scholarly journals Subfertile Female Androgen Receptor Knockout Mice Exhibit Defects in Neuroendocrine Signaling, Intraovarian Function, and Uterine Development But Not Uterine Function

Endocrinology ◽  
2009 ◽  
Vol 150 (7) ◽  
pp. 3274-3282 ◽  
Author(s):  
K. A. Walters ◽  
K. J. McTavish ◽  
M. G. Seneviratne ◽  
M. Jimenez ◽  
A. C. McMahon ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Knockout Mice ◽  
Growth And Development ◽  
Direct Evidence ◽  
Female Fertility ◽  
Corpora Lutea ◽  
Wild Type ◽  
Uterine Growth ◽  
Uterine Function ◽  
Uterine Development

Female androgen receptor (AR) knockout mice (AR−/−) generated by an in-frame Ar exon 3 deletion are subfertile, but the mechanism is not clearly defined. To distinguish between extra- and intraovarian defects, reciprocal ovarian transplants were undertaken. Ovariectomized AR−/− hosts with wild-type (AR+/+) ovary transplants displayed abnormal estrus cycles, with longer cycles (50%, P < 0.05), and 66% were infertile (P < 0.05), whereas AR+/+ hosts with either AR−/− or surgical control AR+/+ ovary transplants displayed normal estrus cycles and fertility. These data imply a neuroendocrine defect, which is further supported by increased FSH (P <0.05) and estradiol (P <0.05), and greater LH suppressibility by estradiol in AR−/− females at estrus (P <0.05). Additional intraovarian defects were observed by the finding that both experimental transplant groups exhibited significantly reduced pups per litter (P < 0.05) and corpora lutea numbers (P < 0.05) compared with surgical controls. All groups exhibited normal uterine and lactation functions. AR−/− uteri were morphologically different from AR+/+ with an increase in horn length (P < 0.01) but a reduction in uterine diameter (P < 0.05), total uterine area (P < 0.05), endometrial area (P < 0.05), and myometrial area (P < 0.01) at diestrus, indicating a role for AR in uterine growth and development. Both experimental transplant groups displayed a significant reduction in uterine diameter (P < 0.01) compared with transplanted wild-type controls, indicating a role for both AR-mediated intraovarian and intrauterine influences on uterine physiology. In conclusion, these data provide direct evidence that extraovarian neuroendocrine, but not uterine effects, as well as local intraovarian AR-mediated actions are important in maintaining female fertility, and a disruption of AR signaling leads to altered uterine development.

scholarly journals Subfertility in androgen-insensitive female mice is rescued by transgenic FSH

2017 ◽  
Vol 29 (7) ◽  
pp. 1426 ◽  
Author(s):  
K. A. Walters ◽  
M. C. Edwards ◽  
M. Jimenez ◽  
D. J. Handelsman ◽  
C. M. Allan
Keyword(s):  
Androgen Receptor ◽  
Litter Size ◽  
Ovarian Function ◽  
Reproductive Function ◽  
Antral Follicle ◽  
Female Fertility ◽  
Wild Type ◽  
Female Reproduction ◽  
Androgen Insensitivity ◽  
Female Mice

Androgens synergise with FSH in female reproduction but the nature of their interaction in ovarian function and fertility is not clear. In the present study, we investigated this interaction, notably whether higher endogenous FSH can overcome defective androgen actions in androgen receptor (AR)-knockout (ARKO) mice. We generated and investigated the reproductive function of mutant mice exhibiting AR resistance with or without expression of human transgenic FSH (Tg-FSH). On the background of inactivated AR signalling, which alone resulted in irregular oestrous cycles and reduced pups per litter, ovulation rates and antral follicle health, Tg-FSH expression restored follicle health, ovulation rates and litter size to wild-type levels. However, Tg-FSH was only able to partially rectify the abnormal oestrous cycles observed in ARKO females. Hence, elevated endogenous FSH rescued the intraovarian defects, and partially rescued the extraovarian defects due to androgen insensitivity. In addition, the observed increase in litter size in Tg-FSH females was not observed in the presence of AR signalling inactivation. In summary, the findings of the present study reveal that FSH can rescue impaired female fertility and ovarian function due to androgen insensitivity in female ARKO mice by maintaining follicle health and ovulation rates, and thereby optimal female fertility.

scholarly journals Androgen actions via androgen receptor promote PTEN inactivation induced uterine cancer

2015 ◽  
Vol 22 (5) ◽  
pp. 687-701 ◽  
Author(s):  
Jaesung (Peter) Choi ◽  
Reena Desai ◽  
Yu Zheng ◽  
Mu Yao ◽  
Qihan Dong ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Uterine Cancer ◽  
Serum Testosterone ◽  
Cowden Syndrome ◽  
Corpora Lutea ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Uterine Growth ◽  
Uterine Cancers ◽  
Reproductive Cancers

Haploinsufficient inactivating phosphatase and tensin homolog (Pten) mutations cause Cowden syndrome, an autosomal dominant risk genotype for hormone dependent reproductive cancers. As androgen actions mediated via the androgen receptor (AR) supports uterine growth and may modify uterine cancer risk, we hypothesized that a functional AR may increase PTEN inactivation induced uterine cancer. To test the hypothesis, we compared the PTEN knockout (PTENKO) induced uterine pathology in heterozygous PTENKO and combined heterozygous PTEN and complete AR knockout (PTENARKO) female mice. PTENKO induced uterine pathology was significantly reduced by AR inactivation with severe macroscopic uterine pathology present in 21% of PTENARKO vs 46% of PTENKO at a median age of 45 weeks. This could be due to reduced stroma ERα expression in PTENARKO compared to PTENKO uterus, while AR inactivation did not modify PTEN or P-AKT levels. Unexpectedly, while progesterone (P4) is assumed protective in uterine cancers, serum P4was significantly higher in PTENKO females compared to WT, ARKO, and PTENARKO females consistent with more corpora lutea in PTENKO ovaries. Serum testosterone and ovarian estradiol were similar between all females. Hence, our results demonstrated AR inactivation mediated protection against PTENKO induced uterine pathology and suggests a potential role for antiandrogens in uterine cancer prevention and treatment.

scholarly journals Postnatal uterine development in Inverdale ewe lambs

Reproduction ◽  
2008 ◽  
Vol 135 (3) ◽  
pp. 357-365 ◽  
Author(s):  
Kanako Hayashi ◽  
Anne R O'Connell ◽  
Jennifer L Juengel ◽  
Ken P McNatty ◽  
George H Davis ◽  
...  
Keyword(s):  
Uterine Horn ◽  
Wild Type ◽  
Endometrial Gland ◽  
Antral Follicles ◽  
Ewe Lambs ◽  
Large Numbers ◽  
Uterine Growth ◽  
Uterine Glands ◽  
Gland Development ◽  
Uterine Development

Postnatal development of the uterus involves, particularly, development of uterine glands. Studies with ovariectomized ewe lambs demonstrated a role for ovaries in uterine growth and endometrial gland development between postnatal days (PNDs) 14 and 56. The uterotrophic ovarian factor(s) is presumably derived from the large numbers of growing follicles in the neonatal ovary present after PND 14. The Inverdale gene mutation (FecXI) results in an increased ovulation rate in heterozygous ewes; however, homozygous ewes (II) are infertile and have ‘streak’ ovaries that lack normal developing of preantral and antral follicles. Uteri were obtained on PND 56 to determine whether postnatal uterine development differs between wild-type (++) and II Inverdale ewes. When compared with wild-type ewes, uterine weight of II ewes was 52% lower, and uterine horn length tended to be shorter, resulting in a 68% reduction in uterine weight:length ratio in II ewes. Histomorphometrical analyses determined that endometria and myometria of II ewes were thinner and intercaruncular endometrium contained 38% fewer endometrial glands. Concentrations of estradiol in the neonatal ewes were low and not different between ++ and II ewes, but II ewes had lower concentrations of testosterone and inhibin-α between PNDs 14 and 56. Receptors for androgen and activin were detected in the neonatal uteri of both ++ and II ewes. These results support the concept that developing preantral and/or antral follicles of the ovary secrete uterotrophic factors, perhaps testosterone or inhibin-α, that acts in an endocrine manner to stimulate uterine growth and endometrial gland development in the neonatal ewes.

scholarly journals Altered Differentiation and Proliferation of Prostate Epithelium in Mice Lacking the Androgen Receptor Cofactor p44/WDR77

Endocrinology ◽  
2010 ◽  
Vol 151 (8) ◽  
pp. 3941-3953 ◽  
Author(s):  
Shen Gao ◽  
Hong Wu ◽  
Fen Wang ◽  
Zhengxin Wang
Keyword(s):  
Androgen Receptor ◽  
Growth And Development ◽  
Target Gene ◽  
Secretory Proteins ◽  
Wild Type ◽  
Altered Expression ◽  
Prostate Development ◽  
Differentiation And Proliferation ◽  
Prostate Epithelium ◽  
Prostate Growth

Although it has been observed that various cofactors modulate activity of the androgen receptor (AR), the specific relationship between AR cofactors and prostate development and functions has not been well studied. To determine whether AR cofactor p44/WDR77 is important in prostate growth and development, we examined prostate architecture in p44/WDR77-null mice and wild-type (WT) littermates. Prostate glands from p44/WDR77-deficient animals were not only smaller than those from WT mice but also had fewer branches and terminal duct tips and were deficient in production of secretory proteins. The p44/WDR77-null prostate tissue was less differentiated and hyperproliferative relative to WT littermates. In addition, the altered expression of androgen-regulated genes was observed in the p44/WDR77-null prostate. Thus, these results suggest that the AR cofactor p44/WDR77 plays important roles in prostate growth and differentiation by modulating AR-target gene expression.

scholarly journals Use of NK1knockout mice to analyze substance P-induced edema formation

1999 ◽  
Vol 277 (2) ◽  
pp. R476-R481 ◽  
Author(s):  
Thong Cao ◽  
Norma P. Gerard ◽  
Susan D. Brain
Keyword(s):  
Mast Cell ◽  
Substance P ◽  
Knockout Mice ◽  
Direct Evidence ◽  
Wild Type ◽  
Edema Formation ◽  
Dependent Component ◽  
Neurokinin 1 ◽  
Dose Dependent ◽  
Mast Cell Degranulating

The mechanisms involved in tachykinin-induced neurokinin-1 (NK1) receptor-mediated edema formation have been studied in anesthetized wild-type and NK1knockout mice. Intradermally injected substance P (30–300 pmol), NK1agonists septide (3–30 pmol) and GR-73632 (3–30 pmol), and the mast cell-degranulating agent, compound 48/80 induced dose-dependent edema in wild-type skin, measured by the accumulation of intravenously injected125I-labeled albumin. Septide was 3–10× more potent than substance P. The tachykinins were inactive in knockout mice, but compound 48/80 induced a significantly greater edema ( P < 0.05) than that observed in paired wild-type mice. Capsaicin (which releases endogenous neuropeptides) and exogenous tachykinins induced edema formation, which was reduced by the mast cell amine histamine H1antagonist mepyramine ( P < 0.05). These findings confirm that tachykinins mediate edema formation via the NK1receptor and provide direct evidence that the septide-sensitive binding site is on the NK1receptor. Furthermore, results suggest that edema induced by the tachykinins, although totally dependent on NK1receptor-mediated mechanism, contains a mast cell-dependent component. The evidence is in keeping with an NK1receptor on mast cells.

scholarly journals Theca-Specific Estrogen Receptor-α Knockout Mice Lose Fertility Prematurely

Endocrinology ◽  
2009 ◽  
Vol 150 (8) ◽  
pp. 3855-3862 ◽  
Author(s):  
Sungeun Lee ◽  
Dong-Wook Kang ◽  
Susan Hudgins-Spivey ◽  
Andree Krust ◽  
Eun-Young Lee ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Knockout Mice ◽  
Critical Role ◽  
Serum Testosterone ◽  
Estrogen Receptor Α ◽  
Corpora Lutea ◽  
Wild Type ◽  
Female Reproduction ◽  
Estrogen Action ◽  
Theca Cells

Estrogen receptor-α (Esr1) mediates estrogen action in regulating at all levels of the hypothalamic-pituitary-ovarian axis. Whereas the importance of Esr1 in hypothalamus and pituitary has been demonstrated by loss of fertility in the neuron- and pituitary-specific Esr1 knockout mice, whether Esr1 plays a critical role in the ovary remains to be determined. In the ovary, Esr1 is mainly expressed in the theca/interstitial cells and germinal epithelium and thus is believed to mediate estrogen action in these cells. In this study, we assessed the importance of Esr1 in the ovarian theca cells in regulating female reproduction. The Cre-LoxP approach was used to selectively delete the Esr1 gene in the theca cells, and the reproductive consequence of the deletion was measured. Adolescent theca-specific Esr1 knockout (thEsr1KO) mice (&lt;4 months of age) are fertile and cycling. However, they begin to display an erratic pattern of estrous cycles and become infertile before they reach the age of 6 months. The ovaries of thEsr1KOmice (≥4 months) have fewer corpora lutea but more antral follicles than the age-matching wild-type mice. The numbers of 17-hydroxylase-expressing cells are largely increased in the interstitium of the thEsr1KO mouse ovary. Interestingly, whereas basal levels of serum testosterone and FSH were mildly elevated, LH level was either markedly lower or undetectable in the thEsr1KO mice. When superstimulated by exogenous gonadotropins, thEsr1KO mice released significantly fewer oocytes that wild-type littermates and developed multiple hemorrhagic cysts. Taken together, this study demonstrates that theca Esr1 plays a critical role in regulating female reproduction.

scholarly journals A Screen for Genes That Function in Abscisic Acid Signaling in Arabidopsis thaliana

Genetics ◽  
2002 ◽  
Vol 161 (3) ◽  
pp. 1247-1255 ◽  
Author(s):  
Eiji Nambara ◽  
Masaharu Suzuki ◽  
Suzanne Abrams ◽  
Donald R McCarty ◽  
Yuji Kamiya ◽  
...  
Keyword(s):  
Abscisic Acid ◽  
Growth And Development ◽  
Plant Hormone ◽  
The Other ◽  
Aba Signaling ◽  
Wild Type ◽  
Plant Growth And Development ◽  
Diverse Range ◽  
Abscisic Acid Signaling ◽  
Aba Insensitive

Abstract The plant hormone abscisic acid (ABA) controls many aspects of plant growth and development under a diverse range of environmental conditions. To identify genes functioning in ABA signaling, we have carried out a screen for mutants that takes advantage of the ability of wild-type Arabidopsis seeds to respond to (−)-(R)-ABA, an enantiomer of the natural (+)-(S)-ABA. The premise of the screen was to identify mutations that preferentially alter their germination response in the presence of one stereoisomer vs. the other. Twenty-six mutants were identified and genetic analysis on 23 lines defines two new loci, designated CHOTTO1 and CHOTTO2, and a collection of new mutant alleles of the ABA-insensitive genes, ABI3, ABI4, and ABI5. The abi5 alleles are less sensitive to (+)-ABA than to (−)-ABA. In contrast, the abi3 alleles exhibit a variety of differences in response to the ABA isomers. Genetic and molecular analysis of these alleles suggests that the ABI3 transcription factor may perceive multiple ABA signals.

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