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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 8 2951-2956
Copyright © 1999 by The Endocrine Society

Original Studies

Androgen and Follicle-Stimulating Hormone Interactions in Primate Ovarian Follicle Development

Stacie Weil, Keith Vendola, Jian Zhou and Carolyn A. Bondy

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: Carolyn Bondy, National Institutes of Health, Building 10/10N262, 10 Center Drive, Bethesda, Maryland 20892. E-mail: bondyc{at}exchange.nih


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
We have previously shown that androgens stimulate early stages of follicular development and that granulosal androgen receptor (AR) gene expression is positively correlated with follicular growth. The present study was aimed at elucidating potential interactions between FSH and androgens in follicular development. Study groups included eight normal cycling rhesus monkeys (five follicular and three luteal-phase), eight testosterone (T)-treated, and four FSH-treated animals. Examination of sequential ovary sections revealed selective colocalization of AR and FSH receptor (FSHR) messenger RNAs (mRNAs) in healthy, growing follicles. Moreover, individual follicles demonstrate a highly significant (P < 0.001) positive correlation between FSHR and AR mRNA levels in all study groups. Androgen treatment significantly increased granulosa cell FSHR mRNA abundance (by approximately 50–100%, depending on follicle size). FSH treatment increased granulosa AR mRNA levels only in primary follicles. The finding that T augments follicular FSHR expression suggests that androgens promote follicular growth and estrogen biosynthesis indirectly, by amplifying FSH effect, and may partially explain the enhanced responsiveness to gonadotropin stimulation noted in women with polycystic ovary syndrome.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
WE HAVE recently shown that androgens stimulate early stages of follicular growth in the rhesus monkey ovary (1, 2). Primary, secondary, and tertiary (small antral) follicles are significantly increased in number, and granulosa and thecal cell proliferation are significantly increased in T- and dihydrotestosterone-treated animals (1, 2). Furthermore, granulosa cell androgen receptor (AR) gene expression is positively correlated with proliferation and negatively correlated with apoptosis in the monkey ovary (3). Evidence from in vitro models is conflicting, with some data suggesting antiproliferative or atretogenic effects (4), whereas other data indicate that androgens promote follicular growth (5, 6). Women with hyperandrogenism have impaired ovulatory function, but this may be caused by excessive numbers of small growing follicles disrupting normal hypothalamic-pituitary-ovary interaction, as opposed to atretogenic effects by androgen. Supporting this view, ovaries from women with polycystic ovary syndrome (PCOS) have increased numbers of small growing follicles (7). Furthermore, granulosa proliferation and steroidogenesis seem robust in PCOS follicles (8, 9), and androgen blockade results in reduction in follicle number and resumption of ovulatory cycles (10).

The mechanism(s) whereby androgens stimulate follicular growth remain unclear. Because infertile women with PCOS frequently hyperrespond to FSH treatment for ovulation induction (11, 12), and granulosa cells from PCOS ovaries are hyperresponsive to FSH treatment in vitro (13), we considered the possibility that androgens might promote granulosa FSH receptor (FSHR) expression. Therefore, in the present work, we have investigated the relation between follicular AR and FSHR expression, and we examined the effects of androgens on follicular FSHR messenger RNA (mRNA) levels as well as the effects of FSH on AR mRNA levels.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals

Female Rhesus monkeys, 6–13 yr of age (from the NIH Poolesville, MD, colony) were studied under a protocol approved by the NICHD Animal Care and Use Committee. Monkeys were treated with sc pellets (Innovative Research of America, Toledo, OH) containing vehicle (n = 8) or sustained release T (4 mg/kg for 3 days, n = 4; or 0.4 mg/kg for 10 days, n = 4), as previously described (3). Another group (n = 4) received sc injections of recombinant FSH (Metrodin, Serono, Norwell, MA, 35 IU) for 2 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. Serum for hormone measurements was obtained at the time of ovariectomy. Estradiol (E2), T, and FSH were measured by RIA at Covance Laboratories, Inc. Vienna, VA. In the group of eight random cycling control monkeys, five were in the follicular phase of the menstrual cycle, as determined by progesterone levels less than 3.0 ng/dL (E2 = 70 ± 11 pg/mL). Just these follicular-phase animals were used for quantitative analyses comparing AR, FSHR, and aromatase mRNA levels in size-matched follicles in the different treatment groups.

In situ hybridization

The human AR (3), aromatase, and FSHR cDNAs (14) used as templates for riboprobe synthesis were as previously described. 35S-labeled RNA probes were synthesized to an SA of approximately 2 x 108 dpm/µg, as previously described (15). 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 EDTA, 250 µg transfer RNA/mL, 10% dextran sulfate, 10 mmol/L dithiothreitol, and 0.02% each of BSA, Ficoll, and polvinlpryrolidone. Control sections were hybridized with sense probes in the same experiments. 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 4x 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, 1 mmol/L EDTA 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 0.1x SSC at 50 C. Slides were air dried and exposed to Hyperfilm-beta Max (Amersham Pharmacia Biotech, Arlington Heights, IL) for 7 days, dipped in Kodak NTB2 nuclear emulsion, stored with desiccant at 4 C for 14 days, developed, and stained with Mayer’s hematoxylin and eosin for microscopic evaluation.

Quantitative analyses

FSHR, aromatase, and AR mRNA levels were quantified in granulosa cells of follicles classified into groups by diameter: A (<=100 µm), B (101–380 µm), C (381–620 µm), D (621–1000 µm), and E (>1 mm), as described in Table 1Go and Ref. 1 . Hybridization signal was quantified using darkfield illumination on a Laborlux microscope (Leitz, Rockleigh, NJ). Grains overlying an area of 500 µ2 were captured at 400x magnification via a solid-state monochrome video camera, and the data was analyzed with a Macintosh PowerPC system using NIH Image v 1.57 (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 mRNA signal in follicles 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. A P value < 0.05 was considered significant. Correlation between AR and FSH mRNA levels was analyzed using Spearman’s rank correlation.


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  		Table 1. Follicle classification

 

   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
AR mRNA is concentrated in a subpopulation of follicles in the primate ovary (Fig. 1AGo). We have previously shown that these AR-expressing follicles are healthy and growing, as determined by high proliferation and low apoptosis indices (3). To investigate potential interactions between FSH and androgen in follicle growth, we compared FSHR and AR mRNA localization in sequential ovary sections (Fig. 1Go). This comparison shows that AR and FSHR mRNAs are selectively coexpressed in the same subpopulation of follicles. Moreover, the abundance of FSHR mRNA is positively correlated with that of AR mRNA in follicles from random-cycling, androgen-treated, and FSH-treated monkeys (P < 0.001, Fig. 2Go).



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  		Figure 1. AR (A) and FSHR (B) mRNAs are colocalized in the monkey ovary. These are representative film autoradiographs taken from sequential ovary sections. The arrows point to follicles that are negative for both mRNAs. There is a so-called edge artifact noted along the lower border of the AR autoradiograph. Bar = 2.5 mm.

 


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  		Figure 2. Correlation between AR and FSHR mRNA levels in individual follicles. A, Data from untreated, random cycling monkeys (n = 8); B, data from T-treated (both 3- and 10-day) monkeys (n = 8); C, data from FSH-treated monkeys (n = 4).

 
Given these observations, we considered that androgens might regulate FSHR gene expression. To test this hypothesis, we compared granulosa FSHR mRNA levels in size-matched follicles from androgen-treated monkeys and follicular-phase control animals (Fig. 3Go). Monkeys were treated with T for 3 and 10 days. Circulating T levels were very elevated, and E2 levels were suppressed in T-treated monkeys (Table 2Go). FSHR mRNA levels were significantly increased in large antral follicles after just 3 days of T treatment (Fig. 4AGo). After 10 days, FSHR mRNA levels were increased, from approximately 50% to 100% in follicles of all sizes in the monkey ovary (Fig. 4AGo).



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  		Figure 3. Increased FSHR gene expression in follicles from T-treated monkeys. Representative film autoradiographs from follicular-phase control (Con) (A), 3-day T-treated (3dT) (B), 10-day T-treated (10dT) (C), and FSH-treated monkeys (D) are shown. E shows an autoradiograph from a section hybridized to a sense (Sen) probe. Note the increased number of follicles in the androgen-treated ovaries. Bar = 2 mm.

 

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  		Table 2. Hormone levels

 


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  		Figure 4. A, Effect of T treatment on follicular FSHR mRNA levels. Data are means ± SEM for five animals in the control group and four in each of the T-treatment groups. B, Effect of FSH treatment (FSH-Tx) on follicular AR mRNA levels. Data are means ± SEM for five animals in the control group and four in the FSH-treated group. RNA levels were quantified by grain counting, as described in Materials and Methods. *, P < 0.05; **, P < 0.01, compared with control.

 
We also considered the possibility that FSH stimulates AR gene expression. Thus, we compared granulosa AR mRNA levels in control, follicular-phase monkeys, and FSH-treated animals. FSH treatment did not alter AR mRNA levels in larger follicles (Fig. 4BGo) but did result in a dramatic increase in AR mRNA in primary follicles (Figs. 4BGo and 5Go). FSH treatment had only modest effects on FSHR mRNA levels (Fig. 3DGo), which did not achieve statistical significance (data not shown).



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  		Figure 5. AR mRNA in primary follicles of control (A and B) and FSH-treated (C and D) monkeys. Signal is concentrated primarily over granulosa cells in primary follicles, two of which are seen in C and D (double arrowheads). E and F show nonspecific signal in sense probe hybridized tissue. Bar = 50 µ.

 
Aromatase mRNA is selectively expressed in AR/FSHR-positive follicles (Fig. 6Go). Aromatase mRNA levels are not significantly altered in T-treated animals (data not shown) but are predictably increased in FSH-treated animals (Fig. 6DGo). LH receptor mRNA levels were also examined in these treatment groups, and no significant differences were obtained (not shown).



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  		Figure 6. Effects of androgen and FSH treatment on aromatase gene expression in the primate ovary. Representative film autoradiographs from follicular-phase control (A), 3-day T- (B), 10-day T- (C), and FSH-treated (D) animals.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study presents evidence of positive, complementary interactions between FSH and androgen effects in primate follicle development in vivo. We have shown that androgen- and FSHR mRNAs are selectively colocalized in growing follicles in the normal cycling primate ovary. Moreover, AR mRNA levels are positively correlated with FSHR mRNA levels in granulosa cells from normal cycling-, androgen-treated, and FSH-treated animals. T increases FSHR mRNA levels in follicles at all stages of development, whereas FSH increases AR mRNA in primary follicles. Our previous work demonstrated that androgens increase follicle cell proliferation and suppress granulosa cell apoptosis (1) and that AR gene expression is positively correlated with granulosa proliferation and negatively correlated with apoptosis (3). Taken together, these observations strengthen the view that androgens (in addition to serving as precursors for ovarian estrogen synthesis) also have a fundamental trophic role in primate ovarian follicular development.

The observation that FSH treatment markedly increases AR gene expression in primary follicles is novel and interesting. The factors regulating follicular AR expression have been unknown. AR mRNA (3) and immunoreactivity (16, 17) range from low to undetectable in primordial and primary follicles of normal-cycling monkeys. Furthermore, androgen treatment stimulates a slight increase in granulosa cell AR mRNA level in larger follicles but is without effect on AR expression in primary follicles (3). Notably, androgen-treatment is associated with a marked decrease in thecal and interstitial AR mRNA levels (3). The present data, showing a robust, FSH-induced induction of AR gene expression in the smallest ovarian follicles, suggests a potential physiological mechanism whereby FSH may promote early follicular development.

Androgen-induced increases in granulosal FSHR expression are expected to promote FSH action, leading to increased aromatase expression and conversion of androgen to estrogen. Indeed, androgens amplify FSH-induced aromatase expression in cultured rat (18) and primate (19) granulosa cells. The present data suggest that this in vitro effect may be caused by androgen augmentation of FSHR expression. Consistent with this indirect mode of action, we found that T is without effect on follicular aromatase gene expression in a situation where FSH is presumably suppressed because of high circulating T levels (see suppressed E2 levels, Table 2Go). The fact that the aromatase substrate T facilitates (albeit indirectly) aromatase production provides yet another regulatory element to the complex two-cell paradigm of ovarian estrogen biosynthesis.

The androgen-induced augmentation of granulosa FSHR gene expression shown in the present study could explain enhanced follicular growth as well as estrogen biosynthesis in response to FSH. The mechanism whereby androgen increases granulosa FSHR gene expression is unclear. This could be an indirect effect, caused, for example, by increased local IGF1 production. Supporting this possibility, we have shown that IGF1 stimulates granulosa FSHR gene expression in the mouse (14). Moreover, IGF1 and IGF1 receptor expression are increased in granulosa and thecal cells in virtually all follicles in the androgen-treated monkeys (Ref. 2 , Vendola et al., manuscript in preparation).

Hyperandrogenism is the cardinal clinical feature of PCOS, and recent genetic evidence suggests that it is also a primary etiology of the disorder (20, 21). Mason et al. (13) have shown that granulosa cells from women with PCOS hyperrespond to FSH in vitro, and the present data suggest that this heightened responsiveness could be attributable to enhanced granulosa FSHR expression caused by hyperandrogenism in these women. Women with PCOS are also prone to hyperrespond to FSH stimulation for ovulation induction in vivo (11, 12), and this could be caused by androgen-induced heightened follicular FSHR expression, as well as to increased numbers of FSH-responsive follicles (22). These observations support the view that PCOS ovulatory dysfunction is not attributable to any intrinsic defect in follicular development, but rather to disordered relations between too many or too-sensitive developing follicles and gonadotropin orchestration of ovulation (23).

Received March 26, 1999.

Revised April 26, 1999.

Accepted May 3, 1999.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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  9. Takayama K, Fukaya T, Sasano H, et al. 1996 Immunohistochemical study of steroidogenesis and cell proliferation in polycystic ovarian syndrome. Hum Reprod. 11:1387–1392.[Abstract/Free Full Text]
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M.-J. Chen, W.-S. Yang, C.-L. Chen, M.-Y. Wu, Y.-S. Yang, and H.-N. Ho
The relationship between anti-Mullerian hormone, androgen and insulin resistance on the number of antral follicles in women with polycystic ovary syndrome
Hum. Reprod., April 1, 2008; 23(4): 952 - 957.
[Abstract] [Full Text] [PDF]

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 ReproductionHome page
H Cardenas, E Jimenez, and W F Pope
Dihydrotestosterone influenced numbers of healthy follicles and follicular amounts of LH receptor mRNA during the follicular phase of the estrous cycle in gilts
Reproduction, March 1, 2008; 135(3): 343 - 350.
[Abstract] [Full Text] [PDF]

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 Biol. Reprod.Home page
K.A. Walters, C.M. Allan, and D.J. Handelsman
Androgen Actions and the Ovary
Biol Reprod, March 1, 2008; 78(3): 380 - 389.
[Abstract] [Full Text] [PDF]

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 Mol Hum ReprodHome page
A. A. Murray, A. K.E. Swales, R. E. Smith, M. D. Molinek, S. G. Hillier, and N. Spears
Follicular growth and oocyte competence in the in vitro cultured mouse follicle: effects of gonadotrophins and steroids
Mol. Hum. Reprod., February 1, 2008; 14(2): 75 - 83.
[Abstract] [Full Text] [PDF]

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C. I. Durnerin, K. Erb, R. Fleming, H. Hillier, S.G. Hillier, C.M. Howles, J.-N. Hugues, A. Lass, H. Lyall, P. Rasmussen, et al.
Effects of recombinant LH treatment on folliculogenesis and responsiveness to FSH stimulation
Hum. Reprod., February 1, 2008; 23(2): 421 - 426.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
K. A. Walters, C. M. Allan, M. Jimenez, P. R. Lim, R. A. Davey, J. D. Zajac, P. Illingworth, and D. J. Handelsman
Female Mice Haploinsufficient for an Inactivated Androgen Receptor (AR) Exhibit Age-Dependent Defects That Resemble the AR Null Phenotype of Dysfunctional Late Follicle Development, Ovulation, and Fertility
Endocrinology, August 1, 2007; 148(8): 3674 - 3684.
[Abstract] [Full Text] [PDF]

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 Mol Hum ReprodHome page
R. Tiwari-Pandey, Y. Yang, J. Aravindakshan, and M.R. Sairam
Normalization of hormonal imbalances, ovarian follicular dynamics and metabolic effects in follitrophin receptor knockout mice
Mol. Hum. Reprod., May 1, 2007; 13(5): 287 - 297.
[Abstract] [Full Text] [PDF]

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 Hum ReprodHome page
C. S. Sipe and B. J. Van Voorhis
Testosterone patch improves ovarian follicular response to gonadotrophins in a patient with Kallmann's syndrome: A Case Report
Hum. Reprod., May 1, 2007; 22(5): 1380 - 1383.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
M. A. Bedaiwy, N. A. Mousa, N. Esfandiari, R. Forman, and R. F. Casper
Follicular Phase Dynamics with Combined Aromatase Inhibitor and Follicle Stimulating Hormone Treatment
J. Clin. Endocrinol. Metab., March 1, 2007; 92(3): 825 - 833.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
S. Rice, K. Ojha, S. Whitehead, and H. Mason
Stage-Specific Expression of Androgen Receptor, Follicle-Stimulating Hormone Receptor, and Anti-Mullerian Hormone Type II Receptor in Single, Isolated, Human Preantral Follicles: Relevance to Polycystic Ovaries
J. Clin. Endocrinol. Metab., March 1, 2007; 92(3): 1034 - 1040.
[Abstract] [Full Text] [PDF]

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 Biol. Reprod.Home page
M.Y. Yang and J.E. Fortune
Testosterone Stimulates the Primary to Secondary Follicle Transition in Bovine Follicles In Vitro
Biol Reprod, December 1, 2006; 75(6): 924 - 932.
[Abstract] [Full Text] [PDF]

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 Biol. Reprod.Home page
M. Orisaka, K. Tajima, T. Mizutani, K. Miyamoto, B. K. Tsang, S. Fukuda, Y. Yoshida, and F. Kotsuji
Granulosa Cells Promote Differentiation of Cortical Stromal Cells into Theca Cells in the Bovine Ovary
Biol Reprod, November 1, 2006; 75(5): 734 - 740.
[Abstract] [Full Text] [PDF]

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K. Lossl, A.N. Andersen, A. Loft, N.L.C. Freiesleben, S. Bangsboll, and C.Y. Andersen
Androgen priming using aromatase inhibitor and hCG during early-follicular-phase GnRH antagonist down-regulation in modified antagonist protocols
Hum. Reprod., October 1, 2006; 21(10): 2593 - 2600.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
R. V. Mehta, P. J. Malcom, and R. J. Chang
The Effect of Androgen Blockade on Granulosa Cell Estradiol Production after Follicle-Stimulating Hormone Stimulation in Women with Polycystic Ovary Syndrome
J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3503 - 3506.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
B. Cole, K. Hensinger, G. A. R. Maciel, R. J. Chang, and G. F. Erickson
Human Fetal Ovary Development Involves the Spatiotemporal Expression of P450c17 Protein
J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3654 - 3661.
[Abstract] [Full Text] [PDF]

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 Biol. Reprod.Home page
W. Luo and M. C. Wiltbank
Distinct Regulation by Steroids of Messenger RNAs for FSHR and CYP19A1 in Bovine Granulosa Cells
Biol Reprod, August 1, 2006; 75(2): 217 - 225.
[Abstract] [Full Text] [PDF]

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 Hum ReprodHome page
J. Balasch, F. Fabregues, J. Penarrubia, F. Carmona, R. Casamitjana, M. Creus, D. Manau, G. Casals, and J. A. Vanrell
Pretreatment with transdermal testosterone may improve ovarian response to gonadotrophins in poor-responder IVF patients with normal basal concentrations of FSH
Hum. Reprod., July 1, 2006; 21(7): 1884 - 1893.
[Abstract] [Full Text] [PDF]

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 Hum ReprodHome page
N. Massin, I. Cedrin-Durnerin, C. Coussieu, J. Galey-Fontaine, J.P. Wolf, and J.-N. Hugues
Effects of transdermal testosterone application on the ovarian response to FSH in poor responders undergoing assisted reproduction technique--a prospective, randomized, double-blind study
Hum. Reprod., May 1, 2006; 21(5): 1204 - 1211.
[Abstract] [Full Text] [PDF]

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 Endocr. Rev.Home page
N. S. Macklon, R. L. Stouffer, L. C. Giudice, and B. C. J. M. Fauser
The Science behind 25 Years of Ovarian Stimulation for in Vitro Fertilization
Endocr. Rev., April 1, 2006; 27(2): 170 - 207.
[Abstract] [Full Text] [PDF]

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 ReproductionHome page
V. Sander, C. G. Luchetti, M. E. Solano, E. Elia, G. Di Girolamo, C. Gonzalez, and A. B. Motta
Role of the N, N'-dimethylbiguanide metformin in the treatment of female prepuberal BALB/c mice hyperandrogenized with dehydroepiandrosterone.
Reproduction, March 1, 2006; 131(3): 591 - 602.
[Abstract] [Full Text] [PDF]

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 Hum ReprodHome page
R. Homburg
Clomiphene citrate--end of an era? a mini-review
Hum. Reprod., August 1, 2005; 20(8): 2043 - 2051.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
G. A. R. Maciel, E. C. Baracat, J. A. Benda, S. M. Markham, K. Hensinger, R. J. Chang, and G. F. Erickson
Stockpiling of Transitional and Classic Primary Follicles in Ovaries of Women with Polycystic Ovary Syndrome
J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5321 - 5327.
[Abstract] [Full Text] [PDF]

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 Hum ReprodHome page
S.K. Goswami, T. Das, R. Chattopadhyay, V. Sawhney, J. Kumar, K. Chaudhury, B.N. Chakravarty, and S.N. Kabir
A randomized single-blind controlled trial of letrozole as a low-cost IVF protocol in women with poor ovarian response: a preliminary report
Hum. Reprod., September 1, 2004; 19(9): 2031 - 2035.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
Y.-C. Hu, P.-H. Wang, S. Yeh, R.-S. Wang, C. Xie, Q. Xu, X. Zhou, H.-T. Chao, M.-Y. Tsai, and C. Chang
Subfertility and defective folliculogenesis in female mice lacking androgen receptor
PNAS, August 3, 2004; 101(31): 11209 - 11214.
[Abstract] [Full Text] [PDF]

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 Biol. Reprod.Home page
T.E. Hickey, D.L. Marrocco, R.B. Gilchrist, R.J. Norman, and D.T. Armstrong
Interactions Between Androgen and Growth Factors in Granulosa Cell Subtypes of Porcine Antral Follicles
Biol Reprod, July 1, 2004; 71(1): 45 - 52.
[Abstract] [Full Text] [PDF]

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 ReproductionHome page
T. Waterhouse, S.-L. Cox, M. Snow, G. Jenkin, and J. Shaw
Offspring produced from heterotopic ovarian allografts in male and female recipient mice
Reproduction, June 1, 2004; 127(6): 689 - 694.
[Abstract] [Full Text] [PDF]

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 Hum Reprod UpdateHome page
S. Jonard and D. Dewailly
The follicular excess in polycystic ovaries, due to intra-ovarian hyperandrogenism, may be the main culprit for the follicular arrest
Hum. Reprod. Update, March 1, 2004; 10(2): 107 - 117.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
A. J. Zeleznik, L. Little-Ihrig, and S. Ramasawamy
Administration of Dihydrotestosterone to Rhesus Monkeys Inhibits Gonadotropin-Stimulated Ovarian Steroidogenesis
J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 860 - 866.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
A. Belgorosky, C. Pepe, R. Marino, G. Guercio, N. Saraco, E. Vaiani, and M. A. Rivarola
Hypothalamic-Pituitary-Ovarian Axis during Infancy, Early and Late Prepuberty in an Aromatase-Deficient Girl Who Is a Compound Heterocygote for Two New Point Mutations of the CYP19 Gene
J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5127 - 5131.
[Abstract] [Full Text] [PDF]

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 Hum ReprodHome page
M.F.M. Mitwally and R.F. Casper
Aromatase inhibition reduces gonadotrophin dose required for controlled ovarian stimulation in women with unexplained infertility
Hum. Reprod., August 1, 2003; 18(8): 1588 - 1597.
[Abstract] [Full Text] [PDF]

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 Hum ReprodHome page
D. de Ziegler
Associate editor's commentary: The dawning of the non-cancer uses of aromatase inhibitors in gynaecology
Hum. Reprod., August 1, 2003; 18(8): 1598 - 1602.
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 Hum ReprodHome page
J. Tesarik
Effects of LH on oocyte yield and developmental competence
Hum. Reprod., June 1, 2003; 18(6): 1358 - 1360.
[Full Text] [PDF]

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 EndocrinologyHome page
C. R. Harlow, M. Rae, L. Davidson, P. C. Trackman, and S. G. Hillier
Lysyl Oxidase Gene Expression and Enzyme Activity in the Rat Ovary: Regulation by Follicle-Stimulating Hormone, Androgen, and Transforming Growth Factor-{beta} Superfamily Members in Vitro
Endocrinology, January 1, 2003; 144(1): 154 - 162.
[Abstract] [Full Text] [PDF]

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S. Yeh, M.-Y. Tsai, Q. Xu, X.-M. Mu, H. Lardy, K.-E. Huang, H. Lin, S.-D. Yeh, S. Altuwaijri, X. Zhou, et al.
Generation and characterization of androgen receptor knockout (ARKO) mice: An in vivo model for the study of androgen functions in selective tissues
PNAS, October 15, 2002; 99(21): 13498 - 13503.
[Abstract] [Full Text] [PDF]

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 Hum ReprodHome page
A. P. Cheung, S. M. Pride, B. H. Yuen, and L. Sy
In-vivo ovarian androgen responses to recombinant FSH with and without recombinant LH in polycystic ovarian syndrome
Hum. Reprod., October 1, 2002; 17(10): 2540 - 2547.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
C. R. Harlow, L. Davidson, K. H. Burns, C. Yan, M. M. Matzuk, and S. G. Hillier
FSH and TGF-{beta} Superfamily Members Regulate Granulosa Cell Connective Tissue Growth Factor Gene Expression in Vitro and in Vivo
Endocrinology, September 1, 2002; 143(9): 3316 - 3325.
[Abstract] [Full Text] [PDF]

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 J. Virol.Home page
A. L. Greenway, D. A. McPhee, K. Allen, R. Johnstone, G. Holloway, J. Mills, A. Azad, S. Sankovich, and P. Lambert
Human Immunodeficiency Virus Type 1 Nef Binds to Tumor Suppressor p53 and Protects Cells against p53-Mediated Apoptosis
J. Virol., February 22, 2002; 76(6): 2692 - 2702.
[Abstract] [Full Text] [PDF]

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G. Cheng, Z. Weihua, S. Makinen, S. Makela, S. Saji, M. Warner, J.-A. Gustafsson, and O. Hovatta
A Role for the Androgen Receptor in Follicular Atresia of Estrogen Receptor Beta Knockout Mouse Ovary
Biol Reprod, January 1, 2002; 66(1): 77 - 84.
[Abstract] [Full Text]

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 EndocrinologyHome page
H. Wang, K. Andoh, H. Hagiwara, L. Xiaowei, N. Kikuchi, Y. Abe, K. Yamada, R. Fatima, and H. Mizunuma
Effect of Adrenal and Ovarian Androgens on Type 4 Follicles Unresponsive to FSH in Immature Mice
Endocrinology, November 1, 2001; 142(11): 4930 - 4936.
[Abstract] [Full Text] [PDF]

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O. Barbier, C. Girard, L. Berger, M. El Alfy, A. Belanger, and D. W. Hum
The Androgen-Conjugating Uridine Diphosphoglucuronosyltransferase-2B Enzymes Are Differentially Expressed Temporally and Spatially in the Monkey Follicle throughout the Menstrual Cycle
Endocrinology, June 1, 2001; 142(6): 2499 - 2507.
[Abstract] [Full Text] [PDF]

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 Hum ReprodHome page
D. P. Levy, J. M. Navarro, G. L. Schattman, O. K. Davis, and Z. Rosenwaks
The role of LH in ovarian stimulation: Exogenous LH: let's design the future
Hum. Reprod., November 1, 2000; 15(11): 2258 - 2265.
[Abstract] [Full Text] [PDF]

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