Reduced levels of stromal sex hormone-binding globulin and androgen receptor dysfunction in the sperm storage region of the rat epididymis (original) (raw)

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Impairment of sperm characteristics unrelated to hormonal alterations in rats treated with cimetidine

International Journal of Reproduction, Contraception, Obstetrics and Gynecology, 2014

Cimetidine is an H 2-receptor antagonist that inhibits the action of histamine on the acid producing cells of the gastric mucosa, thus reducing hydrochloric acid secretion. Cimetidine has been found to possess clinically significant anti androgen properties at high dosage. 1 It is reported to directly antagonize the binding of testosterone and dihydrotestosterone to the androgen receptors in animals. 1 Cimetidine is commonly used in the treatment of duodenal and gastric ulcers, gastroesophageal reflux disease (GERD), other pathological hypersecretory condition (e.g. Zollinger-Ellison disease), heart burn and in the prevention of upper gastrointestinal bleeding. A study has shown that after 12 months administration of 150-950mg/kg of cimetidine on experimental animals, there was a significant reduction in the size of the prostate, testes and seminal vesicles especially in the high dosage groups. 2 Twelve months treatment of dogs with cimetidine at a dosage of 41-50 mg/kg resulted in reduction in prostate weight. Both human and animal studies have shown that cimetidine crosses the feto-placental barrier, with high

Toxicant-induced acceleration of epididymal sperm transit: Androgen-dependent proteins may be involved

Reproductive Toxicology, 1997

Previously we established that a 4-d exposure to chloroethylmethanesulphonate (CEMS), a chemical that significantly reduces serum testosterone (T) levels, resulted in a significant decrease in cauda epididymal sperm reserves in adult male rats while homogenization-resistant testicular spermatid numbers were unaffected. This epididymis-specific alteration occurred whether or not circulating T levels were maintained using T-filled Silastic implants. To determine whether this epididymis-specific decrease in sperm number was the result of decreased epididymal transit time, the vas deferens was ligated at its midpoint just prior to the first of 4 d of exposure to CEMS with and without T implantation. If epididymal sperm transit was accelerated due to treatment, there would be fewer sperm in the caput/corpus and more sperm in the cauda/vas of the treated animals compared to control. The number of sperm in the caput/corpus decreased significantly (P < 0.05) while the number of sperm in the cauda/vas increased significantly in both the CEMS and CEMS + T animals. Daily sperm production was unaffected, but transit time through the caput/corpus epididymidis was decreased significantly in both treatment groups. To determine if testicular fluid played a role in the epididymis-specific decline in sperm numbers, the efferent ducts were ligated at the same time the vas deferens was ligated. Again, the number of sperm in the caput/corpus decreased significantly with treatment while there was a reciprocal increase in the number of cauda/vas sperm relative to controls. Finally, to determine whether an androgenmediated process might be involved, the known antiandrogen hydroxyflutamide (HFLUT) was given to castrated, T-implanted animals in which the fertilizing ability of epididymidal sperm is maintained over 4 days. Once again, the number of sperm in the caput/corpus decreased significantly while there was a reciprocal increase in cauda/vas sperm. A quantitative evaluation of the protein profile in homogenates of the caput/corpus epididymidis revealed treatment-related diminutions in two proteins CC9 (Mr = 42 kDa, p1 = 4.2) and CC34 (Mr = 35 kDa, p1 = KS), and the level of each of these proteins in the caput/corpus was significantly correlated with the decrease in cap&corpus sperm number. Thus, both CEMS and HFLUT accelerate sperm transit through the proximal segment of the epididymis; and, while this effect is not dependent on the testis, it may involve a lesion in androgen-dependent epididymal function. 0 1997 Elsevier Science Inc.

Cimetidine (Tagamet) Is a Reproductive Toxicant in Male Rats Affecting Peritubular Cells1

Biology of Reproduction, 2000

Cimetidine (Tagamet) is a potent histaminic H2-receptor antagonist, extensively prescribed for ulcers and now available without prescription. Cimetidine is a known testicular toxicant, but its mechanism of action remains uncertain. Rats were treated i.p. with cimetidine either at 50 mg/kg or 250 mg/kg body weight for 59 days. Accessory sex organ weights, but not testis weight, were significantly reduced in the high dose treated groups. FSH levels were significantly elevated in both treated groups, but testosterone levels were unchanged. A high degree of variability characterized testis histology, with most tubules appearing normal and some tubules (15-17%) partially lacking or devoid of germ cells. Morphometry showed that although seminiferous tubule volume was not significantly changed, the volume of peritubular tissue was reduced in the high dose group. There was extensive duplication of the basal lamina, lamina densa in both apparently normal spermatogenic tubules and severely damaged tubules. Apoptotic peritubular myoid cells were also found. TUNEL labeling confirmed extensive apoptotic cell death in peritubular cells, but revealed apoptosis of vascular smooth muscle. Given that 1) peritubular myoid cell apoptosis occurs in apparently normal tubules, that 2) basal lamina disorders are found, and that 3) peritubular cells are lost from the testis, it is suggested that the primary event in cimetidine-related damage is targeted to testicular smooth muscle cells. This is the first in vivo-administered toxicant to be described that targets myoid cells, resulting in abnormal spermatogenesis.

Cimetidine (Tagamet) is a reproductive toxicant in male rats affecting peritubular cells

Biology of …, 2000

Cimetidine (Tagamet) is a potent histaminic H2-receptor antagonist, extensively prescribed for ulcers and now available without prescription. Cimetidine is a known testicular toxicant, but its mechanism of action remains uncertain. Rats were treated i.p. with cimetidine either at 50 mg/kg or 250 mg/kg body weight for 59 days. Accessory sex organ weights, but not testis weight, were significantly reduced in the high dose treated groups. FSH levels were significantly elevated in both treated groups, but testosterone levels were unchanged. A high degree of variability characterized testis histology, with most tubules appearing normal and some tubules (15-17%) partially lacking or devoid of germ cells. Morphometry showed that although seminiferous tubule volume was not significantly changed, the volume of peritubular tissue was reduced in the high dose group. There was extensive duplication of the basal lamina, lamina densa in both apparently normal spermatogenic tubules and severely damaged tubules. Apoptotic peritubular myoid cells were also found. TUNEL labeling confirmed extensive apoptotic cell death in peritubular cells, but revealed apoptosis of vascular smooth muscle. Given that 1) peritubular myoid cell apoptosis occurs in apparently normal tubules, that 2) basal lamina disorders are found, and that 3) peritubular cells are lost from the testis, it is suggested that the primary event in cimetidine-related damage is targeted to testicular smooth muscle cells. This is the first in vivo-administered toxicant to be described that targets myoid cells, resulting in abnormal spermatogenesis.

Effects of Cimetidine and Bromocriptine on Germinal Epithelium and Spermatogenesis

 Abstract— The present study was designed to see the influence of parenterally administered drugs cimetidine and bromocriptine on the germinal epithelium of adult male albino rats and its relation with spermatogenesis.Ninety adult young male albino rats between the ages of 60 to 120 days were selected. The animals were divided into three groups. Cimetidine was administered in a dose of 200 mg/kg body weight to group B intramuscularly and in addition to cimetidine, bromocriptine in a dose of 2.5 mg/day intramuscularly was given to group C. Normal saline was administered intramuscularly to control group A. Spermatogonia, spermotocytes,and spermatids were studied under oil immersion. The spermatogenesis was normal in almost all of the tubules of group B but a few of them were seen lined with only Sertoli cells and all the other germ cells like spermatogonia, primary spermatocyes, spermatids early and late, and spermatozoa were absent indicating total atrophy with both Sertoli cells and Leydig cells hyperplasia. However, the seminiferous tubules of group C were showing disorganisation/ disruption or both at the level of basal compartment of germinal epithelium in small quadrants, a quarter, half or more than half of their tubules indicating partial atrophy. Both normal and abnormal germinal epithelium was seen in same/different tubules but a few of them were seen lined with only Sertoli cells and all the other germ cells like spermatogonia, primary spermatocytes,spermatids early and late, and spermatozoa were absent. On the basis of the results of present study we could not exclude the possibility that besides the known anti-androgenic effect of cimetidine, a possible interference of cimetidine on the histoarchitecture of the seminiferous epithelium, as well as lack of other biochemical factors essential for spermatogenesis could be involved in the testicular changes/ alterations of both groups B and C.

Cimetidine-induced Leydig cell apoptosis and reduced EG-VEGF (PK-1) immunoexpression in rats: Evidence for the testicular vasculature atrophy

Reproductive Toxicology, 2015

The antiulcer drug cimetidine has shown to cause changes in the testicular microvasculature of adult rats. Since Leydig cells (LC) produce the pro-angiogenic factor, EG-VEGF (endocrine gland-derived vascular endothelial growth factor), also known as prokineticin 1 (PK-1), this study examined the effect that cimetidine might have on LCs in testes with damaged vasculature. Rats received intraperitoneal injections of 100mg/kg of cimetidine (cimetidine group) or saline vehicle (control group) for 50 days. Serum testosterone levels were measured by chemiluminescence immunoassay and testicular sections were subjected to TUNEL and immunohistochemical reaction for caspase-3, 17β-HSD6, CD163 (ED2 macrophage), PK-1 and the androgen receptor (AR). LCs in the cimetidine group showed TUNEL and caspase-3 positive labeling and apoptotic ultrastructural features. Moreover, the presence of 17β-HSD6-positive inclusions inside macrophages and the reduced number of LCs, AR immunoreactivity and serum testosterone levels correlated with a decrease in either the number of PK-1immunostained LCs or PK-1 immunoreactivity. Although it is not clear which cell type is the primary target of cimetidine in the testicular interstitial compartment, these findings support a direct link between cimetidine-induced testicular vascular atrophy and LC damage.

The Effect Of Estrogen On The Male Reproductive System Of Rats Receiving Cimetidine

‫الخالصة‬ ‫اسة‬ ‫الدر‬ ‫هذه‬ ‫في‬ ‫استخدم‬ 25 ‫االستروجين‬ ‫استعمال‬ ‫تداخل‬ ‫مدى‬ ‫اسة‬ ‫لدر‬ ‫سوي‬ ‫بالغ‬ ‫ذكر‬ ‫جرذ‬ ‫الذكري‬ ‫التناسمي‬ ‫الجهاز‬ ‫فعالية‬ ‫عمى‬ ‫بالسيميتدين‬ ‫البالغة‬ ‫الجرذان‬ ‫معاممة‬ ‫تأثير‬ ‫في‬ ‫قميمة‬ ‫بجرعة‬ . ‫المعاممة‬ ‫مجموعة‬ ‫و‬ ‫ة‬ ‫السيطر‬ ‫مجموعة‬ ‫تضمنت‬ ‫مجاميع‬ ‫خمس‬ ‫الى‬ ‫ائيا‬ ‫عشو‬ ‫انات‬ ‫الحيو‬ ‫قسمت‬ G1 ‫جرعة‬ ‫السيمتيدين‬ ‫أعطيت‬ ‫التي‬ 50 ‫ممغم‬ \ ‫كغم‬ ‫من‬ ‫األنبوب‬ ‫اسطة‬ ‫بو‬ ‫الفم‬ ‫يق‬ ‫طر‬ ‫عن‬ ‫الجسم‬ ‫وزن‬ ‫المعدي‬ ‫ل‬ ‫مدة‬ 60 ‫بجرعة‬ ‫ادايول‬ ‫االسر‬ ‫حقنت‬ ‫و‬ ‫يوم‬ 0.01 µg ‫الجمد‬ ‫تحت‬ ‫ل‬ ‫مدة‬ 10 ‫متتالية‬ ‫أيام‬ ‫المعاممة‬ ‫مجموعة‬ ‫و‬ ‫بة‬ ‫لمتجر‬ ‫األول‬ ‫اليوم‬ ‫من‬ G2 ‫جرعة‬ ‫السيمتيدين‬ ‫أعطيت‬ ‫التي‬ 50 ‫ممغم‬ \ ‫كغم‬ ‫الجس‬ ‫وزن‬ ‫بجرعة‬ ‫ادايول‬ ‫االسر‬ ‫وحقنت‬ ‫الفم‬ ‫يق‬ ‫طر‬ ‫عن‬ ‫م‬ 0.01 µg ‫مدة‬ ‫الجمد‬ ‫تحت‬ 10 ‫أيام‬ ‫اليوم‬ ‫من‬ ‫متتالية‬ 20 -30 ‫المعاممة‬ ‫مجموعة‬ ‫و‬ ‫بة‬ ‫التجر‬ ‫من‬ G3 ‫جرعة‬ ‫السيمتيدين‬ ‫أعطيت‬ ‫التي‬ 50 ‫ممغم‬ \ ‫بجرعة‬ ‫ادايول‬ ‫االسر‬ ‫وحقنت‬ ‫الفم‬ ‫يق‬ ‫طر‬ ‫عن‬ ‫الجسم‬ ‫وزن‬ ‫كغم‬ 0.01 µg ‫مدة‬ ‫الجمد‬ ‫تحت‬ 10 ‫الي‬ ‫من‬ ‫متتالية‬ ‫أيام‬ ‫وم‬ 40 -50 ‫المعاممة‬ ‫مجموعة‬ ‫و‬ G4 ‫جرعة‬ ‫السيمتيدين‬ ‫أعطيت‬ ‫التي‬ 50 ‫ممغم‬ \ ‫بجرعة‬ ‫ادايول‬ ‫االسر‬ ‫وحقنت‬ ‫الفم‬ ‫يق‬ ‫طر‬ ‫عن‬ ‫الجسم‬ ‫وزن‬ ‫كغم‬ 0.01 µg ‫مدة‬ ‫الجمد‬ ‫تحت‬ 10 ‫اليوم‬ ‫من‬ ‫متتالية‬ ‫أيام‬ 50 -60 , ‫بعد‬ ‫و‬ ‫قبل‬ ‫الجرذان‬ ‫وزن‬ ‫اخذ‬ ‫تم‬ ‫انتهاء‬ ‫بة‬ ‫التجر‬ . ‫تم‬ ‫قتل‬ ‫اليوم‬ ‫في‬ ‫انات‬ ‫الحيو‬ 61 , ‫حيث‬ ‫س‬ ‫تم‬ ‫الدم‬ ‫حب‬ ‫ة‬ ‫مباشر‬ ‫بقميل‬ ‫القتل‬ ‫قبل‬ ‫أنبوب‬ ‫اسطة‬ ‫بو‬ ‫العين‬ ‫من‬ ‫و‬ ‫التستوستيرون‬ ‫هرمون‬ ‫مستوى‬ ‫لقياس‬ ‫شعري‬ FSH ‫المصل‬ ‫في‬ . ‫األعضاء‬ ‫ان‬ ‫أوز‬ ‫حساب‬ ‫تم‬ ‫كذلك‬ ‫بخ‬ ‫البر‬ ‫و‬ ‫الخصى‬ ‫وهي‬ ‫التناسمية‬ ( ‫الذيل‬ ‫و‬ ‫الجسم‬ ‫و‬ ‫أس‬ ‫الر‬ ) ‫البروستات‬ ‫و‬ ‫المنوية‬ ‫الحويصمة‬ ‫و‬ . ‫تم‬ ‫المئوية‬ ‫النسبة‬ ‫و‬ ‫الكمي‬ ‫النطف‬ ‫عدد‬ ‫حساب‬ ‫الميتة‬ ‫و‬ ‫الحية‬ ‫النطف‬ . ‫من‬ ‫كل‬ ‫وزن‬ ‫في‬ ‫يادة‬ ‫ز‬ ‫لوحظ‬ ‫في‬ ‫المنوية‬ ‫الحويصمة‬ ‫وزن‬ ‫نقصان‬ ‫مع‬ ‫البروستات‬ ‫و‬ ‫الخصى‬ ‫ال‬ ‫المعاممة‬ ‫مجاميع‬ G3, G4 ‫نة‬ ‫مقار‬ The Effect Of Estrogen On The Male Reproductive System Of Rats … 99 ‫ة‬ ‫السيطر‬ ‫بمجموعة‬ . ‫كما‬ ‫هرمون‬ ‫مستوى‬ ‫في‬ ‫يادة‬ ‫ز‬ ‫لوحظ‬ FSH ‫حين‬ ‫في‬ ‫ة‬ ‫السيطر‬ ‫بمجموعة‬ ‫نة‬ ‫مقار‬ ‫طيل‬ ‫التستوستيرون‬ ‫مستوى‬ ‫يتغير‬ ‫لم‬ ‫ة‬ ‫في‬ ‫بة‬ ‫التجر‬ ‫ة‬ ‫فتر‬ ‫كافة‬ ‫ال‬ ‫مجاميع‬ . ‫حدث‬ ‫انخفاض‬ ‫عدد‬ ‫في‬ ‫نة‬ ‫مقار‬ ‫الميتة‬ ‫لمنطف‬ ‫المئوية‬ ‫النسبة‬ ‫في‬ ‫يادة‬ ‫ز‬ ‫و‬ ‫الحية‬ ‫لمنطف‬ ‫المئوية‬ ‫النسبة‬ ‫و‬ ‫الكمية‬ ‫النطف‬ ‫ة‬ ‫السيطر‬ ‫بمجموعة‬ . ‫أذى‬ ‫إحداث‬ ‫الى‬ ‫السيمتيدين‬ ‫أدى‬ ‫تثبيط‬ ‫و‬ ‫يتداخل‬ ‫ولم‬ ‫الذكري‬ ‫التناسمي‬ ‫لمجهاز‬ ‫الضار‬ ‫التأثير‬ ‫هذا‬ ‫عكس‬ ‫في‬ ‫االستروجين‬ .

Cimetidine-induced vascular cell apoptosis impairs testicular microvasculature in adult rats

Histology and histopathology, 2012

Cimetidine, an H₂ receptor antagonist used for treatment of gastric ulcers, exerts antiandrogenic and antiangiogenic effects. In the testes cimetidine impairs spermatogenesis, Sertoli cells and peritubular tissue, inducing apoptosis in the myoid cells. Regarding the importance of histamine and androgens for vascular maintenance, the effect of cimetidine on the structural integrity of the testicular vasculature was evaluated. Adult male rats received cimetidine (CMTG) and saline (CG) for 50 days. The testes were fixed in buffered 4% formaldehyde and embedded in historesin and paraffin. In the PAS-stained sections, the microvascular density (MVD) and the vascular luminal area (VLA) were obtained. TUNEL method was performed for detection of cell death. Testicular fragments embedded in Araldite were analyzed under transmission electron microscopy. A significant decrease in the MVD and VLA and a high number of collapsed blood vessel profiles were observed in CMTG. Endothelial cells and v...

NF-kB overexpression and decreased immunoexpression of AR in the muscular layer is related to structural damages and apoptosis in cimetidine-treated rat vas deferens

Reproductive Biology and Endocrinology, 2013

Background Cimetidine, histamine H2 receptors antagonist, has caused adverse effects on the male hormones and reproductive tract due to its antiandrogenic effect. In the testes, peritubular myoid cells and muscle vascular cells death has been associated to seminiferous tubules and testicular microvascularization damages, respectively. Either androgen or histamine H2 receptors have been detected in the mucosa and smooth muscular layer of vas deferens. Thus, the effect of cimetidine on this androgen and histamine-dependent muscular duct was morphologically evaluated. Methods The animals from cimetidine group (CMTG; n=5) received intraperitoneal injections of 100 mg/kg b.w. of cimetidine for 50 days; the control group (CG) received saline solution. The distal portions of vas deferens were fixed in formaldehyde and embedded in paraffin. Masson´s trichrome-stained sections were subjected to morphological and the following morphometrical analyzes: epithelial perimeter and area of the smoo...