Deprenyl reinitiates estrous cycles, reduces serum prolactin, and decreases the incidence of mammary and pituitary tumors in old acyclic rats.

The purpose of this study was to investigate the effects of long term treatment with deprenyl, a monoamine oxidase-B inhibitor, on estrous cyclicity, serum PRL, incidence of mammary and pituitary tumors, and monoamine metabolism in the medial basal hypothalamus (MBH) and striatum (ST) of old female rats. Acyclic female Sprague-Dawley rats (15-16 months old) were treated sc with 0, 0.25, or 2.5 mg deprenyl/kg BW.day for more than 8 months. Body weight and food intake were measured every week, and the estrous cycles and development of mammary tumors were monitored throughout the treatment period. At the end of the treatment period, the concentrations of catecholamines, serotonin, and their metabolites in the MBH and ST were determined by HPLC with electrochemical detection. The wet weights of the pituitary, heart, liver, lung, kidney, adrenals, uterus, and ovaries were recorded. Trunk blood was collected for measurement of serum PRL concentrations by RIA. Deprenyl treatment temporarily reestablished estrous cycles in most of the rats. The incidence of pituitary and mammary tumors was markedly reduced in the deprenyl-treated rats compared with that in the saline-treated control rats. Deprenyl had no significant effect on the weights of internal organs. The high dose of deprenyl (2.5 mg/kg) decreased serum PRL concentrations significantly. There were no significant differences in body weight or food intake between the control and deprenyl-treated groups. Deprenyl decreased the concentrations of the monoamine metabolites, dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid, in both the MBH and ST. It had no effect on the concentrations of norepinephrine and dopamine in the MBH, but significantly increased norepinephrine concentrations in the ST and serotonin concentrations in both the MBH and ST (P < 0.05). It is concluded that deprenyl treatment exerted these effects via suppression of monoamine metabolism.

Deprenyl reduces serum prolactin concentrations in rats.

The effects of i.v. administration of deprenyl (2.5, 5, and 10.0 mg/Kg body wt), a monoamine oxidase inhibitor, on serum prolactin (PRL) concentrations were investigated in female Sprague-Dawley rats. In the rats treated with the highest dose (10 mg/Kg), serum PRL decreased by 48% (p < 0.05) within 30 min and remained depressed during a 240-min period. Serum PRL concentrations also decreased by 38% (p < 0.05) within 30 min in the rats treated with the 5 mg dose and remained low during the remainder of the period of observation. Serum PRL levels showed no change in the group treated with 2.5 mg of deprenyl/Kg BW, except at 240 min when it was 48% (p < 0.05) below the pretreatment levels. In the control group, injected with the vehicle (0.5 ml saline) no decreases in PRL levels were observed. The average serum PRL concentrations during the entire posttreatment period were 45% above the pretreatment levels in the control group, whereas they were 31% and 43% below the respective pretreatment levels in the 5 and 10 mg groups, respectively. In the 2.5 mg group, the average serum PRL levels during the posttreatment period were not different from those in the pretreatment period. It is concluded that deprenyl is a potent inhibitor of PRL release in the rat.

Underfeeding-induced suppression of mammary tumors: counteraction by estrogen and haloperidol.

The purpose of this study was to investigate the mechanism by which underfeeding induces regression of carcinogen-induced mammary tumors in the rat and to determine if tumor regression in underfed rats could be prevented on a chronic basis by maintaining elevated circulating levels of estrogen and/or prolactin (PRL) by treatment with estradiol benzoate (EB) and a dopamine receptor blocker, haloperidol (HAL). Female rats with 7,12-dimethylbenzanthracene-induced mammary tumors were fed ad libitum (full-fed), half-fed (HF), or half-fed and treated wtih EB (HF+EB), HAL (HF+HAL), or both (HF+EB+HAL) for 15 weeks. Tumor diameter, tumor number, and body weight were determined each week. At the end of the experiment, hypothalamic concentrations of catecholamines, indoleamines, and their metabolites were determined by high performance liquid chromatography. Tumor diameter, tumor number, and body weight increased progressively in the full-fed rats, but decreased significantly in the HF rats. Treatment of HF rats with EB, HAL, or both prevented tumor regression, but had no effect on body weight, which declined continuously. In the HF rats, there was an increase in the concentration of dopamine and a decrease in the concentration of serotonin in the hypothalamus, whereas treatment with HAL reversed these effects. EB had no effect on neurotransmitter concentrations in the HF rats, but treatment of HF+EB animals with HAL decreased the dopamine concentration. The changes in dopamine and serotonin observed in HF rats are known to inhibit PRL secretion, whereas HAL, which blocked these changes, is a well established stimulator of PRL secretion. Since the mammary tumors are dependent on PRL for development and growth, it is probable that the regression of these tumors in the HF rats was ultimately due to a decrease in PRL secretion, and the prevention of this regression in HF+HAL rats was ultimately due to an increase in PRL secretion. EB, a potent PRL stimulator, probably blocked tumor regression in HF+EB rats by increasing PRL secretion by a direct effect on the pituitary.

Anti-ageing interventions and their neuroendocrine aspects in mammals.

A number of interventions for delaying or reversing declines in body functions due to ageing are critically reviewed here, including their relation to neuroendocrine function. Diets severely deficient in calories retard the ageing of body tissues, inhibit the development of disease and tumours, and significantly prolong the lifespan of rats and mice. Such diets also decrease hormone secretion, reduce the metabolism of the whole body, and lower gene expression. Administration of hormones, thymic peptides and other immune factors, and appropriate drugs can improve declining immune function in old rats and mice, thereby increasing resistance to infection, autoimmune disease and tumours. In old rats, correction of faults that develop in the neuroendocrine system with age--particularly in the hypothalamus--can restore oestrous cycles, increase the secretion of growth hormone, increase protein synthesis, inhibit development of disease and tumours, and prolong life. Antioxidants administered to rats and mice in an attempt to reduce damage to cells caused by free radicals, do not significantly retard ageing or prolong the lifespan of these animals. Regular, moderate exercise in elderly humans decreases incidence of heart disease, improves lung function, reduces bone loss, and produces other beneficial effects. Suitable drugs that will improve memory function in elderly humans remain to be developed, although a few have produced small improvements albeit with undesirable side effects. Overall, the neuroendocrine and immune approaches offer the best prospects for delaying and reversing declines in body functions due to ageing.

A comparison between hormone levels and T lymphocyte function in young and old rats.

There is growing evidence that changes in hormone secretion during aging can alter some functions of the thymus. In order to identify further relationships between changes in endocrine and thymic function during aging we measured the circulating levels of prolactin (PRL), growth hormone (GH) thyrotropin (TSH) thyroxine (T4) and triiodothyronine (T3), and determined their relation to a number of T lymphocyte functional indices in 20 young (4 months) and 20 old (28-30 months) Long-Evans male rats. Half of the young and old rats were chronically cannulated in order to obtain sequential plasma samples for measuring PRL, GH and TSH by RIA. Total T4 and T3 were measured by RIA in the trunk serum of all animals. Thymus and spleen cell cultures from each rat were established and used to assess the ability of thymocytes to respond to mitogens and lymphokines as well as to measure the levels of IL-2 production by splenic lymphocytes. Mean plasma GH and serum T4 were significantly lower in old as compared to young rats (P less than 0.05 and P less than 0.001 for GH and T4, respectively), while PRL, TSH and T3 did not show significant age changes. Thymic cell number showed a 100-fold decrease in old as compared to young animals (10.6 +/- 3.0) x 10(6) vs. (898 +/- 98) x 10(6) cells, respectively) whereas no age change was detected in spleen cell numbers. The proliferative response of thymocytes exposed to Con A, IL-1, Con A + IL-1 or Con A + IL-2, was consistently higher in young than in old animals while the capacity of splenocytes to release IL-2 in response to Con A was not statistically different in young and old rats. The age changes in serum T4 showed a significant correlation with those in thymocyte count as well as with those in IL-1 + Con A- and IL-2 + Con A-induced thymocyte proliferation. Plasma GH showed a significant inverse correlation with splenocyte IL-2 release. Our results suggest, although do not prove, that the lower T4 and GH secretion that typically develops in old rats may play a causal role in some of the changes that occur in thymic-dependent functions during aging.

Differential effect of aging on serum levels of prolactin and alpha-melanotropin in rats.

Prolactin (PRL) and alpha-melanocyte-stimulating hormone (alpha-MSH) are the only two pituitary hormones whose basal secretion is under tonic dopaminergic inhibition exerted by the hypothalamus. In the female rat, continuous exposure to estrogens is believed to depress hypothalamic dopaminergic activity and lead to the appearance of PRL-secreting pituitary adenomas during aging. Since there is no information about the impact of aging on circulating alpha-MSH levels, it was of interest to assess and compare the serum levels of PRL and alpha-MSH in male and female rats of different ages. Young (3-4 months) and old (24-25 months) male and female Sprague-Dawley rats as well as senescent (33-35 months) females were killed by decapitation between 10 AM and 1 PM, and pituitaries were immediately removed and dissected. Hormones were measured in unextracted trunk serum by radioimmunoassay. Serum PRL levels were (mean +/- SE), 18.4 +/- 2.0, 26.8 +/- 3.8, 19.8 +/- 2.5, 43.0 +/- 7.5, and 193.5 +/- 47.6 ng/ml for young and old males, and young, old, and senescent females, respectively. Serum alpha-MSH levels were 243.2 +/- 15.2, 252.9 +/- 24.8, 320.0 +/- 31.3, 234.7 +/- 19.1, and 374.0 +/- 29.7 pg/ml for young and old males, and young, old and senescent females, respectively. Anterior pituitary and neurointermediate lobe weights increased significantly with age in both sexes, although the change was particularly conspicuous in the females. We conclude that aging does not have a major impact on circulating alpha-MSH levels in rats and that melanotrophs probably have a greater ability than prolactotrophs to withstand age-associated alterations in central regulatory mechanisms.

Role of hypothalamic catecholamines in aging processes.

Defects that develop in the hypothalamic area of the brain are believed to initiate many declines in body functions in aging rats and mice. The decreases found in hypothalamic norepinephrine and dopamine are particularly important since they lead to reduced gonadotropic hormone secretin and cessation of estrous cycles in female rats and a decrease in testosterone secretion in male rats, lower GH and somatomedin (IGF-I) secretion and reduced protein synthesis, diminished thyroid hormone secretion and lower body metabolism, higher PRL secretion and development of numerous mammary and pituitary tumours, and reduced immune competence. The reduction in hypothalamic norepinephrine and dopamine activity is believed to be due to damage and loss of neurons owing to toxic products formed during metabolism of norepinephrine and dopamine; to the damaging effects to neurons produced by the chronic action of estrogen, PRL, and indirectly by adrenal glucocorticoids; and to changes in enzymes responsible for synthesis and metabolism of norepinephrine and dopamine. When old rats are given drugs that elevate norepinephrine and dopamine, most of the above and other decrements of aging are delayed or reversed, and length of lifespan may be prolonged. Decreases in hypothalamic norepinephrine and dopamine have also been reported in elderly human subjects, but it is unknown whether these are related to declines in body functions.

Aging: hypothalamic catecholamines, neuroendocrine-immune interactions, and dietary restriction.

The decline in hypothalamic catecholamine (CA) activity with age in rats leads to a reduction in hormone secretion by the neuroendocrine system, and results in decreased reproductive function, a reduction in protein synthesis, development of numerous mammary and pituitary tumors, and probably contributes to the decline in immune function. Some of these same effects can be produced in young rats by administration of drugs that lower hypothalamic CA activity. Administration of drugs to old rats that elevate hypothalamic CA activity can inhibit or reverse the reproductive decline, increase protein synthesis, induce regression of mammary and pituitary tumors, decrease disease incidence, probably elevate immune function, and significantly extend the life span. Therefore, hypothalamic CA have a critical role in the development of aging processes. When young or mature rats or mice are fed a caloric restricted diet, aging processes are inhibited and life span is significantly lengthened. These effects are believed to be mediated primarily via the neuroendocrine system, since calorie restriction results in decreased secretion of hypothalamic, pituitary, and target gland hormones. The decline in hormone secretion leads to a reduction in most body functions, lowers whole body metabolism, and reduces gene expression, and thereby results in a decreased rate of aging of body tissues and longer life. These effects of caloric restriction can be counteracted by administration of hormones, providing evidence that the favorable effects on aging are mediated by reducing hormone secretion.

Changes in somatotropin and thyrotropin secretory patterns in aging rats.

In order to clarify whether pituitary enlargement influences the secretory patterns of growth hormone (GH) and thyrotropin (TSH) in old rats, we studied the correlation between pituitary weight and plasma levels of GH and TSH in Sprague-Dawley rats of different age and sex. Young female (3-4 months; YF), old female (25 months; OF), and senescent female (33-35 months; SF) rats and young male (3-4 months; YM) and old male (24-26 months; OM) rats carrying chronic intraatrial cannulas were used. Sequential blood samples were removed through the cannulas while the animals remained conscious and undisturbed. Plasma TSH and GH as well as serum thyroxine (T4) and triiodothyronine (T3) were measured by radioimmunoassay. At two years of age, both males and females showed a consistent decline in GH pulse amplitude without change in trough levels. By 33-35 months of age, females showed a reversal in the previous pattern of change for GH secretion: pulse amplitude, trough levels, and mean plasma GH increased significantly with respect to the old females. The correlation between mean plasma GH and anterior pituitary (AP) weight was positive and significant (p less than 0.01) for females but nonsignificant for males. Old and senescent rats showed significantly lower serum T4, but not T3, than young animals while plasma TSH increased with age in both sexes.(ABSTRACT TRUNCATED AT 250 WORDS)

Gonadal function in aging rats and its relation to pituitary and mammary pathology.

In the female rat, aging is characterized by a high incidence of prolactin (Prl)-secreting pituitary adenomas and mammary tumors. In contrast to this, old males show only a moderate to low incidence of pituitary and mammary pathology. Since gonadal steroids and Prl are thought to be key factors in the genesis of the above neoplastic pathologies, it was of interest to compare the serum levels of progesterone (P), estradiol (E2), testosterone (T) and Prl with the incidence of pituitary and mammary tumors in aging male and female rats. Young (3-4-month; YF), old (25-month; OF) and senescent (33-35-month; SF) female and young (3-4-month; YM) and old (24-26-month; OM) male Sprague-Dawley rats were killed by decapitation and their pituitaries weighed. Serum sex steroids and Prl were measured by RIA. The average life span of females but not males was markedly extended by systematic removal of mammary tumors. Females showed a rising incidence of mammary tumors after 14 months of age. In males, this pathology which began to appear at 16 months, had a much lower incidence than in females at all ages. Serum levels of E2 were (means +/- S.E.M.) 22.0 +/- 1.6; 18.9 +/- 0.8; 32.9 +/- 2.5; 37.3 +/- 2.0 and 32.2 +/- 3.0 pg/ml for YM, OM, YF, OF and SF, respectively. Serum P was 1.4 +/- 0.3; 1.6 +/- 0.2; 10.4 +/- 2.2; 9.7 +/- 3.3 and 6.8 +/- 0.8 ng/ml for YM, OM, YF, OF and SF, respectively. Serum T was 1578.9 +/- 188.7; 807.6 +/- 103.0; 197.5 +/- 11.8; 223.7 +/- 25.5 and 176.9 +/- 20.7 pg/ml for YM, OM, YF, OF and SF, respectively. Finally, serum Prl was 14.9 +/- 1.7; 21.9 +/- 4.0; 15.9 +/- 1.4; 52.4 +/- 9.4 and 170.8 +/- 31.1 ng/ml for YM, OM, YF, OF and SF, respectively. A strong correlation was found between serum Prl and anterior pituitary weight in OM, OF and SF, but not between serum Prl and sex steroid levels or sex steroid ratios. We conclude that, although the sex-related differences in mammary and pituitary tumor incidence during aging in rats can be partially accounted for by the different serum profiles of Prl and gonadal steroids in each sex, sex-associated differences in target tissue susceptibility should also be considered as an important determinant of the level of tumor incidence.

Changes in circulating levels of neuroendocrine and thymic hormones during aging in rats: a correlation study.

It is well established that during early life the thymus gland and the neuroendocrine system influence each other's maturation. Furthermore, there is a growing body of evidence indicating that the immune and neuroendocrine systems also function as a bidirectional network during adult life. In order to assess possible changes in the thymic-neuroendocrine network during aging, we undertook to measure and correlate the circulating levels of several neuroendocrine and thymic hormones in young (3 month) and old (26 month) male Sprague-Dawley rats. Sequential plasma samples were obtained from chronically cannulated, nonstressed animals every 30 min for 5 h. Two days later rats were killed between 11:30 a.m. and 1:30 p.m. and trunk serum was obtained. All hormones were measured by radioimmunoassay. Growth hormone (GH), prolactin (PRL), thyrotropin (TSH) and corticosterone were measured in plasma, whereas thyroxine (T4), triiodothyronine (T3), thymosin alpha 1 (T alpha 1) and thymosin beta 4 (T beta 4) were determined in trunk serum. The circulating levels of T3, PRL, corticosterone and T beta 4 did not show significant differences between young and old rats, whereas GH, T4, T alpha 1, and thymus weight showed a significant age-related reduction. The anterior pituitary (AP) weight and plasma TSH were significantly higher in old than in young rats. Three pairs of parameters showed highly significant levels of linear correlation: AP weight vs. T alpha 1; thymus weight vs. T4 and T alpha 1 vs. T4 (p less than 0.01, p less than 0.001 and p less than 0.001, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of underfeeding and refeeding on GH and thyroid hormone secretion in young, middle-aged, and old rats.

The effects of a 50% reduction in normal food intake for a period of 10 weeks were measured on secretion of growth hormone (GH), thyroxine (T4), and triiodothyronine (T3) in 5 1/2-6 1/2-month old, 13 1/2-month-old, and 17 1/2-18 1/2-month-old male rats. In full-fed controls, GH, T3, and T4 were lower in the old and middle-aged than in the young rats. By the 10th week of underfeeding, GH, T3, and T4 were reduced in all age groups, but the decrease in T3 and T4 in the middle-aged and old rats was greater than in the young rats. Pulses of GH ceased in all the underfed groups. Upon refeeding for 5 days, pulses of GH and levels of GH returned to full-fed control values in the young and middle-aged but not in the old rats. T3 values in the young and middle-aged rats returned to full-fed control levels, but remained below control levels in the old rats. T4 values reached control levels in all age groups upon refeeding. The differences in the response to underfeeding and refeeding by the middle-aged and old rats as compared to the young rats may be due to their initially lower secretion of GH and thyroid hormones and to the age-related decrease in neuroendocrine function.

Homeostatic thymus hormone stimulates corticosterone secretion in a dose- and age-dependent manner in rats.

There is increasing evidence that the neuroendocrine system is responsive to hormonal signals generated by the immune systems. In particular, interleukin-1 and thymosin have been shown to stimulate the pituitary-adrenal axis in young animals. We report here that homeostatic thymus hormone (HTH), a well-characterized thymic preparation, increases plasma levels of corticosterone but not prolactin (PRL) in a dose- and age-dependent manner in male Sprague-Dawley rats. Young (3 months) and old (26 months) conscious, free-moving animals carrying an indwelling atrial cannula received the substances to be tested via the cannulas. Plasma samples were taken every 30 min for 5 h and hormones were measured by radioimmunoassay. HTH doses of 1 and 8 mg/kg body weight injected into young rats elicited a 7.8- and 12.8-fold increase in plasma corticosterone, respectively, as compared to saline-injected controls. The HTH-induced peak corticosterone levels were reached within 1.5 and 2.5 h after HTH injection. Plasma PRL was not affected by HTH in either age group. A single dose of 8 mg HTH/kg body weight induced a smaller corticosterone response in old than in young rats, although the time course of the response was similar in both age groups. The present results further suggest the existence of a lymphoid-neuroendocrine axis in young animals. The data also suggest that a disruption in immune-endocrine integration occurs during aging in rats.

Aging and anti-aging effects of hormones.

Hormones can promote or inhibit aging depending on the experimental conditions employed. The aging effects of hormones are demonstrated by reducing hormone secretion by hypophysectomy or chronic underfeeding in young or mature rats. These result in depressing whole body metabolism, growth, body temperature and blood glucose levels, heart rate and vital capacity, gene expression, etc., but delaying aging of tissues, suppressing development of pathology and tumors, and, in underfed rats, prolonging life span. The anti-aging effects of hormones are demonstrated by elevating hormone levels in old rats whose hormones have declined as a result of dysfunctions that develop in the neuroendocrine system with age. An increase of hormones in these rats promotes gene expression, elevates protein synthesis, and enhances metabolism, growth, and function of stimulated organs and tissues.

Differential effect of homeostatic thymus hormone on plasma thyrotropin and growth hormone in young and old rats.

There is increasing evidence that the neuroendocrine system is responsive to hormonal signals generated by the immune system. Thus, interleukin-1, hepatocyte stimulating factor and thymosin have been shown to stimulate adrenocorticotropin, beta-endorphin and luteinizing hormone secretion. We report here that homeostatic thymus hormone (HTH), a well-characterized thymic preparation, reduces plasma thyrotropin (TSH) and growth hormone (GH) in young (3 months) Sprague-Dawley male rats, but fails to do so (TSH) or has a significantly weaker effect (GH) in old (26 months) animals. Young and old conscious, free-moving rats carrying an indwelling atrial cannula received the substances to be tested via the cannulas. Plasma samples were taken every 30 min for 5 h and hormones were measured by RIA. In the young rats, HTH (8 mg/kg body wt) induced a marked reduction in plasma TSH which was significantly greater than the normal circadian decline observed in saline-injected young controls. The old rats displayed high basal levels of TSH which showed no circadian rhythmicity and did not respond to HTH. Plasma thyroxine (T4) showed a significant age-related reduction but was not affected by HTH. The above dose of HTH significantly reduced plasma GH in young and old rats, but the effect was greater in the young animals. Mean basal levels of plasma GH were significantly lower in old than in young rats. The present results suggest that HTH, whose production by the thymus is known to be stimulated by TSH and GH, is involved in an inhibitory feedback loop regulating plasma TSH and GH in young rats. Our data also suggest an age-related desensitization of the TSH and GH systems to thymic influence in this species.

Episodic growth hormone secretory pattern in male rats: relationship to gonadal steroid hormones.

In the present study sequential blood samples were obtained from freely-behaving male rats bearing chronic intracardial venous cannulae. Blood samples were obtained at 20 min intervals for 6 h from intact rats, castrated rats, castrated rats treated with either testosterone propionate (TP) or estradiol benzoate (EB) and intact rats treated with either TP or EB. Intact rats demonstrated normal episodic GH secretion. The mean baseline GH concentration was similar in intact and castrated rats, while the overall mean plasma GH levels and the magnitude of the mean plasma GH secretory spikes were significantly higher in intact rats. Injection of castrated rats with TP completely counteracted the effect of castration on GH secretory pattern. Injection of TP to intact male rats did not induce any significant changes in the GH secretory pattern. Treatment of intact males with EB significantly elevated mean baseline GH concentration, while the magnitude of the mean GH secretory spikes was significantly reduced. When EB was injected to castrated males, the overall mean GH levels and the magnitude of the mean GH secretory spikes were significantly reduced, while the mean baseline GH was significantly elevated. The data of the present work suggest that gonadal steroids are responsible, at least in part, for the differences in GH secretory pattern between males and females; and that the increase in the magnitude of GH secretory spikes in males could account for the greater increase in growth rate at puberty in males than in females.