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Original Studies |
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892
Address all correspondence and requests for reprints to: Stacie Weil, M.D., Building 10, Room 10N262, National Institutes of Health, 10 Center Drive 1862, Bethesda, Maryland 20892-1862.
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Abstract |
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AR mRNA expression was most abundant in granulosa cells of healthy preantral and antral follicles in the primate ovary. Theca interna and stromal cells also expressed AR mRNA, but to a lesser degree than granulosa cells. No significant cycle stage effects were noted in AR mRNA levels; however, larger numbers of animals would be necessary to definitively establish a cycle stage effect. AR mRNA level was significantly increased in granulosa cells and was decreased in theca interna and stromal cells of testosterone-treated monkeys. Importantly, granulosa cell AR mRNA abundance was positively correlated with expression of the proliferation-specific antigen Ki-67 (r = 0.91; P < 0.001) and negatively correlated with granulosa cell apoptosis (r = -0.64; P < 0.001).
In summary, these data show that primate ovary AR gene expression is most abundant in granulosa cells of healthy growing follicles, where its expression is up-regulated by testosterone. The positive correlation between granulosa AR gene expression and cell proliferation and negative correlation with programmed cell death suggests that androgens stimulate early primate follicle development.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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AR immunoreactivity has been detected in granulosa and thecal cells of monkey and human ovaries (7, 8, 9, 10, 11), suggesting that androgens may have AR-mediated effects of follicle development. In the present study we have investigated the cellular localization of AR messenger ribonucleic acid (mRNA) in rhesus monkey using in situ hybridization. To investigate the hormonal regulation of primate ovary AR gene expression, we compared the relative abundance of AR transcripts in monkeys during follicular and luteal phases of the menstrual cycle and in monkeys treated with testosterone (T). To elucidate the functional correlates of AR expression in the primate ovary, we compared the AR mRNA level with indexes of follicular cell proliferation and apoptosis in serial sections through individual follicles. Our studies show that AR gene expression is most abundant in the granulosa cells of small growing preantral and antral follicles and is positively correlated with granulosa cell proliferation and negatively correlated with granuolsa cell apoptosis, suggesting that androgens promote the growth of small follicles in the primate ovary.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Nineteen female rhesus monkeys, 6–13 yr of age, from the NIH Poolesville colony were used in accordance with a protocol approved by the NICHHD animal care and use committee. The random cycling monkeys were divided into three groups. Group I (controls; n = 8) had placebo pellets inserted sc under ketamine anesthesia between their shoulder blades. Group II (n = 4) received sustained release T (4 mg/kg) pellets for 3 days. Group III (n = 4) received sustained release T (0.4 mg/kg) pellets for 10 days. Ovariectomies were performed under ketamine anesthesia via a ventral laparotomy. Ovaries were removed, snap-frozen on dry ice, and stored at -70 C. Serial sections of 10 µm thickness were cut at -15 C, thaw-mounted onto poly-L-lysine-coated slides, and stored at -70 C until used for in situ hybridization or immunohistochemistry.
Serum for hormone measurements was obtained at the time of ovariectomy. Estradiol (E2) and T were measured by RIA at Covance Laboratories (Vienna, VA). For the control group, E2 = 115.5 ± 25.8 pg/mL, and T = 19.5 ± 3.3 ng/dL. For the 3-day T group, E2 = 25.3 ± 7.3 pg/mL, and T = 3170 ± 682 ng/dL. For the 10-day T group, E2 = 18.1 ± 3.1 pg/mL, and T = 1345 ± 233 ng/dL.
In situ hybridization
The human AR complementary DNA was a 3.6-kb fragment containing the entire AR-coding region (nucleotides 1–3580) (12) inserted into the EcoRI-BamHI site of pGem 3Z vector. The orientation of the probe was determined by DNA sequencing. 35S-Labeled RNA probes were synthesized to a specific activity of approximately 2 x 108 dpm/µg as previously described (13). The sections were fixed; soaked for 10 min in 0.25% acetic anhydride, 0.1 mol/L triethanolamine hydrochloride, and 0.9% NaCl; washed; and dehydrated. 35S-Labeled probes (107 cpm/mL) were added to hybridization buffer composed of 50% formamide, 0.2 mol/L NaCl, 50 mmol/L Tris-HCl (pH 8), 2.5 mmol/L ethylenediamine tetraacetate, 250 µg transfer RNA/mL, 10% dextran sulfate, 10 mmol/L dithiothreitol, and 0.02% each of BSA, Ficoll, and polvinlpryrolidone. Coverslips were placed over the sections, and the slides were incubated in humidified chambers overnight (14 h) at 55 C. Slides were washed several times in 4 x SSC (NaCl and sodium citrate, Biofluids, Rockville, MD) to remove coverslips. They were then washed in hybridization buffer, dehydrated, and immersed in 0.3 mmol/L NaCl, 50% formamide, 20 mmol/L Tris-HCl, and 1 mmol/L ethylenediamine tetraacetate at 60 C for 15 min. Sections were then treated with ribonuclease A (20 µg/mL) for 30 min at room temperature, followed by a 15-min wash in 0.1 x SSC at 50 C. Slides were air-dried and exposed to Hyperfilm-ß Max (Amersham, Arlington Heights, IL) for 3–7 days, dipped in Kodak NTB2 nuclear emulsion (Eastman Kodak, Rochester, NY), stored with desiccant at 4 C for 10 days, developed, and stained with Mayer’s hematoxylin and eosin for microscopic evaluation.
Immunohistochemistry
Immunohistochemical detection of the proliferation-specific Ki-67 antigen (14) was performed by the avidin-biotin-immunoperoxidase technique. The mouse antihuman Ki-67 serum (Boehringer Mannheim, Indianapolis, IN) was used at a dilution of 1:50. Fresh frozen tissue sections were fixed in 4% formalin-phosphate-buffered saline (PBS) for 30 min. After sequential blocking in 1% hydrogen peroxide-10% methanol-PBS, avidin-biotin blocking reagent and 10% normal sheep serum, tissue sections were incubated overnight at 4 C with Ki-67 antibody or with 1% PBS as the control. Thereafter, tissue sections were treated with biotinylated sheep antimouse IgG (1:40) for 30 min at room temperature, followed by a 45-min incubation with avidin-biotin-peroxidase complex (Vectastain ABC Elite Peroxidase Kit, Vector Laboratories, Burlingame, CA). The antigen-antibody complex was visualized by incubation with freshly prepared 3,3'-diaminobenzidine (3,3'-diaminobenzidine substrate kit, Vector Laboratories), and the tissue was counterstained with methyl green.
In addition, the Apop Tag (Oncor, Gaithersburg, MD) method for in situ apoptosis detection of programmed cell death was performed according to manufacturer’s directions. Fresh-frozen tissue sections were fixed in cold acetone and cold ethanol-acetate (2:1) at -20 C for 10 and 5 min, respectively. After blocking with 1% BSA-PBS, tissue sections were incubated for 1 h at 37 C with digoxigenin-deoxy-UTP and terminal deoxynucleotide transferase or with 1% PBS as the control. Tissue sections were then incubated in antidigoxigenin-peroxidase for 30 min at room temperature. The antigen-antibody complex was visualized with 3,3'-diaminobenzidine, and sections were stained with methyl green as described above.
Quantitative analyses
AR mRNA abundance was quantified in granulosa cells and theca
interna cells of follicles classified into four groups by diameter: A
(30–100 µm), B (101–380 µm), C (381–620 µm), D (621–1000
µm), and E (>1 mm) as described in Table 1
. Hybridization signal was quantified
using darkfield illumination on a Leitz Laborlux microscope (Leitz,
Rockleigh, NJ). Grains overlying an area of 500 µm2 were
captured at x400 via a solid state monochrome video camera, and the
data were analyzed with a Macintosh PowerPC system using NIH Image
version 1.57 (NIMH, NIH, Bethesda, MD). Background or nonspecific
signal was obtained by similar measurements on sections hybridized to a
control, sense probe. The background counts were subtracted from
experimental data before further analysis. Data on AR mRNA signal in
follicles and stroma from sections from both right and left ovaries
were meaned for each animal. Group means were statistically compared
using ANOVA followed by Fisher’s least significant difference test.
P < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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AR mRNA is abundant and widespread in the primate ovary (Fig. 1). It is concentrated in developing
follicles and is detected at lower levels throughout the ovarian
stroma, particularly in the subcapsular region (Fig. 1). There is
notable heterogeneity in the follicular pattern of AR gene expression,
with only a subpopulation of follicles demonstrating intense AR mRNA
hybridization. AR mRNA appears more abundant in small and medium-sized
follicles compared with the single large preovulatory follicle (Fig. 1B).
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shows AR mRNA localization in
the primate ovary at the cellular level. The signal is most abundant in
granulosa cells of healthy-looking preantral to small antral follicles
(classes B–D; see Table
I for follicle classification), and granulosa
cells of atretic follicles are negative (Fig. 2, A and B, E and F).
Little or no AR mRNA is detected in primary (Fig. 2A) follicles. There
was no statistically significant difference in granulosa AR mRNA levels
in classes B–E (Fig. 3A). However, the great majority of follicles in
the largest class (>1 mm; Fig. 2E) were on the small side,
i.e. 1–2 mm. There were only two follicles larger than 2
mm, and these, particularly the greater than 5-mm preovulatory follicle
(Fig. 1B), had substantially reduced AR mRNA levels compared with
smaller size follicles.
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, C and D).
There were no significant differences between thecal mRNA levels in
B–E follicles (Fig. 3B). AR mRNA is also present in the ovarian
stroma, at significantly greater than background level, although this
hybridization does not show up well in the darkfield photomicrographs
where the exposure was geared to the high signal intensity in the
membrana granulosa. Hormonal regulation
To determine whether AR gene expression is hormonally regulated, we assessed AR mRNA levels in granulosa and thecal cells from monkeys in the follicular (progesterone, <1.5 ng/mL; n = 6) compared with the luteal (n = 2) phase of the cycle. There was a trend for more AR mRNA in follicular phase granulosa cells, but the difference was not statistically significant, probably due to the small number of luteal phase samples (data not shown).
To determine whether T regulates AR gene expression in the primate
ovary, we compared AR hybridization signal in granulosa, thecal, and
stromal cell compartments in control and T-treated monkeys (Fig. 1).
There was a small, but significant, increase in AR mRNA abundance in
granulosa cells of periantral and small antral (>380 µm) follicles
of T-treated animals (Fig. 3A). In
contrast, there was a decrease in AR mRNA levels in theca interna cells
of small follicles (<620 µm) and stromal cells in T-treated groups
(Fig. 3, B and C). These data show that T treatment induces small, but
significant, changes in AR mRNA level, but does not establish whether
this is a direct or an indirect effect.
Functional correlates of AR gene expression
To elucidate potential effects of AR expression in the primate
ovary, we compared AR mRNA abundance with indexes of granulosa cell
proliferation and death in sequential sections from individual
follicles. As shown in Fig. 4, A–C, high
levels of AR mRNA are correlated with high levels of granulosa cell
proliferation, as revealed by detection of the proliferation-specific
antigen, Ki67, and the virtual absence of evidence of apoptotic cell
death in these same follicles. In contrast, low or undetectable levels
of AR mRNA are associated with barely detectable Ki67 immunoreactivity
and abundant apoptotic cell death, as demonstrated by the in
situ DNA end-labeling technique (Fig. 4, D–F). Statistical
analysis of correlations between granulosa cell AR mRNA content and
cell proliferation (Fig. 5) revealed a
highly significant positive correlation (r = 0.94;
P < 0.001) and, conversely, a negative correlation
with apoptosis (r = -0.64; P < 0.001).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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This is, to our knowledge, the first study to investigate AR gene expression at the cellular level in the primate ovary. A previous study reported the presence of AR transcripts in human ovary, without localization, using Northern hybridization (15). Previous immunohistochemical studies have found AR immunoreactivity in granulosa and theca interna nuclei of small growing follicles in the monkey ovary (7, 8). Hillier et al. noted a decrease in AR immunoreactivity in large preovulatory follicles (7); in the few large (>2 mm) preovulatory follicles examined in the present study, AR mRNA levels were also decreased compared to those in smaller antral follicles. In the human ovary, AR immunoreactivity has also been noted in granulosa and theca interna cells of developing follicles and scattered throughout the stroma (9, 10, 11).
Support for a trophic effect by androgens on primate granulosa cells is provided by in vitro studies using monkey granulosa cells (2, 16, 17). Androgen (T or DHT) treatment of granulosa cells from small and preantral follicles increases aromatase expression and progesterone production in response to FSH administration. Granulosa cells from large preovulatory follicles, however, demonstrated decreased responses to FSH after androgen supplementation. The effect of androgen on primate granulosa proliferation has not, to our knowledge, been assessed in vitro. The most compelling evidence that androgens may stimulate early stages of follicular growth comes from our recent observation that monkeys treated in vivo with high dose T for 3–10 days show a marked growth-promoting effect on small and medium-sized follicles (18).
Clinical androgen excess states such as congenital adrenal hyperplasia and exogenous androgen treatment are associated with increased numbers of nonovulatory antral follicles similar to those seen in women with polycystic ovarian syndrome (PCOS) (3, 4, 5, 6, 19, 20). Many of these cystic follicles have healthy steroidogenic and growth characteristics (21, 22). Our findings of increased AR mRNA expression and cell proliferation in T-treated primate ovaries (18) suggest that the increased number of follicles seen in hyperandrogenism is due to the trophic effects of androgen, whether increased locally in the ovary as in PCOS or systemically as in the other conditions. The failure to progress beyond the preovulatory antral stage is most likely due to the influence of excessive androgens on hypothalamic-pituitary function, specifically FSH, which is essential for the emergence of a dominant follicle. Supporting this view, anovulatory women with PCOS have normal sensitivity to exogenous FSH and often hyperrespond to gonadotropin therapy, apparently due to the abnormally large cohort of selectable follicles (23).
Our studies suggest that androgens are not at all atretogenic for the primate ovary. The significant negative correlation between AR mRNA concentration and granulosa cell apoptosis suggests that the androgen effect may actually prevent programmed cell death in the primate ovary. These findings are in contrast to previous studies in the rat, which have contributed largely to the view that androgens are atretogenic (1, 24, 25). The different findings in the primate may be explained by the existence of significant interspecies differences in ovarian follicular development or may be attributed to different experimental conditions. For example, the rat studies involve hypophysectomized juvenile, diethylstilbestrol-treated rats that may not be comparable to the normal cycling in vivo primate model we have studied.
In summary, we have shown that AR mRNA is most abundant in the granulosa cells of healthy developing follicles in the primate ovary, where its expression is correlated positively with cell proliferation and negatively with programmed cell death. Granulosa cell AR mRNA first appears at about the time when mature theca interna cells appear, suggesting that normal follicle growth may depend upon thecal androgens stimulating granulosa cell proliferation and survival in a paracrine mode of action. Excess androgens produced by ovarian stroma or by adrenal glands may stimulate the development and survival of an excessive number of follicles while preventing their maturation through interfering with gonadotropin release, leading to the development of a polycystic ovary.
Received November 24, 1997.
Revised February 23, 1998.
Accepted March 30, 1998.
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