Gonadal Dysfunction in the Spontaneously Diabetic BB Rat: Alterations of Testes Morphology, Serum Testosterone and LH

Murray, Frederick T.; Cameron, Don F.; Orth, Joanne M.; Katovich, M. J.

doi:10.1055/s-2007-1013588

Cited by 30 publications

(18 citation statements)

References 12 publications

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“…Impaired spermatogenesis is apparently not due to deficient Leydig cell function, because expression levels of Leydig cell specific transcripts in Cdk4 À/À testes are similar to wild type (data not shown). As diabetes is associated with sterility in rodents (Murray et al, 1981(Murray et al, , 1985 and sterility coincides with the onset of diabetes in Cdk4 À/À mice, it is possible that infertility is a consequence of the diabetic condition.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the abnormal pancreatic development, reduced growth and infertility in Cdk4 mutant mice

Mettus

Rane

2003

Oncogene

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Cyclin-dependent kinase 4 (Cdk4) and Cdk6, and later Cdk2, in association with their specific cyclin partners, regulate the G1 to S phase cell cycle transition of mammalian cells by phosphorylation of retinoblastoma (Rb) family proteins. Phosphorylation of Rb results in the release of S-phase specific transcription factors; cell cyclepromoting gene expression, and advancement of the cell cycle. Loss of Cdk4 by homologous-targeted disruption leads to a delay in S-phase entry in serum-stimulated mouse embryo fibroblast (MEF) cultures. Homozygous Cdk4-deficient mice display defects in weight gain, fertility and hypoproliferation of specific endocrine cells of the pituitary and pancreas, the latter of which results in a diabetes-like phenotype. In contrast, inheritance of the p16 Ink4a -insensitive Cdk4 R24C mutation leads to spontaneous transformation of MEF cultures in vitro and, in vivo, hyperproliferative disorders that progress to cancer. In this manuscript, we report characterization of the abnormal pancreatic development, reduced growth and infertility in Cdk4 mutant mice. We observe that, whereas Cdk4 is dispensable for early pancreatic development, normal Cdk4 expression is critical for optimal growth of the organism. Also, we observe that loss of Cdk4 may result in insulin insensitivity, implicating an additional role of Cdk4 in b-cell function, in addition to its role in b-cell proliferation. Further, we demonstrate that loss of Cdk4 leads to an age-dependent defect in spermatogenesis and disruption in the timing of the estrus cycle. Taken together, our results indicate that the overall defects in growth, fertility and pancreatic development in Cdk4-deficient mice may be a combination of cell-type specific defects and altered glucose metabolism, as a result of defects in postnatal pancreatic development.

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Section: Discussionmentioning

confidence: 99%

Characterization of the abnormal pancreatic development, reduced growth and infertility in Cdk4 mutant mice

Mettus

Rane

2003

Oncogene

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“…Development and maintenance of the prostate is primarily regulated by androgens (Isaacs 1984;Kyprianou and Isaacs 1988;Colombel and Buttyan 1995). Experimental diabetes induced by streptozotocin (STZ), or spontaneously developed in DP-BB rats, is accompanied by regression of androgen-sensitive reproductive accessory organs such as the prostate, and decreases in serum testosterone levels (Murray et al 1985;Gousse et al 1991). These changes can be prevented and reversed by insulin treatment (Fukumoto et al 1993) supporting a regulatory role for insulin in the control of prostatic growth.…”

Section: Discussionmentioning

confidence: 99%

The effect of castration on endothelins, their receptors and endothelin converting enzyme in rat prostate

Takahashi

Afiatpour

Foster

et al. 2002

Naunyn-Schmiedeberg's Archives of Pharmacology

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We previously have shown that experimental diabetes in rats causes prostatic involution, reduces serum testosterone levels, and causes an upregulation in prostatic endothelin (ET) receptors. Furthermore, insulin treatment normalizes these changes (Saito et al., Mol Cell Biochem 210:1-12, 2000). Since experimental diabetes-induced reduction in serum testosterone may be a factor in the alteration of the ET receptors and of prostatic growth, we investigated the effect of castration, another means of involuting the prostate and decreasing serum testosterone levels, on the expression of ET receptors in ventral and dorsolateral regions of the rat prostate.Three-month-old Sprague-Dawley rats were surgically castrated or sham operated, and then killed on the 7th post-operative day. Biochemical and pharmacological properties, and localization of ET receptors in the rat prostate, were determined by performing a series of binding experiments with [(125)I]ET-1 and by light microscopy autoradiography, respectively. The expression levels of ET-1, ET-3, ET receptor subtypes and endothelin converting enzyme-1 (ECE-1) mRNAs were assessed by relative multiplex reverse transcription polymerase chain reaction (RT-PCR). The total density of ET receptors increases 3.7-fold in the ventral and 2.1-fold in the dorsolateral regions of the castrated rat prostate compared to sham operated animals. Castration causes a 2.4-fold increase in the density of alpha(1)-adrenoceptors (alpha(1)-ARs) in the ventral region of the prostate, but no change in the density of alpha(1)-ARs in the dorsolateral region of the rat prostate. The predominant ET receptor subtype in the rat prostate is the ETA subtype, which is mainly located in the prostatic stroma. In addition, RT-PCR data show an upregulation in the expression of ETB receptor subtype, ET-1 and ECE-1 mRNA in both regions, and a downregulation in the expression of ETA receptor subtype mRNA in the dorsolateral region of the castrated rat prostate. There is no change in the expression of ET-3 mRNA in either region. Castration does not cause significant changes in the pharmacological properties of prostatic ET receptors, i.e., the predominance of ETA receptors in either region of the prostate, or the expression of ETA receptor subtype mRNA in the ventral region of the castrated rat prostate. These results suggest the existence of a region/lobe-specific regulatory role for testosterone in the expression of the ET receptor system in the rat prostate.

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“…It has been reported that circulating gonadotropin levels are increased [16], drastically decreased [8, II,15,17], or unchanged [14] in diabetic male rats. Irrespective of the changes in the gonadotro pin secretion, circulating testosterone (T) levels were decreased in experimentally induced diabetic animals [15][16][17] as well as in spontaneously developed diabetic rats [ 18], suggesting a deran gement in the negative feedback action of T at the hypotha lamic-pituitary level. However, the gonadotropin response to T treatment is poorly understood in diabetic animals.…”

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confidence: 99%

Influence of Diabetes on the Gonadotropin Response to the Negative Feedback Effect of Testosterone and Hypothalamic Neurotransmitter Turnover in Adult Male Rats

Chandrashekar

Steger²,

Bartke³

et al. 1991

Neuroendocrinology

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The influence of diabetes on the gonadotropin response to the negative feedback effect of testosterone (T) and hypothalamic neurotransmitter turnover rates in adult male rats was evaluated. Adult male Sprague-Dawley rats were made diabetic by an intraperitoneal injection of streptozotocin (STZ; 5 mg/100 g body weight) in citrate buffer. Vehicle-injected rats served as controls. On day 9, all rats were bilaterally castrated and treated subcutaneously on alternate days with either peanut oil or T propionate (TP) in peanut oil (100 µg/rat). Plasma follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), and T concentrations were measured by specific radioimmunoassays from blood samples collected on day 1 (before castration) and 2, 4, 6, and 7 days after castration. On day 7 after castration (day 15 after vehicle or STZ treatment), 1 h before autopsy, the rats were injected intraperitoneally with saline or a tyrosine hydroxylase inhibitor, α-methyl-p-tyrosine (25 mg/100 g BW), for the measurements of norepinephrine (NE) and dopamine turnover in median eminence and medial basal hypothalamus (MBH). Circulating FSH, LH, PRL, and Tlevels were significantly lower (FSH and T: p < 0.001; LH and PRL: p < 0.05) in gonad-intact rats treated with STZ than in vehicle-injected animals. The castration-induced increase in plasma LH levels was attenuated in diabetic rats. The suppressive effect of T on LH secretion was significantly greater (p < 0.001) in STZ-treated rats relative to TP-treated nondiabetic controls. Castration in both diabetic and nondiabetic rats increased (p < 0.001) FSH secretion, but these increases were not different until day 6 after castration, when plasma FSH levels in control rats significantly increased (p < 0.01), than in diabetic animals. In STZ-treated rats, the suppressive effect of TP on plasma FSH levels was significantly increased. The NE turnover rates in median eminence and MBH were significantly lower (p < 0.001) in castrated diabetic rats than in castrated controls. The MBH NE turnover was reduced after TP treatment in both subgroups, but the relative decline was much greater (p < 0.01) in diabetic rats. These results clearly indicate that induction of diabetes by STZ treatment reduces gonadotropin and PRL secretion and increases the sensitivity of the hypothalamic-pituitary axis to the negative feedback effect of T on gonadotropin secretion. The effect of diabetes on gonadotropin secretion in the adult male rat is probably due to the suppression of noradrenergic neuronal activity of the hypothalamus.

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Gonadal Dysfunction in the Spontaneously Diabetic BB Rat: Alterations of Testes Morphology, Serum Testosterone and LH

Cited by 30 publications

References 12 publications

Characterization of the abnormal pancreatic development, reduced growth and infertility in Cdk4 mutant mice

Characterization of the abnormal pancreatic development, reduced growth and infertility in Cdk4 mutant mice

The effect of castration on endothelins, their receptors and endothelin converting enzyme in rat prostate

Influence of Diabetes on the Gonadotropin Response to the Negative Feedback Effect of Testosterone and Hypothalamic Neurotransmitter Turnover in Adult Male Rats

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