Effects of long-term testosterone replacement on copulatory activity in old male rats

Various parameters of copulatory behavior were examined in intact and castrated testosterone-(T-)treated male rats of various ages ranging from 3 to 27 months. Serum T levels were controlled by subcutaneous implantation of different sizes of T-filled Silastic capsules at the time of castration. In intact male rats, scores of various parameters of copulatory behavior declined gradually from middle age and no ejaculation was observed in any rats over 22 months of age. When serum T levels were maintained at 0.78-0.87 ng/ml for 6 months from 4 months of age, these rats showed the same copulatory activity as intact rats, except that fewer rats exhibited ejaculation at 8 and 10 months of age and showed decreased total mount frequency at 10 months of age. Even when serum T levels were maintained at 2.95-3.53 ng/ml for a period of 6 months from 18 months of age, copulatory activity still declined gradually and no rats over 22 months of age ejaculated. However, long-term elevation of serum T level could prevent further decline of intromission frequency in old age. These results indicate that the copulatory activity of male rats in response to circulatory T declined with advancing age and that prolonged low levels of serum T had only a minor role in the onset of decreased responsiveness of neural male sexual behavior.     

Effects of castration and testosterone administration on serum lipoproteins and their apoproteins in male spontaneously hypertensive rat

Serum triglyceride and very low density lipoprotein (VLDL) concentrations were higher in male spontaneously hypertensive rat than in male control Wistar Kyoto rat, whereas serum cholesterol, phospholipids, and high density lipoprotein (HDL) concentrations were lower. Castration of hypertensive rats induced an increase in serum cholesterol, phospholipids, and HDL, and a decrease in serum triglyceride and VLDL. The cholesterol content of HDL increased, whereas the triglycerides decreased after gonadectomy of hypertensive rats. These changes in serum lipids and lipoproteins could be reversed by the administration of testosterone. Apolipoprotein E contents in VLDL and HDL of hypertensive rats were low when compared with control rats but rose after castration and could be reduced by testosterone administration. Hypertensive rats accumulated triglycerides and cholesterol in the liver, which resulted in an increase of liver weight. Castration reduced the hepatic lipids as well as liver weight. The effects of castration and testosterone treatment on lipids and lipoproteins were more prominent in spontaneously hypertensive rats than in control rats. These results suggest that testosterone reduces VLDL catabolism which is related to changes of apolipoprotein composition, and that hypertensive rats are more sensitive to testosterone than control rats.     

Comparison of the effects of castration and steroid replacement on incertohypothalamic dopaminergic neurons in male and female rats

The activities of incertohypothalamic (IH) and tuberoinfundibular (TI) dopamine (DA) neurons were compared in selected brain regions of male and female rats by measuring the rate of DA turnover (alpha-methyltyrosine-induced decline in brain DA concentrations). The rates of DA turnover in regions containing TIDA (median eminence) and rostral IHDA (rostral periventricular and medial preoptic nuclei) neurons were greater in diestrous females than in intact males. In contrast, the rate of DA turnover in the caudal IHDA neurons (medial zona incerta), was greater in intact males than diestrous females. These results indicate that the activities of IHDA neurons, like those of TIDA neurons, differ between the sexes but that the sexual differentiation of IHDA neurons is not homogeneous. Two weeks following orchidectomy, the rates of DA turnover were increased in the median eminence and decreased in the medial preoptic nucleus. Testosterone replacement in orchidectomized males produced opposite effects, causing a decrease in DA turnover in the median eminence and an increase in the medial preoptic nucleus. In female rats, the rates of DA turnover were decreased in the median eminence and medial zona incerta and increased in the medial preoptic nucleus 2 weeks following ovariectomy. Only in the median eminence did 2 days of estrogen replacement in ovariectomized rats produce effects opposite those seen after ovariectomy alone. These data show that the activities of IHDA neurons, as estimated from measurements of DA turnover, can be altered by the removal and replacement of the gonadal steroids.     

Relationship between serum concentration of gonadotropins and testosterone in heat exposed-ageing male rats.

Serum follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone of control rats (20–22°C, 30–50% relative humidity) did not vary at 4, 6 and 10 months of age. Prolonged maintenance of rats in a hot environment (33–35°C, 25–40% relative humidity) was accompanied by a significant decrease in testosterone concentration, irrespective of the animal's age or duration of exposure to heat (1, 2 and 7 months), whereas the concentration of FSH and LH remained relatively unaffected. Activity of 17β-hydroxysteroid oxidoreductase (17β-HSD) in the testes of control rats was inversely related to the animals' age. In most cases prolonged exposure to heat augmented the decline in activity of 17β-HSD associated with ageing. These data suggest that increasing in age is accompanied by a decrease in the activity of testicular 17β-HSD without affecting the concentration of FSH, LH and testosterone in blood serum. It is concluded that, within the age limits used in the present experiment, the significant drop in serum testosterone concentration characterizing rats exposed to heat is independent of serum gonadotropin concentration and testicular acitivity of 17β-HSD, as well as the animal's age.     

The aging male: testosterone deficiency and testosterone replacement. An up-date

The significance of the age-related decline of androgens remains unclear in terms of cardiovascular risk, mood and cognition, and prostatic health. Although much research has been undertaken in this area and men's health has received still more attention in the latest years, there are no data based on randomized controlled clinical studies in aging men investigating the long-term effects of androgen replacement therapy on various aspects of the cardiovascular system, the immune system, body composition, and the brain. In men receiving long-term androgen replacement therapy, the safety aspects regarding the prostate are also an area of clinical importance. In this paper we present an up-dated review of the experimental and clinical evidence of androgen deficiency and androgen replacement therapy on carbohydrate metabolism, on coagulation and fibrinolysis, inflammatory effects, effects on lipoprotein metabolism, direct arterial effects, effects on body composition, effects on cognitive function and mood, and prostatic effects. The evidence clearly shows that data for the most part are conflicting, with only very few randomized studies available.     

Regulation of gonadotrophin secretion in male mice from birth to adulthood. Response to LRH injection, castration and testosterone replacement therapy

Plasma LH and FSH concentrations were determined by radioimmunoassay in male mice from birth to adulthood after LRH injection, castration and testosterone replacement therapy. Except at birth for LH, LRH significantly increased circulating levels of both gonadotrophins at all stages studied. It is suggested that a change in the pituitary LH response to LRH occurs around puberty and perhaps represents the time of initiation of pubertal processes. At all stages studied (except the infantile stage for LH) castration resulted in a significant rise in circulating LH and FSH levels. The magnitude of LH response to castration increased with age but not that of FSH. Testosterone replacement therapy, inducing supra-physiological circulating testosterone levels, was ineffective to depress the post-castration rises of LH and FSH levels.     

Substance P and luteinizing hormone-releasing hormone levels in the brain of the male golden hamster are both altered by castration and testosterone replacement

The effects of castration and testosterone (T) replacement on levels of substance P (SP) and luteinizing hormone-releasing hormone (LHRH) were assessed in discrete areas of the male hamster brain. The animals were either castrated, castrated and given a chronically low or high dose of T by Silastic implant, or sham-operated. Brain tissues and trunk blood were collected 3 weeks after surgery. Plasma T levels were maintained within the normal range by the implants but at significantly lower or higher levels than the mean for sham-operated males. Levels of SP and LHRH were quantified in the olfactory bulbs, rostral basal forebrain, anterior hypothalamic and preoptic area, medial basal hypothalamic area, medial basal hypothalamic area and median eminence, and brain stem. In general, castration and T replacement effected opposite changes in levels of SP and LHRH. In the medial basal hypothalamic area and median eminence SP levels were found to be inversely related to the chronic T levels, whereas the LHRH levels were directly correlated. In the anterior hypothalamic and preoptic area, castration reduced levels of SP. Conversely, castration elevated levels of LHRH in this area. This inverse dynamic relationship between changing peptide levels was also observed in the rostral basal forebrain but not in the olfactory bulbs. In most of these forebrain regions, the dose-response curves for the experimental groups could not incorporate the peptide levels in the sham-operated control group. SP levels in the brain stem showed a monotonic inverse relationship to circulating T levels which did include the control group values.(ABSTRACT TRUNCATED AT 250 WORDS)     

An effect of castration and testosterone replacement on a circadian pacemaker in mice (Mus musculus).

Castration of mice in freerunning conditions (total darkness, DD) causes a reduction of running wheel activity in the beginning of the active period (alpha) and stimulates activity at the end of alpha. Simultaneously, the period (tau) of the freerunning rhythm is increased. Both effects are abolished by implantation of a Silastic capsule from which a physiological dose of testosterone is released at a constant rate. The results are tentatively explained by differential endocrine influences on two oscillating components in the pacemaker of the circadian activity rhythm.     

Effects of testosterone replacement in hypogonadal men

Treatment of hypogonadal men with testosterone has been shown to ameliorate the effects of testosterone deficiency on bone, muscle, erythropoiesis, and the prostate. Most previous studies, however, have employed somewhat pharmacological doses of testosterone esters, which could result in exaggerated effects, and/or have been of relatively short duration or employed previously treated men, which could result in dampened effects. The goal of this study was to determine the magnitude and time course of the effects of physiological testosterone replacement for 3 yr on bone density, muscle mass and strength, erythropoiesis, prostate volume, energy, sexual function, and lipids in previously untreated hypogonadal men. We selected 18 men who were hypogonadal (mean serum testosterone +/- SD, 78 +/- 77 ng/dL; 2.7 +/- 2.7 nmol/L) due to organic disease and had never previously been treated for hypogonadism. We treated them with testosterone transdermally for 3 yr. Sixteen men completed 12 months of the protocol, and 14 men completed 36 months. The mean serum testosterone concentration reached the normal range by 3 months of treatment and remained there for the duration of treatment. Bone mineral density of the lumbar spine (L2-L4) increased by 7.7 +/- 7.6% (P < 0.001), and that of the femoral trochanter increased by 4.0 +/- 5.4% (P = 0.02); both reached maximum values by 24 months. Fat-free mass increased 3.1 kg (P = 0.004), and fat-free mass of the arms and legs individually increased, principally within the first 6 months. The decrease in fat mass was not statistically significant. Strength of knee flexion and extension did not change. Hematocrit increased dramatically, from mildly anemic (38.0 +/- 3.0%) to midnormal (43.1 +/- 4.0%; P = 0.002) within 3 months, and remained at that level for the duration of treatment. Prostate volume also increased dramatically, from subnormal (12.0 +/- 6.0 mL) before treatment to normal (22.4 +/- 8.4 mL; P = 0.004), principally during the first 6 months. Self-reported sense of energy (49 +/- 19% to 66 +/- 24%; P = 0.01) and sexual function (24 +/- 20% to 66 +/- 24%; P < 0.001) also increased, principally within the first 3 months. Lipids did not change. We conclude from this study that replacing testosterone in hypogonadal men increases bone mineral density of the spine and hip, fat-free mass, prostate volume, erythropoiesis, energy, and sexual function. The full effect of testosterone on bone mineral density took 24 months, but the full effects on the other tissues took only 3-6 months. These results provide the basis for monitoring the magnitude and the time course of the effects of testosterone replacement in hypogonadal men.     

Progesterone stimulates testosterone secretion in male rats

In male rats, serum testosterone (T) and progesterone (P) levels fluctuate with daily periodicities that appear to be inversely related. To further investigate this interrelationship between serum T and P levels, we studied the effects of exogenous P on serum androgen levels. At 6--8 h after administration of P, serum T and DHT levels were consistently increased without any alterations in the serum LH and FSH levels. Following disruption of the hypothalamo-pituitary-adrenal axis either by adrenalectomy or by anterior hypothalamic deafferentiation, procedures known to abolish serum T and P periodicities, P was again effective in raising serum T concentrations without altering the serum gonadotropin values. These results show that P may directly enhance testicular secretion, and thus support the possibility that the observed adrenal influence on daily testicular T secretion pattern may be hormonally mediated via P secretion.     

The effects of castration on histamine levels and 24-hour rhythm in the male rat hypothalamus.

Holtzman male rats were castrated or sham-operated at 22 days of age and raised in a 12 h light: 12 h dark illumination cycle. At age 63 days they were sacrificed by decapitation at six different times during the light:dark (L:D) cycle, and hypothalamic histamine (H) concentrations were measured using a modified single isotope-enzyme microassay. Hypothalamic H was significantly elevated in the castrated rats at all but two of the six times sampled during the L:D cycle, when compared with the sham-operated controls. Both surgical groups had similar 24-h rhythms of hypothalamic H concentrations, with the peak concentration occurring during the light phase followed by a rapid drop to the minimum 2-3 h later. However, the castrated rats appeared to attain both maximal and minimal concentrations somewhat earlier in the day. These results provide circumstantial evidence that hypothalamic H may have a role in the hypothalamo-hypophyseal-gonadal axis in the male rat.     

Chronic morphine and testosterone treatment. Effects on sexual behavior and dopamine metabolism in male rats

The effects of sustained delivery of morphine and/or testosterone (T) on male rat copulatory behavior, penile reflexes and dopaminergic metabolism in selected brain regions were examined. Castration was followed by (1) a decrease in the number of male rats exhibiting intromissive and ejaculatory behavior in mating tests, (2) decreased erections in ex copula tests, and (3) increases in dopamine and dihydroxyphenylacetic acid (DOPAC) concentrations in the mediobasal hypothalamus (MBH) and the preoptic area-anterior hypothalamus (POA-AH). The decreased incidence of copulatory behavior and penile reflexes seen after castration was effectively prevented by a 4-day treatment with 5-mm T-containing Silastic capsules. Chronic morphine implants, conversely, accentuated the castration-induced decrements in copulatory behavior and prevented the 5-mm-T-induced facilitation, but did not alter the number of animals displaying erection (although the number of erections displayed by testosterone-treated rats was reduced) in ex copula tests. Treatment of castrated rats with 5 mm T, but not morphine alone, nor the combination of 5 mm T plus morphine, significantly reduced dopamine and DOPAC levels in the MBH. In the POA-AH, 5 mm T was without effect, whereas morphine, alone or in combination with 5 mm T, reduced the levels of dopamine and DOPAC. These data suggest that (1) the decline in sexual behavior induced by chronic morphine is primarily due to a failure of sexual arousal, and not of erectile ability, and (2) although the decline in sexual activity seen after castration is associated with alterations in dopaminergic metabolism, the effects of morphine and testosterone on sexual activity are opposite and dissociated from alterations in dopaminergic metabolism.