scholarly journals Subfertility with Defective Folliculogenesis in Female Mice Lacking Testicular Orphan Nuclear Receptor 4

2008 ◽  
Vol 22 (4) ◽  
pp. 858-867 ◽  
Author(s):  
Lu-Min Chen ◽  
Ruey-Sheng Wang ◽  
Yi-Fen Lee ◽  
Ning-Chun Liu ◽  
Yu-Jia Chang ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Ovarian Function ◽  
Corpora Lutea ◽  
Orphan Nuclear Receptor ◽  
Estrous Cycles ◽  
Female Mice ◽  
Preovulatory Follicles ◽  
Direct Binding ◽  
Normal Spermatogenesis ◽  
Functional Analyses

Testicular orphan nuclear receptor 4 (TR4) plays essential roles for normal spermatogenesis in male mice. However, its roles in female fertility and ovarian function remain largely unknown. Here we found female mice lacking TR4 (TR4−/−) displayed subfertility and irregular estrous cycles. TR4−/− female mice ovaries were smaller with fewer or no preovulatory follicles and corpora lutea. After superovulation, TR4−/− female mice produced fewer oocytes, preovulatory follicles, and corpora lutea. In addition, more intensive granulosa apoptosis was found in TR4−/− ovaries. Functional analyses suggest that subfertility in TR4−/− female mice can be due to an ovarian defect with impaired folliculogenesis rather than a deficiency in pituitary gonadotropins. Molecular mechanism dissection of defective folliculogenesis found TR4 might induce LH receptor (LHR) gene expression via direct binding to its 5′ promoter. The consequence of reduced LHR expression in TR4−/− female mice might then result in reduced gonadal sex hormones via reduced expression of enzymes involved in steroidogenesis. Together, our results showed TR4 might play essential roles in normal folliculogenesis by influencing LHR signals. Modulation of TR4 expression and/or activation via its upstream signals or unidentified ligand(s) might allow us to develop small molecule(s) to control folliculogenesis.

scholarly journals 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 ◽  
2007 ◽  
Vol 148 (8) ◽  
pp. 3674-3684 ◽  
Author(s):  
K. A. Walters ◽  
C. M. Allan ◽  
M. Jimenez ◽  
P. R. Lim ◽  
R. A. Davey ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Ovarian Function ◽  
Gene Dosage ◽  
Early Embryo ◽  
Ovulation Rate ◽  
Corpora Lutea ◽  
Cell Stage ◽  
Gene Dosage Effect ◽  
Female Mice ◽  
Age Dependent

The role of classical genomic androgen receptor (AR) mediated actions in female reproductive physiology remains unclear. Female mice homozygous for an in-frame deletion of exon 3 of the Ar (AR−/−) were subfertile, exhibiting delayed production of their first litter (AR+/+ = 22 d vs. AR−/− = 61 d, P < 0.05) and producing 60% fewer pups/litter (AR+/+: 8.1 ± 0.4 vs. AR−/−: 3.2 ± 0.9, P < 0.01). Heterozygous females (AR+/−) exhibited an age-dependent 55% reduction (P < 0.01) in pups per litter, evident from 6 months of age (P < 0.05), compared with AR+/+, indicating a significant gene dosage effect on female fertility. Ovulation was defective with a significant reduction in corpora lutea numbers (48–79%, P < 0.01) in 10- to 12- and 26-wk-old AR+/− and AR−/− females and a 57% reduction in oocytes recovered from naturally mated AR−/− females (AR+/+: 9.8 ± 1.0 vs. AR−/−: 4.2 ± 1.2, P < 0.01); however, early embryo development to the two-cell stage was unaltered. The delay in first litter, reduction in natural ovulation rate, and aromatase expression in AR+/− and AR−/− ovaries, coupled with the restored ovulation rate by gonadotropin hyperstimulation in AR−/− females, suggest aberrant gonadotropin regulation. A 2.7-fold increase (AR+/+: 35.4 ± 13.4 vs. AR−/−: 93.9 ± 6.1, P < 0.01) in morphologically unhealthy antral follicles demonstrated deficiencies in late follicular development, although growing follicle populations and growth rates were unaltered. This novel model reveals that classical genomic AR action is critical for normal ovarian function, although not for follicle depletion and that haploinsufficiency for an inactivated AR may contribute to a premature reduction in female fecundity.

Depression of ovarian function and plasma progesterone and estradiol-17β in female goats chronically infected with Trypanosoma congolense

1988 ◽  
Vol 117 (4) ◽  
pp. 477-484 ◽  
Author(s):  
B. M. Mutayoba ◽  
S. Gombe ◽  
E. N. Waindi ◽  
G. P. Kaaya
Keyword(s):  
Post Infection ◽  
Ovarian Function ◽  
Trypanosoma Congolense ◽  
Corpora Lutea ◽  
Estrous Cycles ◽  
Plasma Progesterone ◽  
Tertiary Stage ◽  
Fourth Cycle ◽  
The Individual ◽  
Estradiol 17Β

Abstract. Adult normocyclic female goats experimentally infected with Trypanosoma congolense developed irregular and shorter estrous cycles before complete cessation at the fourth cycle post-infection. This was followed within a month by a decline in the mean plasma progesterone and estradiol-17β levels. The peak luteal progesterone as well as pre-ovulatory estradiol-17β level declined progressively from the second to the fourth cycle post-infection. The ovaries became atretic with reduced numbers of primordial and primary follicles. The larger follicles became atretic at the tertiary stage with subsequent lack of corpora lutea formation. The rapidity of ovarian dysfunction appeared to be related to the degree of susceptibility of the individual infected goats.

scholarly journals Ovarian function in ewes after treatment with mifepristone early during the oestrous cycle

Reproduction ◽  
2003 ◽  
pp. 205-210 ◽  
Author(s):  
EM Paslay ◽  
U Salli ◽  
F Stormshak ◽  
Keyword(s):  
Ovarian Function ◽  
Venous Blood ◽  
Oestrous Cycle ◽  
Corpora Lutea ◽  
Blood Samples ◽  
Treatment Groups ◽  
Significant Difference ◽  
Preovulatory Follicles ◽  
Prostaglandin F ◽  
The Mean

The aim of this study was to determine whether endogenous progesterone regulates synthesis and secretion of luteal oxytocin. In Expt 1, mature ewes (n = 5 per group) were assigned randomly to control or mifepristone (RU486) treatment groups. Ewes were injected s.c. twice a day with vehicle or 10 mg RU486 on days 5-7 of the oestrous cycle (oestrus = day 0). On day 8, after an i.v. injection with prostaglandin F(2alpha) (250 microg cloprostenol), venous blood samples were collected at frequent intervals to determine plasma oxytocin concentrations. Plasma oxytocin concentrations of RU486-treated ewes were not significantly different from those of control ewes. In Expt 2, ewes were injected s.c. each day with vehicle or 175 mg RU486 on days 2-5 of the oestrous cycle followed by administration of prostaglandin F(2alpha) on day 6. Four of five RU486-treated ewes showed 'split-oestrus' (oestrous behaviour for 36 h and then again at 84-108 h after the onset of initial oestrus). There was no significant difference in mean plasma oxytocin or progesterone concentrations between treatment groups. The mean masses of mature corpora lutea from control and RU486-treated ewes on day 6 of the oestrous cycle did not differ significantly (394.8 +/- 28.8 versus 319.5 +/- 48.3 mg). RU486-treated ewes contained mature corpora lutea, new corpora lutea (two of four ewes) and preovulatory follicles (>or= 10 mm, two of four ewes). The average interoestrous interval for RU486-treated ewes was 9 days more than that for control animals (26.2 +/- 2.9 versus 17 +/- 0.5 days; P < 0.025).

scholarly journals Effect of single-chain ovine gonadotropins with dual activity on ovarian function in sheep

Reproduction ◽  
2014 ◽  
Vol 148 (2) ◽  
pp. 129-136 ◽  
Author(s):  
Heloisa M Rutigliano ◽  
Betty M Adams ◽  
Albina Jablonka-Shariff ◽  
Irving Boime ◽  
Thomas E Adams
Keyword(s):  
Ovarian Function ◽  
Single Injection ◽  
Corpora Lutea ◽  
Single Chain ◽  
Comparable Amount ◽  
Free Protein ◽  
Preovulatory Follicles ◽  
Ovulatory Follicles ◽  
The Impact ◽  
Follicle Maturation

We examined the half-life and biological activity of two single-chain proteins that combined portions of ovine FSH and LH. We proposed the hypothesis that these chimeric proteins would display LH and FSH activities and would promote follicle maturation in ewes. Estrus activity was synchronized using progestogen-impregnated vaginal pessaries. To negate the impact of endogenous LH and FSH, animals received serum-containing antibodies against GNRH 1 day before pessary removal (PR). At PR sheep (five animals per group) received a single injection (10 IU/kg, i.v.) of either the ovine-based (oFcLcα) gonadotropin analog, an ovine-based analog containing oLHβ truncated at the carboxyl terminus (oFcL(ΔT)cα), or a human-based gonadotropin analog (hFcLcα). Control animals received a comparable amount of gonadotropin-free protein. Ovulation was induced 3 days after PR using human chorionic gonadotropin (1000 IU, i.v.). Ovaries were collected 11 days after PR. Neither estradiol (E2) or progesterone (P4) production, development of preovulatory follicles or corpora lutea (CL) were noted in control animals receiving gonadotropin-free protein. Significant increase in the synthesis of E2 and P4 was noted in sheep receiving the dually active gonadotropin analogs. The number of CLs present 11 days after PR was significantly increased in sheep receiving the chimeric glycoproteins compared with control animals. The magnitude of the secretory and ovarian responses did not differ between hFcLcα and oFcLcα or between oFcLcα and oFcL(ΔT)cα. Immunoactivity of LH and FSH was low in control animals, but was significantly elevated in sheep receiving the gonadotropin analogs. In conclusion, ovine-based gonadotropin analogs are functionally active in sheep and a single injection is adequate to induce the development of multiple ovulatory follicles.

scholarly journals Deficient melanocortin-4 receptor causes abnormal reproductive neuroendocrine profile in female mice

Reproduction ◽  
2017 ◽  
Vol 153 (3) ◽  
pp. 267-276 ◽  
Author(s):  
Xiaolin Chen ◽  
Lili Huang ◽  
Hwee Y Tan ◽  
Hongzhuo Li ◽  
Ying Wan ◽  
...  
Keyword(s):  
Corpora Lutea ◽  
Chinese Translation ◽  
Estrous Cycles ◽  
Female Mice ◽  
Reproductive Ability ◽  
Melanocortin 4 Receptor ◽  
Pulsatile Mass ◽  
Pathological Mechanism ◽  
Lh Release ◽  
Lh Secretion

Deletion of the melanocortin-4-receptor (Mc4r) gene in mice causes hyperphagia, followed by hyperinsulinemia, obesity and progressive infertility. Evidence shows that the number of developed corpora lutea is reduced in obese MC4R-knockout (MC4R KO) female mice, but the mechanism is unclear. The effect of hyperphagia and obesity by MC4R KO on pulsatile luteinizing hormone (LH) secretion and ovulation remains unknown. In MC4R KO mice and wild-type littermates (WT LM) during the diestrus period throughout different ages, we examined and monitored their metabolic status, pulsatile LH profiles, follicular morphology and the number of corpora lutea. MC4R KO mice were hyperphagic, obese, hyperglycemic, hyperinsulinemic and demonstrated insulin resistance and hepatic steatosis. Irregular estrous cycles and significant changes in the LH secretion profiles were observed in sexually matured 16- to 28-week MC4R KO mice, without any difference in testosterone levels. In addition, MC4R KO mice at 16 weeks of age had significantly fewer corpora lutea than same age WT LM mice. The ovary examinations of MC4R KO mice at 28 weeks of age showed predominantly antral and preovulatory follicles with no corpora lutea. These findings were consistent with the decrease in total, pulsatile, mass and basal LH releases in MC4R KO mice. The characteristics of hormone profiles in obese MC4R KO mice indicate that MC4R plays an important role in regulating LH release, ovulation and reproductive ability probably via hyperphagia-induced obesity. Further study of correlation between metabolic and reproductive regulatory hormones is warranted to dissect the pathological mechanism underlying obesity-induced infertility.Free Chinese abstract: A Chinese translation of this abstract is freely available athttp://www.reproduction-online.org/content/153/3/267/suppl/DC1.

scholarly journals Assessment of NR4A Ligands that Directly Bind and Modulate the Orphan Nuclear Receptor Nurr1

2020 ◽  
Author(s):  
Paola Munoz-Tello ◽  
Hua Lin ◽  
Pasha Khan ◽  
Ian Mitchelle S. de Vera ◽  
Theodore M. Kamenecka ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Protein Nmr ◽  
Effector Proteins ◽  
Orphan Nuclear Receptor ◽  
Parkinson’S Diseases ◽  
A Cell ◽  
Direct Binding ◽  
Cell Type Specific ◽  
Independent Effects ◽  
Small Molecule Modulators

ABSTRACTNurr1/NR4A2 is an orphan nuclear receptor transcription factor implicated as a potential drug target for neurological disorders including Alzheimer’s and Parkinson’s diseases. Previous studies identified small molecule modulators of NR4A nuclear receptors including Nurr1 and Nur77/NR4A1; it remains unclear whether these ligands affect Nurr1 through direct binding or indirect non-binding mechanisms. We assessed a panel of twelve ligands reported to affect NR4A activity for Nurr1-dependent and Nurr1-independent transcriptional effects and binding to the Nurr1 ligand-binding domain (LBD). Most of the NR4A ligands show Nurr1-independent effects on transcription in a cell type-specific manner, suggesting they may function through binding to effector proteins whose downstream activities influence Nurr1 function. Protein NMR spectroscopy structural footprinting data show that 4-amino-7-chloroquinoline derivatives (amodiaquine and chloroquine) and cytosporone B directly bind the Nurr1 LBD. In contrast, other NR4A ligands including commercially available compounds such as C-DIM12, celastrol, camptothecin, IP7e, isoalantolactone, and TMPA do not bind the Nurr1 LBD. Interestingly, previous crystal structures indicate that cytosporone B analogs bind to surface pockets in the Nur77 LBD, but protein NMR data indicate cytosporone B likely binds to the Nurr1 orthosteric pocket. These findings should influence medicinal chemistry efforts that desire to optimize Nurr1-binding ligands as opposed to ligands that function through binding to Nurr1 effector proteins.

scholarly journals The Orphan Nuclear Receptor Nr5a2 Is Essential for Luteinization in the Female Mouse Ovary

Endocrinology ◽  
2014 ◽  
Vol 155 (5) ◽  
pp. 1931-1943 ◽  
Author(s):  
Kalyne Bertolin ◽  
Jan Gossen ◽  
Kristina Schoonjans ◽  
Bruce D. Murphy
Keyword(s):  
Nuclear Receptor ◽  
Granulosa Cells ◽  
Female Mouse ◽  
Follicular Development ◽  
Corpora Lutea ◽  
Orphan Nuclear Receptor ◽  
Primary Follicle ◽  
Down Regulation ◽  
Steroid Synthesis ◽  
Antral Follicles

In the ovary, the follicular granulosa cells express the nuclear receptor Nr5a2 (nuclear receptor subfamily 5 group A member 2), also known as liver receptor homolog-1, and after ovulation, Nr5a2 expression persists in the corpus luteum. Previous studies demonstrated that Nr5a2 is required for both ovulation and luteal steroid synthesis. Our objectives were to analyze the temporal sequence in the regulatory effects of Nr5a2 in the ovary, with focus on its contribution to luteal function. We developed a female mouse model of granulosa-specific targeted disruption from the formation of the antral follicles forward (genotype Nr5a2Cyp19−/−). Mice lacking Nr5a2 in granulosa cells of antral follicles are infertile. Although their cumulus cells undergo expansion after gonadotropin stimulation, ovulation is disrupted in those mice, at least in part, due to the down-regulation of the progesterone receptor (Pgr) gene. The depletion of Nr5a2 in antral follicles permits formation of luteal-like structures but not functional corpora lutea, as evidenced by reduced progesterone levels and failure to support pseudopregnancy. Progesterone synthesis is affected by depletion of Nr5a2 due to, among others, defects in the transport of cholesterol, evidenced by down-regulation of Scarb1, Ldlr, and Star. Comparison of this mouse line with the models in which Nr5a2 is depleted from the primary follicle forward (genotype Nr5a2Amhr2−/−) and after the ovulatory signal (genotype Nr5a2Pgr−/−) demonstrates that Nr5a2 differentially regulates female fertility across the trajectory of follicular development.

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