Human Reproduction

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Human Reproduction, Vol. 14, No. 9, 2328-2332, September 1999
© 1999 European Society of Human Reproduction and Embryology

Androgens promote insulin-like growth factor-I and insulin-like growth factor-I receptor gene expression in the primate ovary

Keith Vendola, Jian Zhou, Jie Wang and Carolyn A.Bondy¹

Developmental Endocrinology Branch, NICHD, NIH, Bethesda, MD 20892, USA

	Abstract

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It has recently been shown that androgens increase the growth of immature follicles in the primate ovary. In the present study the effect of androgens on ovarian insulin-like growth factor I (IGF-I) and IGF-I receptor gene expression was investigated. The study groups included five follicular phase, placebo-treated controls, and four testosterone- and three dihydrotestosterone (DHT)-treated rhesus monkeys. The treatment period was 5 days. Both testosterone and DHT treatment resulted in significant, 3–4-fold increases in IGF-I mRNA concentration in granulosa, thecal and interstitial compartments. Likewise, both androgens induced significant increases in the amount of IGF-I receptor mRNA, most notably in thecal cells and less markedly in granulosa and interstitium (P < 0.05). These changes in amounts of IGF system mRNA were documented in growing follicles up to the small antral (1 mm diameter) stage. Larger follicles were too few in number for significant comparisons. By contrast, amounts of ovarian insulin receptor mRNA were not appreciably altered by androgen treatment. These data suggest that IGF-I and its cognate receptor may mediate androgen-induced ovarian follicular and thecal–interstitial growth.

Key words: folliculogenesis/granulosa cells/PCOS/testosterone/theca

	Introduction

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Hyperandrogenism is associated with generalized ovarian overgrowth, involving increased follicle numbers, stromal volume, capsular thickness and thecal hypertrophy (Hughesdon, 1982). Since thecal–interstitial tissue may produce androgens, the cause-and-effect relationship between hyperandrogenism and ovarian hypertrophy has been unclear. However, some clinical data suggest that androgens may initially cause the ovarian overgrowth. For example, androgen-producing tumours, congenital adrenal hyperplasia and exogenous androgen treatment have all been associated with the development of the hypertrophic polycystic ovary (PCO) phenotype (Kase et al., 1963; Dunaif et al., 1984; Lobo, 1984; Futterweit, and Deligdisch, 1986; Spinder et al., 1989; Pache et al., 1991). Supporting the concept that androgens promote growth of ovarian tissue, it has recently been shown that short-term androgen treatment stimulates increased growth of immature follicles, thecal hyperplasia and capsular thickness (Vendola et al., 1998, 1999), and that granulosa cell androgen receptor gene expression is positively correlated with proliferation and negatively correlated with apoptosis (Weil et al., 1998).

The mechanism(s) whereby androgens promote ovarian growth are unclear. Insulin-like growth factors (IGF) have been strongly implicated in ovarian functions (Adashi, 1998; Giudice et al., 1996). Insulin-like growth factor-I (IGF-I) expression predominates in murine species (Hernandez et al., 1989; Zhou et al., 1991; Adashi et al., 1997), where its expression is significantly correlated with granulosa proliferation and follicular growth (Zhou et al., 1995). Moreover IGF-I gene deletion results in murine infertility due to impaired follicular development (Baker et al., 1996; Zhou et al., 1997). In ovaries of larger species, IGF-I expression tends to be less and IGF-II expression more prominent (Zhou et al., 1996; Perks et al., 1995). In the human ovary, IGF-I expression is minimal and IGF-II is highly abundant (Geisthovel et al., 1989; Hernandez et al., 1992; Zhou and Bondy, 1993; El-Roeiy et al., 1994). Despite variability in IGF expression, expression of the IGF-I receptor, which subserves both IGF-I and IGF-II (Willis et al., 1998), is highly conserved across species (Bondy et al., 1994). It has recently been shown that androgen treatment increased the recruitment of primordial follicles into the growth pool, and that this effect was correlated with increased IGF-I and IGF-I receptor gene expression by primordial follicle oocytes (Vendola et al., 1999). In the present study, we compared IGF-I, IGF-II, IGF-I receptor and insulin receptor concentrations in granulosal, thecal and interstitial compartments of androgen-treated monkeys and follicular phase normal cycling controls.

	Materials and methods

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As described in previous reports on this work (Vendola et al., 1998, 1999; Weil et al., 1998), female rhesus monkeys (Macacca mulatta), 6–13 years of age, from the National Institutes of Health (NIH, Bethesda, MD, USA) 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. Animals had vehicle-, testosterone- or dihydrotestosterone (DHT)-containing pellets (Innovative Research of America, Toledo, OH, USA) inserted s.c. under ketamine anaesthesia. Ovaries were removed after 5 days of treatment and 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 and thaw-mounted onto poly-L-lysine-coated slides and stored at –70°C.

RNA probes for detection of IGF-I, IGF-II, IGF-I receptor and insulin receptor mRNA were synthesized as previously described (Zhou and Bondy, 1993), and used for in-situ hybridization as previously reported in detail (Bondy et al., 1993). Non-specific signal 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. Slides were air-dried and exposed to Hyperfilm-beta Max (Amersham, Arlington Heights, IL, USA) for 5 (IGF-II and IGF-I receptor) or 10 days (IGF-I and insulin receptor), then dipped in Kodak NTB2 nuclear emulsion, stored with desiccant at 4°C for 14 days (IGF-I receptor) or 21 days (IGF-I and insulin receptor). Slides were developed and stained with Mayer's haematoxylin and eosin for microscopic evaluation.

Quantification of mRNA
To quantify hybrid signal in the ovary interstitium, measurements were taken on randomly chosen 500 µm² areas of tissue between follicles in the ovarian cortex, excluding thecal cells. To quantify hybrid signal in granulosa and thecal cells, 500 µm² areas overlying dense, homogeneous populations of granulosa or thecal cells were scored in follicles of two size ranges determined by largest cross-section diameter: 100–380 and 620-1000 µm (class B and D, as described in Vendola et al., 1998). The former were pre-antral with 3–6 layers of granulosa cells and an early thecal layer. The latter were small antral follicles with well-developed theca (Vendola et al., 1998). There were no significant differences between values for class B and D follicles in any of the groups. Therefore, data for the two follicle populations were pooled and are presented simply as granulosa and theca cell values. These values represent the vast majority of follicles beyond the primary stage. There are too few large antral follicles (0–2 per animal) to obtain meaningful statistical data, and intermediate size follicles (class C, 380–620 µm) are encompassed by the flanking classes. Hybrid signal was quantified by computerized silver grain counting using NIH Image, 1.57 and a Leica Laborlux microscope at a magnification of x400 under oil. Slide identifications were masked prior to analysis. Non-specific signal was determined as the number of grains over the relevant cell population in sense probe-hybridized sections; this count was subtracted from raw antisense counts prior to further analysis. The mean was taken from eight to ten measurements for each cell compartment for each animal. Group means for control, testosterone and DHT animals were compared using analysis of variance (ANOVA), followed by Fisher's least significant difference test if appropriate. P < 0.05 was taken as significant.

	Results

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Hormone concentrations in the different treatment groups are shown in Table I. Effects of testosterone and DHT on ovarian IGF-I receptor and insulin receptor mRNA are illustrated in film autoradiographs in Figure 1. IGF-I and insulin receptors display similar cellular patterns of gene expression in the monkey ovary. Both are highly abundant in the membrana granulosa and are present but less abundant in thecal–interstitial cells (Bondy et al., 1994). However, insulin receptor mRNA expression is not appreciably altered by androgens, while IGF-I receptor mRNA clearly is increased in testosterone, and DHT-treated animals. The quantification of insulin receptor mRNA levels in the different treatment groups showed no significant differences (data not shown). The data for amounts of IGF-I receptor are shown in Figure 2. IGF-I receptor mRNA was most robustly increased in thecal cells of androgen-treated animals, with lesser effects seen in granulosa and interstitial compartments. There was no significant difference between testosterone and DHT effects on the amount of IGF-I receptor mRNA.

View this table: [in this window] [in a new window]   Table I. Hormone concentrations in different treatment groups

 

View larger version (117K): [in this window] [in a new window]   Figure 1. Effect of androgens on insulin-like growth factor-I (IGF-I) (A–C) and insulin (D–F) receptor (InR) mRNA in the monkey ovary. Representative film autoradiographs illustrate in-situ hybridization results from control (Con), placebo-treated (A and D), testosterone (T)-treated (B and E), and dihydrotestosterone (DHT)-treated (C and F) monkeys. The IGF-I receptor (IGFR) films were exposed for 5 days and the insulin receptor films were exposed for 10 days. (G) Autoradiograph from an IGF-I receptor sense (Sen) probe hybridized ovary section exposed for 10 days to illustrate non-specific signal. Bar = 2.5 mm

 

View larger version (13K): [in this window] [in a new window]   Figure 2. Quantification of androgen effects on amount of insulin-like growth factor-I (IGF-I) receptor mRNA in (A) thecal (TH), (B) granulosal (GC) and (C) interstitial (INT) compartments. Data represent the means ± SEM for four follicular phase control, four testosterone treated and three dihydrotestosterone (DHT)-treated animals. *P < 0.05; **P < 0.003. RNA unit = Grams/500µm2.

 
IGF-I mRNA is very scarce in the normal cycling primate ovary. Androgen treatment, however, stimulates a remarkable increase in the amount of IGF-I mRNA in all major cell compartments (Figures 3 and 4). In thecal cells, testosterone induced a 3-fold (P = 0.002) and DHT a 4-fold (P < 0.0001) increase in the amount of IGF-I mRNA. In this cell population, the DHT effect was significantly greater than that of testosterone (P = 0.02). In other cell compartments, however, both androgens produced ~3-fold increases in IGF-I mRNA. Ovarian amounts of IGF-II mRNA were not changed by androgen treatment (data not shown).

View larger version (68K): [in this window] [in a new window]   Figure 3. Androgens increase insulin-like growth factor-I mRNA in rhesus monkey ovary. Representative dark-field photomicrographs from control (A) and dihydrotestosterone-treated animals (B). The hybrid signal is present in granulosa (GC) and theca cells (TH), and in the interstitium between follicles (INT). (C) Non-specific signal generated by a sense probe. Bar = 100 µm.

 

View larger version (12K): [in this window] [in a new window]   Figure 4. Quantification of androgen effects on amount of insulin-like growth factor-I (IGF-I) mRNA in (A) thecal (TH), (B) granulosal (GC) and (C) interstitial (INT) compartments. Data represent the mean ± SEM for four follicular phase control, four testosterone-treated and three dihydrotestosterone (DHT)-treated animals. *P < 0.01; **P < 0.005. mRNA unit = Grams/500µm2.

 

	Discussion

Top Abstract Introduction Materials and methods Results Discussion References

 
Previous studies have shown that short-term androgen treatment stimulates multiple facets of ovarian growth (Vendola et al., 1998, 1999). Androgens stimulate the earliest stages of follicle development, as shown by significantly increased numbers of primary follicles present in the ovaries of testosterone- and DHT-treated monkeys (Vendola et al., 1999). This early development is associated with induction of IGF-I and IGFR receptor expression by primordial follicle oocytes (Vendola et al., 1999), suggesting that `resting oocytes' are activated in some way by androgens, thus triggering follicle development. In addition, the growth of follicles up to the small antral stage (<1 mm in diameter) is stimulated by androgens (Vendola et al., 1998). Androgen treatment results in pronounced increases in granulosa and theca cell proliferation and thecal compartment expansion (Vendola et al., 1998). The present study has shown that androgen treatment augments granulosal and thecal IGF-I and IGF-I receptor mRNA concentrations in developing follicles up to the small antral stage (~1 mm in diameter). Larger antral follicles also appeared to demonstrate increased IGF-I/receptor expression, but were too few in number to permit quantitative comparisons between groups. Testosterone and DHT treatment yield comparable results, indicating that this is an androgen receptor-mediated effect. Taken together, these data suggest that androgen-induced ovarian growth may be mediated by enhanced local IGF-I effect.

The possibility that androgen-induced proliferation of granulosa and theca cells is mediated by local IGF-I action has a precedent in the uterus, where IGF-I is thought to be involved in oestrogen's proliferative effects (`oestromedin hypothesis'). Oestradiol's dramatic effects on uterine growth are spatiotemporally correlated with increased local IGF-I production (Murphy et al., 1987; Norstedt et al., 1989; Adesanya et al., 1996). It has recently been shown that oestradiol treatment fails to induce uterine growth in the IGF-I–/– targeted gene deletion mouse (Adesanya et al., 1999), supporting the view that IGF-I is critical to oestrogen's growth-promoting effects in the uterus. Androgens also stimulate IGF-I production and growth in the murine uterus (Sahlin et al., 1994) and dihydroepiandrosterone, an androgen precursor, increases IGF-I production in cultured murine granulosa cells (Yan et al., 1997). These data are consistent with the present findings of androgen-induced up-regulation of IGF-I expression in the primate ovary. To our knowledge, there have been no previous studies evaluating androgen effect on IGF-I receptor expression. The present data suggest that androgen-induced augmentation of local IGF-I and IGF-I receptor expression is instrumental in the stimulation of ovarian follicular and thecal–interstitial growth. However, available evidence from ovaries from women with polycystic ovarian syndrome (PCOS) has not yielded any consistent evidence for abnormal IGF-I concentrations (El-Roeiy et al., 1994; Voutilainin et al., 1996; Yap et al., 1997). This could be due to sampling limitations inherent in working with surgical specimens, which make it difficult to obtain sufficient numbers of size-matched follicles to allow meaningful statistical comparisons. Alternatively, the acute augmentation of IGF-I and IGF receptor expression observed in our short-term studies may be a transient response to hyperandrogenism, no longer apparent in chronic conditions.

Since thecal–interstitial cells are androgenic, the fact that androgens promote ovarian thecal–interstitial growth (Vendola et al., 1998) may create the substrate for self-perpetuating hyperandrogenism. It is possible that even transient extra-ovarian hyperandrogenism stimulates excessive follicle and associated thecal–interstitial growth, which then becomes the source of ovarian hyperandrogenism. This sequence of events might account for the development of PCOS in girls with congenital adrenal hyperplasia (Lobo, 1984). These observations may also help to explain why androgen receptor blockade is associated with reduction in follicle number and ovarian size in young women with PCOS (de Leo et al., 1998).

	Acknowledgments

 
We are grateful to Ricardo Dreyfuss for expert photomicrography.

	Notes

 
¹ To whom correspondence should be addressed at: Bg 10, Rm 10N262, NIH, 10 Center Dr 1862, Bethesda, MD 20892–1862, USA

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Submitted on April 19, 1999; accepted on June 17, 1999.

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