding was consistent with an earlier report in which initial E2 responses to daily gonadotropin stimulation in PCOS were considerably less compared with responses found in normal women (4). These apparent divergent observations reflect the complex interplay between gonadotropin stimulation and granulosa cell responsiveness during ovulation induction in women with PCOS.

In previous efforts to determine the ability of granulosa cells to release E2 in response to increasing doses of gonadotropin, we and others have conducted in vitro studies which demonstrated that cultured granulosa cells from PCOS women were far more sensitive to FSH stimulation compared with cells from normal women (5, 6). That these in vitro results were in marked contrast to prior in vivo findings prompted a clinical investigation to examine the functional capacity of granulosa cells by initiating dose-response studies within individual women with PCOS.


   Subjects and Materials
Top
 Abstract
 Introduction
 Subjects and Materials
Results
 Discussion
 References
 
Subjects

Sixteen women with PCOS and seven normal women with regular menstrual cycles were recruited for study. All PCOS subjects exhibited clinical and biochemical evidence of hyperandrogenism and were either oligomenorrheic or amenorrheic. In PCOS and normal control groups, the mean ages (± SE) were 27.0 ± 1.2 and 28.6 ± 1.4 yr, respectively, and not significantly different. The mean BMI was significantly greater in PCOS subjects compared with the BMI of normal women (32.6 ± 9.9 vs. 28.8 ± 5.0 kg/m2, respectively; P < 0.01), whereas the waist-to-hip ratios were similar in both groups. Each PCOS subject exhibited ultrasound evidence of bilaterally enlarged polycystic ovaries. Late-onset congenital adrenal hyperplasia was excluded by a serum 17-hydroxyprogesterone (17-OHP) level of less than 3 ng/ml (< 9.1 nmol/liter). Circulating TSH and prolactin levels were normal and not significantly different between groups. The normal subjects were monitored by menstrual calendar for 6 months and by urinary LH testing for 1 month before study to establish the regularity of their cycles. None of the subjects in either group had received any hormone medication for at least 3 months before study. The study had been approved by the Institutional Review Board at the University of California, San Diego, and written informed consent was obtained from each participant before study.

Procedures

Each subject was admitted to the General Clinical Research Center at the University of California, San Diego, on the day of testing on four separate occasions. In PCOS subjects, testing was performed at a minimum interval of at least 2 wk, whereas normal subjects were tested at a minimum interval of at least one cycle during the midfollicular phase defined as d 5–8. On each occasion after baseline sampling, r-hFSH was administered as an iv bolus at a dose of 0, 37.5, 75, or 150 IU in a randomized fashion. The r-hFSH (Gonal-F) was kindly provided by Serono Laboratories, Inc. (Norwell, MA). None of the PCOS subjects had experienced recent ovulation, as evidenced by serum progesterone (P4) levels of less than 1 ng/ml (< 3.0 nmol/liter) at the baseline sample. Blood samples were drawn through an indwelling iv catheter at half hour intervals for 2 h before and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 20, and 24 h after r-hFSH administration. Samples were allowed to clot, and sera were separated by centrifugation and stored at -20 C until assayed. Individual serum samples were analyzed in the same assay in duplicate.

Assays

Serum LH and FSH concentrations were measured by RIA with intra- and interassay coefficients of variation (CV) of 5.4% and 8.0%, respectively, for LH and 3.0% and 4.6% for FSH (Diagnostic Products Corp., Los Angeles, CA). Serum concentrations of estrone (E1), E2, androstenedione (A), and testosterone (T) were measured by well established RIA with intraassay CV less than 7%. P4, 17-OHP, and dehydroepiandrosterone sulfate (DHEAS) were measured by RIA with intraassay CV less than 7% (Diagnostic Systems Laboratories, Inc., Webster, TX). Serum insulin levels were measured by a double antibody RIA with an assay sensitivity of 2 µU/ml and intra- and interassay CV of 7% and 9%, respectively. Plasma glucose levels were determined by the glucose oxidase method (YSI, Inc., Yellow Springs, OH) with an intraassay CV less than 2% and an interassay CV of 3%.

Statistical analysis

Baseline hormone values between PCOS and normal women were compared by group t tests using SPSS software (SPSS, Inc., Chicago, IL). E2 responses were analyzed separately as maximum concentration, absolute maximal change from baseline, percentage maximal change from baseline, and area under the curve. Where applicable, significance testing was two-sided at a 5% significance level. No adjustments were made to control for the overall significance level affected by multiple comparisons (except for Dunnett’s tests). A significant dose-response relationship for each group was tested with simple linear regression. Dose and group effects and time and group effects on serum E2 were tested using two-factor repeated measures analyses of covariance with adjustments for stimulated FSH levels. In the case of significant dose-group interaction, between-group differences were tested relative to dose (7). Dunnett’s tests were used to compare all higher doses to the baseline dose. If a significant difference was detected between groups at a particular dose, a two-group repeated measures analysis of covariance with adjustments for stimulated FSH levels as a covariate was performed to determine the effects of time and group at that dose. For significant time-group interaction, between-group comparisons were performed relative to time. Dunnett’s tests were used to conduct within-group comparisons of E2 responses at each time point relative to baseline levels. SAS software, version 8 of the SAS System for Windows (SAS Institute Inc., Cary, NC), was used for the statistical analyses.


   Results
Top
 Abstract
 Introduction
 Subjects and Materials
 Results
Discussion
 References
 
Baseline studies

Baseline hormone values are shown in Table 1Go. In PCOS, mean (±SE) circulating levels of LH, T, A, E1, and fasting insulin were significantly greater than those of normal controls. Serum FSH, DHEAS, 17-OHP, E2, P4, and fasting glucose levels were similar in both groups.


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  		Table 1. Mean endocrine—metabolic values (±SE) of PCOS and normal subjects

 
Serum FSH levels in response to r-hFSH administration

Intravenous administration of r-hFSH at all doses resulted in an instantaneous rise of circulating FSH levels, with peak values measured at 30 min after injection (Fig. 1Go). In PCOS, the increases in serum FSH were dose-related, with maximum concentrations of 9.5 ± 0.7, 15.3 ± 2.2, and 22.0 ± 1.2 mIU/ml attained at doses of 37.5 IU, 75 IU, and 150 IU, respectively. Thereafter, the decline in FSH followed a double exponential curve with an initial fast component reflecting clearance from the circulation and a later slow component resulting from tissue redistribution with a return to baseline at 24 h. A similar pattern of FSH response was noted for normal subjects at each dose. The profile of serum FSH response was consistent with that previously reported for r-hFSH (8). Serum LH responses to each dose of r-hFSH were unaltered over 24 h.



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  		Figure 1. Mean serum FSH concentrations after iv administration of the indicated doses of r-hFSH to PCOS (n = 16) and normal controls (n = 7) at t = 0 h. The 0-IU dose of r-hFSH is saline control.

 
E2 responses to r-hFSH administration

Before the administration of each dose of r-hFSH, mean basal levels of serum E2 in PCOS and normal controls were similar. Mean (±SE) serum E2 responses to a given dose of r-hFSH, expressed as maximum concentration, absolute increment, percentage change, and area under the curve in PCOS and normal subjects are shown in Table 2Go. After injection of saline (r-hFSH, 0-IU dose), there were no significant changes in circulating E2 levels in either group, as expected. As can be seen, administration of increasing doses of r-hFSH resulted in significant and progressive increases of E2 in PCOS subjects at all doses. By comparison, significant increases in E2 were seen in normal women only at the 75-IU and 150-IU doses, compared with responses observed after saline injection.


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  		Table 2. Mean (±SE) serum E2 responses to graded doses of r-hFSH in PCOS and normal women

 
Comparison between groups failed to detect statistical differences in mean E2 responses at 37.5-IU and 75-IU doses of r-hFSH, although a small, but not significant increase of E2 in PCOS subjects was observed at the 75-IU dose (Fig. 2Go). With the 150-IU dose of r-hFSH, there was a substantial rise of mean E2 levels in PCOS subjects, which was significantly greater than that observed in the normal control group (P < 0.0001). Regression analysis of maximal E2 concentrations in response to r-hFSH in each individual PCOS and control subject is shown in Fig. 3Go. The dose-response relationship in the group of women with PCOS (r = 0.82) was significantly greater (P < 0.01) than that of normal controls (r = 0.71). These observations, in all probability, reflect the propensity for increased E2 production in PCOS once a threshold dose of FSH had been exceeded.



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  		Figure 2. Mean (± SE) maximal serum E2 response after iv injections of the indicated doses of r-hFSH to PCOS and normal controls. Increase in serum E2 is expressed as percentage from baseline. The 0-IU dose of r-hFSH is saline control. *, P < 0.0001, PCOS vs. normal control.

 


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  		Figure 3. Regression analysis of maximal serum E2 response in PCOS and normal control women against dose of r-hFSH (PCOS, r = 0.82, P < 0.001; normal, r = 0.71, P < 0.001). Slope of linear regression line for PCOS women (solid line) is significantly greater, compared with that of normal women (dashed line; P < 0.01).

 
Time-course of E2 response to r-hFSH

The pattern of serum E2 responses over 24 h after each dose of r-hFSH in PCOS subjects and normal women is shown in Fig. 4Go. After r-hFSH administration, initial rises of E2 in both groups were noted by 3 h at 37.5-IU and 75-IU doses, whereas significant increases of E2 were advanced by 1 h at the 150-IU dose. The consistency of the elapsed time interval to the initiation of the E2 rise after iv injection of r-hFSH indicated the length of time required for induction of detectable aromatase enzyme activity in granulosa cells.



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  		Figure 4. Mean (±SE) serum E2 levels after iv administration of the indicated doses of r-hFSH to PCOS (n = 16) and normal controls (n = 7) at t = 0 h. The 0-IU dose of r-hFSH is saline control. Mean (±SE) baseline levels of serum LH and FSH are also shown.

 
The E2 response to r-hFSH attained maximal concentrations by 6 h because significant increases beyond that time were not apparent in either group. In PCOS, the increase of E2 at 6 h after injection of 37.5 IU and 75 IU of r-hFSH resulted in circulating concentrations that were not different from those observed in normal controls. However, administration of 150 IU of r-hFSH to PCOS subjects at 6 h resulted in a distinctly greater rise (P < 0.0001) of the serum E2 compared with normal controls, because the E2 increment was 1.8-fold higher than the corresponding increase found in the normal group (Fig. 4Go). At the 150-IU dose, the rate of E2 responsiveness to r-hFSH in PCOS appeared to be accelerated compared with controls, as evidenced by a more rapid rise of E2. In normal women the maximum E2 response, 139 ± 10 pg/ml (510 ± 37 pmol/liter), occurred at 6 h, whereas a comparable stimulated value in PCOS, 138 ± 9 pg/ml (507 ± 33 pmol/liter), was achieved by 4 h after r-hFSH (Fig. 5Go). Collectively, these data indicated that in PCOS women, the acute E2 response to 150 IU of r-hFSH was of greater magnitude and more rapid in comparison to normal women.



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  		Figure 5. Incremental response of serum E2 to administration of r-hFSH (150 IU) in PCOS and normal women. Mean (±SE) levels of serum E2 in PCOS are significantly greater than those of normal control at 4 h (*, P = 0.001) and at 6 h (**, P < 0.0001) after r-hFSH. Note the advanced rise of serum E2 in PCOS compared with control subjects at equivalent levels of response.

 
At the highest doses of r-hFSH tested (75 IU and 150 IU), the duration of maximal responsiveness in PCOS was 6 h, after which there was a progressive and linear decline in serum E2 of about 40% by 24 h. By comparison, the late response pattern in normal women receiving corresponding doses of r-hFSH was characterized by a persistence of elevated serum E2 once maximal concentrations had been achieved. There were no discernible differences in the patterns of E2 response to 37.5 IU of r-hFSH between PCOS and normal women.

None of the PCOS subjects ovulated, nor did they experience any menstrual bleeding after r-hFSH administration, indicating the lack of any functional effects. Normal ovulatory women did not notice any alteration in their menstrual patterns.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Materials
 Results
 Discussion
References
 
The results of this study have demonstrated that in women with PCOS, the capacity for E2 production in response to the stimulatory effects of r-hFSH was clearly enhanced compared with that of normal women, as evidenced by the significantly greater magnitude and increased rate of response after 150 IU. Notably, this difference was dose-dependent and only manifested beyond a defined dose range or threshold, because increases in circulating E2 in response to 37.5 IU and 75 IU of r-hFSH were similar in both PCOS and normal women. The continued amplification of E2 responses to increasing doses of r-hFSH in PCOS subjects compared with normal controls may be explained by greater granulosa cell responsiveness in the presence of an abundance of aromatase substrate because profiles of circulating FSH levels at each dose were essentially identical in both groups. That the PCOS ovary contains two to three times more antral follicles than the normal ovary suggests a mechanism whereby the significantly greater production of E2 in response to the highest dose of r-hFSH may have been the result of a larger number of stimulated granulosa cells (9). At lower doses, although sufficient to stimulate granulosa cells in an equivalent portion of responsive follicles from both groups, the comparatively minor increments of serum FSH appeared to have been inadequate to provoke differences in total E2 production. By contrast, the normal ovary has fewer antral follicles, and saturation of the FSH receptor population may have limited E2 production. This explanation is consistent with the recent report in which comparative E2 responses to FSH in PCOS and normal women during ovulation induction were more likely related to the number of stimulated ovarian follicles than to differences in the FSH threshold (10).

Alternatively, we have previously demonstrated in vitro that PCOS granulosa cells are extremely sensitive to FSH stimulation. In cultured granulosa cells obtained from 4- to 7-mm follicles of polycystic ovaries, FSH induced an approximately 4-fold increase in E2 levels compared with baseline (5). Comparison of the ED50 for FSH-stimulated E2 production revealed an 8-fold higher granulosa cell sensitivity to FSH in PCOS in contrast to that observed in normal cells (11). The current in vivo study has shown that PCOS women exhibited significantly increased granulosa cell responsiveness to FSH by nearly 2-fold after the 150-IU dose of gonadotropin. However, that E2 responses to lower amounts of r-hFSH were similar in PCOS and normal women evokes the notion of a putative aromatase inhibitor within the ovarian microenvironment of the polycystic ovary. In PCOS, the abundance of aromatase substrate would have been expected to result in greater E2 production in response to all doses of r-hFSH compared with that found in normal women. In this regard, it is noteworthy that administration of exogenous r-hFSH in low pharmacological amounts uniformly induced aromatase gene expression within 3 h, which suggests that aromatase inhibition, if present in PCOS, is relatively mild.

Whether these results reflect increased numbers of stimulated follicles or increased granulosa cell sensitivity to FSH or both, the linear trend analysis of increasing E2 responsiveness to higher doses of r-hFSH in the PCOS group compared with normal ovulatory women clearly demonstrated the susceptibility of the granulosa cell to gonadotropin stimulation. This susceptibility is, in part, the underlying basis for ovarian hyperstimulation and underscores the importance of low-dose gonadotropin treatment for ovulation induction in these PCOS women (12).

In contrast to normal ovulatory women, it was clear that the release of E2 from PCOS granulosa cells was relatively transient during the 24-h time period following a single iv injection of r-hFSH at all doses tested. After maximal stimulation, the progressive decline of serum E2 levels was equivalent to at least a 40% reduction from peak values, whereas maximal responses were maintained in normal controls because only minimal decreases were observed up to 24 h. It is unclear why PCOS granulosa cells were unable to sustain the release of E2 because stimulatory levels of FSH after r-hFSH were equivalent in both groups, and previous studies have demonstrated significant amounts of bioactive FSH within the follicular fluid of PCOS ovaries (13). Alternatively, responsive follicles within the PCOS ovary are likely comprised of a heterogeneous population of granulosa cells, most of which are in various stages of atresia. As a result, in PCOS women, normal or robust E2 release may reflect increased numbers of responsive follicles, whereas the relatively temporary nature of this response suggests impaired granulosa cell function.

These results in PCOS are strikingly similar to previous in vitro data from our group that compared the time-course of FSH-stimulated responses in granulosa cells from PCOS and normal ovaries (5, 11). Although the initial E2 rise was greater in cultured granulosa cells of PCOS, subsequent production was minimal compared with normal cells. Treatment of the PCOS granulosa cells with IGF-I resulted in continued E2 production, which suggested that IGF-I or similar peptides may facilitate granulosa cell function. This is consistent with studies that have demonstrated decreased IGF-II levels and increased IGF binding protein (IGFBP)-4 concentrations in follicular fluid from androgen-dominant follicles, as would be expected in PCOS (14, 15). In addition, the lack of IGFBP protease activity found in these androgenized follicles may have predisposed to an environment dominated by IGFBP-4, thereby minimizing IGF-II bioavailability (16). The possibility also exists that factors other than IGFBP may exact an inhibitory effect on FSH action.

In conclusion, we have determined that in PCOS women, the capacity of the granulosa cell to produce E2 in response to r-hFSH is significantly greater than that observed in normal women. Notably, increased E2 responsiveness was only apparent once the FSH threshold had been exceeded. In PCOS women, the release of E2 was transient, particularly at higher doses of r-hFSH, which suggested an abnormality of the granulosa cell and/or an inability to respond to FSH.


   Acknowledgments
 
We are grateful to Mr. Jeff Wong and the nurses and staff of the General Clinical Research Center for their dedicated care. We also thank Sandra Stanton for assistance in the preparation of this manuscript.


   Footnotes
 
This research was supported by National Institute of Child Health and Human Development/National Institutes of Health (NIH) through a cooperative agreement (U54 HD12303-20) as part of the Specialized Cooperative Centers Program in Reproduction Research and in part by NIH Grant M01 RR00827.

Abbreviations: A, Androstenedione; CV, coefficient(s) of variation; DHEAS, dehydroepiandrosterone sulfate; E1, estrone; E2, estradiol; IGFBP, IGF binding protein; 17-OHP, 17-hydroxyprogesterone; PCOS, polycystic ovary syndrome; P4, progesterone; r-hFSH, recombinant human FSH; T, testosterone.

Received August 13, 2002.

Accepted December 20, 2002.


   References
Top
 Abstract
 Introduction
 Subjects and Materials
 Results
 Discussion
 References
 

  1. Wang CF, Gemzell C 1980 The use of human gonadotrophins for the induction of ovulation in women with polycystic ovarian disease. Fertil Steril 33:479–486[Medline]
  2. Hamilton-Fairley D, Franks S 1990 Common problems in induction of ovulation. Bailliere’s Clin Obstet Gynaecol 4:609–625
  3. Rebar R, Judd HL, Yen SS, Rakoff J, Vandenberg G, Naftolin F 1976 Characterization of the inappropriate gonadotropin secretion in polycystic ovary syndrome. J Clin Invest 57:1320–1329
  4. DeFazio J, Meldrum DR, Lu JK, Vale WW, Rivier JE, Judd HL, Chang RJ 1985 Acute ovarian responses to a long-acting agonist of gonadotropin-releasing hormone in ovulatory women and women with polycystic ovarian disease. Fertil Steril 44:453–459[Medline]
  5. Erickson GF, Magoffin DA, Cragun JR, Chang RJ 1990 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 70:894–902[Abstract]
  6. Mason HD, Willis DS, Beard RW, Winston RM, Margara R, Franks S 1994 Estradiol production by granulosa cells of normal and polycystic ovaries: relationship to menstrual cycle history and concentrations of gonadotropins and sex steroids in follicular fluid. J Clin Endocrinol Metab 79:1355–1360[Abstract]
  7. Winer BJ, Brown DR, Michels KM 1991 Statistical principles in experimental design, 3rd ed. New York: McGraw-Hill
  8. Cotonnec J, Porchet HC, Beltrami V, Khan A, Toon S, Rowland M 1994 Clinical pharmacology of recombinant human follicle-stimulating hormone (FSH). I. Comparative pharmacokinetics with urinary human FSH. Fertil Steril 61:669–678[Medline]
  9. Hughesdon PE 1982 Morphology and morphogenesis of the Stein-Leventhal ovary and of so-called "hyperthecosis." Obstet Gynecol Surv 37:59–77[Medline]
  10. Van Der Meer M, De Boer JAM, Schats R, Schoemaker J 1998 Cohort size rather than follicle-stimulating hormone threshold level determines ovarian sensitivity in polycystic ovary syndrome. J Clin Endocrinol Metab 83:423–426[Abstract/Free Full Text]
  11. Erickson GF, Garzo VG, Magoffin DA 1989 Insulin-like growth factor I (IGF) regulates aromatase activity in human granulosa and granulosa luteal cells. J Clin Endocrinol Metab 69:716–724[Abstract]
  12. White DM, Polson DW, Kiddy D, Sagle P, Watson H, Gilling-Smith C, Hamilton-Fairley D, Franks S 1996 Induction of ovulation with low-dose gonadotropins in polycystic ovary syndrome: an analysis of 109 pregnancies in 225 women. J Clin Endocrinol Metab 81:3821–3824[Free Full Text]
  13. Erickson GF, Magoffin DA, Garzo VG, Cheung AP, Chang RJ 1992 Granulosa cells of polycystic ovaries: are they normal or abnormal? Hum Reprod 7:293–299[Abstract/Free Full Text]
  14. Cataldo NA, Giudice LC 1992 Insulin-like growth factor binding protein profiles in human ovarian follicular fluid correlate with follicular functional status. J Clin Endocrinol Metab 74:821–829[Abstract]
  15. Cataldo NA, Giudice LC 1992 Insulin-like growth factor binding protein profiles in follicular fluid in polycystic ovarian syndrome. J Clin Endocrinol Metab 74:695–697[Abstract]
  16. Yap OW, van Dessel HJ, Chandrasekher YA, Fauser BC, Giudice LC 1997 Insulin-like growth factors and insulin-like growth factor binding proteins in androgen-dominant ovarian follicles from testosterone-treated female-to-male trans-sexuals. Fertil Steril 68:252–258[CrossRef][Medline]



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J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5957 - 5962.
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