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Endocrinology Vol. 138, No. 11 5000-5005
Copyright © 1997 by The Endocrine Society

ARTICLES

Role of Androgens in Testicular Tumor Development in Inhibin-Deficient Mice1

Weinian Shou, Teresa K. Woodruff and Martin M. Matzuk

Departments of Pathology (W.S., M.M.M.), Cell Biology (M.M.M.), and Molecular and Human Genetics (M.M.M.), Baylor College of Medicine, Houston, Texas 77030; and the Departments of Medicine, and Neurobiology and Physiology, Northwestern University (T.K.W.), Chicago, Illinois 60611

Address all correspondence and requests for reprints to: Dr. Martin M. Matzuk, Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030. E-mail: mmatzuk{at}bcm.tmc.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
To understand gonadal tumor development, we have previously created a mouse model in which mice deficient in the inhibins develop gonadal sex cord-stromal tumors with essentially 100% penetrance. These tumors develop as early as 4 weeks of age and cause cancer cachexia-like symptoms and subsequent death in the inhibin-deficient mice. Gonadectomized inhibin-deficient mice eventually develop adrenal cortical tumors with nearly 100% penetrance. These studies have identified inhibin as a novel secreted tumor suppressor protein with specificity for the gonads and adrenal glands. Sex steroids have been implicated to influence gonadal tumor development in humans and mice. To determine the role of androgens in gonadal tumorigenesis in inhibin-deficient male mice, we have used a genetic intercross strategy, breeding inhibin {alpha} mutant mice with tfm (testicular feminization, a naturally occurring androgen receptor mutant) carrying females to eventually generate compound mutant male mice that lack inhibins and carry the tfm mutation. These compound mutant mice, like inhibin-deficient mice, continue to develop testicular tumors and the accompanying cancer cachexia-like wasting syndrome. Consistent with these findings, elevated levels of activins A and B secreted from the gonadal tumors are seen in the adult compound mutant mice as well as the secondary pathological consequences of these high activin levels in the livers and glandular stomachs. However, in contrast to male mice lacking only inhibin, in which essentially 100% of the testicular tumors are hemorrhagic, 65% of the tumors in these compound mutant male mice are less hemorrhagic, and approximately 50% of the compound mutants live longer than 17 weeks of age (95% of the male mice lacking only inhibin die by 12 weeks). These results suggest that androgens are not required for testicular tumor development in inhibin-deficient mice, but may play a regulatory role in testicular tumor progression.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
LOSS OF negative growth control in mammalian cells leads to tumorigenesis. Similar to other malignancies, ovarian and testicular cancers arise through multiple genetic alterations. One reason for the complexity of ovarian and testicular cancers is that normal ovarian and testicular function is modulated by extragonadal (e.g. the pituitary gonadotropins, FSH, and LH) and intragonadal regulators (e.g. sex steroids and gonadal peptides such as the inhibins and activins) (1). Inhibins, growth regulatory members of the transforming growth factor-ß superfamily, are heterodimeric growth factors ({alpha}:ßA or {alpha}:ßB) that share a common subunit (ßA or ßB) with activins (Fig. 1AGo). Although inhibins and activins are structurally related, their functions are often opposite (1). As the name implies, inhibins were originally discovered as gonadal endocrine peptides (Sertoli cell and granulosa cell products) that feedback onto the gonadotrophs of the pituitary to inhibit FSH synthesis and secretion (2). Later studies have demonstrated important paracrine and autocrine roles of the inhibins in embryonic, extraembryonic (i.e. placenta), and adult tissues, including the gonads and adrenal gland (2).



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  		Figure 1. Structures of the inhibins and activins, and strategy for generating the Xtfm/Y, inham1/inham1 mutants. A, There are two inhibin heterodimers, inhibin A ({alpha}:ßA) and inhibin B ({alpha}:ßB). These forms share common ß-subunits with the activin ß:ß dimers. There are three activins, activin A (ßA:ßA), activin B (ßB:ßB), and activin AB (ßA:ßB), which differ in the combination of ß-subunits. Mice homozygote for the targeted deletion of the {alpha}-subunit gene (inham1/inham1) lack the {alpha}-subunit and therefore are deficient in inhibins. B, Female mice heterozygous for the testicular feminization mutation (Xta/Xtfm) were obtained from Jackson Laboratories. Ta is an X-chromosome marker for the tabby gene. Compound heterozygous female mice (Xtfm/X, inham1/+) were generated initially. These mice were intercrossed with male mice heterozygous for inhibin {alpha} (X/Y, inham1/+) to obtain feminized male mice (Xtfm/Y, inham1/inham1) with mutations in both the androgen receptor and both inhibin {alpha} genes. The compound mutants were obtained at an expected Mendelian frequency of 1:16 from second round intercrosses.

 
To study gonadal growth and differentiation, we have previously created an animal model in which mice deficient in the inhibins develop gonadal sex cord-stromal tumors with nearly 100% penetrance (3). Early tumors in males (4 weeks of age) are focal intratubular lesions that are undifferentiated Sertoli cell tumors. Early tumors in females are also focal granulosa or Sertoli cell tumors. At a later stage, the tumors in females are often mixed granulosa/Sertoli cell tumors and can often be described as nodular granulosa cell tumors that closely resemble sex cord-stromal tumors seen in human females. Late stage tumors in males are predominantly hemorrhagic, mixed, and focally invasive undifferentiated gonadal stromal tumors (3). Inhibin-deficient male and female mice that develop gonadal tumors eventually die of a severe cancer cachexia-like wasting syndrome, with 95% of the mice succumbing to the cachexia by 12 and 17 weeks of age, respectively (4). This cachexia-like syndrome includes severe weight loss, anemia, hepatocellular necrosis, lethargy, and a block in the terminal differentiation of multiple gastric epithelial cell lineages, including parietal cells and zymogenic cells in the glandular stomach (Li, Q., S. M. Karam, K. A. Coerver, M. M. Matzuk, J. I. Gordon, manuscript submitted). Gonadectomized inhibin-deficient male and female mice live longer, develop adrenal tumors, and eventually die from a similar wasting syndrome (4). These studies have identified inhibin as a novel secreted tumor suppressor protein with specificity for the gonads and adrenal glands.

Recently, our group has demonstrated that the pituitary gonadotropins (LH and FSH) are essential modifier factors for gonadal tumor development in inhibin-deficient mice (6). Compound homozygous mutant mice that lack inhibin and have suppressed gonadotropin levels due to a mutation in the GnRH gene [the hypogonadal (hpg) mutation] do not develop the wasting syndrome, do not exhibit malignant gonadal or adrenal tumors, and can survive for more than 1 yr. Similarly, Beamer and colleagues (7, 8) used granulosa cell tumor-prone SWR inbred mice and ovarian transfer experiments to demonstrate that gonadotropins are required for tumor development and that exogenously supplied hCG, but not FSH, can induce the tumors. In addition, they have shown that the androgenic steroid precursor, dehydroepiandrosterone, can induce the tumors (7), suggesting that the hCG effect is mediated through the production of ovarian androgens. Thus, androgens may also act as important modifier factors for granulosa cell tumor development. In addition, the tumors that develop in male inhibin-deficient mice often resemble human juvenile granulosa cell tumors, and nearly every tumor secretes estrogens (2). Therefore, we hypothesized that androgens may also play a role in testicular tumor development and/or progression in inhibin-deficient mice. To determine the possible modifier functions of androgens in gonadal tumorigenesis, we have generated compound mutant mice that lack both the inhibin {alpha}-subunit and androgen receptor by crossing inhibin {alpha} heterozygote males with tfm (testicular feminization) heterozygote females (Xtfm/X). Tfm is an X-linked mutation in the androgen receptor gene that results in the feminization of mutant male (Xtfm/Y) mice (9, 10). Although androgens are produced by Xtfm/Y mice, their tissues are incapable of responding to androgens. The testes in these mice are small and not fully descended, and spermatogenesis is blocked at meiotic prophase (11). Thus, the generation of inhibin and androgen receptor compound mutant mice (Xtfm/Y, inham1/inham1) allowed us to determine whether androgens influence the development and/or progression of testicular tumors in inhibin-deficient male mice.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Generation of mice
Generation of inhibin heterozygote (inham1/+) and homozygote (inham1/inham1) mice was described previously (3). Female mice heterozygous for the testicular feminization mutation (Xtfm/X) were obtained from Jackson Laboratories (Bar Harbor, ME). The original strain is JR1809, which is maintained as a balanced stock with tabby (Ta) on one X-chromosome (e.g. Xta/Xtfm). Xta/Xta and Xta/Y mice are identified by striping in their coat color. Compound heterozygous female mice (Xtfm/X, inham1/+) that lacked the striping in their coat color were generated initially (Fig. 1BGo). These mice were intercrossed with male mice heterozygous for the inhibin {alpha} mutation (inham1/+) to obtain feminized male mice (Xtfm/Y, inham1/inham1) with mutations in both the androgen receptor and both inhibin {alpha} genes. The compound mutants were obtained at an expected Mendelian frequency of 1:16 from second round intercrosses (Xtfm/X, inham1/+ x X/Y, inham1/+). All mice were maintained and treated according to the NIH Guide for the Care and Use of Laboratory Animals.

Southern blot analysis
Southern blot analysis was performed on tail DNA samples using 32P-labeled probes as previously described (3). The Xtfm/Y genotype was determined using a Y-chromosome-specific probe. Xtfm/Y mice were identified as Y-chromosome positive but phenotypically female externally genitalia.

Histological analysis
The compound mutant mice and control littermate mice were weighed weekly. Histological analysis was performed on the testes, stomachs, and livers of the mice. The tissues were fixed in 10% buffered formalin for more than 24 h (stomach, livers, and testicular tumors) or in Bouin’s solution (testes) for 24 h or less. The testes were subsequently placed in a lithium carbonate-saturated 70% ethanol solution with daily changes for approximately 1 week. All specimens were subjected to dehydration in a graded series of ethanol, embedded in paraffin wax, and cut at 4 µm using a microtome. The testis or testicular tumor sections were stained with hematoxylin and periodic acid-Schiff reagent. Liver and stomach sections were stained with hematoxylin and eosin.

Serum analysis
Activin assays were performed on serum from compound mutants and control mice. Blood was obtained from anesthetized mice by cardiac puncture. The blood was allowed to clot in Microtainer serum separator tubes (Becton Dickinson, Mountain View, CA) before centrifugation and separation of the serum. Serum was frozen at -20 C before analysis. Serum activin A and activin B levels were determined by enyzme-linked immunosorbent assays as described (12).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Xtfm/Y, inham1/inham1 compound mutant male mice continue to develop a cancer cachexia-like syndrome similar to that in inham1/inham1 mutant mice
The first overt sign of gonadal tumor development in inhibin-deficient mice is severe weight loss and development of a characteristic hunchback and sunken eye appearance (4). Many of the male and female inhibin-deficient mice begin to lose weight around 6–7 weeks of age, and more than 95% of the mice die by 12 and 17 weeks of age, respectively (4). This wasting syndrome (cancer cachexia-like syndrome) secondary to gonadal tumor development (4, 13) allowed us to monitor tumor development in mutant mice. Similar to inham1/inham1 mutant mice, compound mutant (Xtfm/Y, inham1/inham1) mice deficient in both androgen receptors and inhibins continue to develop this cancer cachexia-like wasting syndrome (Fig. 2Go). These compound mutant (Xtfm/Y, inham1/inham1) mice begin to lose weight at the same age as inhibin-deficient mice (6–7 weeks of age), which indicates that tumors initiate at approximately the same age. The weight curve (Fig. 2Go) of compound mutants (Xtfm/Y, inham1/inham1) parallels the curves for mice deficient in inhibin alone.



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  		Figure 2. Body weights (mean ± SEM) of Xtfm/Y, inham1/inham1 (n = 23) and inham1/inham1 male (n = 40) mice. Weights were recorded weekly.

 
We had previously shown that the cancer cachexia-like syndrome was secondary to the elevated activin levels secreted by the gonadal tumors (13). Liver and stomach pathology of compound mutants (Xtfm/Y, inham1/inham1) demonstrates hepatocellular necrosis and depletion of parietal cells in the glandular stomach, which is similar to the liver and stomach pathology seen in mice lacking only inhibin (inham1/inham1) (Fig. 3Go) (13). This result suggests that the cancer cachexia-like syndrome seen in compound mutants (Xtfm/Y, inham1/inham1) is caused by elevated activin levels similar to those in inhibin-deficient mice (inham1/inham1). However, approximately 50% of the compound mutant mice (12 of 23) lived longer (17–21 weeks of age) than male inhibin-deficient mice (inham1/inham1; 95% die by 12 weeks of age). These observations suggest that tumors continued to develop in the absence of androgen effects, but that the absence of androgen receptors may have an effect on the rate of tumor progression.



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  		Figure 3. Histological analysis of stomachs and livers from wild-type and compound mutants. A, Glandular stomach from an adult control mouse. Note the abundance of the large eosinophilic parietal cells between arrows that encompass the lower half of the epithelial layer. B, Glandular stomach of a compound mutant male mouse. Note the absence of parietal cells in a comparable region adjacent to the junction of the squamous epithelial-lined forestomach and the glandular region. B is magnified 2-fold compared with A. C, A liver from an adult control mouse, showing a central vein on the left and a portal tract on the right. The hepatocytes are uniform around the central vein. D, A liver from a compound mutant male, showing two central veins on the left and a portal tract on the right. Centrolobular necrosis and abundant lymphocyte infiltration (small cells with prominent nuclei) are seen around the central veins.

 
Activin levels in Xtfm/Y, inham1/inham1 compound mutants
Previous work had demonstrated that the gonadal sex cord-stromal tumors in inhibin-deficient mice produce elevated serum levels of activins, which cause the severe cancer cachexia-like wasting syndrome and pathological effects seen in the livers and stomachs of these mutants (13). As Xtfm/Y, inham1/inham1 compound mutants survive longer than male inhibin-deficient mice (inham1/inham1), it was important to know whether the activin levels in compound mutants were correlated to the longer survival time. Activin assays were performed on the serum from adult Xtfm/Y, inham1/inham1 compound mutants that had tumors. When analyzed by enzyme-linked immunosorbent assays, both activin A and activin B serum levels were elevated in these compound mutants compared with those in wild-type controls and were not significantly different compared with the high serum levels observed in inhibin-deficient mice (Fig. 4Go). Therefore, these results suggest that the longer survival time of the compound mutants (Xtfm/Y, inham1/inham1) cannot be attributable to differences in activin levels.



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  		Figure 4. Serum activin levels in male mice. Comparison of serum activin A and B levels in wild-type, inhibin-deficient (inham1/inham1) and compound mutant (Xtfm/Y, inham1/inham1) adult male mice. Values at each point are the mean ± SEM. Mice analyzed in this study were as follows: wild type, n = 5; inhibin-deficient, n = 10; and tfm+/inhibin-deficient, n = 7.

 
Xtfm/Y, inham1/inham1 compound mutants develop multifocal testicular tumors
The early testicular tumors (4 weeks of age) in inhibin-deficient mice are clonal lesions (3). These tumor foci progress very rapidly and become focally invasive and locally very aggressive, with prominent hemorrhage in essentially 100% of the inhibin-deficient male mice (Fig. 5Go, B and E). As compound mutants (Xtfm/Y, inham1/inham1) began to lose weight at 6 weeks of age, we postulated that these compound mutants initiated tumor formation at approximately the same age as inhibin-deficient mice. At 3 weeks of age, the testes of compound mutant (Xtfm/Y, inham1/inham1) mice appear to be grossly and histologically identical to those of Xtfm/Y mice (typical Xtfm/Y mice have small testes with a block in spermatogenesis). No signs of tumor formation were observed. This is consistent with the findings in mice lacking only inhibin (3), in which the earliest tumor lesions in males were not observed until at least 4 weeks of age. However, testes isolated from 5-week-old compound mutant (Xtfm/Y, inham1/inham1) mice were 2–3 times larger than those in the same age Xtfm/Y mice. Histological analysis revealed that compound mutants (Xtfm/Y, inham1/inham1) develop multifocal and nonhemorrhagic lesions (Fig. 5CGo), almost resembling a hyperplastic state, as opposed to the more common focal hemorrhagic lesions seen in inhibin-deficient mice (Fig. 5BGo). These intratubular lesions have mitotically active, undifferentiated granulosa/Sertoli cell tumors (Fig. 5Go, F and I), similar to the testicular tumors of inhibin-deficient mice (3). Interestingly, 65% of the testicular tumors in older compound mutant mice are less hemorrhagic (Fig. 5HGo), suggesting that these tumors may progress more slowly than tumors in inhibin-deficient (inham1/inham1) mice.



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  		Figure 5. Gross and histological analysis of the testes and testicular tumors. Sections through a testes of a 5-week-old Xtfm/Y mouse (A; magnification, x5) and an age-matched wild-type mouse (D; magnification, x20X). Normal spermatogenesis is seen in the seminiferous tubules of the wild-type mouse (D), but spermatogenesis is blocked in the Xtfm/Y mouse (A). Sections through testicular tumor from a 5-week-old inham1/inham1 male mouse at x5 (B) and x20 (E) magnifications. As previously described (3), early tumors are focal (B) with prominent hemorrhage (arrow in B and h in E). Sections through a testicular tumor from a 5-week-old Xtfm/Y, inham1/inham1 mutant mouse at x5 (C) and x20 (F) magnifications. Note the multifocal lesions in this testicular tumor at the right side vs. some typical Xtfm/Y seminiferous tubules at the left side (C). A section through a less hemorrhagic testicular tumor from a compound mutant mouse (15 weeks) at x40 magnification (I) demonstrates typical nuclear/cytoplasmic features of these tumors. G and H, Gross analysis of a testicular tumor from a compound mutant mouse. Hemorrhagic tumors are found in 35% of compound mutants (G, top), but 65% of the tumors are less hemorrhagic (H). Testes from an Xtfm/Y mouse are shown as controls (G, bottom).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We have previously generated inhibin-deficient mice using a gene-targeting strategy in embryonic stem cells and identified inhibin as a novel secreted tumor-suppressor specific for the gonads and adrenal glands (2, 3, 4). Inhibin-deficient mice develop focally invasive gonadal sex cord-stromal tumors and die from a severe wasting syndrome, a cancer cachexia-like syndrome, that is secondary to elevated circulating activin levels secreted from the gonadal tumors (4, 13). Because the tumors initiate as focal lesions, and not all cells of the gonads develop and form tumors, other secondary events/factors must be necessary for malignant growth. These may include altered regulation/modulation of protein hormones [e.g. the gonadotropins LH and FSH (6)], important gonadal growth factors [e.g. activins (13) and Mullerian inhibiting substance (14)], steroids (e.g. estrogens and androgens), or other unknown tumor suppressor proteins. Identification of these modifier factors is critical to understand the complex process of gonadal sex cord-stromal tumor formation and progression. Recently, we have identified the gonadotropins as essential modifier factors for gonadal tumor development in inhibin-deficient mice (6). Mice deficient in inhibin {alpha}-subunit and GnRH, which have suppressed gonadotropin levels (LH and FSH), fail to develop tumors beyond the premalignant stage (6). In contrast, our present study using a similar genetic approach suggests that androgens, in contrast to gonadotropins, are not essential for testicular tumor development in inhibin-deficient mice. Compound mutant mice deficient in both androgen receptors and inhibins continue to develop sex cord-stromal tumors. However, androgens may modify some aspects of the tumor progression. In contrast to more focal lesions in inhibin-deficient mice, compound mutant mice develop multifocal lesions at an earlier age, and 65% of these tumors progress to less hemorrhagic tumors at later stages, suggesting that androgens may have certain regulatory roles in testicular tumor progression in inhibin-deficient mice. One possibility is that the lack of androgens influences either the local invasiveness of the tumor and/or has an effect on testicular tumor angiogenesis (e.g. secreting less of the angiogenic factors).

The impact of gonadotropins on gonadal tumor development in inhibin-deficient mice may be either by their direct mitogenic effects or via their steroidogenic output. As suggested by Beamer and colleagues, androgens may play very important roles in ovarian granulosa cell tumorigenesis in SWXJ mice (7, 8). Antisteroids have also been shown to be effective in suppressing ovarian epithelial tumor cell growth (15). Our study indicates that the modifier role of gonadotropins is not mediated through the actions of androgens in male inhibin-deficient mice. However, ovarian tumor development in either of these mouse models may use a different mechanism to regulate or modulate the malignant process. It will be interesting, therefore, to determine whether androgens have a direct impact on ovarian tumor development in inhibin-deficient mice by injecting antiandrogens into inham1/inham1 mutant mice. These findings, however, do not rule out a role for estrogens in the tumorigenesis in both male and female inhibin-deficient mice. As shown previously (2), almost all of the inhibin-deficient male and female mice have elevated circulating levels of estradiol that originate from gonadal tumors. Similar genetic approaches will be used by intercrossing mice carrying a mutation in the estrogen receptor gene (ERm1) (16) with inhibin mutant mice to generate inham1/inham1, ERm1/ERm1 mice.


   Acknowledgments
 
We thank Ms. Shirley Baker for excellent help in the preparation of the manuscript, Dr. T. Rajendra Kumar for critical reading of the manuscript, and Mr. Anthony Lau for assistance with computer graphics.


   Footnotes
 
1 This work was supported in part by NIH Grant CA-60651 from the NCI (to M.M.M.) and the American Cancer Society, Illinois Division (Grant 96–17; to T.K.W.). Back

Received June 9, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Vale W, Bilezikjian LM, Rivier C 1994 Reproductive and other roles of inhibins and activins. In: Knobil E Neill JD (eds) The Physiology of Reproduction. Raven Press, New York, pp 1861–1878
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  3. Matzuk MM, Finegold MJ, Su J-GJ, Hsueh AJW, Bradley A 1992 {alpha}-Inhibin is a tumour-suppressor gene with gonadal specificity in mice. Nature 360:313–319[CrossRef][Medline]
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  5. Deleted in proof
  6. Kumar TR, Wang Y, Matzuk MM 1996 Gonadotropins are essential modifier factors for gonadal tumor development in inhibin-deficient mice. Endocrinology 137:4210–4216[Abstract]
  7. Tennent BJ, Shultz KL, Beamer WG 1993 Genetic susceptibility for C19 androgen induction of ovarian granulosa cell tumorigenesis in SWXJ strains of mice. Cancer Res 53:1059–1063[Abstract/Free Full Text]
  8. Beamer WG, Shultz KL, Tennent BJ, Shultz LD 1993 Granulosa cell tumorigenesis in genetically hypogonadal-immunodeficient mice grafted with ovaries from tumor-susceptible donors. Cancer Res 53:3741–3746[Abstract/Free Full Text]
  9. Charest NJ, Zhou Z-X, Lubahn DB, Olsen KL, Wilson EM, French FS 1991 A frameshift mutation destabilizes androgen receptor messenger RNA in the Tfm mouse. Mol Endocrinol 5:573–581[Abstract/Free Full Text]
  10. He WW, Kumar MV, Tindall DJ 1991 A frame-shift mutation in the androgen receptor gene causes complete androgen insensitivity in the testicular-feminized mouse. Nucleic Acids Res 19:2373–2378[Abstract/Free Full Text]
  11. Green MC 1990 Genetic variants and strains of the laboratory mouse. Oxford University Press, Oxford
  12. Wong WL, Garg SJ, Woodruff T, Bald L, Fendly B, Lofgren JA 1993 Monoclonal antibody based ELISAs for measurement of activins in biological fluids. J Immunol Methods 165:1–10[CrossRef][Medline]
  13. Coerver KA, Woodruff TK, Finegold MJ, Mather J, Bradley A, Matzuk MM 1996 Activin signaling through activin receptor type II causes the cachexia-like syndrome in inhibin-deficient mice. Mol Endocrinol 10:1534–1543
  14. Matzuk MM, Finegold MJ, Mishina Y, Bradley A, Behringer RR 1995 Synergistic effects of inhibins and Müllerian-inhibiting substance on testicular tumorigenesis. Mol Endocrinol 9:1337–1345[Abstract/Free Full Text]
  15. Slotman BJ, Rao BR 1989 Response to inhibition of androgen action on human ovarian cancer cells in vitro. Cancer Lett 45:213–220[CrossRef][Medline]
  16. Lubahn DB, Moyer JS, Golding TS, Couse JF, Korach KS, Smithies O 1993 Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc Natl Acad Sci USA 90:11162–11166[Abstract/Free Full Text]



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Right arrowPubmed/NCBI databases
*Gene*GEO Profiles
*HomoloGene*UniGene
*Substance via MeSH
Medline Plus Health Information
*Testicular Cancer
*Testicular Disorders

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals