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 ◽  
...  

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.

1979 ◽  
Vol 29 (1) ◽  
pp. 17-23 ◽  
Author(s):  
R. G. Gunn ◽  
J. M. Doney ◽  
W. F. Smith

ABSTRACTIn two experiments over 2 years, 57 North Country Cheviot and 82 South Country Cheviot hill ewes were differentially group-fed indoors over a 2-month period to achieve either good or moderate body con- dition. Over 5 weeks prior to mating, ewes in good condition were brought down in condition by restricted feeding and ewes in mod- erate condition were raised in condition by a high level of feeding. The ewes were thus in moderately-good condition at mating. After mating, ewes were maintained in this condition until killed either on return to service or at 29 ± 8 days for counts of corpora lutea and viable embryos.Ovulation rate in each breed was positively related to the level of pre-mating food intake at the condition level studied. Embryo mortality, as ova loss, was not influenced overall by the level of pre-mating food intake but loss of multiple-shed ova was greater than that of single-shed ova in ewes which had been on restricted feeding before mating. Although a greater proportion of ewes in the North Country Cheviot breed were not pregnant at slaughter, this could not be identified as a breed difference since the breeds were studied in different years.


2017 ◽  
Vol 29 (7) ◽  
pp. 1426 ◽  
Author(s):  
K. A. Walters ◽  
M. C. Edwards ◽  
M. Jimenez ◽  
D. J. Handelsman ◽  
C. M. Allan

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.


2013 ◽  
Vol 305 (6) ◽  
pp. E717-E726 ◽  
Author(s):  
Xiaobing B. Cheng ◽  
Mark Jimenez ◽  
Reena Desai ◽  
Linda J. Middleton ◽  
Shai R. Joseph ◽  
...  

Homozygous androgen receptor (AR)-knockout (ARKO) female mice are subfertile due to both intra- and extraovarian (neuroendocrine) defects as defined by ovary transplantation. Using ARKO mice, this study set out to reveal the precise AR-regulated pathways required for optimal androgen-regulated ovulation and fertility. ARKO females exhibit deficient neuroendocrine negative feedback, with a reduced serum luteinizing hormone (LH) response to ovariectomy (OVX) ( P < 0.01). Positive feedback is also altered as intact ARKO females, at late proestrus, exhibit an often mistimed endogenous ovulatory LH surge. Furthermore, at late proestrus, intact ARKO females display diminished preovulatory serum estradiol (E2; P < 0.01) and LH ( P < 0.05) surge levels and reduced Kiss1 mRNA expression in the anteroventral periventricular nucleus ( P < 0.01) compared with controls. However, this reduced ovulatory LH response in intact ARKO females can be rescued by OVX and E2 priming or treatment with endogenous GnRH. These findings reveal that AR regulates the negative feedback response to E2, E2-positive feedback is compromised in ARKO mice, and AR-regulated negative and positive steroidal feedback pathways impact on intrahypothalamic control of the kisspeptin/GnRH/LH cascade. In addition, intraovarian AR-regulated pathways controlling antral to preovulatory follicle dynamics are disrupted because adult ARKO ovaries collected at proestrus have small antral follicles with reduced oocyte/follicle diameter ratios ( P < 0.01) and increased proportions of unhealthy large antral follicles ( P < 0.05) compared with controls. As a consequence of aberrant follicular growth patterns, proestrus ARKO ovaries also exhibit fewer preovulatory follicle ( P < 0.05) and corpora lutea numbers ( P < 0.01). However, embryo development to the blastocyst stage is unchanged in ARKO females, and hence, the subfertility is a consequence of reduced ovulations and not altered embryo quality. These findings reveal that the AR has a functional role in neuroendocrine regulation and timing of the ovulatory LH surge as well as antral/preovulatory follicle development.


1992 ◽  
Vol 134 (1) ◽  
pp. 11-18 ◽  
Author(s):  
R. G. Glencross ◽  
E. C. L. Bleach ◽  
B. J. McLeod ◽  
A. J. Beard ◽  
P. G. Knight

ABSTRACT To study the effects of immunoneutralization of endogenous inhibin on gonadotrophin secretion and ovarian function, prepubertal heifers (n = 6) were actively immunized against a synthetic peptide replica of the N-terminal sequence of bovine inhibin α subunit bIα(1–29)Tyr30) coupled to ovalbumin. In contrast to ovalbumin-immunized controls (n=6), bIα(1–29)Tyr30-immunized heifers had detectable inhibin antibody titres (% binding to 125I-labelled bovine inhibin at 1:2000 dilution of plasma) of 17 ± 3% (s.e.m.) at puberty, rising to 31 ± 5% by the end of the study period 7 months later. Neither age (immunized: 295 ± 8 days; controls: 300 ± 5 days) nor body weight (immunized: 254 ± 13 kg; controls 251 ± 9 kg) at onset of puberty differed between groups. Although the difference did not reach statistical significance, mean plasma FSH concentrations recorded in inhibin-immunized heifers remained 35–40% higher than in controls throughout the 12-week period leading up to puberty (P = 0·14) and during nine successive oestrous cycles studied after puberty (P=0·10). Plasma LH concentrations did not differ between groups at any time during the study. Inhibin immunization had no effect on oestrous cycle length (immunized: 19·8±0·5 days; controls: 19·9±0·5 days). However, in comparison with controls, inhibinimmunized heifers had more medium sized (≥0·5 to <1 cm diameter) follicles during both the preovulatory (95%, P<0·001) and post-ovulatory (110%, P < 0·05 waves of follicular growth and more large (>1 cm diameter) follicles during the preovulatory wave (49%, P<0·05). In addition, the number of corpora lutea observed during the post-ovulatory phase of each cycle was significantly greater in the inhibin-immunized group (43%, P<0·01), as was the recorded incidence of cycles with multiple ovulations (19/56 in the inhibin-immunized group compared with 0/54 in controls; P<0·001). All six inhibinimmunized heifers had at least one cycle with multiple ovulation whereas none of the control heifers did so. These results support the conclusion that immunoneutralization of endogenous inhibin using a synthetic peptide-based vaccine can enhance ovarian follicular development and ovulation rate in heifers. Whether this ovarian response is dependent upon the expected increase in secretion of FSH remains to be established. Journal of Endocrinology (1992) 134, 11–18


Reproduction ◽  
2002 ◽  
pp. 527-533 ◽  
Author(s):  
H Cardenas ◽  
WF Pope ◽  

Treatment with testosterone increases ovulation rate in pigs. The present study was conducted to examine the effects of 5alpha-dihydrotestosterone (DHT), a non-aromatizable androgen receptor ligand, on ovulation rate and amounts of androgen receptor and FSH receptor mRNAs in postpubertal gilts. In Expt 1, ovulation rate in response to daily i.m. injections of 0, 6, 60 or 600 microg DHT kg(-1) body weight from day 13 of the oestrous cycle (day 0 = day 1 of oestrus) to the following oestrus increased with each dose of DHT (P < 0.05). The mean increase in number of corpora lutea ranged from approximately three to 17 over the three dosages of DHT. In Expt 2, gilts treated daily with 60 microg DHT kg(-1) body weight during the early follicular phase (from day 13 to day 16), coincident with follicular recruitment, or the late follicular phase (day 17 to oestrus), had higher (P < 0.05) rates of ovulation compared with gilts that received vehicle, and were not different from gilts treated with DHT from day 13 to oestrus. Percentage recovery of day 3 embryos was not altered when gilts were treated from day 13 to day 16 or from day 17 to oestrus; however, treatment of gilts with DHT from day 13 to oestrus decreased recovery of day 3 (Expt 1) or day 11 (Expt 2) conceptuses. Daily administration of 6 microg DHT kg(-1) body weight to gilts from day 13 of the oestrous cycle to the following oestrus (Expt 3) did not affect the relative amounts of androgen receptor mRNA, but increased (P < 0.05) the amounts of FSH receptor mRNA in preovulatory follicles as determined by RT-PCR. The results of these experiments indicate that androgens may regulate ovulation rate in gilts. One of the roles of androgens might be regulation of the amounts of FSH receptor mRNA in ovarian follicles.


2020 ◽  
Vol 98 (6) ◽  
Author(s):  
André L Mallmann ◽  
Lidia S Arend ◽  
Gabriela S Oliveira ◽  
Ana P G Mellagi ◽  
Rafael R Ulguim ◽  
...  

Abstract AbstractThe effects of two feed levels offered during two estrous cycles before insemination were evaluated on the reproductive performance of gilts. A total of 93 gilts (PIC Hendersonville, TN) were individually housed and manually fed twice a day with 2.1 or 3.6 kg/d of a corn and soybean meal-based diet (3.15 Mcal ME/kg and 0.64% standardized ileal digestible lysine), during two estrous cycles before breeding (cycle 1, between first and second estrus; cycle 2, between second and third estrus). Gilts were weighed at the beginning of the experiment, at second and third estrus, and at slaughter (30.2 ± 1.2 d of gestation). Follicles were counted at second estrus, and the embryo-placental units and the corpora lutea were individually counted, measured, and weighed at slaughter. Gilts fed 3.6 kg/d had greater BW gain during cycle 1 and cycle 2 (P &lt; 0.001; + 9.8 kg and + 10.0 kg, respectively) becoming heavier at second and third estrus (P &lt; 0.001). At second estrus, gilts fed 3.6 kg/d had 1.6 more medium-large follicles (P = 0.074) but no difference in follicle size (P = 0.530) was observed. Gilts fed 3.6 kg/d in cycle 1 or cycle 2 had a greater ovulation rate at third estrus (P &lt; 0.016) than those receiving 2.1 kg/d. Also, 3.6 kg/d in cycle 2 increased early embryo mortality (P = 0.006; 2.3 vs. 1.1 dead embryos) and consequently reduced total embryo survival (P = 0.002; 84.6 vs. 90.1%). Gilts fed 3.6 kg/d during cycle 1 had two more total embryos (P &lt; 0.001; 17.2 vs. 15.1) and two more vital embryos on day 30 (P &lt; 0.001; 16.7 vs. 14.5) in comparison with gilts fed 2.1 kg/d. The coefficient of variation for placental length was greater for gilts fed 3.6 kg/d during cycle 1 (P = 0.003). No further significant effects of feeding levels were observed on embryo and placental traits (P ≥ 0.063). These results suggest that the feeding level during the first cycle after pubertal estrus is crucial to set ovulation rate and potential litter size for breeding at next estrus. However, flush feeding gilts before insemination can negatively impact litter size by reducing embryo survival when breeding at third estrus.


1975 ◽  
Vol 85 (3) ◽  
pp. 465-470 ◽  
Author(s):  
R. G. Gunn ◽  
J. M. Doney

SUMMARYOne hundred and fifty-six Scottish Blackface ewes were differentially group-fed over a 2-month period to achieve three distinct levels of body condition (good, moderate and very poor). Over 5 weeks prior to mating, one group of good-condition ewes was maintained in that condition, one group of good- and one of moderate-condition ewes were brought down in condition by restricted feeding and one group of moderate and the very poor condition ewes were raised in condition by a high level of feeding. Ewes were therefore in good, moderately good or poor condition at mating. After mating, ewes were killed either on return to service or at 25 ± 5 days for counts of corpora lutea and viable embryos.Poor body condition, irrespective of feeding level, was associated with a delay or suppression of oestrus and with a high return-to-service rate. Ovulation rate was positively related to body condition at mating but not to the level of pre-mating food intake at the condition levels studied.Embryo mortality decreased as body condition at mating increased and the interaction between condition and the level of pre-mating food intake had a differential effect on mortality of single- and multiple-shed ova. The lowest rate of embryo mortality was found in ewes in moderately good condition which had been well-fed before mating.


1979 ◽  
Vol 29 (1) ◽  
pp. 11-16 ◽  
Author(s):  
R. G. Gunn ◽  
J. M. Doney

ABSTRACTIn two experiments over 2 years, 113 North Country Cheviot and 132 South Country Cheviot hill ewes were differentially group-fed over a 10-week period to achieve either good or moderate body con- dition. Ewes were maintained in these levels of condition over the 5 weeks prior to mating. After mating, ewes were killed either on return to service or between days 23 and 85 for counts of corpora lutea and viable embryos.Ovulation rate in each breed was positively related to body condition at mating. Embryo mortality, as ova loss, was not influenced overall by breed, type of ovulation, year of recording, or body condition. Although comparisons of loss were partly confounded by a differen- tial distribution in the number of ova shed in each breed and body condition group, there was an apparent breed difference in loss of single- and multiple-shed ova. Potential lambing rate therefore showed greater response to improved body condition at mating in the North Country Cheviot breed than it did in the South Country Cheviot.


2019 ◽  
Vol 31 (1) ◽  
pp. 224
Author(s):  
K. Karl ◽  
F. Jimenez-Krassel ◽  
E. Gibbings ◽  
K. E. Latham ◽  
J. J. Ireland

Cattle with an unknown antral follicle count (AFC) during follicular waves respond to different FSH doses during superovulation in a curvilinear fashion with the highest doses decreasing or not increasing ovulatory follicle number, number of transferable embryos, and number of corpora lutea (CL). These observations support the hypothesis that heifers treated with different FSH doses during superovulation will reach a superovulation maximum (SOVmax) and that doses exceeding SOVmax are excessive, resulting in a decrease in ovarian function. To test this hypothesis, we used eight 12-month-old Holstein heifers with a low AFC (&lt;10 follicles ≥3mm in diameter, index for small ovarian reserve). These 8 heifers were subjected to 4 different superovulations with a 21-day intervals between each superovulation. During each superovulation, which began on Day 1 of a synchronized oestrous cycle before selection of a dominant follicle, 2 of the 8 heifers were treated (twice-daily FSH injections×4 days) with 20, 40, 80, or 120mg of Folltropin-V (Vetoquinol, Lure, France). At the end of the study, the same 8 heifers had been superovulated 4 times with each of the 4 FSH doses. To enhance ovulation rate in response to hCG, each superovulated heifer was injected with 3 different injections of prostaglandin F2α (PGF2α) spaced 12h apart to induce luteolysis of the original CL. Two PGF2α injections were given after each FSH injection on the last day of FSH treatment and the last PGF2α injection was given after the hCG (2500IU) injection, which was 12h after the last FSH injection. Daily ultrasonography was used to measure AFC and number of ovulatory follicles and CL during the study. Results of t-test analysis showed that at time of hCG, AFC was greater (P&gt;0.05) for heifers treated with the 40-mg (mean±s.e.m., 27±3.7) v. 20-mg (17.9±2.5) FSH dose, but the response to higher FSH doses (27.9±4.4; 27±3.3) did not differ from the response to the 40-mg dose. Number of ovulatory follicles was greater (P&lt;0.05) for heifers treated with the 40-mg (17.5±2.3) v. 20-mg (10.1±1.4) FSH dose, but the response to higher doses (18.9±3.3; 17.3±2.4) did not differ from the response to the 40-mg dose. At Day 7 post-hCG, CL number was greater (P&lt;0.05) for heifers treated with the 40-mg (13.8±2.9) v. 20-mg (7.4±1.4) dose, but response to higher doses (9.9±3.2; 9.1±2.3) did not differ from the response to the 40-mg dose. Ovulation rate (ovulatory follicle number divided by CL number) was greater (P&lt;0.05) for heifers treated with the 40-mg (79±0.08%) v. 80-mg (52±0.09%) or 120-mg (53±0.09%) dose, but similar to that of heifers treated with 20-mg (73±0.09%) FSH dose. These results support the conclusion that the 40-mg FSH dose achieves SOVmax and FSH doses greater than SOVmax in cattle with a low AFC and small ovarian reserve are excessive and detrimental to ovarian function. This project was supported by Agriculture and Food Research Initiative Competitive Grant no. 2017-67015-26084 from the USDA National Institute of Food and Agriculture (Washington, DC).


2008 ◽  
Vol 22 (4) ◽  
pp. 858-867 ◽  
Author(s):  
Lu-Min Chen ◽  
Ruey-Sheng Wang ◽  
Yi-Fen Lee ◽  
Ning-Chun Liu ◽  
Yu-Jia Chang ◽  
...  

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.


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