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PubMed1979

Separation and determination of testosterone and testosterone esters in selected pharmaceutical formulations.

A rapid quantitative procedure is presented for the separation of testosterone esters from their hydrolysis products through the use of the acetonitrile-infusorial earth column. The method was applied to testosterone cypionate, testosterone enanthate, and testosterone propionate. Recovery and replication of reference standard testosterone and its three esters through the proposed method ranged from 99.1 to 100.3%, and the percent relative standard deviation ranged from 0.6 to 1.0%. Two samples can be separated into testosterone and testosterone ester fractions in about 1.5 hr. The analyses of 20 injectable and one buccal tablet formulations made by 12 different manufacturers are reported.

Drug Stability↗
PubMed1985

Intratesticular distribution of testosterone in rats and the relationship to the concentrations of a peptide that stimulates testosterone secretion.

Methods have been established and validated for quantitative assessment of the distribution of testosterone in the testis, by measurement of testosterone concentrations in whole testis, in isolated seminiferous tubules and in testicular interstitial fluid. These measurements were made in individual rats injected 2-40 h previously with saline (0.9% NaCl) or a potent antiserum to ovine LH. Testosterone concentrations in interstitial fluid and seminiferous tubules were closely correlated (r = +0.98; n = 60) and their relationship was log linear over a 200-fold range. However, although the concentrations of testosterone in interstitial fluid and seminiferous tubules decreased progressively with time after LH antiserum injection, this decrease was far more pronounced for interstitial fluid. In association with this change there was a significant increase in the amounts of a locally-produced factor in interstitial fluid which stimulates basal and hCG-stimulated testosterone production by isolated purified Leydig cells. This increase was reversed by injection of hCG but not by peripheral injection of a dose (20 mg) of testosterone propionate which restored normal intratesticular concentrations of testosterone. It is concluded that the tubular 'conservation' of testosterone, which occurs as interstitial fluid levels of this steroid decrease, may be a consequence of restricted diffusion of testosterone out of the tubules, but is also associated with increased amounts of a peptide stimulator of testosterone production.

Animals↗
PubMed1992

Increase in testosterone sensitivity induced by constant light in relation to melatonin injections in rats.

In this experiment we investigated whether the lack of the nocturnal melatonin peak under constant light would cause an increase in testosterone sensitivity. Castrated rats were kept under periodic or constant light for one week. They received a daily injection of vehicle, testosterone propionate (125 micrograms), melatonin (50 micrograms) or testosterone plus melatonin (125 micrograms + 50 micrograms). Serum and pituitary gonadotrophins and pineal melatonin were measured at the end of the experiment. Under constant light, testosterone injections reduced the serum luteinizing hormone concentration in castrated rats to that in intact rats, but, under periodic light, the decrease was smaller. Melatonin did not reverse the stronger effect of testosterone under constant light. The serum melatonin peak produced by the exogenous melatonin injection had a higher amplitude, shorter duration and earlier appearance than the physiological melatonin peak. Exogenous melatonin did not modify the physiological melatonin secretion, measured either as serum melatonin concentration or pineal melatonin content on the consecutive day. We conclude that the increase in testosterone negative feedback sensitivity of castrated rats under constant light was not due to the absence of the nocturnal melatonin pulse.

Animals↗
PubMed1992

[Study on ethane dimethane sulphonate (EDS)-induced spermatogenic damage and protective drugs against this damage in the rat].

The effects of a single administration of ethane dimethane sulphonate (EDS), which has a direct cytotoxic effect on Leydig cells, was assessed for its spermatogenic damage and intratubular androgen level in SD male adult rats. The protective effect of human chorionic gonadotropins (hCG) (s.c.), testosterone propionate (TP) (s.c.) and intratesticular administration of testosterone microcrystal suspension (Tmcs) against the spermatogenic damage in rats EDS given was also evaluated. EDS caused a decrease of the seminiferous tubular diameter and impaired spermatogenesis remarkably; moreover, it also caused significant decreases in intratubular androgen levels. These results suggest that EDS-treated SD male adult rats may be suitable as a model for hormone dependent infertility. The administration of hCG and intratesticular Tmcs prevented tubular damage and increased the intratubular T level. On the other hand, the administration of TP prevented tubular damage while remarkably decreasing intratubular androgen level. In this connection, it was inferred that priming of rats with TP caused an increase in intratubular androgen binding protein, which would stimulate spermatogenesis. The fact that a single injection of Tmcs caused no tubular damage suggests that intratubular T level is one of the factors playing an important role in spermatogenesis and that an intratesticular injection of Tmcs may be useful for the treatment of some cases of idiopathic male infertility.

Androgens↗
PubMed1988

Brain-enhanced delivery of testosterone using a chemical delivery system complexed with 2-hydroxypropyl-beta-cyclodextrin.

Enhanced brain delivery of testosterone was suggested by application of a dihydropyridine in equilibrium pyridinium salt redox system. The drug delivery method is based upon the NAD+ in equilibrium NADH coenzyme system and utilizes the covalent attachment of testosterone to a dihydropyridine-type carrier. Upon administration of two such testosterone chemical delivery systems (T-CDS1 or T-CDS2), serum LH levels were suppressed by 71-87% after 24 hours and maintained through 5 days (28%) with T-CDS1. An equimolar dose of testosterone or testosterone propionate failed to suppress serum LH. Peripheral testosterone target tissues (seminal vesicles and prostate gland) were only slightly stimulated by T-CDS1. Complexation of T-CDS1 with 2-hydroxypropyl-beta-cyclodextrin allowed a lowering of the effective LH-suppressing dose of T-CDS1 from 25 mg/kg to 10 mg/kg, presumably by increasing the solubility of T-CDS1 in the blood. These findings suggest that testosterone can be effectively delivered to the central nervous system (CNS) with minimal peripheral effect, and the delivery of T-CDS1 to the CNS can be improved via complexation with 2-hydroxypropyl-beta-cyclodextrin.

Animals↗
PubMed1994

[Action mechanism of synthetic androgens].

The most common androgen supplement used in Japan involves intramuscular injection of testosterone esters, such as, testosterone enanthate and testosterone propionate. As orally active androgens, derivatives of testosterone, such as, methyltestosterone and fluoxymesterone have also been used. These synthetic androgens have most commonly been used as replacement androgens in male patients with hypergonadotropic hypogonadism, as well as, hypogonadotrophic hypogonadism. The use in idiopathic male infertility and in elderly men with erectile dysfunction, however, has been shown to be less effective. Furthermore, relatively high doses of synthetic androgens are given in athletes to ensure success in sports and are used as hormonal methods for male contraception.

Female↗
PubMed1985

Neonatal androgen abolishes clock-timed gonadotrophin release in prepubertal and adult female hamsters.

Testosterone propionate (100 micrograms) or oil was injected within 24 h of birth. At 25 days of age blood samples were obtained at 14:00, 17:00 and 20:00 h. There was a significant increase in serum LH, FSH and progesterone concentrations between 14:00 and 17:00 h in the controls, followed by a decrease at 20:00 h. These rhythms were absent in testosterone propionate-injected animals. Ovariectomy of adults was followed by similar increases of LH and FSH in androgenized and oil-injected females (gonadectomy response) but the large surge of gonadotrophins observed in controls 1 day after implantation of an oestradiol-containing capsule (positive feedback) was not detectable in androgenized females. These results show that the initial effects of neonatal androgenization on cyclic gonadotrophin release in the female are present before puberty and are separable from effects on steroid modulation of gonadotrophin secretion.

Animals↗
PubMed2006

[Effect of gender and neonatal androgenization on dendroarchitectonics of neurons in the dorsomedial nucleus of amygdala].

The aim of this study was to establish gender-associated differences in dendroarchitectonics of neurons in dorsomedial nucleus of amygdala and the role of androgens in their formation during the period of sexual differentiation of the brain. Using Golgi method, it was demonstrated that the quantitative characteristics of long-axon sparsely branched neurons of all classes--neuroblastoform, short-dendrite and reticular--reflected the influence of gender. Specifically, it was detected that long-axon sparsely branched neurons had more branching primary dendrites and greater total dendrite length in adult males as compared to females. In adult females, androgenized neonatally by injection of 1250 mg of testosterone propionate on their postnatal day 5, the neuronal characteristics were different from those in normal females, and these differences were even more pronounced in comparison with males.

Age Factors↗
PubMed2004

Androgens increase spine synapse density in the CA1 hippocampal subfield of ovariectomized female rats.

The effects of androgen on the density of spine synapses on pyramidal neurons in the CA1 area of the hippocampus were studied in ovariectomized (OVX) adult female rats. Treatment of OVX rats with testosterone propionate (TP; 500 microg/d, s.c., 2 d) significantly increased spine synapse density (from 0.661 +/- 0.016 spine synapse/microm3 in OVX rats to 1.081 +/- 0.018 spine synapse/microm3 after TP treatment). A smaller, but still statistically significant, increase in synapse density (0.955 +/- 0.029 spine synapse/microm3) was observed in OVX animals after treatment with the nonaromatizable androgen dihydrotestosterone (DHT; 500 microg/d, s.c., 2 d). Administration of 1 mg of letrozole, a powerful nonsteroidal aromatase inhibitor, 1 hr before the steroid injections almost completely blocked the synaptic response to testosterone, resulting in a mean synapse density (0.723 +/- 0.003 spine synapse/microm3) only slightly higher than in OVX control rats. By contrast, the response to DHT was unaffected by letrozole pretreatment. These data suggest that androgen secretion during the female reproductive cycle may contribute to cyclical changes in hippocampal synaptic density. They also indicate that androgen treatment may be as effective as estrogen replacement in reversing the decline in hippocampal CA1 spine synapses that follows loss of ovarian function. Induction of hippocampal synapse formation by androgen is not mediated entirely via intracerebral estrogen biosynthesis, however, because aromatase-independent mechanisms also significantly affect CA1 spine synapse density.

Animals↗
PubMed2003

Testosterone undecanoate: a useful tool for testosterone administration in rats.

A major obstacle of testosterone (T) treatment in experimental animals is the difficulty of maintaining long-term physiologic/anabolic steady serum levels after exogenous T administration. In two complementary studies we investigated the pharmacokinetic properties of different T formulations in male rats. Study I. Mature male Wistar rats (> 380 g, n = 4 - 7/group) were divided into four treatment groups: (1) sham-operated non orchiectomised (non-ORX) and placebo; (2) orchiectomised (ORX) and subcutaneous testosterone pellets (TP) (15, 25, 75 mg/60 days release or placebo pellets); (3) ORX and a single injection of testosterone undecanoate (TUD) (31, 62.5 or 125 mg/kg body weight subcutaneously (s.c.) or vehicle; (4) ORX and testosterone propionate (Tprop) (10, 20, 40 mg/month) or vehicle as a single injection s.c. Serum T was measured at baseline and in weekly intervals for 4 weeks. Study II. Mature male Wistar rats (180 - 200 g) were randomly assigned to one of 5 experimental groups (n = 5 - 6/group): (1) normal untreated rats (controls); (2) ORX untreated rats, and non-ORX rats receiving one of three treatment options; (3) 250 mg/kg body weight TUD i.m. (TUD 250); (4) 500 mg/kg body weight TUD i.m. (TUD 500); (5) 100-mg testosterone pellet/90 days release s.c. (TP 100). Serum T was measured at baseline and in intervals for 6 weeks after T administration. In both studies, the kinetic profile of TUD showed favourable continuous steady state levels over several weeks. In contrast, testosterone release by subcutaneous pellets resulted in a shorter than expected duration of elevated serum T levels with high inter-individual variability. Tprop administration led to only a short-lasting serum T increase with low serum T levels already 14 days after injection. In conclusion, a single injection of TUD (100 mg/kg body weight s.c.) is effective in inducing physiological testosterone levels in ORX rats for a minimum of four weeks. High dose TUD (500 mg/kg body weight i.m.) given as a single injection results in supraphysiological anabolic testosterone concentrations for up to six weeks in non-ORX rats. TUD was superior to other T release preparations and represents a convenient and effective tool for T administration in experimental animals.

Anabolic Agents↗
PubMed2005

Effects of androgens and estrogens on crowings and distress callings in male Japanese quail, Coturnix japonica.

In male Japanese quail, crowing behavior is considered to be strictly androgen-dependent. It was previously shown that in chicks, treatment with either testosterone or 5alpha-dihydrotestosterone (5alpha-DHT; a non-aromatizable androgen) induced crowing with motivation for distress calling in acutely isolated conditions. Many studies, however, have shown that the potencies of testosterone and 5alpha-DHT in activating crowing in castrated males are different. To clarify the effects of androgenic and estrogenic actions on the production of crows and distress calls, we injected quail daily from 11 to 42 days after hatching (Day 11 to 42) with testosterone propionate (TP), 5alpha-DHT, estradiol benzoate (EB) or vehicle and examined their calling behaviors both in a recording chamber (acutely isolated conditions) and in their home-cages (well-acclimated conditions). Both TP- and 5alpha-DHT-treated birds began to crow by Day 13 when isolated in the recording chamber. The TP-treated birds, however, crowed less frequently than 5alpha-DHT-treated ones. This, combined with the observations that distress calling was strongly inhibited in EB-treated birds, suggests that estrogen converted from testosterone may inhibit the motivation for distress calling. On the other hand, after chronic treatment of TP, but not of 5alpha-DHT, birds began to crow intensely in their home-cages earlier than vehicle treated controls, suggesting that estrogen is needed to initiate crowing behavior in sexually active males. Taken together, it is suggested that estrogenic actions affect the motivation underlying vocal behaviors, while the androgenic action is indispensable in generating crowing.

Aggression↗
PubMed2004

[Gender-associated and androgen dependent neonatal dendrite morphology in neurons of the posterior cortical nucleus of the amygdala].

The aim of this study was to establish gender-associated differences in dendroarchitectonics of neurons in posterior cortical nucleus of amygdala and the role of androgens in their formation during the period of sexual differentiation of rat brain. Using Golgi method, it was demonstrated that long-axon sparsely branched neurons had more primary dendrites in males, while long-axon densely branched neurons had greater total dendrite length in females. In mature female rats that received 1250 mg of testosterone propionate on their postnatal day 5, the number of primary dendrites in long-axon sparsely branched neurons was increased, while the dendrites in long-axon densely branched neurons were elongated as compared to those in control females.

Amygdala↗
PubMed2004

Sex differences in adult suprachiasmatic nucleus neurons emerging late prenatally in rats.

The suprachiasmatic nucleus (SCN) is implicated in the control of circadian rhythms of gonadal function. Although several structures surrounding the SCN are sensitive to the effects of gonadal steroids, similar effects in the SCN remain unclear. For example, there are conflicting data on whether the SCN is sexually differentiated. This study attempted to determine sex differences in the number of SCN cells generated during late gestation, and if testosterone mediates these differences. Pregnant female rats were treated with 5-bromo-2'-deoxyuridine (BrdU; 50 mg/kg) on gestational day 18 (E18), the day when aromatase activity peaks in the developing rat fetus. These animals were also given injections of oil or testosterone propionate (10 mg/0.1 mL peanut oil) from E15 until parturition. Litters were allowed to survive until adulthood and were killed on postnatal day 60 (PN60). Following fixation, brain sections containing the SCN from these rats were processed for BrdU immunocytochemistry. A second set of SCN sections was processed for immunocytochemistry detecting BrdU and some of the cell groups prevalent within the SCN. Data showed that female rats have a higher number of cells labeled with BrdU in the SCN, particularly in the medial and caudal SCN. This sex difference was abolished in animals treated with testosterone during late gestation. Double immunocytochemistry revealed that BrdU-labeled cells were neurons expressing calbindin-D28K, vasoactive intestinal peptide and, to a lesser degree, vasopressin. Our results unveiled a previously unknown effect of gonadal steroids on the developing SCN, which may contribute to the emergence of gender-specific circadian rhythms.

Aging↗
PubMed2005

Leptin secretion in horses: effects of dexamethasone, gender, and testosterone.

Five experiments were performed to evaluate the effects of dexamethasone (DEX), gender, and testosterone on plasma leptin concentrations in horses. In experiment 1, plasma leptin, insulin, glucose, and IGF-1 concentrations were increased (P < 0.01) in stallions following five daily injections of DEX (125 microg/kg BW). In experiment 2, leptin concentrations increased (P < 0.01) in mares, geldings, and stallions following a single injection of DEX, and the response was greater (P < 0.01) in mares and geldings than in stallions. The gender effect was confounded by differences in body condition scores and diet; however, based on stepwise regression analysis, both BCS and gender were significant sources of variation in the best fit model for pre-DEX leptin concentrations (R(2) = 0.65) and for maximum leptin response to DEX (R(2) = 0.75). In experiment 3, in which mares and stallions were pair-matched based on age and body condition and fed similar diets, mares again had higher (P < 0.01) leptin concentrations than stallions after DEX treatment as used in experiment 2. In experiment 4, there was no difference (P > 0.1) in plasma leptin response in mares following four single-injection doses of DEX from 15.6 to 125 microg/kg BW. In experiment 5, treatment of mares with testosterone propionate every other day for 5 days did not alter (P > 0.1) plasma leptin concentrations or the leptin response to DEX. In conclusion, multiple injections of DEX increase leptin concentrations in stallions, as does a single injection in mares (as low as 15.6 microg/kg BW), geldings and stallions. The greater leptin levels observed in mares and geldings relative to stallions were due partially to their greater body condition and partially to the presence of hyperleptinemic individuals; however, even after accounting for body condition and diet, mares still had greater leptin concentrations than stallions after DEX administration. Elevation of testosterone levels in mares for approximately 10 days did not alter leptin concentrations in mares.

Adipose Tissue↗
PubMedDate not supplied

[Neonatal androgenization of female rats during sex differentiation of the brain modifies neuronal organization of the amygdala complex].

Sex differences in neuron dendroarchitectonics of the amygdala posterior cortical nucleus of adult rats were described for the first time using the Golgi method. Long-axon sparse-branched neurons in male rats possessed a larger number of primary dendrites, while female rats had long-axon dense-branched neurons with longer dendrites. Injection of testosterone propionate at 1250 g to females on day 5 after birth resulted in a greater number of primary dendrites of long-axon sparse branched neurons in adults, as compared to that in the control. Dendrites of long-axon sparse-branched neurons became much longer, thus enlarging the dendrite area.

Amygdala↗
PubMed2005

Dendroarchitectonics of neurons in the posterior cortical nucleus of the amygdaloid body of the rat brain as influenced by gender and neonatal androgenization.

The aim of the present work was to identify gender-related differences in the dendroarchitectonics of neurons in the posterior cortical nucleus of the amygdaloid body and the role of androgens in forming the dendroarchitectonics during the period of sexual differentiation of the rat brain. Golgi staining showed that long-axon, sparsely branched neurons in males had large numbers of primary dendrites, while long-axon densely branched neurons had a greater total dendrite length in females. Administration of testosterone propionate (1250 microg) to females on postnatal day 5 increased the number of primary dendrites in long-axon, sparsely branched neurons in adults as compared with the number in control females; treatment also produced a significant increase in dendrite length in long-axon, densely branched neurons, leading to an increase in the area of the dendritic field.

Amygdala↗
PubMedDate not supplied

[Morphological characteristics of the uterine reaction of androgenized rats in the neonatal period to the administration of sex steroids].

In female rats subjected to early neonatal androgenization (50 micrograms of testosterone propionate) the uterus at the age of maturity is of normal sizes and mass whereas its hydro-structure is substantially changed: the content of stromal elements is increased and the number of glands in the endometrium is decreased. The endometrium of androgenized female rats is not sensitive to progesterone influence manifested in the absence of the collagenolytic effect of progesterone and the stimulation of uterine gland formation. It may determine stable sterility of neonatally androgenized female rats after restoration of ovulation in them.

Animals↗