Biomedical subjects

G F Weinbauer

Publications and source records attributed to G F Weinbauer.

At least 109 records · Page 6Linked to original sources

PubMed1986

New injectable testosterone ester maintains serum testosterone of castrated monkeys in the normal range for four months.

Two groups of four long-term orchidectomized cynomolgus monkeys, Macaca fascicularis, weighing 2.8-4.6 kg received either a single intramuscular injection of 40 mg of a new testosterone ester, testosterone-trans-4-n-butylcyclohexyl-carboxylate (20 Aet-1) in an aqueous suspension or 32.8 mg testosterone oenanthate dissolved in sesame oil. Both preparations contained equal amounts of testosterone, namely 23.6 mg. Testosterone oenenthate injections resulted in supraphysiological serum testosterone levels for eight days followed by a rapid decline so that the lower physiological limit was reached after three weeks. In contrast, 20 Aet-1 produced a moderate increase of serum testosterone levels into the physiological range. Serum testosterone remained in this range for a period of 18 weeks. Thus it appears that the 20 Aet-1 may provide a long desired, new modality of testosterone substitution for hypogonadal men as well as for methods of male fertility control.

Animals↗

PubMed1986

Testosterone stimulates pituitary and serum FSH in GnRH antagonist-suppressed rats.

Thirty days of continuous treatment of adult male rats with 35 micrograms/day of the potent GnRH antagonist, (N-Ac-D-Nal (2)1, D-pCl-Phe2, D-Trp3, D-hArg (Et2)6, D-Ala10)-GnRH (RS-68439) reduced serum FSH to values below the limit of detection of the assay. Testosterone supplementation in the form of subcutaneous testosterone-filled silastic capsule implants present during an additional 30 days of GnRH antagonist administration restored serum FSH to values comparable to those observed after vehicle treatment. Pituitary FSH content, which was substantially reduced after GnRH antagonist treatment, was completely restored after concurrent testosterone supplementation. These results show that, under conditions of GnRH receptor blockade, testosterone is capable of stimulating pituitary and serum FSH in adult male rats.

Animals↗

PubMed1986

Transport of carnitine by the epididymis of the cynomolgus macaque (Macaca fascicularis).

Unravelled tubules from the monkey caput and cauda epididymidis were perfused through the lumen in vitro during immersion in an organ bath kept at scrotal temperature and containing [3H]carnitine and [14C]inulin. The specific transport of carnitine from the bath to the lumen was constant for 4 h and reached a steady-state value of about 90 pmol/30 min per cm perfused length in the cauda and about 30 pmol/30 min/cm in the caput. These regional variations in carnitine transport differ from those found in the rat epididymis but may be relevant to human epididymal physiology.

Animals↗

PubMed1986

Testosterone maintains pituitary and serum FSH and spermatogenesis in gonadotrophin-releasing hormone antagonist-suppressed rats.

Groups of adult male rats were treated continuously for 30 days with either vehicle or the potent gonadotrophin-releasing hormone (GnRH) antagonist. (N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Trp3,D-hArg(Et2)6,D-Ala10 )- GnRH (RS 68439; 35 micrograms/day). In addition, groups of vehicle- and antagonist-treated rats received s.c. testosterone implants sufficient to maintain serum testosterone concentrations 3.5- to 5-fold higher than those of vehicle-treated control rats. After 30 days of antagonist treatment serum LH, FSH and testosterone concentrations were at or below the detection limits of their respective assays and pituitary FSH content and GnRH receptor binding were reduced, relative to control animals, by 77 and 98% respectively. Testis weight in antagonist-treated rats was reduced by 75% and spermatogenesis was suppressed to an extent comparable to that observed in hypophysectomized rats. Testosterone, which caused a 40% reduction in serum FSH relative to control animals, prevented the antagonist-induced fall in both serum and pituitary FSH, but not GnRH receptors, below that observed in the vehicle plus testosterone-treated group. Furthermore, spermatogenesis in the antagonist plus testosterone-treated group was indistinguishable from that observed in control animals. It is concluded that testosterone is capable of maintaining serum and pituitary FSH levels in vivo, under conditions which presumably render the pituitary insensitive to hypothalamic GnRH.

Animals↗

PubMed1986

Gonadotrophin-releasing hormone (GnRH) overcomes GnRH antagonist-induced suppression of LH secretion in primates.

If the suppressive effects of gonadotrophin-releasing hormone (GnRH) antagonists on gonadotrophin secretion are mediated through GnRH-receptor occupancy alone, it should be possible to restore serum gonadotrophin levels by displacing the antagonist with exogenous GnRH. To test this hypothesis, eight adult crab-eating macaques (Macaca fascicularis), weight 4.7-7.6 kg, were subjected to the following treatment regimens. A GnRH-stimulation test was performed before and 4, 12 and 24 h after a single s.c. injection of the GnRH antagonist (N-Ac-D-p-Cl-Phe1,2, D-Trp3, D-Arg6, D-Ala10)-GnRH (ORG 30276). The stimulation tests were performed with 0.5, 5.0 or 50 micrograms GnRH given as a single i.v. bolus. Blood was taken before and 15, 30 and 60 min after each bolus for analysis of bioactive LH and testosterone. The GnRH-challenging doses were given as follows: 0.5 microgram GnRH was injected at 0 and 4 h, followed by 5.0 micrograms after 12 h and 50 micrograms after 24 h. One week later, 5.0 micrograms GnRH were given at 0 and 4 h, followed by 50 micrograms after 12 h and 0.5 microgram after 24 h. Finally, after another week, the GnRH challenges began with 50 micrograms at 0 and 4 h, followed by 0.5 microgram at 12 h and 5.0 micrograms at 24 h. This design permitted comparison of the LH and testosterone responses with respect to the dose of GnRH and the time after administration of GnRH antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Regulation of primate testicular function by GnRH analogues.

The potential of GnRH analogues for regulating testicular function is reviewed. Our experiments showed that constant infusion of GnRH agonists effectively suppressed testicular function in monkeys. In men, however, spermatogenesis could not be suppressed to achieve azoospermia uniformly. GnRH antagonists, although at much higher dosages than agonists, caused a more rapid and uniform inhibition of testis function. Spermatogenesis was reversibly disrupted at the spermatogonial level. Concomitant testosterone supplementation, used to maintain libido and potency, attenuated the antitesticular effects of GnRH analogues. In monkeys testosterone appears to stimulate spermatogenesis directly on the testicular level, while evidence has been obtained that in rats testosterone can also stimulate the release and synthesis of FSH under antagonist mediated blockage of pituitary GnRH receptors. When extrapolating to human studies special care has to be exerted in the selection of testosterone substitution regimens. Although the agonistic and antagonistic analogues of GnRH ultimately exert their antireproductive effects via inhibition of gonadotropin secretion the antagonists may have the greater potential for male fertility regulation due to quicker pituitary and testicular suppression.

Animals↗

PubMed1985

Focal testicular destruction following intratesticular injection of glycerol in rats.

Single intratesticular injections of glycerol have been reported to block spermatogenesis in rats without a concomitant change in the serum levels of testosterone and gonadotrophins (Wiebe & Barr 1983, 1984). The present studies were designed in order to confirm these effects and to cast light on the mechanism of action of glycerol. Groups of adult rats received intratesticular injections of either 200 microliter distilled water, glycerol or NaCl-solution. Following the injection of distilled water testicular histology appeared unaltered except for a few empty tubules around the injection site, which probably resulted from injection trauma. Injection of glycerol solution (greater than 3500 mosmol) caused partial tubule destruction. The most severely affected tubules were devoid of cells and filled with amorphous material. Serum FSH concentrations increased sharply in the first week and remained elevated during the entire study period of 8 weeks. Injection of an equi-osmolar NaCl-solution had very similar effects to glycerol on the testes and on hormone levels, suggesting that hyperosmolarity of the injected solutions rather than a specific action of the compounds caused the testicular damage. It is concluded that a single intratesticular injection of glycerol causes severe testicular damage and, in contrast to previous suggestions, appears unsuitable for male fertility regulation.

Animals↗

PubMed1985

Acute and chronic effects of a gonadotrophin-releasing hormone antagonist on pituitary and testicular function in monkeys.

The effects of a potent gonadotrophin-releasing hormone (GnRH) antagonist, (N-Ac-D-rho-Cl-Phe1,2,D-Trp3-D-Arg6-D-Ala10)-GnRH (Org 30276), on pituitary and testicular function of adult macaque monkeys were investigated. After a study to find the correct dose in castrated monkeys, five intact adult male animals were treated with daily s.c. injections of 5 mg antagonist for 9 weeks. The treatment resulted in an immediate decline in serum LH and testosterone in three out of five animals. The two hormones remained suppressed during the 9-week treatment period. Testosterone and LH responses to a bolus injection of GnRH (50 micrograms i.v.) were blunted or abolished during the antagonist treatment. Testicular volumes decreased markedly and ejaculates obtained at the end of treatment were azoospermic or contained only few dead sperm. Histological examination of the testes showed complete disruption of seminiferous epithelium in these animals. A decrease of body weight was observed in the treated animals. When the treatment was ceased, all inhibitory effects of GnRH antagonists were reversible. In the other two animals no consistent suppression of pituitary or testicular function could be observed during this period, nor was a doubling of the treatment dose for a further 8 weeks capable of fully suppressing endocrine and seminal parameters in these monkeys. It is concluded that GnRH antagonist treatment is capable of rapidly decreasing serum LH and testosterone and disrupting spermatogenesis in this primate species. Suppression effected by antagonist treatment is more rapid than that caused by GnRH agonists. The individual responses to the tested doses, however, vary markedly.

Animals↗

PubMed1984

Reversible inhibition of testicular function by a gonadotropin hormone-releasing hormone antagonist in monkeys (Macaca fascicularis).

The potential of a gonadotropin-releasing hormone (GnRH) antagonist to inhibit reproductive functions in a male nonhuman primate (Macaca fascicularis) was evaluated. Continuous infusion of 2 mg/day of [N-Ac-D-Nal(2)1, D-pCl-Phe2, D-Trp3, D-hArg(Et2)6, D-Ala10]-GnRH (RS-68439) via osmotic minipumps for 9 weeks caused immediate and sustained reduction of serum luteinizing hormone and testosterone concentrations and led to azoospermia in three animals and to sperm counts less than 5 X 10(6) in a fourth. Testicular histology showed severe atrophy of Leydig cells and tubules. The endocrine parameters returned to normal within 2 weeks of termination of treatment. Seminiferous tubule function was restored 14 to 18 weeks after treatment, as indicated by normal ejaculate parameters. It is concluded that chronic GnRH antagonist treatment reversibly inhibits pituitary and testicular function in a nonhuman primate. GnRH antagonists may thus have a potential for clinical use in fertility control and in treatment of androgen-dependent tumors.

Animals↗

PubMed1983

Ultrastructural analysis of rat testes after gossypol acetic acid (GAA) treatment.

The present investigations were carried out to show the histological and ultrastructural alterations in rat testes 10 weeks after gossypol acetic acid treatment (dose: 30 mg gossypol acetic acid/kg/day). the morphological findings in the interstitial compartment were compared with the data from studies carried out to investigate the testosterone biosynthesis in gossypol acetic acid treated rats. No morphological changes in the epididymal and vasal epithelia were found; however, the germinal epithelial cells showed vacuolisation, pycnosis, disconnections of junctions, cytolysis and exfoliation of germ cells from the epithelium. The Sertoli cells were affected, too. Gossypol acetic acid seemed to stimulate the physiological activity pathologically; cellular organelles as mitochondria, endoplasmic reticulum, lysosomal vacuoles, pigment granules and nuclei were either enlarged in size and number or malformed in shape. The cellular contact was often restricted to spots or completely disconnected. If gossypol acetic acid was administered for a longer period of time some Sertoli cells were found to be unable to withstand the toxic stimulus, and the cells became necrotic too. In contrast to the toxic process in the germinal and Sertoli cells the Leydig cell compartment did not show any changes in fine structure, and therefore testosterone biosynthesis is presumed to be intact.

Animals↗

PubMed1983

The endocrine status of gossypol - treated male rats.

Male adult Wistar rats were exposed daily or every other day to oral gossypol acetic acid (GAA) concentrations of 2.5-30 mg/kg for 10-20 weeks. Controls received the GAA-suspension medium or were left completely untreated. The serum concentrations of testosterone, LH and FSH as well as the weight of testis, epididymis, prostate, seminal vesicle, coagulating gland, and pituitary were determined. The accessory sex organs were prepared for light microscopy. Significant antifertility effect in these animals was achieved at GAA-dosage of 15 mg/kg and higher. GAA-administration neither altered the serum hormonal profiles nor the reproductive organ weights in comparison to the controls. Accordingly, light microscopical examination revealed no alterations in the histological picture of prostate, seminal vesicle and coagulating gland when compared with the controls. The results indicate that GAA does not interfere with the hypothalamic-pituitary-gonadal axis in male adult rats.

Animals↗

PubMedDate not supplied

Effect of gossypol on testicular testosterone production in vitro.

Testicular minces were utilized to study the effect of gossypol on testosterone production. Testosterone production was assessed in both control nd gossypol treated groups after 0 to 4 hours incubation in the presence of hCG. Media testosterone was measured by radioimmunoassay. Gossypol did not alter testosterone production when present in incubates at the concentrations of 3.5 x 10(-5) M, 7 x 10(-5) M and 3.5 x 10(-4) M. Preincubation of testis mince with gossypol (7 x 10(-6) M, 7 x 10(-5) M, 3.5 x 10(-4) M) for 1 to 4 hours did not alter subsequent hCG induced testosterone production in mature rats. Testosterone production however, was inhibited in immature rat testis when the whole testis was incubated for 4 hours with different concentrations of gossypol (7 x 10(-6) M, 7 x 10(-5) M, 3.5 x 10(-4) M). In vivo testosterone production was not inhibited in the immature rat testis 24 hours after oral administration of gossypol (100 mg/kg).

Animals↗

PubMedDate not supplied

Reversibility of long-term effects of GnRH agonist administration on testicular histology and sperm production in the nonhuman primate.

The present investigation evaluates the long-term effects of GnRH agonist treatment on testicular histology, sperm production and the subsequent recovery of these parameters. Four adult rhesus monkeys (M. mulatta) were treated with the GnRH agonist nafarelin (D-Nal(2)6-GnRH), released from i.m.--injected poly-D,L-lactic-co-glycolide microspheres for 20 months. Monthly injection of the GnRH agonist preparation uniformly suppressed serum levels of bioactive LH and testosterone. The size of the testis was reduced to about 30% of pretreatment. Sperm counts were suppressed to azoospermia for a total period of 53 and 77 weeks, respectively, in two monkeys and the other two animals were extremely oligozoospermic. Evaluation of testicular biopsy material after 6, 12 and 20 months of treatment revealed decreased seminiferous tubule diameter, spermatogenic disruption at the level of spermatogonia or spermatocytes, accumulation of lipid droplets and secondary lysosomes in the Sertoli cell cytoplasm, and increased thickness of the tubular wall compared with pretreatment histology. Electron microscopic examination revealed that the increased wall thickness was due to an enlargement of the inner collagen layer. No evidence of fibrosis or calcification could be obtained. Leydig cells were atrophic. Serum hormones, testis size and sperm counts returned to pretreatment values within 5 to 8, 13 to 16, and 18 weeks, respectively, after termination of treatment. Testicular histology, assessed 8 months after cessation of treatment, was indistinguishable from pretreatment. It is concluded that GnRH agonist-containing microspheres are a feasible modality for sustained administration of GnRH agonists and GnRH agonist-induced suppression of pituitary and testicular function is reversible following withdrawal of treatment. Thus, GnRH agonists may have a potential for regulation of male fertility and, presumably, also for treatment of precocious puberty.

Animals↗

PubMedDate not supplied

Antifertility efficacy of gossypol acetic acid in male rats.

Fertility response and sperm motility of male Wistar rats exposed to various concentrations (2.5 - 30 mg / kg / day) of gossypol acetic acid (GAA) was studied. GAA was given orally. A marked reduction in fertility occurred when rats received more than 15 mg / kg / day of GAA for 5 - 10 weeks (p less than 0.01); dosage below 15 mg had no antifertility effect even after 20 weeks. There is some evidence that GAA administration (30 mg / kg) every other day for 10 weeks had no antifertility effect. A clear relationship between the inhibition of sperm motility and GAA administration was observed (p less than 0.01). The interrelationships between fertility, sperm motility and GAA treatment were analyzed by Yates' chi-square test and Fisher's exact test.

Animals↗

PubMedDate not supplied

Toxicity of gossypol at antifertility dosages in male rats: statistical analysis of lethal rates and body weight responses.

The lethal rates and body weight responses of male Wistar rats following oral treatment with gossypol acetic acid (GAA) at dosages of 2.5-30 mg/kg were analysed by various statistical procedures. Daily treatment with GAA for 10 weeks was associated with lethal rates significantly different from placebo groups in both the low dose (2.5, 5.0, and 7.5 mg/kg, p less than 0.05) and high dose groups (15, 20 and 30 mg/kg, p less than 0.01). The pronounced mean body weight gain observed in placebo groups, was suppressed in the GAA-treated groups at each dose level after 10 weeks. This indicates decreased appetite and/or lessened feed utilisation caused by GAA activity. GAA administration at a dose of 30 mg/kg every other day exerted identical deleterious effects as daily treatment. As derived from the antifertility responses of the GAA treatment groups it was evident that the toxic activity of GAA was not related to its antifertility efficacy. It is concluded that GAA has remarkable toxicity at antifertility dosages in rats.

Administration, Oral↗

PubMedDate not supplied

Comparison of the antigonadotropic activity of three GnRH antagonists (Nal-Glu, Antide and Cetrorelix) in a non-human primate model (Macaca fascicularis).

We compared the antigonadotropic activity of the GnRH antagonists Nal-Glu, Antide and Cetrorelix in a non-human primate model (Macaca fascicularis). Orchidectomized animals received a single subcutaneous injection at doses of 250 micrograms kg-1 (n = 4), 625 micrograms kg-1 (n = 4) and 1250 micrograms kg-1 (n = 3) of the compounds Nal-Glu ([Ac-D-Nal(2)1, D-4-Cl-Phe2, D-Pal3, Arg5, D-Glu(AA)6, D-Ala10]-GnRH), Antide (Nal-Lys, [Ac-D-Nal1, D-4-Cl-Phe2, D-Pal3, Nic-Lys5, D-Nic-Lys6, Ip-Lys8, D-Ala10]-GnRH) or Cetrorelix ([Ac-D-Nal1, D-4-Cl-Phe2, D-Pal3, D-Cit6, D-Ala10]-GnRH). Blood samples were collected before and 3, 6, 12, 24, 48, 72, and 96 h after GnRH antagonist administration. Serum was analysed for concentrations of bioactive LH and immunoactive LH and FSH. All three compounds decreased LH secretion within 3-12 h (P < 0.05) and FSH secretion within 12-48 h (P < 0.05) after injection. Major differences between the GnRH antagonists were observed with regard to the effective dose and duration of action. At a dose of 250 micrograms kg-1 Nal-Glu and Antide only transiently suppressed LH and FSH release, whereas Cetrorelix induced complete inhibition (P < 0.05) which lasted for the entire observation period. At a dose of 625 micrograms kg-1 Cetrorelix exhibited the longest duration of action and Nal-Glu the shortest. At the highest dose of 1250 micrograms kg-1 Nal-Glu, Antide and Cetrorelix markedly inhibited LH and FSH secretion throughout the entire study period.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Effect of acute androgen withdrawal by GnRH antagonist on epididymal sperm motility and morphology in the cynomolgus monkey.

Hormonal male contraception requires an induction phase before azoospermia and contraceptive safety are achieved. The nature of spermatozoa that may be ejaculated during this induction phase was studied in a nonhuman primate. The GnRH antagonist Cetrorelix was administered daily to five cynomolgus monkeys to induce testicular regression, and the vehicle was given to five control animals. Within 16 days, the antagonist reduced androgens by 80% in the serum and by 50% in the epididymis. Sperm were obtained by mincing different epididymal regions and were examined for morphology (subjectively) and motility (objectively) after removal of the organs 16 and 25 days after continuous treatment. Spermatozoa entering the epididymis of monkeys undergoing regression differed from those of vehicle-treated controls in their greater susceptibility to disruption during preparation for morphological staining. The acquisition of motility by sperm in the epididymides attached to regressing testes occurred in the same epididymal region as controls but did not achieve the median velocities attained by sperm in controls during epididymal passage. Values for most sperm motion parameters developed as in the controls, and, during epididymal passage, sperm developed resistance to stresses encountered during preparation for morphological analysis. These observations suggest that spermatozoa ejaculated before spermatogenesis ceases may be potentially fertilizing because epididymal maturation continues in an androgen-deprived organ. From these preclinical studies, it can be concluded that in men, applying hormonal contraception precautions against pregnancy must be recommended before azoospermia is induced, since the epididymis can partially compensate for poor-quality sperm produced by a regressing testis even when levels of circulating androgens and tissue androgens are low.

Androgen Antagonists↗

PubMedDate not supplied

Estradiol and high-dose dihydrotestosterone treatment causes changes in cynomolgus monkey prostate volume and histology identical to those caused by testosterone alone.

To evaluate the effects of testosterone (T), dihydrotestosterone (DHT), and estradiol (E2) on the regulation of prostate growth and tissue composition, the following study was conducted in a nonhuman primate model. Fifteen adult, long-term castrated cynomolgus monkeys were randomly assigned to receive implants filled with T (0.19 +/- 0.01 g), DHT alone (0.21 +/- 0.01 g), or (99%) DHT + (1%) E2 (0.21 +/- 0.01 g). Prior to and at 4-week intervals during the treatment phase of 252 days, prostate volumes (PV), body weight, ejaculate weight, hormone levels (of T, DHT, and E2), and red blood cell count were measured. Five adult, intact monkeys served as controls for prostate volume and histology. At the end of the study, histological analysis of an ultrasound-guided prostate biopsy was performed. T levels increased significantly in the T group compared with baseline (P < 0.01) and with the DHT and DHT + E2 groups (P < 0.05). Both groups receiving DHT showed higher DHT levels than did animals in the T group (P < 0.001). E2 levels in all groups increased over time (P < 0.05), although significant differences (P < 0.01) could only be detected between the DHT + E2 and the DHT group. Prostate volume in all groups increased (at baseline: T = 1.03 +/- 0.12 ml, DHT = 1.08 +/- 0.15 ml, DHT + E2 = 1.13 +/- 0.09; at day 252: T = 5.83 +/- 1.00, DHT = 4.72 +/- 0.9, DHT + E2 = 5.05 +/- 0.62) over time (P < 0.001), whereas no differences could be detected between the groups. Prostate biopsy could be performed successfully in 15 out of 20 monkeys. Prostate tissue evaluation between the treatment groups and the evaluated intact monkeys revealed no differences in the status of secretory epithelia, nuclear chromatin, excretory vacuoles, interstitial stroma, smooth muscles, and total functional status, whereas the prostate of a long-term castrated monkey showed severe atrophy. Thus, both androgens fully restored prostate volume and ejaculatory function. Highly supraphysiological DHT serum levels are not associated with abnormal volumetric or histological changes of the prostate. Comparing the DHT group with the DHT + E2 group, an additional stimulatory effect of normal or slightly elevated estrogens on the prostate cannot be found in the presence of highly supraphysiological DHT levels.

Animals↗