Influence of a prolonged tamoxifen administration on steroidogenesis by incubated rat testes

Tamoxifen was administered i.m. for 9 days to adult male rats in a daily dose of 100 micrograms or 1 mg. The treatment resulted in a significant reduction of the plasma levels of testosterone and LH, without modification of the plasma levels of FSH and of the testes weight. Upon incubation, the testes from the tamoxifen-treated rats produced less testosterone and 7 alpha-hydroxytestosterone, but metabolized [4-14C]testosterone in the same way as the control animals. Small doses of hCG (0.5 i.u. for 9 days) were unable to modify the tamoxifen effect on the testicular function, while tamoxifen significantly inhibited the increase of the plasma levels of testosterone induced by the administration of moderate doses of hCG (1.5 i.u. or 2.5 i.u. for 9 days) to hypophysectomized rats. Tamoxifen treatment, however, did not modify significantly the reactivity of the testes towards high doses of hCG (10 i.u.), administered either 2 h before sacrifice or for 9 days. It is concluded that a prolonged administration of tamoxifen in the rat has, besides an indirect effect resulting from a decrease of the LH levels, a direct inhibitory influence on the testicular testosterone formation, which can be reversed by high doses of hCG.     

LH and testosterone responses to five doses of a GnRH analogue (buserelin acetate) in 12-month-old Thoroughbred colts

To determine the responsiveness of the pituitary-gonadal axis of peri-pubertal colts to GnRH, buserelin (0.5, 1, 5, 10 and 40 microg) was given to 13 male Thoroughbred yearlings ( n=3-8 colts per dose). Jugular venous blood samples were taken at -10, 0, 10, 20, 30, 40, 60, 120 and 180 min relative to buserelin administration. Increases (P < 0.05) in LH concentrations occurred in colts that received 5, 10, or 40 microg buserelin, but not in those that received 0.5 or 1 microg. Peak LH concentrations and mean area under the curve were higher (P < 0.05) in colts receiving 40 microg buserelin than in those that received 0.5 or 1 microg. Increases ( P< 0.05) in testosterone concentrations occurred in some, but not all, colts that received 1, 5, 10, or 40 microg buserelin. Neither peak concentration nor area under the curve of testosterone differed significantly among doses of buserelin. The percentage of horses that responded to the buserelin increased with increasing dose, with only the highest dose eliciting LH and testosterone responses in all colts. In conclusion, peri-pubertal colts exhibited a dose-response release of LH following buserelin treatment, but individual colts responded in an "all or nothing" manner, such that each either had an LH response or did not. Some colts that exhibited a significant LH response had no subsequent increase in plasma testosterone concentrations; perhaps the pituitary LH response may not have been great enough to stimulate the Leydig cells in these individuals.     

Brood Reduction via Intra-clutch Variation in Testosterone - An Experimental Test in the Great Tit

In birds, yolk androgen concentrations in eggs can increase or decrease over the laying sequence and common hypotheses hold that this serves to favour the competitive ability of either first- or last-hatched chicks depending on the prevailing conditions, and thus promote brood reduction or maintenance of original brood size respectively. Intra-clutch variation of testosterone can shift relative competitive ability of siblings and hence competitive dynamics. In a natural population of great tits, we experimentally investigated the effects and function of maternal testosterone on offspring phenotype in relation to the laying position of the egg in a context of hatching asynchrony. To this end, we created three types of clutches where either the first three or the last three eggs of a clutch were injected with testosterone (T) dissolved in sesame oil, and the remaining eggs with sesame oil only, or where all eggs of a clutch were injected with sesame oil. Increased levels of yolk T in the last-laid eggs resulted in the last-hatched chicks being significantly lighter and smaller than their siblings, while increased levels of T in the first-laid eggs had no direct effect on the first-hatched chicks, but an indirect negative effect on their siblings. Our results suggest that females can potentially adjust offspring phenotype by modulating, over the laying sequence, the amounts of T deposited in the eggs. These results are in contradiction, however, with current hypotheses and previous findings, which suggest that under good conditions higher levels of maternally derived T in the last-laid eggs should mitigate the negative effects of hatching asynchrony.     

Yolk testosterone stimulates growth and immunity in house finch chicks

Female birds deposit variable amounts of androgens, such as testosterone, into the yolks of their eggs. Evidence suggests that yolk androgens play an important role in the determination of offspring phenotype. While androgens are generally regarded as anabolic and immunosuppressive, studies of the behavioral and physiological effects of yolk androgens on offspring of several avian species have been conflicting, leaving the adaptive significance associated with deposition patterns of yolk androgens unclear. We injected either a physiological dose of testosterone or a control vehicle into house finch (Carpodacus mexicanus) eggs and examined the effects of these injections on offspring growth and immunity. Two days after hatching, nestlings from eggs treated with testosterone were significantly larger than nestlings from eggs treated with a control injection, suggesting a stimulatory effect of yolk androgens in early development. By 8 d after hatching, however, this effect disappeared, and chicks from the two treatment groups were similar in size. Nestlings in the testosterone treatment group showed a significantly larger swelling response to phytohemagglutinin than control nestlings 15 d after hatching, which is close to fledging. Overall, our observations show that when food resources are abundant, testosterone stimulates both early growth and immunity in developing house finches.     

Brood Reduction in White Storks Mediated through Asymmetries in Plasma Testosterone Concentrations in Chicks

We hypothesized that increasing chick plasma testosterone concentrations, transmitted from the mothers via their eggs, enhances survival of their offspring and that the fitness of the young, depending on the maternal hormones, is influenced by parental quality. To test our hypotheses we distinguished the broods of white storks Ciconia ciconia L. where chicks died and those where all chicks survived. We analysed the plasma testosterone concentrations in the chicks, the ability of the chicks to be first to receive food and the mass of chicks before fledging in relation to their hatching order and recorded the body mass of parents and food mass delivered by them.
Female storks used the asymmetries in testosterone concentrations within a brood to control brood size and adjusted the number of young hatched to match the parental ability to rear offspring. Females of poor condition altered the testosterone concentrations to produce large differences between the chicks: The first-hatched chicks, which had high plasma testosterone levels, responded faster to the feeding parent and received more food than did their younger siblings. One or two later-hatched chicks, which had lower testosterone levels, died in these broods. Females in good condition produced small differences in testosterone concentrations between the chicks and all chicks survived in their brood. Chicks that were raised by the females of poor condition in reduced broods were heavier than chicks that were raised by females of good condition in broods where all chicks survived.
We suggest that the control of brood size by testosterone concentration, transmitted by the mother to the chicks, is a hormonal means of condition-dependent reproductive strategy in the white stork.     

Hormonal stimulation and paternal experience influence responsiveness to infant distress vocalizations by adult male common marmosets,Callithrix jacchus

Parental experience and hormones play a large role in the common marmoset (Callithrix jacchus) father's care of their offspring. We tested the effect of exogenous estradiol or testosterone on the responsiveness of common marmosets to respond to infant distress vocalizations and whether males who haven't become fathers yet (paired males) would have increased responsiveness to infant distress calls with either steroid or whether parental experience is the most important component for the onset of paternal care. Sixteen male marmosets (8 fathers, 8 paired males) received a vehicle, low dose or high dose of estradiol and additional 16 males were tested with testosterone at three doses for their response either to a vocal control or a recording of an infant distress call for 10 min. Without steroid stimulation fathers were significantly more likely to respond to the infant distress stimulus than paired males. Low dose estradiol stimulation resulted in a significant increase in fathers' behavioral response towards the infant distress stimulus but not in paired males. Fathers also showed a significant increase in infant responsiveness from the vehicle dose to the estradiol low dose treatment, but not to the estradiol high dose treatment. Testosterone treatment did not show significant differences between infant responsiveness at either dose and between fathers and paired males. We suggest that neither steroid is involved in the onset of paternal care behaviors in the marmoset but that estradiol may be involved in facilitating paternal motivation in experienced fathers.     

Androgen and estrogen stimulation of ornithine decarboxylase activity in mouse kidney

In the present work, the activity of mouse renal ornithine decarboxylase (ODC) from CBA female mice was used as a biological marker to detect (anti)androgenic activity of different groups of endocrine disruptors and steroids. Daily injections of testosterone or dihydrotestosterone (DHT) into 60 day old female mice for 4 days increased renal ODC activity in a dose-dependent manner that reached up to 100-fold (testosterone) or 250-fold (DHT) above the baseline when the highest dose, 200 microg/mouse, was used. Administration of flutamide concurrently with testosterone (75 microg/mouse) caused a potent decrease of ODC induction in a dose-dependent manner, suppressing the enzyme activity at the doses of 0.1 and 0.5 mg/mouse by about 88 and 95%, respectively. In contrast, estradiol at the doses of 0.5 and 1 mg/mouse induced a significant stimulation of renal ODC activity in a dose-dependent manner when it was given alone or in combination with testosterone. Using a sensitive increase in ODC activity in response to androgens as an end point, we did not detect an antiandrogenic effect of several antiandrogens, such as cyproterone acetate, spironolactone, p,p'DDE and vinclozolin. Also, none of these antiandrogens were able to change the basal level of renal ODC activity, with the exception of cyproterone acetate that at a dose of 0.1 mg/mouse stimulated ODC activity. The data obtained suggest that mouse renal ODC from CBA females is not strictly androgen-specific and cannot be used for estimation of antiandrogenic effects of compounds having an affinity to different types of receptors.     

Induction and Maintenance of Maternal Behaviour in the Domestic Hen: Influence of Testosterone and Oestradiol Treatments

Confining an adult hen with two newly-hatched chicks induced a gradual emergence of maternal behaviour in the hen. The aim of the experiments presented here was to analyse the effects of testosterone or oestradiol treatments on the induction and maintenance of maternal behaviour in hens with no previous maternal experience. The ability of a hen to positively respond towards chicks was not altered by either testosterone or oestradiol injections. However, testosterone therapy prevented both the appearance and the maintenance of the most typical call, clucking. Testosterone injected hens responded to chicks with a contact-type call, but oestradiol treated ones did not. These results indicate that some aspects of maternal behaviour can be modulated by peripheral levels of hormones.     

Effects of steroid hormones on total brain Na(+)-k+ ATPase activity in Oreochromis mossambicus

The effects of administration of cortisol, corticosterone, testosterone, progesterone and a synthetic estrogen. diethylstilbestrol (DES) on total brain Na(+)-K+- ATPase were investigated in tilapia, O. mossambicus. Exogenous administration of 0.125 and 0.25 microg/g body weight of glucocorticoids and 0.125, 0.25 and 0.5 microg/g body weight of DES for 5 days significantly stimulated Na+(-) K+ ATPase activity by 14-41% in the brain, while 0.5 microg/g body weight of glucocorticoids did not evoke any response on the activity of the enzyme. Progesterone (0.125 and 0.25 microg/g body weight) administration significantly decreased the enzyme activity by 21-36% and high dose (0.5 microg/g body weight) was ineffective. Testosterone exhibited a biphasic effect on Na(+)-K+ ATPase activity--a low dose stimulated by 14% while middle and high doses inhibited it by 19-24%. The results seem to be the first report on the effect of steroids on brain ATPase activity in a teleost. When 0.25microg/g body weight of actinomycin D or puromycin was administered prior to the treatment of similar doses of hormones, the inhibitors significantly inhibited the effect of the hormones by 24-52%. This clearly shows that the effect of the hormones was sensitive to the action of inhibitors suggesting a possible genomic mode of action under long-term treatment. The results suggest that cortisol, corticosterone and DES may possibly stimulate the co-transport of glucose and excitation of membrane potential while progesterone and testosterone inhibit them in the brain of O. mossambicus by regulating the activity of Na(+)-K+ ATPase.     

Mercury Reduces Avian Reproductive Success and Imposes Selection: An Experimental Study with Adult- or Lifetime-Exposure in Zebra Finch

Mercury is a global pollutant that biomagnifies in food webs, placing wildlife at risk of reduced reproductive fitness and survival. Songbirds are the most diverse branch of the avian evolutionary tree; many are suffering persistent and serious population declines and we know that songbirds are frequently exposed to mercury pollution. Our objective was to determine the effects of environmentally relevant doses of mercury on reproductive success of songbirds exposed throughout their lives or only as adults. The two modes of exposure simulated philopatric species versus dispersive species, and are particularly relevant because of the heightened mercury-sensitivity of developing nervous systems. We performed a dosing study with dietary methylmercury in a model songbird species, the zebra finch (Taeniopygia guttata), at doses from 0.3 – 2.4 parts per million. Birds were exposed to mercury either as adults only or throughout their lives. All doses of mercury reduced reproductive success, with the lowest dose reducing the number of independent offspring produced in one year by 16% and the highest dose, representing approximately half the lethal dose for this species, causing a 50% reduction. While mercury did not affect clutch size or survivorship, it had the most consistent effect on the proportion of chicks that fledged from the nest, regardless of mode of exposure. Among birds exposed as adults, mercury caused a steep increase in the latency to re-nest after loss of a clutch. Birds exposed for their entire lifetimes, which were necessarily the offspring of dosed parents, had up to 50% lower reproductive success than adult-exposed birds at low doses of methylmercury, but increased reproductive success at high doses, suggesting selection for mercury tolerance at the highest level of exposure. Our results indicate that mercury levels in prey items at contaminated sites pose a significant threat to populations of songbirds through reduced reproductive success.     

Effect of nonylphenol on serum testosterone levels and testicular steroidogenic enzyme activity in neonatal, pubertal, and adult rats.

Previous dose range-finding studies with nonylphenol (NP) administered to rats in a soy- and alfalfa-free diet showed apparent feminization of several endpoints in male rats at doses of 25 ppm and above. One possible mechanism contributing to these effects is a reduction of testosterone at critical developmental periods. The present study was conducted as an adjunct to a multigeneration study and was designed to examine the effect of NP on testosterone production. Male rats in the F1 and F2 generations were exposed through their dams or directly to various dietary doses of NP (0, 25, 200 and 750 ppm) throughout gestation and until sacrifice at either postnatal day 2 (PND2), PND50, or PND140. Male pups in the F3 generation were examined only on PND2. At PND2, serum testosterone levels were significantly decreased in all groups exposed to NP in the F1 generation, but not in the F2 or F3 generations. The activity of 17alpha-hydroxylase/C17, 20 lyase (P450c17) in PND2 testicular homogenates was not affected by NP treatment. In F1 and F2 PND50 and PND140 rats, NP treatment did not affect serum testosterone levels. The absolute dorsolateral prostate weight was increased in the 200 and 750 ppm dose groups only in the F1 PND50 rats, however, no significant effects were observed in other male reproductive organs. NP treatment did not affect P450c17 activity in microsomes prepared from testes of F1 PND50 or PND140 rats. However, P450c17 activity was significantly decreased in testicular microsomes of F(2) PND50 (200 and 750 ppm dose groups) and PND140 (25, 200, and 750 ppm dose groups) rats. A decrease in testicular beta-nicotinamide adenine dinucleotide phosphate (NADPH) P450 reductase was also observed in all PND50 and PND140 NP-exposed rats of the F1 and F2 generations. The ability of NP to directly inhibit P450c17 activity in vitro at concentrations of 1-100 microM was also demonstrated. These results indicate that NP can inhibit the activity of enzymes involved in testosterone synthesis, but suggest minimal effects on testosterone or testosterone-dependent endpoints via this mechanism.     

The hormonal control of begging and early aggressive behavior: experiments in black-headed gull chicks

The hormonal control of begging and sibling competition is largely unknown, but recent evidence suggests a role for steroid hormones. We tested the influence of the aromatizable androgen testosterone (T), the non-aromatizable androgen 5alpha-dihydrotestosterone (DHT), and 17beta-estradiol (E) on both begging behavior and aggressive behavior in black-headed gull chicks (Larus ridibundus). Chicks of this species have a conspicuous begging display, while their frequently performed early aggressive behavior is facilitated by testosterone and important for territorial defense. Hormone treatment was applied by implants between days 6 and 16 after hatching. Behavior was tested by means of standard stimulus tests. The results were validated in a second experiment under semi-natural conditions. Begging was suppressed by T and DHT and not affected by E. Aggressive Pecking was strongly facilitated by T. The erect threat posture, characteristic for older chicks, was facilitated by T, DHT, and E and the nest-oriented threat display, typical for young chicks, only by T and DHT. Growth was suppressed in the T group. The results indicate that androgen production, needed for territorial defense, has costs in terms of a suppression of begging and growth. It is discussed to what extent older chicks may avoid these costs by converting testosterone to estrogen and why pre-natal and post-natal exposure to androgens differ in their effect on begging behavior.     

Effect of estradiol-filled polydimethylsiloxane subdermal implants in adult male rats on the reproductive system, fertility, and progeny outcome

Combinations of testosterone and estradiol have been proposed as potential male contraceptives. For any compound to be an acceptable male contraceptive, it must be demonstrated either to prevent pregnancy completely or, if contraceptive failure occurs, to not have any adverse effect on pregnancy outcome. We have previously established that increasing doses of testosterone given via subdermal implants to adult male rats will decrease spermatogenesis and fertility but will not result in an increased incidence of pre- or postimplantation loss or in abnormal progeny. In the present study, we have monitored the effects of a dose of estradiol that has been proposed for the contraceptive regimen, as well as doses three and seven times as large, on progeny outcome. Adult male Sprague-Dawley rats received s.c. implants of estradiol-filled polydimethylsiloxane capsules of varying lengths and, after three months, were each mated twice to two females in proestrus. The smallest dose of estradiol (the dose used in the contraceptive formulation) did not have any significant effects on any of the measured parameters of the male reproductive system, or on the incidence of pre- or postimplantation loss or on progeny outcome. With increasing doses of estradiol, there was a marked reduction in fertility. This reduction in fertility was not associated with a sufficient decrease in epididymal sperm reserves to account for the decrease in number of females impregnated, but was associated with a major reduction in seminal plugs; this would suggest that the large doses of estradiol were decreasing male sexual behavior.(ABSTRACT TRUNCATED AT 250 WORDS)     

The adrenocortical stress-response of Black-legged Kittiwake chicks in relation to dietary restrictions

In this study we examined hormonal responses of Black-legged Kittiwake (Rissatridactyla) chicks to experimental variations in energy content and nutritional quality (low or high lipid to protein ratio, LPR) of their food. Starting at the age of 10 days, chicks were fed either high or low LPR fish at 30, 50, 70 and 100% of ad libitum energy intake. After 20 days of treatment, chicks were exposed to a standardized acute handling and restraint stress protocol, where a baseline sample was taken immediately after taking a chick from the nest, and three additional blood samples were taken at intervals up to 50 min. Testosterone and corticosterone titres in plasma were measured via radioimmunoassay. We found that baseline testosterone levels were not significantly affected by the experimental treatments. Food-restricted chicks had elevated baseline and acute stress-induced levels of corticosterone compared to chicks fed ad libitum. An elevation of circulating levels of corticosterone in energetically stressed individuals was further magnified by low nutritional quality of food. Baseline and acute stress-induced corticosterone levels of chicks were negatively correlated with their fat reserves. We conclude that the physiological condition of Black-legged Kittiwake chicks can be assessed reliably by measuring circulating levels of corticosterone. We discuss short- and long-term effects of elevated corticosterone secretion in food-stressed nest-bound chicks. Accepted: 13 April 1999     

The effect of oxytetracycline on growth and lipid metabolism in poultry

The effect of oxytetracycline at doses of 0.291, 0.461, 0.922, 1.383 and 1.844 g/l in drinking water on the growth rate, lipid metabolism, GOT, GPT, calcium and magnesium was studied on one-day-old chicks and laying hens (Gallus domesticus). Oxytetracycline at a dose of 0.461 g/l increased body weight gain in one-day-old chicks. Oxytetracycline had no effect on hepatic triglyceride and phospholipid levels while cholesterol levels were decreased in one-day-old chicks and increased in laying hens. Oxytetracycline tended to decrease serum cholesterol and to increase serum triglyceride concentrations while its effect on serum phospholipids were inconsistent. Oxytetracycline, although inconsistent, tended to increase GPT and GOT activities in both young chicks and laying hens. Higher doses of oxytetracycline resulted in fatty changes in the hepatocytes and cells of the kidney tubules and lungs in both young chicks and laying hens. With the exception of hepatic phospholipids, all other parameters were higher in laying hens than in young chicks.     

The effects of testosterone on the distractability of chicks by irrelevant and relevant novel stimuli

Young male chicks were trained to run for a food reward in a runway; half the sample were subsequently injected with testosterone oenanthate (Ts) and half with the oil vehicle only (Cs). Two days later, they were given a series of tests in the runway to investigate the effect which changing the colour or pattern of either the runway walls or the food dish had on their times to run and feed continuously. In two experiments, it was generally found that Ts showed more pronounced decreases in running times when the colour or pattern of the food dish was changed but Cs showed more pronounced decreases in running times following changes in the walls of the runway. These results supported predictions derived from the hypothesis of Andrew (1972a) that testosterone increases persistence of ‘activated search specifications’. Alternative possible explanations in terms of fear, response perseveration, or attention-switching were briefly discussed, and it was concluded that these could not account for the present results and those found in related studies.     

Deprivation and repletion of androgen in vivo modifies triacylglycerol synthesis by rat hepatocytes

Given the same quantity of fatty acid, livers from male rats esterify less fatty acid and secrete less triacylglycerol in very-low-density lipoprotein than do livers from female animals. To elucidate the role of testosterone in maintenance of this male pattern, conversion of [1-14C]oleic acid into triacylglycerol was assessed in vitro by rat hepatocytes (male) following gonadectomy and replacement with testosterone. Following castration, incorporation of fatty acid into triacylglycerol was increased. In contrast, esterification of exogenous fatty acid into phospholipid, cholesteryl esters, and diacylglycerol was unchanged. Treatment with testosterone (75 micrograms/day) reduced incorporation of exogenous fatty acid into triacylglycerol. Higher doses of testosterone (200 or 100 micrograms/day) modified the effect, such that inhibition was observed only at low oleate (0.5 mM) concentrations. At higher substrate concentrations (1.0-2.0 mM) the inhibitory effect was no longer observed. Further, a similar dose-dependent effect of testosterone was observed following in vivo treatment of castrate females with testosterone. These data support the concept of a regulatory role of testosterone in hepatic triacylglycerol synthesis. These findings also demonstrate a biphasic effect of testosterone, an effect that is dependent not only upon the dose of testosterone administered, but also on the concentration of fatty acid to which the hepatocyte is exposed in vitro.     

Characterization of LH and testosterone responses to intramuscular injection of GnRH in tropical postpubertal bulls

Five Zebu x British crossbred bulls 17 months of age and of uniform liveweight (320+/-3 kg) were used to study testosterone responses to single intramuscular doses of exogenous gonadotropin-releasing hormone (GnRH). The eight dose levels used were 0, 31.25, 62.5, 125, 250, 500, 1000, and 2000 ng GnRH/kg live weight. Plasma samples for hormone responses were collected at 30-minute intervals from zero to three hours and at one-hour intervals from three to seven hours postinjection. Luteinizing hormone (LH) and testosterone responses were measured as peak heights or as areas under response curves. Increasing the dosage of GnRH increased the time to reach the peak LH response, the height and duration of the response, and the area under the response curve. The maximum LH peak height was reached by the 1 mug/kg dose. In contrast to LH, testosterone responses reached the same peak heights (two hours postinjection of GnRH) for all doses of GnRH. The only effect of increased dosage was to increase the duration of response. Testosterone responses showed repeatable differences (P<0.01) between animals, but LH responses did not. It was demonstrated that the testosterone status of bulls can be accurately assessed by simply measuring testosterone in a single plasma sample collected two to three hours after the intramuscular injection of 100 mug or more (dose unimportant) of GnRH per bull.     

Divergent effects of phenothiazines on Leydig tumor cell steroidogenesis and adenylate cyclase activity

The dose and temporal (1-24 h) effects of two phenothiazines, chlorpromazine and trifluoperazine, on steroidogenesis and adenylate cyclase activity of gonadotropin-responsive Leydig tumor cells (M5480A) in primary culture were examined. At low doses (e.g. 0.1-1 microM) these antipsychotic drugs were slightly inhibitory (trifluoperazine) or without effect (chlorpromazine), while at 25 microM each drug was weakly stimulatory to basal testosterone production. Trifluoperazine was, in general, inhibitory to HCG-stimulated testosterone production, but chlorpromazine exhibited paradoxical effects. At 5 and 10 microM this neuroleptic agent increased HCG-stimulated steroidogenesis, while at 25 microM testosterone production was inhibited. In a particulate fraction prepared from the tumor the activity of adenylate cyclase was stimulated 3.4-fold in the presence of 10 microM 5'-guanylimidodiphosphate and 5-fold in the presence of HCG plus the non-hydrolyzable GTP analogue. Between doses of 1-100 microM neither drug altered the basal activity of adenylate cyclase. Trifluoperazine at doses of 1-100 microM inhibited 5'-guanylimidodiphosphate-stimulated adenylate cyclase activity both with and without added gonadotropin. At doses of 1-10 microM chlorpromazine had no effect on adenylate cyclase activity, but it stimulated activity in the dose range of 20-100 microM. Interestingly, in the presence of 5'-guanylimidodiphosphate this drug did not alter the stimulated enzymic activity achieved with a maximal dose of HCG. Therefore, these phenothiazines exhibit quite divergent dose-dependent effects and their actions must occur at multiple loci. Also, it seems unlikely that the effects of these agents on steroidogenesis and adenylate cyclase activity can be reconciled solely in terms of calmodulin-mediated processes.     

Comparative protective actions of gonadotrophins and testosterone against the antispermatogenic action of ethane dimethanesulphonate

After a single dose of ethane dimethanesulphonate (EDS) (75 mg/kg) to rats the prolonged antispermatogenic action is due to a temporary elimination of the functional Leydig cell population. Replacement therapy with testosterone propionate (3 mg/day) maintains the spermatogenic epithelium but the EDS effect develops when hormone treatment is discontinued. In contrast, a short treatment with hCG (10-100 i.u./day) or LH (714 micrograms/day), starting before the EDS dose, permanently protects the spermatogenic epithelium. FSH treatment was completely ineffective. Although histological protection of spermatogenesis appeared complete with testosterone or hCG, effects on fertility remained but over different periods of time. Antispermatogenic and antifertility effects were produced in mice using much higher doses of EDS (5 X 250 mg/kg) but there was no protection from androgen or hCG. It is suggested that EDS binds to Leydig cells irreversibly, interfering with the action of gonadotrophin. At the dose level used the evidence suggests that the degree of reaction renders most of the Leydig cell population non-viable. A direct cytotoxic effect of the compound upon the spermatogenic epithelium might account for the inability of testosterone or hCG alone or in combination to maintain fertility at normal levels.