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Androgens Promote Oocyte Insulin-Like Growth Factor I Expression and Initiation of Follicle Development in the Primate Ovary¹

^a Section on Women's Health, Developmental Endocrinology Branch, NICHD, NIH, Bethesda, Maryland 20892

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
In the study reported here, we investigated the effect of androgens on recruitment of resting, primordial follicles into the actively growing pool. Healthy, random-cycling female rhesus monkeys were treated with testosterone, dihydrotestosterone (DHT), or vehicle for 3–10 days, after which ovaries were collected for histological analysis. The first stage of follicle growth is the formation of the primary follicle, consisting of an oocyte surrounded by a single layer of cuboidal granulosa cells. The number of primary follicles was significantly increased over time in testosterone-treated animals. In situ hybridization showed that androgen treatment resulted in an increase to 3-fold in insulin-like growth factor I (IGF-I) and to 5-fold in IGF-I receptor mRNA in primordial follicle oocytes. DHT effects were comparable to those of testosterone, showing that these are androgen receptor-mediated phenomena. These data show that androgens promote initiation of primordial follicle growth and implicate oocyte-derived IGF-I in this activation process.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Hundreds of thousands of dormant oocytes are embedded in the cortex of the primate ovary at the time of birth [1, 2]. Each of these oocytes is enveloped by a single layer of crescent-shaped granulosa cells forming the primordial follicle. This nonrenewable stock of primordial follicles is steadily depleted as a result of two processes: atresia and entry into the growth pool [3]. The factors governing these processes, which begin in utero and continue throughout the reproductive life span, remain unknown. While FSH is clearly essential for later stages of follicular development, its role in the initiation and early stages of follicular growth is uncertain (reviewed in [3]). Recent evidence that ovarian follicles undergo early stages of development in mice and humans with genetic deficiencies in FSH or the FSH receptor [4, 5] argues against an obligate role for FSH in the initiation of follicular growth. A complex maze of cell-cell interactions involving oocyte, granulosa cells, and surrounding stromal tissue has been implicated in primordial follicle survival and early stages of follicle development [3, 6].

The earliest visible sign of primordial follicular recruitment into the growth pool is the transformation of the flattened, squamous-appearing granulosa cells into cuboidal epithelial-type cells, resulting in an increase in follicle diameter [1–3]. The oocyte surrounded by a single layer of cuboidal granulosa cells is termed a primary follicle. After this stage, granulosa cell proliferation commences, and follicle growth is characterized by increasing layers of granulosa cells. The factor or factors involved in triggering the transformation of primordial into primary follicle are unknown, and there is no agent, natural or pharmacological, known to be able to stimulate the process in vivo. Our previous work showed that androgens stimulate granulosa cell proliferation and growth of larger follicles in the nonhuman primate ovary [7]. In the present study, we address the issue of androgen effect upon the earliest stage of follicle development, the transition from primordial to primary follicle.

	MATERIALS AND METHODS

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As described in our previous report [7], female rhesus monkeys (Macacca mulatta), 6–13 yr of age, from the National Institutes of Health (NIH) Poolesville colony were used in accordance with a protocol approved by the National Institute of Child Health and Human Development (NICHD) animal care and use committee. The mean ages of the animals in each group were not significantly different. Animals had pellets (Innovative Research of America, Toledo, OH) containing vehicle (n = 8), testosterone (20 µg/kg, n = 5), or dihydrotestosterone (DHT) (145 µg/kg, n = 5) inserted s.c. under ketamine anesthesia. Ovaries were removed after 5 days of treatment. Two other groups (n = 5 each) had high-dose testosterone pellets (400 µg/kg) for 3 or 10 days. Hormone levels were measured by RIA as previously reported [7]. Ovaries were snap-frozen on dry ice and stored at -70°C or fixed in formalin and embedded in paraffin. Whole frozen ovaries were cut into 10-µm-thick sections along the longitudinal axis on a cryostat at -15°C, which were thaw-mounted onto poly-L-lysine coated slides and stored at -70°C. Paraffin-embedded ovaries were cut in 6-µm-thick sections.

Fresh frozen tissue sections were fixed in 4% formalin for 10 min and then stained with hematoxylin and eosin. Paraffin sections were deparaffinized and then stained with hematoxylin and eosin. The two largest sections from each ovary were chosen for morphometric analysis. A primary follicle was defined as an oocyte surrounded by a single layer of cuboidal granulosa cells. The total number of such follicles was counted microscopically at x200 by a blinded observer for each of the two largest sections for each ovary; these means were pooled to obtain group means.

RNA probes for detection of insulin-like growth factor I (IGF-I) and IGF-I receptor mRNAs were synthesized as previously described and used for in situ hybridization as previously reported [8–10]. Nonspecific background was determined from sense probes hybridized to parallel sections in the same incubations. All sections for each probe were hybridized and exposed in a single batch. Hybridized tissue sections were exposed to nuclear emulsion for 3 wk and then developed, fixed, and counterstained. To quantify the hybrid signal in primordial follicle oocytes, silver grains overlying each oocyte were counted microscopically at a magnification of x400 under oil. At least 50 primordial follicles were scored for each ovary. Nonspecific signal was determined as the number of grains over primordial oocytes in sense probe hybridized sections; this count was subtracted from antisense counts. Mean grain counts for each animal were pooled to obtain group means. Group means for primary follicle number and for primordial oocyte grain counts were compared using ANOVA, followed by Fisher's least-significant difference test. A p value < 0.05 was taken as significant.

	RESULTS

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Primary Follicles

We have previously found that androgens increase the numbers of small- and medium-sized follicles but not large preovulatory follicles, in the rhesus monkey ovary [7]. However, in that prior analysis, we did not specifically enumerate primary follicles as a distinct entity. In the present analysis, to determine whether androgens stimulate the earliest stage of follicle development, we counted the number of primary follicles in the largest ovary sections from each animal. The number of primary follicles was significantly increased in the ovarian cortex of all androgen-treated groups (Fig. 1). There was an increase of almost 50% after 3 days, 75% at 5 days, and 130% at 10 days of testosterone treatment. Five days of testosterone and DHT treatment had comparable results, showing that these are androgen receptor-mediated effects. All the androgen-treated groups had androgen levels greater than or equal to ten times control values (as reported in Table 3 of [7]) at the time of ovariectomy.

View larger version (60K): [in this window] [in a new window]   FIG. 1. Primary follicles were increased in number in androgen-treated monkey ovaries. Micrographs show ovarian cortex from representative control (A) and androgen-treated (B) monkeys. The section shown in B is from a 5-day testosterone-treated animal. Arrows point out examples of primary follicles, which consist of an oocyte surrounded by a single layer of cuboidal granulosa cells. Primordial follicles are indicated by double arrowheads. Bar = 100 µm. The mean ± SEM number of primary follicles per ovary cross section in each treatment group is compared graphically in C. d, Day; T, testosterone. p values: * < 0.003 vs. control; ** < 0.0001 vs. control and 0.003 vs. 3- and 5-day testosterone/DHT treatment groups.

Androgen Induction of Oocyte IGF System

We have previously noted expression of IGF-I and the IGF-I receptor in human oocytes and hypothesized a role for IGF-I in oocyte activation and initiation of follicle development [8]. Therefore, in the present study, we evaluated the effects of androgen treatment on IGF-I and IGF-I receptor gene expression in primordial follicles. In control, vehicle-treated animals, IGF-I mRNA was uniformly detected in oocytes from primary and more advanced follicles but very rarely in primordial follicle oocytes (Fig. 2). For example, only 24.6 ± 6.1% of primordial follicles in control ovaries contained IGF-I mRNA compared to 75.0 ± 2.0% in 3-day testosterone-treated animals (p < 0.0001). Furthermore, the relative abundance of IGF-I mRNA hybrid signal was greater in primordial follicle oocytes from androgen-treated monkeys than in "positive" primordial follicle oocytes from controls (Fig. 2). IGF-I immunoreactivity was also increased in primordial follicle oocytes from androgen-treated monkeys (not shown).

View larger version (134K): [in this window] [in a new window]   FIG. 2. Androgens increased IGF-I expression in primordial follicle oocytes. Paired dark- and brightfield photomicrographs show IGF-I mRNA in ovary sections from vehicle- (A and B) and testosterone-treated (C and D) monkeys. The hybrid signal appears as white grains in the darkfield. IGF-I mRNA was concentrated in the theca-interstitial (TH) cells surrounding large follicles seen at the top of each micrograph. IGF-I mRNA was also localized in the large oocyte in the secondary follicle seen in B, but it was not detected in primordial follicles (arrows). In the testosterone-treated monkey, however, IGF-I mRNA was abundant in primordial follicle oocytes (C and D). Con, control; T, testosterone-treated; GC, granulosa cells. Bar = 100 µm.

In contrast to IGF-I, IGF-I receptor mRNA was detected in virtually all oocytes, including primordial oocytes, in both control and androgen-treated animals. However, IGF-I receptor mRNA was markedly increased in primordial follicle oocytes in the androgen-treated monkeys (Fig. 3). Quantitation of hybridization signal for IGF-I and IGF-I receptor mRNA is shown in Figure 4, A and B. Androgen treatment was associated with an increase to approximately 3-fold in IGF-I mRNA and to more than 5-fold in IGF-I receptor mRNA concentration in primordial follicle oocytes.

View larger version (143K): [in this window] [in a new window]   FIG. 3. Androgens increased IGF-I receptor mRNA in primordial follicles. Darkfield illuminations of the ovarian cortex from representative vehicle-treated (A) and testosterone-treated (B) monkeys show IGF-I receptor (IGFR) mRNA concentrated in follicles in various stages of development. This signal was abundant in granulosa as well as oocytes. In high-magnification brightfield micrographs, silver grains representing IGF-I mRNA are seen concentrated over oocytes in primordial follicles (C and D), and are distinctly more abundant in the testosterone-treated follicles (D). Bar = 200 µm for A and B and 25 µm for C and D.

View larger version (20K): [in this window] [in a new window]   FIG. 4. Quantitation of IGF-I and IGF-I receptor mRNAs in primordial follicle oocytes. Grains overlying oocytes in primordial follicles were counted microscopically at a magnification of x400. Data are shown as means ± SEM for 4–8 animals in each group. T, Testosterone-treated; IGFR, IGF-I receptor. p values: * < 0.0001; ** < 0.003.

In our previous study, we used immunohistochemical detection of the proliferation-specific Ki67 antigen to evaluate androgen effects on follicular cell proliferation, and employed the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling) technique to examine programmed cell death in these ovaries [7]. Re-investigating these sections in the present study, we found that there was neither detectable Ki67 immunoreactivity nor evidence of DNA fragmentation in primordial or primary follicles in any of the treatment groups (data not shown).

	DISCUSSION

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This study has shown that androgen treatment results in significant increases in the number of primary follicles in the primate ovary. Testosterone and DHT treatment yielded comparable results, indicating that this is an androgen receptor-mediated effect. Increased numbers of primary follicles were evident as soon as three days after the start of androgen treatment, and their numbers increased progressively up through ten days, which was the last time point examined. Androgen treatment also resulted in a highly significant, several-fold increase in IGF-I and IGF-I receptor mRNAs in the oocytes of primordial follicles, suggesting that androgen-induced activation of oocyte IGF-I signaling may trigger primordial follicle entry into the growth pool.

There is very little knowledge of the events involved in the initiation of primordial follicle development in vivo [3]. The process occurs in fetal, prepubertal, and adult ovaries, and it remains a great mystery as to why some resting follicles are triggered to start growing in infancy while others may wait 40 yr before beginning to grow.

Gonadotropins do not appear to be involved in the initiation of primordial follicle development, as shown by the fact that mice with Fsh-targeted gene deletion demonstrate apparently normal follicular development up to the preantral stage [4]. There is less information on follicular development in women with FSH receptor deletion or inactivating mutations, but ~50% demonstrate obvious developing follicles [5].

It is not clear from the present data if androgens stimulate the initiation of follicle growth by direct or indirect effects. We have previously described the cellular pattern of androgen receptor gene expression in the rhesus monkey ovary [9], and there are two studies reporting the distribution of androgen receptor immunoreactivity in the nonhuman primate ovary [11, 12]. All three studies agree that androgen receptor expression is most abundant in granulosa cells of healthy growing follicles, particularly in the preantral and early antral stages. One of the immunohistochemical studies (in the marmoset) reported little androgen receptor expression in theca-interstitial compartments or stroma [11]. Our in situ hybridization study [9] and the immunohistochemical study of the rhesus monkey [12] agree that androgen receptor is detected in the theca-interstitium and stroma. None of the studies reported significant androgen receptor expression in primordial follicles, however. These findings suggest that androgens may stimulate increased primordial follicle development by indirect means, possibly by altering the production of stromal factors that normally restrain follicular development in a paracrine fashion. Alternatively, androgen receptor expression may be present but below detection limits in primordial oocytes. A further possibility is the existence of another androgen receptor (beta?) that is not recognized by the current probes. Thus we cannot rule out the possibility of a direct androgen action on the primordial oocytes.

Recent studies of bovine and baboon follicle development in vitro support the view that the ovarian stroma may exert inhibitory effects on primordial follicle development [13, 14]. This is inferred because culturing of small pieces of ovarian cortex yields a higher percentage of primordial follicle growth than culturing of whole murine ovaries [15]. Thus, androgens may act through stromal androgen receptors to suppress the production of factors that restrain primordial follicle development, or to otherwise override the inhibition. Alternatively, androgens may directly stimulate primordial oocyte activation and IGF-I synthesis through oocyte androgen receptors that are not detected by current methodology.

The mechanism whereby androgens promote primordial follicle development appears to involve activation of oocyte IGF-I signaling. The IGF-I receptor is abundant in oocytes from all species investigated, including rats [16], mice [17], pigs [18], monkeys, and humans [8]. IGF-I stimulates oocyte metabolic activity and maturation in vitro [19, 20]. Thus, enhanced IGF-I signaling through increased expression of both the peptide and its receptor in oocytes from androgen-treated monkeys may trigger oocyte activation and initiation of follicle growth.

Our previous work showed increased growth of secondary and small antral follicles in ovaries from androgen-treated monkeys [7]. There was a significant increase in proliferation and decrease in programmed cell death in granulosa cells from these animals. In evaluating the distribution of androgen receptor gene expression in the primate ovary, we found that androgen receptor mRNA abundance was positively correlated with granulosa proliferation and negatively correlated with granulosa cell apoptosis [9], supporting the view that androgens have direct trophic effects upon follicular growth and survival. The present study demonstrates that androgens promote the earliest stages of follicular growth in the primate ovary. These experimental data are consistent with clinical observations of increased numbers of growing follicles, including primary follicles, in ovaries from hyperandrogenemic women with polycystic ovary syndrome (PCOS, [21]). Increased follicle numbers are also seen in testosterone-treated women [22, 23], showing that androgens, whether derived from ovary, adrenal, or exogenous sources, may stimulate excessive ovarian follicular growth. Further support for this notion is provided by the observation that treatment of women with PCOS with androgen receptor blockade results in diminution of follicle numbers [24].

Our work has clearly shown that over the short term, pharmacological doses of androgen are able to significantly increase ovarian follicular growth, including the earliest stages of follicle development. The role of endogenous androgen in the normal process of follicular growth is uncertain, but the concentration of androgen receptor expression in healthy, growing follicles [9, 11, 12] suggests that androgens may play a physiological role in primate follicle growth. Some murine studies support a trophic role for androgens in follicular development [25, 26]. The finding that short-term, high-dose androgen treatment stimulates nonhuman primate primordial follicular development suggests a potential therapeutic role for androgens in the treatment of human infertility due to failure of follicular development, as seen in some types of premature ovarian failure. In addition, androgens may be useful in encouraging human follicle development in vitro.

	FOOTNOTES

 
¹ K.V. and J.Z. contributed equally to the work.

² Correspondence: Carolyn A. Bondy, Bg. 10, Rm. 10N262, NIH, 10 Center Dr. 1862, Bethesda, MD 20892-1862. FAX: 301 402 2922; bondyc{at}exchange.nih.gov

Accepted: March 3, 1999.

Received: January 13, 1999.

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