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Department of Reproductive Medicine (G.A.R.M., K.H., R.J.C., G.F.E.), University of California, San Diego, La Jolla, California 92093; Universidade Federal de São Paulo (E.C.B.), São Paulo, Brazil 01311-940; University of Iowa Carver College of Medicine (J.A.B., S.M.M.), Iowa City, Iowa 52242
Address all correspondence and requests for reprints to: Gregory F. Erickson, Ph.D., Department of Reproductive Medicine, University of California San Diego, La Jolla, CA 92093-0674. E-mail: gerickson{at}ucsd.edu.
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Abstract |
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Introduction |
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One area of active investigation in PCOS has been the ovary (8, 9, 10, 11, 12). This analysis has focused primarily on the granulosa and theca interstitial cells of the small Graafian follicles that accumulate in the cortex of PCOS ovaries. At the differentiation level, the PCOS Graafian follicles appear to be up-regulated as demonstrated by the presence of supraphysiological levels of bioactive FSH in the microenvironment (13), overexpression of FSH receptors in the granulosa cells (14), hypersensitivity to FSH stimulation (13, 15), and enhanced capacity of the theca to produce androgens in response to LH and insulin stimulation (16, 17, 18). These properties can be contrasted with a reduced capacity for follicle cell proliferation, which in turn causes the PCOS Graafian follicle to stop growing. The arrest of Graafian follicle development is paradoxical because one would expect that the high levels of FSH bioactivity in follicular fluid and the super FSH responsiveness of the granulosa cells would lead to the selection of multiple dominant follicles (19), with the continued cytodifferentiation (11, 13, 20) and increased proliferation of granulosa cells (21, 22). Why this does not occur in PCOS ovaries is an enigma.
An important, yet overlooked, question in PCOS is when during folliculogenesis follicle growth and development become abnormal. Based on studies in laboratory animals, it is clear that growing follicles can be disrupted in their growth and development long before they reach the more advanced Graafian stage (23, 24, 25). For example, growth differentiation factor (GDF-9) (26, 27, 28) and bone morphogenetic protein (BMP-15) (24, 29) produced by oocytes have profound growth and differentiation effects on the small preantral follicles. In the absence of bioactive GDF-9 (26) and BMP-15 (30), the process of preantral follicle growth fails to advance beyond the classic primary stage because of the cessation of granulosa cell mitosis. Evidence also points to a key role of oocyte growth factors in regulating cytodifferentiation, including FSH receptor expression and action (31, 32), cumulus expansion (33, 34), and theca androgen production (35, 36). In normal human ovaries, the oocytes of developing follicles express GDF-9 and BMP-15 (37, 38), and GDF-9 is capable of provoking the growth of primary follicles in vitro (39). Collectively, these findings imply that oocyte-derived GDF-9 and BMP-15 are likely to play an important role in regulating cell division, cytodifferentiation, and growth of developing human preantral follicles.
Of potential pathological importance is our recent finding that the temporal pattern of expression of GDF-9 is significantly delayed and reduced in PCOS oocytes during folliculogenesis, particularly at the primary and secondary stages (40). Because GDF-9 plays a pivotal role in normal preantral follicle growth, we hypothesized that quantitative changes might occur in the follicle population in PCOS ovaries with a possible build-up of classic primary follicles. The purpose of the present study is to test this hypothesis.
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Materials and Methods |
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The Institutional Review Board of the University of California, San Diego, and the University of Iowa approved the present study. A total of 37 ovaries were analyzed in this study. Seventeen normal ovaries were obtained from 13 regularly cycling women at various stages of the menstrual cycle (Table 1
), with the exception of three patients who were under sex steroid treatment for dysfunctional uterine bleeding. Surgeries were for nonovarian gynecological reasons (Table 1), and written informed consent had been obtained from each individual. The average age of the women with normal ovaries was 35.4 ± 4.4 yr (range, 26–43 yr). The average body mass index (BMI) was 28.5 kg/m2 (range, 19.7–49.6 kg/m2). Twenty ovary samples from 14 PCOS subjects were analyzed in this study (Table 2). The PCOS ovary samples were obtained from the archives of the Department of Pathology at the University of Iowa. The samples were collected between 1963 and 1997. Surgeries were for nonovarian gynecological reasons with the exception of one woman with a teratoma. Six of the PCOS patients had both ovaries removed because of endometrial carcinoma. The other PCOS ovary samples were obtained from wedge resections performed for treatment of infertility. Diagnosis of PCOS was based on hirsutism, menstrual cycle disturbances (oligomenorrhea or amenorrhea), and histological confirmation of PCOS ovaries as previously described (40). These ovaries appeared to meet the current updated definition for PCOS as recently published from the Rotterdam Conference. In general, the present PCOS ovaries displayed histological and morphological changes typical of those described by Goldzieher and Axelrod (8); they contained large numbers of small Graafian follicles that were encapsulated by a thick layer of theca interstitial cells, had a thickened tunica albuginea composed of collagenous fibers and associated stromal cells, and had no corpora lutea. By comparison, the ovaries from normal cycling women (n = 13) contained relatively few Graafian follicles, had a thinner tunica albuginea, and exhibited a corpus luteum. None of the normal ovaries studied exhibited visual evidence for ovulatory PCOS. The clinical data were obtained from chart reviews. The average age of the PCOS patients was 31.6 ± 6.8 yr (range 21–43). At the time of surgery, eight of the PCOS patients had not received any medications, whereas six were receiving sex hormone therapy (Table 2).
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The ovary samples were fixed in 10% neutral buffered formalin, paraffin embedded, sectioned, and stained with hematoxylin and eosin. Follicles were scored in a random 10-µm section from each ovary. Precisely where in the ovary the sections were obtained was not determined. Two different observers scored follicles independently with similar results. We have considered the primordial follicles as nongrowing. The growing follicles were scored in each ovary section according to the following classification: transitional primary, classic primary, secondary, or Graafian (antral). In the pool of preantral follicles (primordial, primary, and secondary), only those follicles in which the oocyte nucleolus was present (the largest cross-section) were scored. The majority of Graafian follicles did not contain an oocyte in the sections examined. Therefore, all Graafian follicles (healthy and atretic) were scored using the antrum as a marker. Such follicles measured between 0.5 and approximately 8 mm in diameter. To identify atresia in the pool of preantral follicles, the largest cross-section was screened for granulosa cell death as defined by the presence of classic apoptotic bodies (41).
To normalize and validate our data, we calculated the total amount of tissue in both groups (normal and PCOS) by measuring the total area occupied by the ovary tissue on each slide. To make sure there was no bias in the inclusion of both ovaries from a single patient in the statistical analysis, we performed a statistical analysis using only one ovary chosen at random from each subject. We also compared the pairs within the same patient. When these statistical approaches were employed, statistically significant differences between follicle populations were maintained. Because the shapes were so irregular, a digital analysis was performed on each section. The total number of points, e.g. the area in megapixels/mm2, was then used in the sample analysis. The results of the digitalized analysis show that the total surface area examined was the same for the normal and PCOS groups [normal, 0.62 ± 0.13 megapixels/mm2; PCOS, 0.60 ± 0.10 megapixels/mm2 (mean ± SE; P = 0.89)].
Statistical analysis
The number of follicles, ages, and the BMI in PCOS and normal samples were analyzed using one-way ANOVA or Kruskal-Wallis. Analyses were performed using Sigma Stat 2.03 software. A P value < 0.05 was considered to be significant, and the results are presented as the mean ± SE. To exclude the possibility of bias, which may have arisen from inclusion of both ovaries from a single individual in the statistical analysis, a subsequent analysis was performed with only one ovary per subject chosen randomly. With this approach, the statistically significant differences between follicle populations were maintained.
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Results |
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The PCOS patients had a greater BMI compared with normal women, but it was not statistically significant (34.1 ± 2.5 vs. 28.4 ± 2.1 kg/m2, respectively; P = 0.09). There was no statistically significant difference in the mean ages between the PCOS and normal patients (P = 0.129), and there was no difference in the number of follicles scored and the patient’s age (normal, P = 0.91; PCOS, P = 0.52). The possible relationship between medication and follicle number and composition was also analyzed. No effect of sex hormone treatment was found in either the normal or PCOS patients. We compared PCOS patients and normal women with no medication and hormones, respectively. In PCOS women, the results were as follows: primordial, 37.4 ± 11.0 vs. 31.1 ± 9.0 (P = 0.41); primary, 27 ± 7.4 vs. 32.6 ± 4.1 (P = 0.48); secondary, 2.1 ± 0.6 vs. 3.5 ± 0.5 (P = 0.16); Graafian, 8.2 ± 1.6 vs. 10.2 ± 1.3 (P = 0.41). In normal women, the results were as follows: primordial, 34.3 ± 9.0 vs. 13.5 ± 3.6 (P = 0.07); primary, 11.1 ± 2.5 vs. 11.1 ± 1.7 (P = 0.99); secondary, 1.0 ± 0.2 vs. 2.8 ± 2.6 (P = 0.14); Graafian, 5.5 ± 3.2 x 3.5 ± 2.3 (P = 0.10). Therefore, data from patients receiving medications were included in the analysis.
Follicle classification employed
We scored all follicles within the ovary sections. In both normal and PCOS ovaries, the primordial follicles were found mainly in the stroma of the cortex, juxtaposed to the medial edge of the tunica albuginea. They may appear as single isolated primordial follicles or in small clusters. Occasionally, primordial follicles were seen deep in the medullary stroma where they usually appeared as single follicles. A similar pattern of distribution was observed for the primary and secondary follicles in both normal and PCOS ovaries.
Figure 1 shows a representative sample of the follicles that were scored using our classification scheme. Primordial follicles (unilaminar nongrowing follicles) were identified by the presence of an oocyte arrested in the dictyate stage of meiosis and a single layer of flattened or squamous granulosa cells (Fig. 1A). Transitional primary follicles were identified by the presence of a dictyate oocyte enveloped by a single layer of mixed flattened and cuboidal granulosa cells (Fig. 1B). The transition from a nongrowing primordial to a growing primary follicle (the primordial-to-primary transition or recruitment) involves noticeable cytological changes in the granulosa cells in which some become cuboidal or low columnar. Classic primary follicles were identified by the presence of an oocyte surrounded by a single layer of cuboidal granulosa cells (Fig. 1C). Secondary follicles were identified by an oocyte surrounded by two to eight layers of granulosa cells with no antrum being present (Fig. 1D). If a follicle was found in the beginning stages of forming a second layer of granulosa cells (the primary-to-secondary transition), it was scored as a secondary follicle. Graafian follicles contained a fluid-filled antrum (Fig. 1E).
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The number and composition of the follicles scored in the sections of normal ovaries are shown in Table 3. A total of 707 follicles were scored in 17 normal ovaries (mean number, 42 follicles per sample; range, 11–119). Differential counts showed a mean number of 24 primordial follicles per sample that represented 57% of the total follicle population. The mean number of growing primary follicles per section was 11, and that represented 26% of the total follicles counted. The number of secondary follicles was small; the mean number was 1.7 follicles per sample, which represented only 4% of the total number of ovarian follicles. All specimens contained Graafian follicles (mean number, 4.7) that represented 11% of the follicle population.
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The number and composition of the follicles scored in the PCOS samples are shown in Table 4. The total number of follicles counted in 20 PCOS samples was 1567 (mean number per sample, 78; range, 14–206). Of all the PCOS follicles counted, 43.5% were at the primordial stage, 39.5% at the primary stage, 4% at the secondary, and 12.8% at the Graafian stage. As with normal, the number of secondary follicles was very low (approximately three per section) in the PCOS ovaries.
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The mean number of follicles per ovary section was used to evaluate differences in follicle populations between PCOS and normal. These data are summarized in Fig. 2. The total number of follicles (growing plus nongrowing) was significantly increased (
2-fold) in PCOS when compared with normal controls. No statistical difference was found in the number of primordial (nongrowing) follicles between normal and PCOS samples. Consequently, this increase in growing follicles in PCOS cannot be explained by increased rates of recruitment of primordial follicles into the pool of growing follicles. Significant increases, however, were found in the number of growing follicles at each stage of development; PCOS ovaries contained 2.7-fold more primary (P < 0.001), 1.8-fold more secondary (P = 0.02), and 2.0-fold more Graafian (P < 0.001) follicles when compared with normal. In the pool of preantral follicles (primordial, primary, and secondary), apoptotic oocytes and granulosa cells were never seen in any section of ovary examined (normal and PCOS), and thus atresia was absent. It is unlikely, therefore, that the increases in growing follicles in PCOS results from changes in preantral atresia.
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To assess further how PCOS affected the pool of primary follicles, we separated them into transitional and classic primary. As shown in Fig. 3A, most of the primary follicles were in transitional form in both PCOS and normal ovaries. A marked increase in the number of transitional primary follicles (2.3-fold; P = 0.001) was seen in the PCOS ovaries compared with that in normal ovaries. Notably, classic primary follicles were quite rare in normal ovaries as evidenced by their relatively small number (2.1 ± 1.4). Conversely, classic primary follicles appeared to be present in much higher numbers (9.4 ± 2.8) in PCOS ovaries (Fig. 3A). Interestingly, the greatest increase in the number of growing follicles present within PCOS ovaries was seen in the pool of classic primary follicles (450%). This build-up of classic primary follicles in PCOS is illustrated in Fig. 3B.
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Discussion |
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Supporting this view is the recent observation by Webber et al. (42) that the proportion of early growing (primary) follicles is higher in anovulatory and ovulatory women with PCOS ovaries compared with that in normal ovaries. Further support for this concept comes from a classical study performed by Hughesdon (43) on full-thickness Stein-Leventhal ovarian wedges wherein the numbers of primary, secondary, and Graafian follicles were found to be twice normal. Thus, these two reports are consistent with our conclusion that the rate of primary follicle growth is reduced in PCOS. It should be noted that in contrast to our results and those of Hughesdon, the Webber group noted an apparent reciprocal decrease in the proportion of primordial follicles. The reason for this apparent discrepancy is not clear, but it emphasizes the importance of investigating further the possible role of recruitment in this pathology.
With respect to mechanism, several possibilities emerge. First is the GDF-9 hypothesis. In animals (25) and humans (38, 40), GDF-9 expression normally begins in oocytes at the primordial/primary follicle transition and continues at high levels throughout primary and secondary follicle growth. This contrasts with PCOS oocytes in which little or no GDF-9 is detectable in primary follicles (40). Support for a potential role of abnormal GDF-9 expression in PCOS oocytes comes from animal studies in which the loss of bioactive GDF-9 results in the arrest of folliculogenesis at the classic primary stage (26, 27, 28, 30). This evidence, together with data from cultured rat ovaries (44, 45), has led to the concept that oocyte-derived GDF-9 is necessary for normal preantral follicle growth through its ability to stimulate granulosa cell proliferation. Results with cultured human ovaries are consistent with this concept (39). Collectively, this evidence supports a model in which a lack of oocyte-derived GDF-9 during the initial stages of PCOS folliculogenesis could reduce the rate of granulosa mitosis, which in turn may slow the rate of follicle growth, which in turn could increase the number of growing and classic primary follicles. An interesting question is whether a newly discovered suppressor of GDF-9 gene activity, germ cell nuclear factor, has a role in this process (46).
The second possibility is the effect of excessive ovarian androgen production. Experiments in monkeys demonstrate that exogenous androgens increase the number of classic primary follicles (47). The mechanism is unclear but appears to be mediated by androgen receptors expressed in the granulosa cells (48, 49). In this context, experiments in monkeys suggest that the androgen-induced increase in the pool of primary follicles might involve the increased expression of IGF-I and IGF-I receptor mRNAs in the oocytes (50). In both normal (51) and PCOS (52) ovaries, androgen receptors are expressed in granulosa cells of preantral follicles. Furthermore, treating women with exogenous androgens leads to the development of bilateral polycystic ovaries (53). Thus, a model for describing changes in the rate of folliculogenesis in PCOS, which takes into account the local effect of increased ovarian androgens on the accumulation of classic primary follicles, could be proposed.
The third possibility is that increased LH secretion influences the growth of primary follicles. It is well recognized that the rate of LH release is increased in women with PCOS (54, 55) and that increased plasma LH contributes to increased androgen production by the theca interstitial cells (9). That this LH alteration might be a part of the mechanism of primary follicle build-up in PCOS ovaries comes from a rather startling study in mice (56). It was found that treating neonatal mice with pregnant mare serum gonadotropin (PMSG) markedly increases the number of growing primary follicles, independent of changes in number of the primordial follicles. Thus, high levels of gonadotropin (PMSG) are capable of slowing the rate of primary follicle growth in the neonatal mouse. The uniqueness of this PMSG effect becomes apparent when one considers that all known factors capable of increasing the size of the pool of growing follicles do so by stimulating primordial follicle recruitment, including kit ligand (57), BMP-4, (58) BMP-7 (59), insulin (60), basic fibroblast growth factor (61), and leukemia inhibitory factor (62). Because this PMSG phenomenon closely resembles what we found here in the PCOS ovaries, it might be worthwhile to determine whether the PMSG-treated neonatal rat might be a novel animal model for human PCOS.
In this light, understanding how PMSG reduces the rate of primary follicle population is an interesting challenge. Two points are clear; PMSG has equal LH and FSH bioactivity (63), and, as discussed already, LH-stimulated theca androgen production is implicated in increasing the number of classic primary follicles in monkey ovaries. Thus, it is possible that increased androgens could mediate the PMSG effect. It is worth noting that IGF-I receptor activation leads to enhanced LH-stimulated androgen production by theca cells (9) and that androgens up-regulate IGF-l receptor expression in primate theca cells (50). Taken together, these findings provide support for the possibility that increased IGF-I receptors could be integrally involved in the LH/PMSG hypothesis to explain the accumulation of primary follicles. It is assumed, but not proven, that the PCOS ovaries in our study were exposed to increased insulin action, which could also act to promote theca androgen production. If true, then elevated insulin levels could be related to the mechanism of the primary follicle accumulation in PCOS.
Another possibility is that the PMSG effect is attributable to its FSH bioactivity. Indeed, the ability of FSH to directly stimulate preantral follicle growth supports this possibility (64). Interestingly, PCOS granulosa cells are supersensitive to FSH stimulation (13, 15), and up-regulation of FSH receptors appears to contribute to this phenomenon (14). In this scenario, androgens have been shown to significantly increase FSH receptor mRNA abundance in primate granulosa cells (65), although its relevance to PCOS awaits confirmation in functional studies.
In summary, the present study points to defects in the ability of primary follicles to grow normally in PCOS. Although the functional significance of this defect remains to be established, one wonders whether it could be linked to functional disruption of gonadotropin-dependent functions resulting in the pathology of PCOS ovaries. We have emphasized the importance of understanding the role of GDF-9, androgens, LH, and FSH in this process. The results could have important implications for understanding the cellular basis of the PCOS disorder.
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Acknowledgments |
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Footnotes |
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Abbreviations: BMI, Body mass index; BMP, bone morphogenetic protein; GDF, growth differentiation factor; PCOS, polycystic ovary syndrome; PMSG, pregnant mare serum gonadotropin.
Received April 5, 2004.
Accepted August 12, 2004.
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