Effect of chronic administration of an aromatase inhibitor to adult male rats on pituitary and testicular function and fertility

2000 ◽  
Vol 164 (2) ◽  
pp. 225-238 ◽  
Author(s):  
KJ Turner ◽  
M Morley ◽  
N Atanassova ◽  
ID Swanston ◽  
RM Sharpe

The aim of the present study was to evaluate the effects of the administration of a potent non-steroidal aromatase inhibitor, anastrozole, on male reproductive function in adult rats. As anastrozole was to be administered via the drinking water, a preliminary study was undertaken in female rats and showed that this route of administration was effective in causing a major decrease in uterine weight (P<0.02). In an initial study in male adult rats, anastrozole (100 mg/l or 400 mg/l) was administered via the drinking water for a period of 9 weeks. Treatment with either dose resulted in a significant increase ( approximately 10%) in testis weight and increase in plasma FSH concentrations (P<0.01) throughout the 9 weeks. Mating was altered in both groups of anastrozole-treated rats, as they failed to produce copulatory plugs. Histological evaluation of the testes from anastrozole-treated rats revealed that spermatogenesis was grossly normal. In a more detailed study, adult rats were treated with 200 mg/l anastrozole via the drinking water for periods ranging from 2 weeks to 1 year. Plasma FSH and testosterone concentrations were increased significantly (P<0.001) during the first 19 weeks of treatment. However, LH concentrations were increased only at 19 weeks (P<0.001) in anastrozole-treated rats, and this coincided with a further increase in circulating and intratesticular testosterone concentrations (P<0.05). No consistent change in inhibin-B concentrations was observed during the study. Suppression of plasma oestradiol concentrations could not be demonstrated in anastrozole-treated animals, but oestradiol concentrations in testicular interstitial fluid were reduced by 18% (P<0.01). Mating was again inhibited by anastrozole treatment, but could be restored by s.c. injection of oestrogen, enabling demonstration that rats treated for 10 weeks or 9 months were still fertile. Testis weight was increased by 19% and 6% after treatment for 19 weeks and 1 year, respectively. Body weight was significantly decreased (P<0.01) by 19 weeks of anastrozole treatment; after 1 year the animals appeared to have less fat as indicated by a 27% decrease in the weight of the gonadal fat pad. The majority of anastrozole-treated animals had testes with normal spermatogenesis but, occasionally, seminiferous tubules showed abnormal loss of germ cells or contained only Sertoli cells. Ten percent of anastrozole-treated animals had testes that appeared to contain only Sertoli cells, and one rat had 'giant' testes in which the tubule lumens were severely dilated. Morphometric analysis of the normal testes at 19 weeks showed no difference in the number of Sertoli cells or germ cells, or the percentage volumes of the seminiferous epithelium, tubule lumens and interstitium between control and anastrozole-treated rats. On the basis of the present findings, oestrogen appears to be involved in the regulation of FSH secretion and testosterone production, and is also essential for normal mating behaviour in male rats. Furthermore, these data suggest that the brain and the hypothalamo-pituitary axis are considerably more susceptible than is the testis to the effects of an aromatase inhibitor. Anastrozole treatment has resulted in a model of brain oestrogen insufficiency.

1998 ◽  
Vol 17 (3) ◽  
pp. 151-156 ◽  
Author(s):  
A S Faqi ◽  
P R Dalsenter ◽  
W Mathar ◽  
B Heinrich-Hirsch ◽  
I Chahoud

1 The aim of this study was to ascertain the reproductive effects of PCB 77 on adult male rats and to determine its concentration in the liver and testis. Adult male rats (n=15/group) were treated subcutaneously with a singledoseof18 mg/kgbw(PC18)orwith60 mg/kg bw (PC60). The substance was dissolved in a 10 ml volume of peanut oil/kg. Control rats received the same volume of the vehicle. The reproductive effects as well as the concentration of PCB 77 in the liver and testis were investigated 1, 4 and 8 weeks after treatment. 2 In both groups, the daily sperm production (DSP; 6106) remained permanently reduced in the PC18 as well as in the PC60 groups throughout the entire investigation period (DSP week 8: control: 31+7; PC18: 22+5; PC60: 20+7). The sperm number (6106) per cauda epididymis was affected only at the 1st and 4th week after treatment (control week 1: 211+67; PC18 week 1: 135+62; PC60 week 1: 142+49). Moreover, a significant increase in the percentage of abnormal sperm was observed 4 weeks following treatment in the PC18 and PC60 groups and 8 weeks after treatment in the PC60 group. Abnormal tails were the most frequent changes observed. 3 The relative testicular and prostata weights (g) were slightly increased in the PC60 group at the 1st and 4th week following treatment (testis weight: control/I: 0.46+0.02; PC60/I: 0.51+0.03). 4 The serum testosterone concentrations and effects on testis morphology were not reported. 5 The maximum concentration of PCB 77 was detected in the liver and testis 1 week after treatment. The concentration declined 4 weeks after treatment in both organs, but still a significant amount of PCB 77 was detectable in the liver as well as in the testis 8 weeks after treatment. 6 The results demonstrate that PCB 77 affects sperm variables when applied to adult rats and that the elimination of PCB 77 in the testis parallels that of the liver.


1973 ◽  
Vol 74 (1) ◽  
pp. 88-104 ◽  
Author(s):  
T. Jolín ◽  
M. J. Tarin ◽  
M. D. Garcia

ABSTRACT Male and female rats of varying ages were placad on a low iodine diet (LID) plus KClO4 or 6-propyl-2-thiouracil (PTU) or on the same diet supplemented with I (control rats). Goitrogenesis was also induced with LID plus PTU in gonadectomized animals of both sexes. The weight of the control and goitrogen treated animals, and the weight and iodine content of their thyroids were determined, as well as the plasma PBI, TSH, insulin and glucose levels. The pituitary GH-like protein content was assessed by disc electrophoresis on polyacrylamide gels. If goitrogenesis was induced in young rats of both sexes starting with rats of the same age, body weight (B.W.) and pituitary growth hormone (GH) content, it was found that both the males and females developed goitres of the same size. On the contrary, when goitrogenesis was induced in adult animals, it was found that male rats, that had larger B.W. and pituitary GH content than age-paired females, developed larger goitres. However, both male and female rats were in a hypothyroid condition of comparable degree as judged by the thyroidal iodine content and the plasma PBI and TSH levels. When all the data on the PTU or KClO4-treated male and female rats of varying age and B.W. were considered together, it was observed that the weights of the thyroids increased proportionally to B.W. However, a difference in the slope of the regression of the thyroid weight over B.W. was found between male and female rats, due to the fact that adult male rats develop larger goitres than female animals. In addition, in the male rats treated with PTU, gonadectomy decreased the B.W., pituitary content of GH-like protein and, concomitantly, the size of the goitre decreased; an opposite effect was induced by ovariectomy on the female animals. However, when goitrogenesis was induced in weight-paired adult rats of both sexes, the male animals still developed larger goitres than the females. Among all the parameters studied here, the only ones which appeared to bear a consistent relationship with the size of the goitres in rats of different sexes, treated with a given goitrogen, were the rate of body growth and the amount of a pituitary GH-like protein found before the onset of the goitrogen treatment. Moreover, though the pituitary content of the GH-like protein decreased as a consequence of goitrogen treatment, it was still somewhat higher in male that in female animals. The present results suggest that GH may somehow be involved in the mechanism by which male and female rats on goitrogens develop goitres of different sizes, despite equally high plasma TSH levels.


1966 ◽  
Vol 44 (1) ◽  
pp. 95-101 ◽  
Author(s):  
J. R. Beaton ◽  
A. J. Szlavko ◽  
J. A. F. Stevenson

The effect of various factors on excretion of a lipid-mobilizing activity in FMS IA (anorexigenic) and in FMS IB (fat-mobilizing) by the fasting rat has been investigated. During fasting, the greatest excretion of such activity in FMS IA and FMS IB occurred in the first 24 hours and diminished thereafter up to 72 hours; and the specific activity of FMS IB was greatest in the first 24 hours whereas that of FMS IA was constant throughout. The hypothalamicobese rat excretes FMS IA and FMS IB in greater than normal amounts. The alloxan-diabetic rat excretes less total activity of FMS IA and IB than do control animals. Young male rats excrete greater amounts of FMS IB, but not of FMS IA, than do adult rats, the greatest excretion per 100 g body weight being observed at approximately 37 days of age. At 27 days of age (prepuberty), male rats excreted a greater total activity of FMS IB but not of FMS IA than did female rats. At 90 days of age (post-puberty), there was no apparent sex difference in the amount of total activity of FMS IB excreted per rat, but when expressed per 100 g body weight, females excreted more FMS IB than did males.


1975 ◽  
Vol 67 (1) ◽  
pp. 71-79 ◽  
Author(s):  
P. DE MOOR ◽  
M. ADAM-HEYLEN ◽  
H. VAN BAELEN ◽  
G. VERHOEVEN

SUMMARY Adult rats of both sexes were either gonadectomized or hypophysectomized and gonadectomized. Three to eight weeks later they were treated for 14 consecutive days with oil or with 75 or 200 μg testosterone propionate (TP) per 100 g body weight. The animals were killed and for each sex the gonadectomized animals were compared with the hypophysectomized-gonadectomized animals as far as their NADPH- and NADH-dependent 3α-hydroxysteroid dehydrogenases (3α-HSD) in renal microsomes, transcortin levels in serum and five organ weights relative to total body weight were concerned. For two of the latter, i.e. the relative kidney and prostatic weights, no significant differences were found. Transcortin levels, relative adrenal weights and renal NADPH-dependent 3α-HSD activities were higher in oil-treated gonadectomized animals than in oil-treated hypophysectomized-gonadectomized animals. The opposite was found for the relative weights of uterus and seminal vesicles and renal NADH-dependent 3α-HSD activities. These differences between gonadectomized and hypophysectomized-gonadectomized animals disappeared after TP treatment as far as transcortin levels were concerned but remained for the five other parameters. After gonadectomy sexual differences subsisted for all parameters studied. But whereas intact male rats had higher NADH-dependent 3α-HSD activities than female rats the opposite was found after gonadectomy. After gonadectomy plus hypophysectomy the between sex differences disappeared as far as transcortin levels were concerned but remained in the other parameters studied.


2008 ◽  
Vol 20 (9) ◽  
pp. 36
Author(s):  
S. M. Ruwanpura ◽  
P. G. Stanton ◽  
D. M. Robertson ◽  
R. I. McLachlan ◽  
Y. Makanji ◽  
...  

Follicle stimulating hormone (FSH) in short-term rat studies supports spermatogenesis at multiple levels, notably spermatogonial development. The role of FSH in supporting full spermatogenesis in rats is still in question as long-term studies have not been possible due the development of neutralising antibodies to heterologous FSH preparations. This study sought to assess the effects of a homologous recombinant rat FSH (rr-FSH) preparation on the long-term restoration of spermatogenesis. Adult rats were GnRH-immunised (GnRH-im) for 12 weeks then, administered an anti-androgen; flutamide (flut), alone or together with rr-FSH (8µg/rat/daily) for 56 days (1 spermatogenic cycle). Germ and Sertoli cell numbers were quantified using an optical disector stereological method. Testis weight, serum FSH and inhibin B and Sertoli cell nuclear volume were significantly reduced to 15%, 13%, 25% and 57% of controls respectively, following GnRH-im+flut treatment. GnRH-im+flut treatment reduced A/I spermatogonial, type B spermatogonial+preleptotene, leptotene+zygotene and early pachytene spermatocyte numbers to 28%, 68%, 50% and 19% (P < 0.001) of controls respectively, with later germ cells rarely observed. After FSH treatment, no significant affect on testis weight, serum FSH and inhibin B or Sertoli cell number were observed. However, rr-FSH treatment significantly increased numbers of A/I spermatogonia, leptotene+zygotene and early pachytene spermatocytes from 28 = >42%, 50 = >69% and 19 = >27% of controls, respectively, while no differences were observed in later germ cell types. rr-FSH also increased (P < 0.05) the volume of Sertoli cell nuclei from 57 = >66% of control. In conclusion, FSH is unable to support full rat spermatogenesis; however, FSH can partially support germ cells notably spermatogonia through to early pachytene spermatocytes, despite the absence of androgenic support.


2004 ◽  
Vol 183 (1) ◽  
pp. 79-90 ◽  
Author(s):  
A Bozec ◽  
F Chuzel ◽  
S Chater ◽  
C Paulin ◽  
R Bars ◽  
...  

In utero exposure to exogenous anti-androgenic compounds induces a wide range of abnormalities of the reproductive system, including hypospermatogenesis, cryptorchidism and hypospadias. By using rats exposed in utero to the anti-androgenic compound flutamide (0.4, 2 or 10 mg/kg per day), it has been shown that hypospermatogenesis in adult testes could be related to (i) a long-term apoptosis in germ cells but not in somatic Leydig and Sertoli cells as evidenced by the TUNEL approach and (ii) alterations in the mRNA and protein expression of pro- (Bax, Bak, Bid) and anti-apoptotic (Bcl-2, Bcl-w) members of the Bcl-2 family. Indeed, the number of apoptotic germ cells increased with the dose of flutamide administered and the apoptotic germ cells were mainly detected at androgen-dependent stages VII–VIII. Moreover, for the Bcl-2-related proteins that were expressed mainly in the germ cells, a decrease in the levels of anti-apoptotic peptides Bcl-w (60%, P=0.003) and Bcl-2 (90%, P=0.0001) was observed at 2 mg/kg per day flutamide and an increase in levels of the pro-apoptotic Bax (2.3-fold, P=0.0004) was detected at 10 mg/kg per day. In contrast, the levels of pro-apoptotic peptide Bak that was mainly expressed in somatic cells decreased (70%, P=0.0008) at 10 mg/kg per day. Such alterations in Bcl-2-related peptides occurred mainly at the protein level except for Bcl-2 (72%, P=0.0001) and Bak (43%, P=00002) transcripts. Together, these results showed that the apoptosis observed in adult germ cells from rats exposed in utero to flutamide may result from a long-term alteration in the balance between pro- and anti-apoptotic Bcl-2-related molecules in favour of pro-apoptotic proteins. These data further supported the concept of an androgen-dependent fetal programming that is in relation with an alteration of the expression of Bcl-2-related genes/proteins promoting apoptosis in testicular germ cells of adult rats with fetal androgen disruption.


1988 ◽  
Vol 116 (1) ◽  
pp. 43-53 ◽  
Author(s):  
M. Laudon ◽  
Z. Yaron ◽  
N. Zisapel

ABSTRACT N-(3,5-dinitrophenyl)-5-methoxytryptamine (ML-23) has recently been synthesized and shown to antagonize the inhibitory effect of melatonin on the release of dopamine in vitro from the hypothalamus of female rats. In the present study the ability of ML-23 to inhibit in vivo the following melatonin-mediated effects was investigated: (1) delayed sexual maturation of young male rats, (2) delayed sexual maturation of young female rats, (3) inhibition of ovulation in mature female rats and (4) re-establishment of oestrous cycles in adult female rats maintained in continuous light. The inhibitory effect of daily melatonin injections, given in the afternoon, on the growth of the prostate gland and seminal vesicles and on serum testosterone concentrations in young male rats was prevented by daily injections of ML-23. Daily injections of ML-23 alone did not affect sexual maturation of young rats. In young male rats treated through the drinking water with melatonin, the growth of the accessory sex organs, but not that of the testes, was delayed and serum concentrations of testosterone were lower than in untreated rats. Administration of ML-23 through the drinking water increased serum concentrations of testosterone but did not significantly affect the weights of the accessory sex organs. Simultaneous administration of ML-23 and melatonin through the drinking water prevented completely, in a dose-dependent manner, the melatonin-mediated decrease in epididymal weights and in serum concentrations of testosterone and partially inhibited the delayed growth of the prostate glands and seminal vesicles. In young female rats treated with melatonin through the drinking water for 30 days, the growth of the ovaries was inhibited and serum concentrations of oestradiol were lower than in untreated rats. The growth of the uterus was not significantly affected. Administration of ML-23 through the drinking water did not significantly affect uterine and ovarian weights or oestradiol concentrations. Simultaneous administration of melatonin and ML-23 through the drinking water prevented completely the melatonin-mediated decrease in ovarian weights and in serum oestradiol concentrations. Ovulation during presumptive oestrus was prevented in adult female rats treated through the drinking water for 7 days with melatonin. Administration of ML-23 alone did not significantly affect the average numbers of ova shed and corpora lutea present. Simultaneous administration of ML-23 and melatonin prevented completely the melatonin-mediated inhibition of ovulation; the average number of ova shed was the same as in controls. Suppression of reproductive cycles occurred in adult female rats after long-term exposure to continuous light. This suppression was prevented by daily injections of melatonin in the afternoon; the incidence of constant oestrus decreased by 80%. Simultaneous injection of ML-23 and melatonin into rats maintained under continuous illumination prevented the effect of melatonin, and all the animals remained in constant oestrus. Administration of ML-23 alone did not alter the incidence of constant oestrus. A tritium-labelled derivative of ML-23 was prepared and administered orally to male rats. Peak concentrations of ML-23 occurred in the blood within 30 min after feeding and disappeared subsequently with a half-life of about 42 min. Intraperitoneal injection of [3H]ML-23 resulted in the appearance of peak concentrations of the drug in the brain within 20 min. The effects of ML-23 on serotonin S1 and S2 receptors, dopamine D2 receptors and melatonin receptors in the brain of the male rat were investigated using [3H]serotonin, [3H]spiperone and 2-[125I]iodomelatonin respectively. The binding of [3H]serotonin to brain synaptosomes and of [3H]spiperone to synaptosomes prepared from the cortical and caudate regions of the cerebrum was unaffected by ML-23 (10 μmol/l), whereas the binding of 2-[125I]iodomelatonin to brain synaptosomes was entirely inhibited. The results demonstrate the potency of ML-23 in antagonizing melatonin-mediated effects in the male and female rat in vivo. The drug may be administered to the animals simply through the drinking water, for relatively long periods without apparent deleterious effects on survival and welfare. ML-23 is accessible to both central and peripheral sites and acts specifically on melatonin but not on serotonin or dopamine receptors in the brain. The availability of a melatonin antagonist offers new opportunities for exploring the physiological role of melatonin in the neuroendocrine system. J. Endocr. (1988) 116, 43–53


2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
B. Nchegang ◽  
C. Mezui ◽  
F. Longo ◽  
Z. E. Nkwengoua ◽  
A. P. Amang ◽  
...  

Objective. We studied prosexual effects ofEremomastax speciosaaqueous extract in male adult rats.Materials and Methods. 100 and 500 mg/kg of extract were administered orally (days 0, 1, 4, 7, 14, and 28 (posttreatment)). The sexual behavior of rats receiving a single dose (500 mg/kg) was also evaluated after pretreatment with Lω-NAME (10 mg/kg), haloperidol (1 mg/kg), or atropine (5 mg/kg). Controls received distilled water or testosterone enanthate (20 mg/kg/day/3 days(s.c.)before the test).Results. The extract (days 1–14) had no significant effect on mount, intromission, and ejaculation frequencies but on day 28 (14 days after treatment), it increased frequency of mounts and intromissions at 500 mg/kg. Mount, intromission, and ejaculation latencies reduced and postejaculatory intervals decreased but the effect did not persist 2 weeks after treatment. Extract prosex effects were greatly reduced by atropine and completely abolished by haloperidol, while Lω-NAME increased mount latency and potentiated extract effect on intromission and ejaculation latencies.Conclusion. In summary,E. speciosaextract can have positive effects on male sexual motivation and performance when administered for two weeks at the dose of 500 mg/kg. The effects (dopaminergic and/or cholinergic dependent) tend to appear during the posttreatment period.


1969 ◽  
Vol 40 (3) ◽  
pp. 734-746 ◽  
Author(s):  
Donald Svoboda ◽  
Daniel Azarnoff ◽  
Janardan Reddy

The liver cells of intact male rats given ethyl-α-p-chlorophenoxyisobutyrate (CPIB) characteristically show a marked increase in microbodies and in catalase activity, while those of intact female rats do not. In castrated males given estradiol benzoate and CPIB the increase in catalase activity and microbody proliferation is abolished, while in castrated females given testosterone propionate and CPIB the livers show a marked increase in microbodies and in catalase activity. No sex difference in microbody and catalase response is apparent in fetal and neonatal rats. Both sexes show a sharp rise in catalase activity on the day of birth, with a rapid decline at 5 days after birth. Thyroidectomy abolishes the hypolipidemic effect of CPIB in rats, but microbody proliferation and increase in catalase activity persists in thyroidectomized male rats, indicating that microbody proliferation can be independent of hypolipidemia. Adrenalectomy does not alter appreciably the microbody-catalase response to CPIB. These experiments demonstrate that (1) in adult rats, hepatic microbody proliferation is dependent to a significant degree upon male sex hormone but is largely independent of thyroid or adrenal gland hormones; (2) hepatic microbody proliferation is independent of the hypolipidemic effect of CPIB; (3) displacement of thyroxine from serum protein may not be sufficient cause for stimulation of microbody formation.


2019 ◽  
Vol 8 (2) ◽  
pp. 113-118
Author(s):  
Fakhri Armin ◽  
Fariba Azarkish ◽  
Ali Atash Ab Parvar ◽  
Aghdas Dehghani

Background: Renal ischemia-reperfusion (RIR) is a common clinical injury that affects the function of other remote organs such as the brain by initiating a cascade of complex and wide-ranging inflammatory responses. RIR also follows a different course in men and women. Since there is little information on the effect of RIR on the brain as a sensitive organ in both males and females, the present research was performed to investigate the effect of gender on RIR-induced brain tissue alterations in adult rats. Materials and Methods: In this study, 28 Wistar rats (14 female and 14 male rats) weighing 200 ± 20 g were divided into the following groups: 1- male sham (MS), 2- female sham (FS), 3- male ischemia (MI) with 3-hour reperfusion (ISC3hr), and 4- Female ischemia (FI) with 3-hour reperfusion (ISC3hr). Bilateral renal ischemia was induced for 45 minutes and blood samples were taken after reperfusion for the measurements of serum blood urea nitrogen (BUN), creatinine (Cr), malondialdehyde (MDA), and nitrite levels. The left kidney was removed for evaluation of MDA and tissue nitrite levels. Right kidney and brain tissue underwent histological examination. Results: Serum BUN level increased in both genders. Serum nitrite level was significantly different between both genders, meaning that it was increased in the female rats as compared to male ones. Overall brain tissue damage was significantly increased in males compared to females. Conclusion: RIR has an effect on the function and tissue of kidney and brain in both genders. Female rats are more susceptible to the nitric oxide system than the male ones. This study showed that male brain tissue was more susceptible to RIR. Therefore, gender is one of the important factors that should be considered in clinical treatments.


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