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T. E. Nass, P. S. LaPolt, H. L. Judd, and J. K. H. Lu

ABSTRACT

To determine whether discernible alterations in neuroendocrine and/or ovarian function precede the loss of regular oestrous cycles in ageing female rats, the present study examined the pattern of gonadotrophin secretion near the time of ovulation and the pattern of ovarian steroid secretion in the early morning of prooestrus in middle-aged (10–12 months old) females displaying regular oestrous cycles and compared these with young (4 months old) animals. In addition, the subsequent reproductive patterns in these animals were observed and correlations between the changes in hormonal profiles and the decline in regular reproductive cyclicity were established. In middle-aged females which subsequently ceased to display regular oestrous cycles (middle-aged non-regular; M-NR) within 1–2 months, the pro-oestrous surge of LH was significantly reduced in magnitude. There was no difference in the LH surge between young females and middle-aged animals which maintained regular oestrous cycles (middle-aged regular; M-R) for at least 2 months. There also was no difference in the magnitude of the pro-oestrous FSH surge or in the secondary rise in FSH in the early morning of oestrus among young, M-R and M-NR females. In a separate group of middle-aged females which subsequently became M-NR, serum concentrations of both oestradiol and testosterone in the early morning of pro-oestrus were markedly raised over those in the young and M-R groups. We suggest that an earlier rise in circulating oestradiol and testosterone concentrations in middle-aged females over many consecutive regular oestrous cycles may gradually render the central nervous system less responsive to the stimulatory feedback effects of ovarian steroids on LH release. As a consequence, the pattern of the pro-oestrous LH surge may be progressively altered in ageing rats until it is inadequate for regular ovulatory function.

J. Endocr. (1984) 100, 43–50

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Y. Amir-Zaltsman, Y. Ausher, B. Gayer, S. Lichter, F. Serour, S. Birkenfeld, and F. Kohen

ABSTRACT

The age-related changes in tissue response to chronic treatment for 1 month with a potent LHRH agonist were investigated in the ageing male rat, and the observed pharmacological effects were compared with orchidectomy. In both young (4 months) and old (22 months) rats, treatment resulted in a significant decrease in the weights of prostates and testes, a decrease in plasma LH and testosterone levels, a loss of LH receptors in the testes and in a complete depletion of prostatic nuclear androgen receptors, reaching levels observed after castration. In young rats, treatment with an LHRH agonist or orchidectomy induced a three- or sixfold increase in prostatic creatine kinase (CK) activity which may have been induced by the local stimulatory effect of oestradiol arising from the conversion of precursor steroids secreted by the adrenal. On the other hand, in old rats, 7 days after orchidectomy or after treatment with an LHRH agonist a twofold increase or no change was induced in prostatic CK activity respectively. SDS gel electrophoresis patterns of cytosolic prostatic proteins of young rats treated with an LHRH agonist or young rats orchidectomized 7 days previously revealed the presence of several intensified proteins, two of them having apparent molecular weight of 67 kDa and 43 kDa, whereas in the old rats treated with LHRH agonist or old rats castrated 7 days previously, these two proteins were not intensified. The results of this study confirmed that continuous treatment with an LHRH agonist to young and old rats induces medical castration since the pharmacological effects observed were the same as those induced with surgical castration. However, in the old rats, the lack of an increase in prostatic CK activity upon treatment with LHRH agonist, and the moderate increase in CK activity upon orchidectomy, suggest that prostatic cells in older rats have decreased sensitivity to hormonal manipulation.

Journal of Endocrinology (1990) 124, 261–268

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S. Matthaei, H. Benecke, H. H. Klein, A. Hamann, G. Kreymann, and H. Greten

ABSTRACT

To examine the cellular mechanism responsible for impaired insulin action in ageing, we determined various in-vitro parameters involved in the pathogenesis of insulin resistance, i.e. basal and insulin-stimulated [14C]3-O-methylglucose transport (30MG), 125I-labelled insulin binding, activation of insulin receptor kinase (IRKA) in intact cells, and number and subcellular distribution of glucose transporters in subcellular membrane fractions of adipocytes from 6- (FR-6) and 24- (FR-24) month-old Fischer rats. Ageing had no effect on basal 30MG (12±4 vs 13±3 fmol/5 × 104 cells, means ± s.e.m.); in contrast, in FR-24 rats insulin-stimulated 30MG was markedly decreased by 43% when compared with that in FR-6 rats (158±14 vs 90±8 fmol/5 × 104 cells; P < 0·01). Insulin binding to adipocytes from FR-6 rats was 2·40±0·38% compared with 2·28±0·47% in FR-24 (P not significant). Moreover, ageing had no significant effect on IRKA, as determined by insulin-stimulated (0, 1, 4 and 500 ng insulin/ml) 32P-incorporation into histone 2B. In subcellular membrane fractions, low density microsomes and plasma membranes, glucose transporter numbers were determined using [3H]cytochalasin B binding and immunodetection using an antiserum against the C-terminal peptide of the hepatoma-G2-glucose transporter. Cytochalasin B binding revealed that in the basal state the intracellular pool of glucose transporters was depleted in FR-24 by about 39% compared with low density microsomes from FR-6: (48·6±7·2 vs 29·8±5·5 pmol/mg membrane protein; P < 0·01). In consequence, in FR-24 there were fewer glucose transporters available for insulin-induced translocation to the plasma membrane (insulin-treated plasma membrane: 23·9±4·2 (FR-6) vs 14·4±3·1 (FR-24) pmol/mg membrane protein; P < 0·01). These results were confirmed by immunoblotting.

In conclusion, (1) maximal insulin-stimulated 30MG was decreased by 43% in cells from FR-24 rats compared with those from FR-6 rats, while basal 30MG was similar in both groups, (2) neither insulin binding nor IRKA were significantly altered in cells from FR-24 rats, and (3) impaired insulin-stimulated 30MG was associated with reduced numbers of glucose transporters in the plasma membrane as a consequence of a depletion of the intracellular pool of glucose transporters in cells from FR-24 rats.

Journal of Endocrinology (1990) 126, 99–107

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G. T. Taylor, M. Bardgett, S. Farr, S. Womack, D. Komitowski, and J. Weiss

ABSTRACT

A paradigm using chronic social stress and multiple measures of the reproductive system were used to assess changes with ageing in the dynamics of endogenous steroid interactions. The 22- to 24-month-old male rats lived for 8 weeks in one of four types of colony, in groups of the same sex or groups of mixed sex including familiar or unfamiliar old males. Measures of endocrinology (circulating steroid levels), behaviour (exploration and sociosexual responses), physiology (body and organ weights and epididymal sperm count) and histology (adrenal and ventral prostate glands) served as markers of activation of the hypothalamic-pituitary-adrenal (HPA) or hypothalamic-pituitary-testicular (HPT) axes. Old males living under stable conditions as familiar same-sex colonies served as the comparison group. Results indicated clear chronic activation of the HPA axis in the unfamiliar all-male colonies and of the HPT axis in the familiar males from mixed-sex colonies, whereas both steroidal axes were stimulated in colonies of unfamiliar males and females. Findings from aged males under chronic stress suggested that reproductive dysfunction may be limited to situations in which activation of the HPA axis occurs without concurrent stimulation of the HPT axis. Data on steroidal interactions from mixed-sex groups suggested that (1) chronic excitation of the HPA failed to suppress function in the reproductive system of the old males, (2) their stress responses were little affected by chronic HPT activation and (3) there was no evidence for stress-induced pathology, even in the vulnerable prostate gland. The conclusion is that increased risks for urogenital pathology with long-term exposure to stress is not an inevitable outcome for ageing male rats nor, perhaps, for other social species living under conditions in which multiple endocrine systems typically undergo simultaneous activation.

Journal of Endocrinology (1993) 137, 115–122

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MA Peters, FH de Jong, KJ Teerds, DG de Rooij, SJ Dieleman, and FJ van Sluijs

Dogs of different ages without testicular diseases were evaluated to study possible age-related changes in hormone concentrations in serum. Dogs with testicular tumours were also investigated to study the relation between tumour type and hormone concentrations; in this study, dogs with Sertoli cell tumours, Leydig cell tumours and seminomas were included. We measured testosterone, oestradiol, LH, FSH and inhibin-like immunoreactivity concentrations in peripheral venous and testicular venous blood of these animals. In normal dogs there appeared to be no age-related changes in the concentrations of the investigated hormones, except for a significant age-related decrease in oestradiol concentrations in testicular venous blood (P<0.02). Dogs with a Sertoli cell tumour had greater oestradiol concentrations and inhibin-like immunoreactivity in both peripheral and testicular venous blood than did dogs without a neoplasm (P<0. 05). Testosterone concentrations were reduced in dogs with Sertoli cell tumours, as were FSH and LH. Feminisation occurred in eight of 13 dogs with a Sertoli cell tumour and in two of 14 dogs with a Leydig cell tumour; it was accompanied by a significantly greater oestradiol concentration than in normal dogs and in dogs with Sertoli cell tumours without signs of feminisation. Dogs with a Leydig cell tumour had greater concentrations of oestradiol and inhibin-like immunoreactivity in both peripheral venous and testicular venous blood than did dogs without a neoplasm (P<0.05). The testosterone concentration in testicular venous blood of these dogs was lower than that in dogs with normal testes. The concentration of LH in peripheral venous blood was also reduced (P<0. 05). Hormone concentrations in dogs with a seminoma were not different from those in normal dogs. It was concluded that seminomas are not endocrinologically active. In contrast, both Sertoli cell tumours and Leydig cell tumours can cause increased oestrogen production leading to signs of feminisation. These tumours also have considerable amounts of inhibin-like immunoreactivity, but only in Sertoli cell tumours does this result in a reduction in FSH concentrations, suggesting that Sertoli cell tumours secrete dimeric inhibin, whereas Leydig cell tumours presumably produce loose alpha-subunits that cross-react in the inhibin assay but are not biologically active.

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W. B. WEHRENBERG, S. F. GOTTLIEB, and E. D. ALBRECHT

SUMMARY

Aged (12- to 14-month-old) C57BL oestrous mice exhibited significantly lower (P < 0·001) ovarian Δ5-3β-hydroxysteroid dehydrogenase (3β-HSD) concentration, specific activity and total content than young (3-month-old) oestrous mice, suggesting a decrease in the potential of the older animals to produce ovarian Δ4-3-oxosteroids. Mice in both age groups maintaining pregnancy to 10 or 18 days post coitum (p.c.) had similar values for activity of ovarian 3β-HSD. In the aged females in which foetal resorption had occurred, the majority of foetuses had been resorbed by 10 days p.c. However, ovarian 3β-HSD activity in these animals was not significantly different from that of young or aged mice maintaining pregnancy. By day 18, however, ovarian dehydrogenase activity in aged females failing to maintain pregnancy had decreased significantly. It is suggested that foetal death in aged mice is not the result of a deficiency in ovarian 3β-HSD, but rather may initiate luteal regression and consequently a decline in 3β-HSD.

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N. A. Roberts, R. N. Barton, and M. A. Horan

ABSTRACT

Healthy men and women aged 19–38 or 67–83, in whom endogenous ACTH secretion was suppressed with dexamethasone, were given successive injections of 60 ng, 150 ng and 250 μg ACTH(1–24) at hourly intervals, and blood samples for measurement of plasma cortisol were taken every 10 min. The response to each injection was taken as the increase in cortisol concentration 20 min later, when there was a peak with the lower doses, with allowance for disappearance of cortisol produced after the previous injection. On average, the responses to 60 and 150 ng ACTH were about 0·4 and 0·7 respectively of the response to 250 μg. There were no consistent effects of age or sex on any index of adrenocortical sensitivity or responsiveness, but some groups showed isolated differences from both their age- and sex-matched counterparts: the response to 60 ng ACTH was low in young men, maximal responsiveness was low in elderly men and the slope of the dose–response curve was high in elderly women. In most of the elderly subjects, plasma ACTH was determined separately under normal conditions. It was negatively correlated with the cortisol responses to 60 and 150 ng ACTH, suggesting that differences in adrenal sensitivity between subjects contribute to the variability of plasma ACTH.

Journal of Endocrinology (1990) 126, 507–513

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P. VAN DER SCHOOT

Department of Endocrinology, Growth and Reproduction, Erasmus University, Medical Faculty, P.O. Box 1738, Rotterdam, The Netherlands

(Received 23 October 1975)

Normal cyclic ovarian activity stops in old female rats: cyclicity may be replaced by absence of ovulation and persistent vaginal cornification (Everett, 1939; Aschheim, 1964/5). In the present study, factors were examined which could contribute to the change from cyclicity to absence of ovulation. Vaginal cyclicity, ovarian microscopy, and the pro-oestrous surge of luteinizing hormone (LH) were compared between old and young rats. Locally bred (R × U)F 1 hybrid females were kept under standard lighting conditions (lights on at 05.00 h; off at 19.00 h). Three- to 5-month-old rats were all cyclic and showed predominantly 5-day cycles. From 7 months onwards a rapid increase occurred in the number of animals with persistent vaginal cornification; cyclic animals kept 5-day cycles (Table 1).

In the first experiment sodium pentobarbitone (Nembutal) was injected

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R. G. GOSDEN

SUMMARY

The uptake in vivo of tritiated oestradiol-17β has been compared in young and aged ovariectomized CBA/H-T6 mice by examining the levels of radioactivity in tissues 1 h after injection. The specificity of oestradiol uptake was demonstrated by previous treatment of some animals with either diethylstilboestrol or progesterone. The levels of radioactivity in whole tissue extracts were similar in both age groups for the uterus, hypothalamus, cerebrum and serum, but the uptake in the pituitary gland was significantly lower in old mice. There was no evidence of altered hormone metabolism with age.

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N. H. Herzberg, E. Goudsmit, J. Kruisbrink, and G. J. Boer

ABSTRACT

Young, middle-aged and aged rats received s.c. testosterone implants for 50–52 days in order to investigate whether supplementation of testosterone in aged rats could normalize the reported reduction of kidney arginine vasopressin (AVP)-binding sites and increase the plasma concentration of AVP. Receptor number, which was measured by means of a membrane-binding assay with [3H]AVP as ligand, was below the detection level in the untreated aged rat. Following testosterone treatment, no effects were seen in the youngest groups, but in the aged group AVP receptors became clearly detectable, albeit with a lower affinity. A remarkable observation was the increase in affinity for renal AVP binding in the middle-aged compared with the young rat. Plasma levels of AVP in control aged rats tended to be higher. Such a tendency was completely absent in the testosterone-treated aged rats. Possible mechanisms underlying the restoration of reduced AVP-binding sites in the kidney of the aged rat by testosterone treatment are discussed.

Journal of Endocrinology (1989) 123, 59–63