Development of a model for the induction of estrogen‐related prostatic hyperplasia in the dog and its response to the aromatase inhibitor 4‐hydroxy‐4‐androstene‐3,17‐dione: Preliminary results

Habenicht, U.‐F.; Schwarz, Klaus; Schweikert, H.U.; Neumann, F.; Etreby, M. El Fathy

doi:10.1002/pros.2990080208

Cited by 61 publications

(21 citation statements)

References 26 publications

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“…Histologically the stimulating action of androstenedione on the stroma, including smooth muscle, was clearly antagonized by 1 -Methyl-ADD. Surprisingly, the epithelial structures also exhibit noticeable inhibition: in our hands blockade of the estrogenic potency of aromatizable androgens has tended so far to cause intensification of the androgenrelated effect [18]. In this context the work of Ewing et a1 [36] may be of interest; they found that young dogs (2.5 years) with BPH produce intratesticularly an estrogenic molecule which cross-reacts with antibodies against 17 fi-estradiol and competitively displaces 17 P-(3H)-estradiol from the estrogen receptor (rat uterus) , without, however, being structurally identical with either estradiol or estrone or estriol.…”

Section: Discussionmentioning

confidence: 85%

Synergic inhibitory effects of the aromatase inhibitor 1‐methyl‐androsta‐1, 4‐diene‐3, 17‐dione and the antiandrogen cyproterone acetate on androstenedione‐ induced hyperplastic effects in the prostates of castrated dogs

Habenicht¹,

Etreby²

1987

The Prostate

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We examined whether the induction of estrogen-related hyperplastic changes in the prostate (ie, activation and stimulation of the stroma, especially of the smooth muscle) of castrated beagle dogs was reproducible. The effectiveness of the aromatase inhibitor 1-methyl-androsta-1, 4-diene-3, 17-dione (1-Methyl-ADD) in antagonizing such estrogen-related alterations was investigated in comparison with a combined treatment of 1-Methyl-ADD and the antiandrogen CPA. These studies have demonstrated the suitability of the androstenedione model for testing the efficacy of aromatase inhibitors. In addition, it has been demonstrated that an aromatase inhibitor in combination with an antiandrogen can synergically inhibit the glandular and stromal components of the prostate.

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Section: Discussionmentioning

confidence: 85%

Synergic inhibitory effects of the aromatase inhibitor 1‐methyl‐androsta‐1, 4‐diene‐3, 17‐dione and the antiandrogen cyproterone acetate on androstenedione‐ induced hyperplastic effects in the prostates of castrated dogs

Habenicht¹,

Etreby²

1987

The Prostate

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“…On the other hand, estradiol-176 elevated PIP levels without having any significant effect on the protein and tissue weights at the dose level studied. Since the involvement of estrogen in stromal hypertrophy is well known, it has been used previously for induction of prostatic hyperplasia in dogs [7]. There is evidence from animal as well as human studies suggesting an important role of the stroma and estrogens in the pathogenesis of benign prostatic hyperplasia (BPH) in man [3, 5 , [2,9,11,12,21,271.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Rat Prostatic Inhibinlike Peptide (PIP) by Steroids and Protein Hormones

Teni

Sheth

1988

Archives of Andrology

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Prostatic inhibinlike peptide (PIP) was detected in the ventral but not in the dorsal lobe of rat prostate.On orchiectomy, PIP concentration in the ventral prostate increased significantly, whereas it decreased on testosterone administration and attained value comparable with that in intact control. Estradiol-170-treated animals exhibited high levels of PIP in absence of significant alterations in the protein content. The effect of prolactin and human chorionic gonadotropin on PIP concentration was not so prominent at the dose levels studied. The present study thus demonstrates negative regulation of PIP by testosterone and stimulatory effect of estradiol-170 on PIP in rat ventral prostrate. INTRODUCTIONThere is a high concentration of prostatic inhibinlike peptide (PIP) in the normal and hyperplastic human prostate [4, 23, 301. Biologically active rat PIP has been shown by in vivo [lo] as well as in vitro studies [20]. High levels of PIP observed in the prostate-rich secretions of human seminal plasma (HSP) have further substantiated its prostatic origin [ 11. The importance of PIP as a prostatic tissue marker [4] and in confirming the prostatic origin of difficult-to-diagnose invasive tumors in metastic lesions [25] has been demonstrated by immunocytochemical localization studies. These data led us to study the status of immunoreactive PIP in the rat ventral and dorsal prostate and its modulation by steroid and protein hormones. MATERIALS AND METHODSSteroid and protein hormones used for the study were procured from Sigma Chemicals. Ninety-dayold male rats of Sprague Dawley strain were divided into the following groups: group I, intact controls; group 11, effect of castration; group 111, in vivo effect of steroid hormones: (a) testosterone (T) (500 pg), subgroup contained a minimum of five rats. All the animals except the intact controls were bilaterally castrated. Twenty-four hours after castration, the animals in groups I11 and IV were treated daily with the above-mentioned doses of respective hormones, administered subcutaneously for six days. Three hours after the last injection, animals of all the groups were killed and prostates excised. The dorsal and ventral lobes were weighed separately and homogenized individually in 0.01 M PBS, pH 7.0, and centrifuged at 800 g for 30 min at 4 "C. The supernatants were stored at -20 "C until analyzed for protein by Lowry's Method [14] and PIP by radioimmunoassay (RIA) [29]. A homologous preparation of PIP isolated from HSP [26] was used as a reference standard and as an antigen for radioiodination using Iz5I, obtained from Radiochemical Centre, Amersham, U. K. Iodination was carried out according to the method of Greenwood et al.[6] with appropriate modifications [29]. The specific activity of the labeled hormone ranged from 100 to 150 pCiIpg PIP. Specific antibodies to PIP were raised in rabbit by active immunization. Details regarding the high specificity of this antiserum and RIA methodology have been described [22]. The sensitivity of the assay was 0.7 to 40 ng o...

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“…Animal experiments have emphasized the potential role of estrogens in the pathogenesis of BPH (32±35). Habenicht et al ®rst demonstrated the effect of aromatase inhibitor, 4-hydroxy-4-androstene-3,17-dione, on the experimentally induced BPH in the dog (36). They suggested that estrogen-related effects could be clearly antagonized by simultaneous treatment with the aromatase inhibitor.…”

Section: Discussionmentioning

confidence: 99%

Effects of a new steroidal aromatase inhibitor, TZA-2237, and/or chlormadinone acetate on hormone-induced and spontaneous canine benign prostatic hyperplasia

Ito

Fukabori²,

Shibata³

et al. 2000

European Journal of Endocrinology

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Objective: It has been known for many years that human benign prostatic hyperplasia (BPH) is composed predominantly of hyperplastic stromal cells rather than epithelial cells. In the present study the effects of a new steroidal aromatase inhibitor on hormone-induced and spontaneous canine BPH were investigated. Methods: (1) Effects of TZA-2237 on hormone-induced canine BPH. Ten castrated beagles were administered testosterone and androstenedione 6 days/week for 8 months, and divided randomly into three groups after 2 months of treatment as follows. Group I served as controls, Group II was given 0.5 and Group III was given 2.5 mg/kg/day TZA-2237 5 days/week for 6 months. (2) Effects of TZA-2237 on spontaneous canine BPH. Twenty aged beagles with BPH were divided into ®ve groups, Group IV was untreated, Group V was treated with 1 and Group VI with 5 mg/kg/day TZA-2237 5 days/week for 31 weeks. Group VII was treated with 5 mg/kg/day Atamestane and Group VIII was treated with 0.3 mg/kg/day chlormadinone acetate (CMA) 5 days/week. (3) Effects of TZA-2237 combined with CMA on spontaneous canine BPH. Three aged beagles with BPH were treated with 1 mg/kg/day TZA-2237 and 0.03 mg/kg/day CMA 5 days/week for 20 weeks (Group IX) and a further three aged beagles with BPH were treated with 0.3 mg/kg/day CMA alone 5 days/week (Group X). Results: Hormone-induced prostatic growth was signi®cantly suppressed in group III compared with that in other groups. In Group III, the intraprostatic aromatase activity, estradiol level and androgen receptor content decreased signi®cantly in comparison with the values in Group I. The prostatic weights in Groups V, VI and VII increased signi®cantly in comparison with the weight in Group IV. Serum LH and testosterone levels in Groups V, VI, and VII increased signi®cantly in comparison with the level in Group IV. The prostatic weight in Group IX was decreased only slightly, but the smooth muscle component was decreased signi®cantly. Conclusions: TZA-2237 is a new, unique and effective aromatase inhibitor that causes inhibition of both epithelial and stromal compartments in hormone-induced canine BPH. Dual inhibition of androgen and estrogen resulted in inhibition of smooth muscle growth, and should prove effective as a new method of treatment given the atrophic effects on not only the epithelium but also the stroma in human BPH.

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Development of a model for the induction of estrogen‐related prostatic hyperplasia in the dog and its response to the aromatase inhibitor 4‐hydroxy‐4‐androstene‐3,17‐dione: Preliminary results

Cited by 61 publications

References 26 publications

Synergic inhibitory effects of the aromatase inhibitor 1‐methyl‐androsta‐1, 4‐diene‐3, 17‐dione and the antiandrogen cyproterone acetate on androstenedione‐ induced hyperplastic effects in the prostates of castrated dogs

Synergic inhibitory effects of the aromatase inhibitor 1‐methyl‐androsta‐1, 4‐diene‐3, 17‐dione and the antiandrogen cyproterone acetate on androstenedione‐ induced hyperplastic effects in the prostates of castrated dogs

Modulation of Rat Prostatic Inhibinlike Peptide (PIP) by Steroids and Protein Hormones

Effects of a new steroidal aromatase inhibitor, TZA-2237, and/or chlormadinone acetate on hormone-induced and spontaneous canine benign prostatic hyperplasia

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