Accessory Sex Organ Weights Research Articles

Effect of early exposure of flutamide on subsequent growth of transplantable rat prostatic tumor (dunning R-3327).

Rat transplantable prostatic tumors (Dunning R-3327) were treated with flutamide before tumors grew palpable, in order to examine the effect of short term treatment of antiandrogen for prostatic cancer in latent period on the growth after appearance of tumor. Flutamide delayed an appearance of the tumor nodule and retarded the growth rate in proportion as treatment began earlier. Flutamide also reduced final tumor volume. Flutamide-treated tumors histologically consisted of small or dilated glandular structure with an increase in stromal area, but androgen receptors were preserved. Flutamide-treated tumor showed slow growth with androgen sensitivity when transplanted to intact rats, showing prolonged influences of antiandrogen on tumor growth. There was no significant difference between flutamide-treated and control groups in weight of accessory sex organs and serum androgen or estrogen levels. In conclusion, flutamide treatment may retard an appearance of prostatic cancer concomitant in benign prostatic hyperplasia.

Fertility after Cryptorchidism: A Comparative Analysis of Early Orchidopexy with and Without Concomitant Hormonal Therapy in the Young Male Rat

Infertility is common in patients with a history of bilateral cryptorchidism, even after successful prepubertal orchidopexy. Recent data suggest that this defect may be partially due to the existence of hormonal abnormalities in some forms of cryptorchidism. To analyze any potential benefit of hormonal therapy, we have evaluated the immediate and long-term effects of chronic hormonal therapy administered following surgical correction of cryptorchidism. First, using young male rats, we examined the effects of chronic human chorionic gonadotropin (HCG) and a luteinizing hormonereleasing hormone agonist (LHRH-A), alone or combined, on acute pituitary-gonadal axis responsiveness to LHRH administration. High doses of HCG and/or LHRH-A induced deleterious effects on the pituitary-testicular axis in terms of suppression of response to LHRH. Therefore, treatment with a low dose of HCG (50 U/kg./day) for 14 days was used, since it produced a significant increase in intratesticular testosterone (ITT).Second, we tested this hormonal regimen in a cryptorchid rat model. Bilateral cryptorchidism was produced by gubernaculum resection at 14 days of age. Early orchidopexy was performed at age 30 days, and HCG therapy was given from 31 to 44 days of age. Follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone (T) levels were determined before and immediately after hormonal therapy, and at sacrifice. Animals were sacrificed at 61 days of age for determination of serum and testicular hormone levels, accessory sex organ weights and testis histology. Five or six animals from each group were retained for breeding studies at the age of 90 days. Hormonal alterations noted immediately following treatment of cryptorchid animals with HCG are not lasting. The data reveal that the fertility defect in bilateral cryptorchidism is partially prevented by early orchidopexy and that adjunctive hormonal therapy is probably of little additional benefit.

Induction of Male Sexual Behavior in the Rat by 7α-Methyl-19-Nortestosterone, an Androgen that does not Undergo 5α-Reduction1

The synthetic steroid 7 alpha-methyl-19-nortestosterone (MENT) binds with high affinity to the androgen receptor and exerts biological effects at some peripheral target tissues with a potency greater than that of naturally occurring androgens. In vivo, MENT does not undergo enzymatic 5 alpha-reduction and as a consequence, its biologic action on prostate and other organs of the male reproductive tract is not amplified as is that of testosterone (T). Thus, in castrated rats, a dose of MENT that will maintain normal muscle mass and gonadotropin levels will not maintain normal prostate and seminal vesicle weights. To investigate the ability of MENT to restore male sexual behavior in castrated rats, varying doses of MENT acetate were administered for 4 wk by use of s.c. mini-osmotic pumps. Animals treated with T acetate (200 micrograms/day) and nontreated intact animals served as positive controls, while a group of animals receiving vehicle alone were the negative controls. Steroid acetates are rapidly converted to T and MENT in blood. Appropriate steroid delivery was assessed by measurement of serum androgen concentrations. Male behavioral parameters were recorded twice per week. At the end of treatment, the weights of sex accessory organs were also recorded. The administration of MENT acetate at daily doses of 100 micrograms and 10 micrograms induced full copulatory behavior in a manner similar to that observed with doses of 200 micrograms T acetate.(ABSTRACT TRUNCATED AT 250 WORDS)

Investigation of a Mechanism for Leydig Cell Tumorigenesis by Linuron in Rats

In a previously conducted 2-year study, a concentration-dependent increase in Leydig cell adenomas was observed in Crl:CD BR (CD) rats fed diets containing the herbicide linuron. Linuron has been shown to be negative in a battery of six tests for genotoxicity; therefore, a nongenotoxic mechanism of tumorgenesis was investigated. Linuron is structurally related to the nonsteroidal antiandrogen, flutamide. Flutamide has also been shown to produce Leydig cell tumors within 1 year, presumably due to sustained hypersecretion of luteinizing hormone (LH) which occurs following disruption of the hypothalamic-pituitary-testicular (HPT) axis. To investigate whether linuron possesses antiandrogenic activity, sexually immature and mature CD rats were administered either 200 mg/kg linuron or 10 mg/kg flutamide (positive control) for 2 weeks. Accessory sex organs were weighed and serum hormone levels were measured to assess androgen status and alterations in the HPT axis. Serum from a multigeneration reproduction study with linuron was also analyzed for serum hormone levels. In addition, competitive receptor binding studies were conducted to evaluate the ability of linuron to bind to the androgen receptor. Linuron decreased accessory sex organ weights in sexually immature and mature linuron-treated rats. Increased serum estradiol and LH levels were observed in sexually mature linuron-treated rats. Serum estradiol and LH levels were also elevated in P 1 and F 1 male rats from the multigeneration reproduction study. These accessory sex organ and hormonal changes are consistent with those seen with the antiandrogen flutamide, the only exception being serum testosterone, which was elevated following exposure to flutamide but not to linuron. The inability of linuron to increase testosterone levels may reflect the lower potency of linuron as an antiandrogen compared with that of flutamide, which is a potent antiandrogen. Additionally, linuron competed with [ 3H]testosterone for binding to the androgen receptor. The IC 50 data for competition to the androgen receptor suggest that linuron is approximately 3.5 times less potent than flutamide. These data are consistent with the effects seen with flutamide and demonstrate that linuron is a less potent antiandrogen than flutamide. Collectively, these data support the hypothesis that linuron produces Leydig cell tumors via an antiandrogenic mechanism where sustained hypersecretion of LH appears to be responsible for the development of Leydig cell hyperplasia and adenomas.

LY207320 (6‐methylene‐4‐pregnene‐3,20‐dione) inhibits testosterone biosynthesis, androgen uptake, 5α‐reductase, and produces prostatic regression in male rats

LY207320 is an in vitro inhibitor (estimated IC50 = 0.06 microM) of steroid 5 alpha-reductase that catalyzes the conversion of testosterone (T) to dihydrotestosterone (DHT). In contrast, LY207320 was only moderately active against rat prostatic 5 alpha-reductase in vivo (32% inhibition at 50.0 mg/kg single dose). LY207320 did, however, inhibit the in vivo uptake of [3H]-T by the prostate. The antiprostatic and endocrine effects of this agent were evaluated following daily (21 days) administration to castrated, androgen-supplemented castrate, and intact rats. LY207320, which has modest progestational competitive binding activity, does not bind to rat prostatic androgen or uterine estrogen cytosolic receptors. In the castrated male rat, subcutaneously (s.c.) administered LY207320 had no androgen agonist activity, as evidenced by a lack of accessory sex organ weight gains. Administration of s.c. LY207320 to intact rats for 21 days at doses greater than 5.0 mg/kg-day produced significant (P < 0.05) reductions of seminal vesicle and ventral prostatic weights (maximal regression = -65% and -40% from control values, respectively at 50.0 mg/kg-day). The compound had no regressive activity on male accessory sex organs when administered orally. LY207320 did not alter circulating prolactin, LH, or corticosterone levels, but at high doses (> or = 50.0 mg/kg-day), lowered circulating T[-67% from intact control levels (P < 0.05)]. Histological analysis of the rat ventral prostates (RVPs) in LY207320-treated rats was consistent with an androgen-deprived state. Decreased circulating androgens and prostatic regression are associated with inhibition of testicular 17 alpha-hydroxy/C17,20-lyase enzyme activity (IC50 = 0.06 microM). These findings support the contention that LY207320 is a physiological antagonist of androgen action in male rats, and that its effects are mediated primarily through inhibition of testicular androgen production rather than accessory sex organ 5 alpha-reductase.

FUNDAMENTAL AND CLINICAL STUDIES ON A NEW NONSTEROIDAL 5α-REDUCTASE INHIBITOR AND A NEW STEROIDAL ANDROGEN-RECEPTOR COMPLEX FORMATION INHIBITOR

In the case of benign prostatic hypertrophy (BPH), operative treatment presents many problems and drug therapy is still important. We have examined the effects of a new steroidal antiandrogen (TZP4238, 17α-acetoxy-6-chloro-2-oxapregna-4, 6-diene-3, 20-dione) and a nonsteroidal 5α-reductase inhibitor (ONO3805, sodium- (-) -4- [2- {2, 3-dimethyl-4- [1- (4-isobutylphenyl) ethoxy] benzoylamino} phenoxy] butyrate), which are effective in reducing prostate weight, using Wistar rats. We also examined the clinical effects of these compounds in patients with BPH. Under endogenous androgen conditions, we assessed the effects of some antiandrogens on reduced accessory sex organ weight. As a result, it was suggested that progestin drugs (TZP4238 etc.) produced this effect at low doses and that the effect lasted for more than six weeks. Under exogenous androgen conditions, that is, without central nervous system action on the prostate, the effect of ONO3805 was almost equal to that of chlormadinone acetate (CMA). Furthermore, we examined TZP4238 and other drugs in terms of on the action of androgen-receptor complex formation in the cytosol and nuclear extracts. TZP4238 showed a competitive inhibitory action, in contrast to ONO3805. On the other hand, only ONO3805 had a 5α-reductase inhibitory action. Among tested compounds neither TZP4238 nor ONO3805 significantly changed blood testosterone concentrations in the rat. Clinical results are as follows : progestin drugs (TZP4238 and CMA) were more effective than others tested in reducing prostate volume and improving voiding disturbance and residual urine volume but produced frequent loss of libido. On the other hand, the 5α-reductase inhibitor was associated with no loss of libido. To maintain the patient's quality of life, it is hoped that a drug based on 5α-reductase inhibition, which has few side effects, will be developed.

Induction of leydig cell adenomas by ammonium perfluorooctanoate: A possible endocrine-related mechanism

Ammonium perfluorooctanoate (C8) produced an increased incidence of Leydig cell adenomas in Crl:CD BR (CD) rats fed 300 ppm for 2 years. A hormonal (nongenotoxic) mechanism was examined since C8 was negative in short-term tests for genotoxicity. Adult male CD rats were gavaged with either 0, 1, 10, 25, or 50 mg/kg C8 for 14 days. In addition, a control group was pair-fed to the 50 mg/kg C8 group. A dose-dependent decrease in body and relative accessory sex organ (ASO) weights was seen, with the relative ASO weights of the 50 mg/kg group significantly less than those of the pair-fed control. Serum estradiol levels were elevated in the 10, 25, and 50 mg/kg C8-treated animals. Estradiol levels in the 50 mg/kg C8 group were 2.7-fold greater than those in the pair-fed control. The increase in serum estradiol levels occurred at the same dose levels as the increase in hepatic β-oxidation activity. A statistically significant downward trend with dose was seen in serum testosterone levels when compared with the ad libitum control. However, when the 50 mg/kg C8-treated rats were compared with their pair-fed control, no significant differences were seen. Challenge experiments, which can identify the presence and location of a lesion in an endocrine axis, were undertaken to clarify the significance of this downward trend in serum testosterone following C8 exposure. In the challenge experiments, adult CD rats were gavaged with either 0 or 50 mg/kg C8 for 14 days. One hour before termination, rats received either a human chorionic gonadotropin (hCG), gonadotropin-releasing hormone (GnRH), or naloxone challenge. Following hCG challenge, serum testosterone levels in the 50 mg/kg C8 were significantly decreased (50%) from those in the ad libitum controls. Similar decreases, although not significant, were seen in serum testosterone following GnRH and naloxone challenge. The challenge experiments suggest that the decrease in serum testosterone following C8 exposure is due to a lesion at the level of the testis. In addition, progesterone, 17α-hydroxyprogesterone, and androstenedione were examined in the 50 mg/kg C8-treated males following hCG challenge. A 60% decrease was observed in androstenedione levels in the C8-treated animals from those in the ad libitum controls; no other differences were seen. These data suggest that the decrease in serum testosterone following hCG challenge may be due to a decrease in the conversion of 17α-hydroxyprogesterone to androstenedione. The observed effects described above can be attributed to the elevated serum estradiol levels. It also has been shown that estrogens can induce Leydig cell tumors in mice. Hence, the elevated estradiol levels in C8-treated rats may be responsible for the decreased relative accessory sex organ weight and serum testosterone levels seen in this study as well as the increased incidence of Leydig cell adenomas in the 2-year feeding study with C8.

Effects of a simulated microgravity model on cell structure and function in rat testis and epididymis.

A tail-suspension (TS) rat model used to simulate microgravity was tested for its effects on the anatomy, cell structure, and function of the testis and epididymis in sexually mature male rats. Rats suspended for 7 days without inguinal canal ligation exhibited a significant (P less than or equal to 0.05) reduction in testis weight compared with controls (1.55 +/- 0.04 to 1.1 +/- 0.02 g). Except for the liver, epididymis, and adrenals of TS rats and TS rats allowed to recover for 7 days, no significant (P less than or equal to 0.05) change was observed in the weight of other body and accessory sex organs. A histological examination of the testes and epididymides of model animals revealed disorganized seminiferous tubules and accumulation of large multinucleated cells and spermatids in the lumen of the epididymis. A significant (P less than or equal to 0.05) increase in serum luteinizing hormone (53.1 +/- 6.7 to 66.2 +/- 10.1 ng/ml) and follicle-stimulating hormone (257 +/- 25 to 305 +/- 38 ng/ml) was observed in TS nonligated rats, whereas serum prolactin and testosterone levels were observed to decline from 8.3 +/- 1.3 to 5.1 +/- 0.29 and 7.1 +/- 1.3 to 3.8 +/- 0.25 ng/ml, respectively. Decreases in testis protein content and testosterone levels of the testis, interstitial fluid, and epididymis were also observed in model animals. These data demonstrate that the suspension procedure used in the National Aeronautics and Space Administration TS model results in the testis and epididymis translocating into the abdominal cavity, causing cellular degeneration and organ dysfunction.

Diet-induced changes in the male reproductive system of rats.

Either quantitative or qualitative modification of diet interferes markedly with the reproductive functions of the rat. The effect of chick mash or cowpeas (Vigna unquiculata) on body growth, accessory sex organ weights, serum testosterone, and epididymal histology was studied. Body growth was markedly decreased in cowpeas fed group. Binucleated, multinucleated giant cells (MGCs), and lymphocytes were found in large numbers in the lumen of caput and cauda epididymis of the cowpea-fed group. No noticeable effect was seen in chick mash-fed group. Serum testosterone levels were significantly decreased in cowpea-fed group. Presence of MGCs in cowpea-fed animals indicates epididymal dysfunction and probably renders them infertile.

Exogenous androgen does not alter hypothalamic proopiomelanocortin gene transcript levels in the sexually immature male rat.

To investigate possible mechanisms whereby the augmentation of hypothalamic proopiomelanocortin (POMC) messenger ribonucleic acid (mRNA) levels occurs with pubertal development, we employed the techniques of testosterone administration and in situ hybridization histochemistry in sexually immature male rats. Six animals from each of the following groups were studied: (1) untreated controls (CTRL); (2) empty capsule (SHAM); (3) testosterone capsule (TEST), and (4) untreated adults (ADLT). Capsules were implanted at 21 days of age. Groups 1-3 were sacrificed at 35 days of life; group 4 at 55 days. Ventral prostate and seminal vesicle weights were obtained to assess the biologic effect of testosterone. Hybridizations were performed on coronal brain slices through the region of the arcuate nucleus using a 35S-labeled oligonucleotide probe complementary to a 30-base sequence within POMC mRNA. Anatomically matched tissue sections (11 per animal, from the retrochiasmatic region rostrally to the premammillary nucleus caudally) were exposed to x-ray film, followed by densitometric analysis. The mean serum testosterone concentration of the TEST group was significantly greater than that of the ADLT animals; values for the CTRL and SHAM rats were undetectable. The accessory sex organ weights of the ADLT animals were greater than those of the TEST rats; both values were greater than those of the CTRL and SHAM groups which were indistinguishable. Increased levels of hypothalamic POMC mRNA were observed in the male rat after pubertal development.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Estrogen on Growth of Androgen-responsive Rat Prostatic Tumor (R 3327).

It has been known that estrogen has synergistic effects with androgen on growth of normal male accessory sex organs of rats. The present study was therefore undertaken to examine the effects of estrogen on androgen-responsive rat Dunning R 3327 prostatic tumor. The weight of male accessory sex organs was suppressed by estrogen on growth of treatment, but synergistic effects of estrogen and androgen on these organs were seen following combined treatment with androgen and estrogen. In contrast to the effects of estrogen on accessory sex organs, estrogen influenced a R 3327 tumor only in the negative direction regardless of whether androgen was injected simultaneously or not. When the dihydrotestosterone injection was reduced from 500 to 100 micrograms/rat/day after the tumor appeared as subcutaneous nodules, the weight of the accessory sex organs was similar to that of the control animals. However, this amount of dihydrotestosterone increased tumor growth equally when compared to those treated with a pharmacological dose of dihydrotestosterone. Therefore, the response of R 3327 tumor to androgen was different from that of the accessory sex organs.

Effect of lithium chloride on testicular steroidogenesis and gametogenesis in immature male rats

The present study was performed on immature male rats aged 35 days. Subcutaneous injections of lithium chloride at a daily dose of 2.0 mg/kg for 15 days resulted in significant inhibition of spermatogenesis at stage VII of the seminiferous epithelial cycle. Spermatogonia A, preleptotene spermatocytes and step 7 spermatids were decreased in number in comparison to controls. Serum levels of FSH, LH, PRL, and testosterone were decreased. Activities of testicular delta 5-3 beta-hydroxysteroid dehydrogenase and 17 beta-hydroxysteroid dehydrogenase were suppressed along with a low caudal epididymal sperm count in comparison with controls. When the treatment was prolonged for 20 and 25 days, it showed an additional significant diminution in accessory sex organ weights and number of midpachytene spermatocytes at stage VII in comparison to control animals of corresponding age. It is concluded that lithium has an adverse effect on testicular function in immature rats by reducing serum levels of FSH, LH, PRL, and testosterone. Furthermore, since hormonal changes and altered spermatogenic activities were evident when the serum concentration of lithium was within the therapeutic range, our data may have some potential clinical implications.

Inhibition of the pituitary-gonadal axis in nude male mice by continuous administration of LHRH agonists and antagonists

Analogues of LHRH can be used for the treatment of sex hormone-dependent tumours. The nude mouse is a valuable model for the investigation of transplanted human cancers, but there is a body of literature reporting that the function of the pituitary-gonadal axis in normal (immunocompetent) and nude (immunocompromised) mice, unlike that of other species, cannot be suppressed by the administration of LHRH agonists and antagonists. To explore this view further, long-term experiments were carried out in nude male mice, in which sustained-release formulations of the agonist [D-Trp6]-LHRH and of two new potent antagonists were used which permitted a continuous release of the peptides into the circulation. Nude male mice were treated for 28-30 days with 50 micrograms of antagonists [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Trp3,D-Cit6, D-Ala10]-LHRH (SB-30) or [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Pal(3)3, D-Cit6,D-Ala10]-LHRH (SB-75)/day delivered by osmotic minipumps. Some mice were injected twice a day with 25 micrograms SB-75. Other groups received microcapsule preparations of the agonist [D-Trp6]-LHRH, releasing 25 or 12.5 micrograms/day for 30 days. At autopsy, in mice which received 50 micrograms SB-30 or SB-75/day by minipumps, there was a significant decrease in weights of testes, ventral prostate and seminal vesicles compared with controls. [D-Trp6]-LHRH microcapsules at either dose also reduced weights of testes and accessory sex organs. Serum LH and testosterone were significantly reduced in all groups treated with analogues. There was a greater decrease in testicular weights and serum testosterone in nude mice which received SB-75 in a continuous fashion from minipumps than in animals injected twice a day.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of a nonsteroidal antiandrogen, Anandron, on the reproductive system and fertility in male rats

The effect of Anandron, a nonsteroidal antiandrogen, on the reproductive system and fertility of adult male rats was studied. Administered at a daily oral dose of 5 mg and 10 mq (per rat) for 30 days, it caused a significant increase in the plasma testosterone levels. Spermatogenic arrest in about 20 to 50% of the tubules in 9 out of 16 rats and stimulation of Leydig cells was observed in rats treated with the higher dose. Although a reduction occurred in accessory sex organ (epididymis, seminal vesicles, SV; ventral prostate, VP; dorsal prostate, DP and coagulating gland, CG) weight, no parallel reduction was evident in the secretory indices of the epididymis (glycerylphosphorylcholine and sialic acid), VP (alkaline phosphatase) and CG (fructose). However, there was a reduction in the total content per organ of these constituents. Females mated with treated males showed postimplantation loss indicating an adverse effect of Anandron during spermiogenesis. The results suggest that the peripheral antiandrogenic potency of Anandron in intact animals is insufficient to completely neutralize the elevated levels of androgens. A microdose (1 μg) of estradiol efficiently neutralized the central stimulatory effect of Anandron and potentiated its antiandrogenic action. The potential use of such a combination for ‘Fertility Regulation’ in male is discussed.

The tumor-inhibiting effect of diethylstilbestrol and its diphosphate on the Nb-H and Nb-R prostatic carcinomas of the rat

For many years, diethylstilbestrol (DES) and its diphosphate (DESPP; Honvan) have been standard therapies for prostatic carcinoma. The effects of DES, its monophosphate (DESP) and of DESPP on the weights of accessory sex organs of mice and rats, and on the experimental Noble Nb-H and Nb-R prostatic carcinomas of the rat were, therefore, compared. In intact mature mice, all three compounds led to a strong and dose-dependent inhibition of seminal vesicle weights and testosterone levels, whereas only a slight antiandrogenic activity in castrated mice was found. In intact rats, DES, DESP and DESPP strongly inhibited accessory sex organ weights and testosterone levels. In castrated rats, however, no antiandrogenic activity was determinable. The prostate carcinoma-inhibiting effects of DES and DESPP were tested in comparison with castration in the transplantable hormone-sensitive Nb-H and Nb-R prostatic carcinoma in rats. Whereas castration caused only a retardation of tumor growth, DES and DESPP (3 x 0.1 mg/kg and 1.0 mg/kg weekly s.c.) led to an almost complete inhibition, which was significantly (P less than 0.01) better than the effect of castration. As the weights of accessory sex organs were identically reduced by either castration or the estrogens, a direct tumor-inhibiting effect of DES and DESPP in addition to their testosterone-lowering activity is obvious. This was proved in an experiment with castrated rats. The only slightly inhibitory activity of castration was strongly potentiated by concomitant administration of DES. Moreover, histological examinations revealed that Nb-H and Nb-R tumors were much more damaged by treatment with DES or DESPP than after castration. Morphometry of the tumors showed that tumor reduction is associated with a decrease in the ratio of the epithelial to the stromal density, i.e. there was an even more pronounced decrease in epithelial cells than that found by merely measuring tumor area. These studies show that the prostate carcinoma-inhibiting effect of DES and DESPP in the Nb model is superior to the effect of castration and that they act directly on the tumor cells used, even in castrated rats.

Endocrine effects of a new histamine H 2-receptor antagonist, nizatidine (LY139037), in the male rat

A new orally active histamine H 2-receptor antagonist, nizatidine (LY139037), was evaluated in male rats for effects on mechanisms regulating accessory sex organ growth and function. Cimetidine antagonized androgen binding to cytosolic receptors in vitro while nizatidine had no effect. Nizatidine and cimetidine were administered at the ED50, 5 × ED50, or 10 × ED50 doses for inhibition of gastric acid secretion previously determined using in vivo dog and rat models. The relative potencies of both agents to antagonize histamine H 2-receptor-mediated gastric acid secretory responses have been confirmed in human clinical trials. Neither nizatidine nor cimetidine antagonized the in vivo uptake or nuclear translocation of radiolabeled androgen into the hypothalamic-preoptic-amygdala, pituitary, or ventral prostate. Nizatidine, given at doses equal to and 10× the ED50 gastric acid secretion inhibitory values, and cimetidine (10× ED50 value) had no effect on the response of male accessory sex organs to a submaximally stimulating dose of androgen in castrated rats. High doses of dietary nizatidine (>500 mg/kg-day) administered for 6 months did not alter intact rat male accessory sex organ weights or circulating androgen levels relative to untreated controls. Acute administration of either nizatidine or cimetidine produced transient elevations in plasma prolactin (PRL) levels. Cimetidine was more potent and consistent than nizatidine in producing these increases in circulating PRL. The data described herein support the contention that unlike cimetidine, nizatidine is not a pharmacological antagonist of androgen action and has less of a stimulatory effect upon plasma prolactin. Taken together, these studies indicate that in the male rat, nizatidine exhibits a large therapeutic index between its gastric antisecretory activity and potential endocrinological effects.

A STUDY OF THE ANDROGENIC ACTIVITY OF ANTI-ANDROGEN

To investigate the androgenic activity of steroidal and nonsteroidal anti-androgens, the effect of several compounds on some parameters as an androgenic activity was measured in the ventral prostate (VP) and seminal vesicle gland (SV) of castrated male rats. Ornithine decarboxylase (ODC) activity, arginase activity, androgen receptor (AR) in cytosol and nucleus, histological examination and weight of accessory sex organs were used as parameters for androgenic activity. The ventral prostate weight was increased by the administration of not only steroidal anti-androgen, medroxyprogesterone (MPA), chlormadinone acetate (CMA) and cyproterone acetate (CPA), but also estradiol-17 beta(E2) and nonsteroidal anti-androgen, AA 560. However flutamide (Flu) failed to increase VP weight. In SV, the tendency to increase weight by the administration of these compounds was also observed. However, it was not obvious as in VP. It was proven by the measurement of the parameters that all tested compounds except Flu had an androgenic activity. It seems that the androgenic activity was caused by a different mechanism because the parameter response to the administrated compounds was not identical.

Prenatal exposure to a low‐frequency electromagnetic field demasculinizes adult scent marking behavior and increases accessory sex organ weights in rats

Pregnant Sprague-Dawley dams were exposed to a low-level, low-frequency pulsed electromagnetic (EM) field (15 Hz, 0.3 msec duration, peak intensity 8 gauss) for 15 min twice a day from day 15 through day 20 of gestation, a period in development that is critical for sexual differentiation of the male rat brain. No differences in litter size, number of stillborns, or body weight were observed in offspring from field-exposed dams. At 120 days of age, field-exposed male offspring exhibited significantly less scent marking behavior than controls. Accessory sex organ weights, including epididymis, seminal vesicles, and prostate, were significantly higher in field-exposed subjects at this age. However, circulating levels of testosterone, luteinizing hormone, and follicle-stimulating hormone, as well as epididymal sperm counts, were normal. These data indicate that brief, intermittent exposure to low-frequency EM fields during the critical prenatal period for neurobehavioral sex differentiation can demasculinize male scent marking behavior and increase accessory sex organ weights in adulthood.

3‐(Cyclohexenonyl)‐4‐(4‐hydroxyphenyl)‐hexanes: Antiandrogenes Derived from the Estrogen Hexestrol

Selective Birch-reduction of one of the phenolic rings of meso- or d,l-HES led to compounds 6a and 6b which exert a higher binding affinity to the androgen receptor as the respective parent HES. In vivo testing of 6a and 6b shows that 6a has the same potency in reducing accessory sex organ weights and testosterone levels in the intact mouse as has meso-HES, but strongly decreased estrogenic activity. Syntheses and testing of 7 having no ethyl side chains revealed the necessity of these groups for biological activity.

Suppression of pituitary-testis function in rats treated neonatally with a gonadotrophin-releasing hormone agonist and antagonist: acute and long-term effects

The acute and long-term effects of pituitary-testis suppression with a gonadotrophin-releasing hormone (GnRH) agonist, D-Ser(Bu(t))6des-Gly10-GnRH N-ethylamide (buserelin; 0.02, 0.1, 1.0 or 10 mg/kg body weight per day s.c.) or antagonist, N-Ac-D-Nal(2)1,D-p-Cl-Phe2,D-Trp3,D-hArg(Et2)6,D-Ala10 -GnRH (RS 68439; 2 mg/kg body weight per day s.c.) were studied in male rats treated on days 1-15 of life. The animals were killed on day 16 (acute effects) or as adults (130-160 days; long-term effects). Acutely, the lowest dose of the agonist decreased pituitary FSH content and testicular LH receptors, but with increasing doses pituitary and serum LH concentrations, intratesticular testosterone content and weights of testes were also suppressed (P less than 0.05-0.01). No decrease was found in serum FSH or in weights of accessory sex organs even with the highest dose of the agonist, the latter finding indicating continuing secretion of androgens. The GnRH antagonist treatment suppressed pituitary LH and FSH contents and serum LH (P less than 0.05-0.01) but, as with the agonist, serum FSH remained unaltered. Testicular testosterone and testis weights were decreased (P less than 0.01) but testicular LH receptors remained unchanged. Moreover, the seminal vesicle and ventral prostate weights were reduced, in contrast to the effects of the agonists. Pituitary LH and FSH contents had recovered in all adult rats treated neonatally with agonist and there was no effect on serum LH and testosterone concentrations or on fertility.(ABSTRACT TRUNCATED AT 250 WORDS)