Androgen-dependent fighting behaviour in male mice

The influence of testosterone propionate, 17 alpha-methyl-testosterone and cyproterone acetate on isolation induced fighting behaviour of mice was studied in a simple testing procedure. Decreased aggressiveness has been established in mature, sexual experienced and isolated male mice both following castration and administration of the antiandrogen cyproterone acetate, respectively. Replacement therapy with testosterone propionate s.c. and 17 alpha-methyl-testosterone p.o. has been shown to restore the decreased level of aggresiveness after castration.     

Influence of chlormadinone acetate on hypothalamic differentiation in male rats

The effect of chlormadinone acetate on adult male rats during the hypothalamic differentiation phase was studied. Psychic intersexuality with increased male and increased female sexual behavior was observed both before and after postpuberal castration and sex hormone replacement. Organ weights of testes, seminal vesicles, and ventral prostrates were normal, but penis and adrenal gland weights were significantly smaller. Body growth was also significantly reduced compared with control animals. The effects of chlormadinone acetate on androgen-dependent brain differentiation are discussed and compared with analogous effects of cyproterone acetate and orchidectomy.     

Effects of an antiandrogen,cyproterone acetate,on the kidney of the three-spined stickleback (Gasterosteus aculeatus L.)

The fine structure of the kidney is studied in the sexually mature male three-spined stickleback after administration of an antiandrogen, cyproterone acetate. Under these conditions, the dedifferentiation of renal tubules is characterized by the same involutive processes as those induced by castration, with the difference that cyproterone acetate only begins to act after 14 days whereas after castration the first signs of involution are visible after 7 days. The ultrastructural modifications affect the nucleoli, the rough endoplasmic reticulum and the Golgi apparatus. They reflect an inhibition of the secretory process. The results obtained demonstrate that administration of cyproterone acetate to male sticklebacks has an inhibitory effect on renal target cells, apparently indistinguishable from the changes induced by lack of male sex hormone, and that this drug may be a valid substitute for castration in fish.     

The fine structure of the rat pineal and the influence of anti-androgens and castroation]

The pineal body, along with the hypothalamus-hypophysis system, is in the centre of sexual hormone regulation and, in addition to other functions, develops an antigonadotropic action through its organ specific hormone (melatonin). In order to clarify further open questions and to analyse more closely the morphology of the fine structure of the organ, light and electron microscopic studies were made of the pineal bodies of sexually mature male rats after hormonal castration by the administration of cyproterone and cyproterone acetate. The findings were compared with results obtained in the pineal bodies of surgically castrated animals of the same strain. Epiphysectomy was performed 3, 6, 9 and 12 weeks after castration or application of antiandrogen. In the pineal bodies, "light" and "dark" pineal cells and an interstitial cell form could be detected electronmicroscopically. The interstitial cells are found localised near the vessels in particular; their ramifications reach into the perivascular cleft. The light pineal cells preponderate and react essentially in the series; they are therefore considered as the really active form of parenchyma cells. Increased cell activity is already observed three weeks after treatment with antiandrogen: the nucleoli are enlarged, the ribosomes, the mitochondria and ergastoplasm are increased, the endoplasmic reticulum quantified and extended, and also the Golgi regions. The cells are consequently enlarged. Lysosomes also appear which frequently enter the liposomes. The changes in the liposomes after application of antiandrogen are remarkable. Initially they are evacuated, partially drawn out. Later the liposomes are enlarged and increased and often fill the cell body. These pineocytes form an appendage to the castration cells of the hypophysis. The liposomes are in a very close spatial, formal genetic relationship to the Golgi apparatus and to the rough walled reticulum. The larger liposomes apparently arise also through the confluence of smaller ones. Three structural elements of the liposomes could be indentifed: a homogenous, a lamellar and a granular component. The fine morphological reactions are most marked after cyproterone acetate. For the first time, bundles of "microtubuli" are described, the significance of which is not yet clear. They probably arise from the endoplasmic reticulum, they are only found after cyproterone acetate and are presumably due to the gestagen component of the cyproterone acetate. These structures have not previously been observed, either in pineal bodies or in other organs. The structures found after antiandrogen are not so outstandingly recognisable after surgical castration. The biological differences of the surgical compared with hormonal castration therefore seem to be reflected in the cell picture of the pineocytes. Consequently, the pineal body, after treatment with antiandrogen, shows cytostructural changes similar to those of increased anabolism...     

Different behavior of the rat vas deferens of castrated animals and those treated with cyproterone acetate

The effects of castration and treatment with the antiandrogen cyproterone acetate (CPA) on the responses of the vas deferens of the rat induced by phenylephrine, KCl and BaCl2 has been studied. Both castration and CPA induced a spontaneous motility in the rat vas deferens. Castration produces a decrease of the response amplitude induced by phenylephrine and KCl and an increase of those induced by BaCl2 in animals killed 30 days after castration. CPA increases the response amplitude induced by phenylephrine and KCl without modifying those induced by BaCl2. These results suggest that the antiandrogen CPA produces modifications qualitatively different from castration.     

Estrogenic and antifertility effect of cyproterone acetate in female gerbils, meriones hurriane Jerdon

Effects of cyproterone acetate, a steroidal synthetic compound, on the reproductive organs of female gerbils have been investigated. This agent causes reduction of ovarian weights indicative of suppression of pituitary gonadotrophins. Estrogenic nature of cyproterone acetate was investigated in intact and ovariectomized gerbils taking uterine weight, vaginal keratinization and glycogen contents are parameters of estrogenic action. Cyproterone acetate in ovariectomized gerbils induced vaginal keratinization, increase in uterine weight, protein, RNA, glycogen and sialic acid contents of uterus, thus indicating an estrogenic activity. The histological and biochemical parameters lead to the conclusion that cyproterone acetate possesses estrogenic properties.     

Short-term effect of androgen deprivation on intraluminal pressure and contractility of the rat epididymis

Short-term effects of bilateral castration, cyproterone acetate and unilateral efferent duct ligation on intraluminal pressures and spontaneous contractions in different regions of the epididymis were studied in the rat. Ligation of the efferent ducts for 5 days did not alter pressures or spontaneous contractions in any region of the epididymis. However, bilateral castration produced time-dependent changes in pressures and contractions in different segments. In the caput, the amplitude, but not the basal pressure or the frequency, of spontaneous contractions increased by Day 1 after operation. In the corpus, increments in the basal pressure and the amplitude of contractions occurred by Day 5 whilst the frequency of contractions was not changed. Similar effects were observed in the cauda by 3 days after castration. Changes in all regions of the epididymis were also mimicked by cyproterone acetate treatment (10 mg/rat per day, s.c. for 21 days). In addition, this drug increased the amplitude of contractions in the cauda. The effect of castration was abolished by testosterone propionate (0.2 mg/kg per day, i.m. for 5 days). The results support the suggestion that an enhancement of sperm transport through the rat epididymis occurs shortly after castration. The results also suggest that, in normal rats, androgens suppress the contractility of the epididymal tubule to ensure an optimal rate of sperm transport.     

Behavioural and Physiological Effects of Testosterone Propionate and Cyproterone Acetate in Immature Male Domestic Ducks,Anas platyrhynchos

The behavioural and morphological effects of testosterone propionate and of the anti-androgen cyproterone acetate were studied in male domestic ducks. Testosterone was also measured by radioimmunoassay in the plasma of these birds to relate the behaviour to the actual circulating levels of hormone. Testosterone stimulates sexual behaviour but has few effects on social displays. There is no correlation between the individual variations of plasma testoterone and sexual behaviour.     

Effects of castration, 5 alpha-dihydrotestosterone and cyproterone acetate on enzyme activity in the mouse epididymis

The influence of castration, androgen replacement therapy and cyproterone acetate on the activity of beta-glucuronidase, acid and alkaline phosphatases and glucose-6-phosphate dehydrogenase was studied in the caput, corpus and cauda epididymidis of the mouse. The results add further evidence that the epididymis is not uniform but has regional differences in activity. Thus beta-glucuronidase was found to be androgen-dependent only in the cauda epididymidis, whereas glucose-6-phosphate dehydrogenase was under androgenic control in the caput epididymidis. The response of alkaline and acid phosphatases to castration and to androgen replacement was different in different segments.     

Effect of cyproterone acetate on the pregnancy-blocking ability of male mice and the possible chemical nature of the pheromone

Even though castration abolished the ability of alien males to induce implantation failure (the Bruce effect) in newly inseminated females, treatment of intact alien males with the steroidal antiandrogen, cyproterone acetate, for 14 days (short term) did not significantly depress their ability to induce the Bruce effect. However, prolonged treatment (42 days) with cyproterone acetate suppressed the pregnancy-blocking ability of alien males to some extent, possibly due to the antigonadotrophic properties of the drug. Ovariectomized alien females treated with implants of testosterone (androgenized females) exhibited the ability to block implantation in newly inseminated females, but concurrent treatment of androgenized females with cyproterone acetate did not depress this ability. The results strongly suggest that the pheromone involved in the male-induced implantation failure is not the product of an androgen-dependent tissue, but is likely to be a product of androgen metabolism.     

Behavioral and hormonal responses of male zebra finches to antiandrogens

After it was shown that the sexual behavioral patterns of male zebra finches are dependent on testosterone, the effects of treatment with two antiandrogens were investigated. The antiandrogens cyproterone (Cy) and cyproterone acetate (CyA) were used in this study. The results show that injections of CyA depress the sexual activity of the birds as measured by the amount of courtship song. The undirected song, too, is negatively influenced by a higher dosage of CyA. With the same dosage of Cy neither of these effects is observed. Radioimmunoassay for plasma testosterone showed that birds treated with CyA had lower, and birds treated with Cy had higher, testosterone levels in comparison with control animals. CyA is described as an antiandrogen with gestagenic side effects while Cy acts as a pure antiandrogen without side effects. Presumably the gestagenic side effects of CyA stop the production of testosterone by negative feedback mechanisms. This negative feedback combined with the antiandrogenic activity seems to account for the effects of CyA on behavior. Cy has no gestagenic side effect but is antiandrogenic with respect to blocking of androgen receptors. The organism tries to compensate for this deficit by increasing the testosterone production. The antiandrogenic activity of Cy probably is neutralized by this stimulated testosterone production.     

Effect of cyproterone acetate on testis of albino rats: ultrastructural and biochemical approach

The animals were treated with cyproterone acetate (1 mg/100 g body weight) for 60 days after which the testicular tissue was studied at the ultrastructural level to determine the stage at which the effect took place and to study the magnitude of the effect. The testis showed changes in Sertoli cells, Leydig cells, germ cells and in the spermatids. To correlate these changes, important marker enzymes and other biochemical parameters essential for spermatogenesis were studied after 30 days and 60 days of the treatment. They registered a decrease in their levels as compared with the controls.     

Effect of antiandrogen cyproterone acetate on the action of testosterone on mouse kidney.

The loss of endogenous testosterone in castrated male mice leads to a marked decrease in seminal vesicle and kidney tissue weight. 21 days' administration of exogenous testosterone abolished the effect of castration on the seminal vesicles and kidney tissue. The antiandrogen cyproterone acetate produced significant changes in the target tissue for androgens, i.e. in the seminal vesicles. In every case it blocked the action of both exogenous and endogenous testosterone on the seminal vesicles, but failed to block the "renotropic" action of testosterone, expressed as relative kidney weight. Contrary to its effect on the seminal vesicles, it did not influence relative kidney weight in normal animals. It likewise did not block the effect of exogenous testosterone on kidney tissue. The mechanism of the action of cyproterone acetate in androgen-dependent tissues is known to consist in inhibition of androgen binding to specific cell receptors in the target tissues. Some of the specific androgen receptors in mouse kidney are evidently different in character from those in the accessary sex glands, that being the reason why cyproterone acetate has an antiandrogenic, but not an antirenotropic effect. In agreement with experiments on rats, adrenal weight also decreases in mice after the administration of cyproterone acetate.     

Androgen metabolism by rat epididymis. 3. Effect of castration and anti-androgens.

The in vivo and in vitro metabolism of 3H-testosterone by rat epididymis and the changes in epididymal weight have been studied after castration and treatment with anti-androgens. The utilization of 3H-testosterone was greatly reduced after castration as was the formation of 5alpha-reduced 17 beta-hydroxy metabolites. The formation of the 17 -keto metabolites was unaffected. Castration had no effect on the ratio between water and ether soluble radioactivity. Administration of testosterone propionate, necessary for giving normal stimulated prostate weight (150 mug/day), restored the metabolism of testosterone to approximately normal values. Estradiol benzoate and progesterone inhibited metabolism of testosterone in vitro and greatly reduced the formation of DHT (17 beta-hydroxy-5alpha-androstan-3-one) and 3 alpha-diol(5 alpha-androstane-3 alpha-17 beta-diol) by experiments both in vivo and in vitro. No effect of cyproterone acetate could be demonstrated on either the in vitro or in vivo metabolism of testosterone. Castration for 14 days reduced the epididymal weight to about 30% of that found in intact animals. Administration of testosterone propionate restored the epididymal weight to about 80% of normal. Estradiol benzoate and cyproterone acetate given to intact rats led to a decrease in the epididymal weight. Progesterone had no such effect. In 14 days castrated rats receiving testosterone propionate all three anti-androgens reduced the weight of the epididymis. In conclusion, our results show that the metabolic conversion of testosterone in epididymis to DHT and 3 alpha-diol is dramatically dependent on the hormonal status of the animal; castration or treatment with anti-androgens causes a reduced formation of the "active" androgens whilst testosterone replacement treatment restores the metabolism of testosterone to normal.     

Effects of castration on thiol status in rat spermatozoa and epididymal fluid

Mammalian spermatozoa gain their fertilizing ability as they mature in the epididymis, a process which is accompanied by oxidation of sperm protein thiols. Since sperm maturation is dependent upon normal androgenic support to the epididymis, the present work was designed to study the effects of castration on thiol status. Spermatozoa and epididymal fluid were isolated from the epididymides of male rats 5 days after castration or after 11 daily injections of the antiandrogen, cyproterone acetate. Spermatozoa and epididymal fluid were labeled with the fluorescent thiol labeling agent monobromobimane. Intact spermatozoa were evaluated by fluorescence microscopy, protein thiols were analyzed by electrophoresis, and fertilizing ability was examined after insemination of sperm suspension into the uterine horns of immature superovulated female rats. We found that both treatments resulted in an increase in cauda sperm thiols as shown by increased fluorescence in the intact spermatozoa. Protamines and nonbasic proteins were found to have increased levels of reactive thiols. The protein profiles of epididymal fluid from castrated rats were different from those of the controls, and the fluorescence patterns corresponded to the protein profiles. Our results indicate that testosterone withdrawal leads to inhibition of sperm thiol oxidation. Mol. Reprod. Dev. 47:295–301, 1997. © 1997 Wiley-Liss, Inc.     

Further regression of seminal vesicles of castrated guinea pig by administration of cyproterone acetate

It has been established that a low level of secretory activity persisted in seminal vesicles of guinea pigs long after castration and that this may be due to a higher extratesticular androgen level in this animal. A RIA study revealed that the normal serum testosterone concentration of the guinea pigs was comparable to that of the rats, but the basal serum testosterone level after castration was ten times higher than rats under a similar condition. It was also shown that cyproterone acetate did not significantly lower the basal serum testosterone concentration in the castrated guinea pigs. The higher basal serum testosterone level is believed to be responsible for the slow and incomplete regression of this gland in the guinea pigs. There was a significant reduction in wet weight of the seminal vesicles after the treatment of castrated guinea pigs with cyproterone acetate. Ultrastructural study showed that there were both qualitative and quantitative changes in the cytoplasmic organelles. The Golgi apparatus further reduced in size and in the number of associated vesicles and vacuoles. There was a marked decrease in the number and size of secretory granules and lysosomes and an increase in the degree of undulation of the basement membrane. Accumulation of lipid droplets and glycogen was commonly observed. All these morphological evidences showed that further regression of the castrated guinea pig seminal vesicles can be achieved by cyproterone acetate treatment.     

Estradiol-17 beta inhibition of androgen uptake, metabolism and binding in epididymis of adult male rats in vivo: a comparison with cyproterone acetate

The effects of estradiol-17 beta on androgen uptake, metabolism and binding were studied in rat epididymis in vivo in comparison with cyproterone acetate. Steroids (250 ug/100 g body weight) were injected 5 min prior to 3H-testosterone in castrate rats. Estradiol-17 beta inhibited 3H-testosterone uptake into epididymal cytosol by 58% as compared to 38% by cyproterone acetate. 3H-Testosterone uptake into epididymal nuclei was inhibited 95% by estradiol-17 beta and 83% by cyproterone acetate. Total bound radioactivity in cytosol fractions was reduced to a greater extent by estradiol-17 beta than cyproterone acetate when either 3H-testosterone or 3H-dihydrotestosterone was injected. Binding of 3H-dihydrotestosterone to nuclear receptors was completely abolished by estradiol-17 beta; whereas approximately 20% binding remained in the nuclear extract after cyproterone acetate treatment. Metabolism of 3H-testosterone in vivo was also altered by estradiol-17 beta, resulting in diminished conversion to 3H-dihydrotestosterone. Cyproterone acetate, on the other hand, did not affect 3H-testosterone metabolism. Estradiol-17 beta and cyproterone acetate inhibited in vitro binding of 3H-dihydrotestosterone to the intracellular cytoplasmic receptor, but not the intraluminal androgen binding protein (ABP). These data suggest that estradiol-17 beta may have a more potent antiandrogenic effect on the epididymis than cyproterone acetate due to inhibition of 5 alpha reduction of testosterone as well as binding to the androgen receptor.     

Theoretical and experimental principles and clinical aplications of the antiandrognes (author's transl)

It is reported the accumulated experience over the last ten years on a synthetic gestegen with a powerful antiandrogenic action: the cyproterone acetate. The effects on androgen dependent processes like: structure and function of genital accesory glands, on skin and sebaceous glands, bone maturation and growth, libido and testicular function are reported, together with the clinical results obtained in the treatment of acne, hirsutism, sexual perversions and as male anticonceptive. The influence of cyproterone acetate on the androgen dependent embrionary processew of differentiation are also discussed as wll as the female anticonceptive action and its effects on other endocrine systems.     

Some contrasting effects of surgical and “chemical” castration on the behavior of male cynomolgus monkeys (Macaca fascicularis)

In nonhuman primates, surgical castration reduces plasma testosterone levels and male sexual behavior, and testosterone replacement restores them. Chemical castration with compounds that lower plasma testosterone levels is used clinically in the treatment of certain forms of cancer and to reduce aberrant sexual behavior in male sex offenders. In the United States, medroxyprogesterone acetate (MPA) is the drug most used to help reduce serious sexual behavioral problems in men. We were therefore interested in comparing the behavioral effects of MPA treatment (40 mg once a week) in 4 intact male cynomolgus monkeys (4 pairs, 120 tests) with data from an earlier study in our laboratory on 4 males observed before and after surgical castration (16 pairs, 192 tests). Both MPA treatment and surgical castration reduced plasma testosterone to very low levels and decreased ejaculatory activity, but MPA treatment additionally affected measures of male sexual motivation (decreased numbers of male mounting attempts and increased mounting attempt latencies) which were not primarily affected by surgical astration. However, surgical castration decreased intromission ability (percentage of intromitted thrusts per test) and male yawning behavior more rapidly than did MPA treatment. This suggested a hypothesis that different mechanisms could be involved in the behavioral effects—namely, that surgical castration may act primarily via testosterone-dependent peripheral mechanisms, while chemical castration with MPA does so primarily via central mechanisms regulating sexual motivation.     

Oestrogenic activity of cyproterone acetate in female mice

Effects of cyproterone acetate, a synthetic steroidal compound, on the reproductive organs of female mice have been investigated. This agent caused reduction of ovarian weights indicative of suppression of pituitary gonadotrophins. Oestrogenic nature of cyproterone acetate was investigated in intact and ovariectomized animals taking uterine weight, vaginal keratinization and other biochemical oestrogen sensitive parameters. Cyproterone acetate in ovariectomized animals induced vaginal keratinization increase in uterine weight and uterine protein, RNA, glycogen and sialic acid contents. These effects were parallel to the effects of oestradiol dipropionate in ovariectomized animals, thus indicating oestrogenic activity of the compound.