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Downregulation of Androgen, Estrogen and Progesterone Receptor Genes and Protein Is Involved in Aging-Related Erectile Dysfunction

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Downregulation of Androgen, Estrogen and Progesterone Receptor Genes and Protein Is Involved in Aging-Related Erectile Dysfunction International Journal of Impotence Research (2003) 15, 391–396 & 2003 Nature Publishing Group All rights reserved 0955-9930/03 $25.00 www.nature.com/ijir Downregulation of androgen, estrogen and progesterone receptor genes and protein is involved in aging-related erectile dysfunction M Shirai1, M Yamanaka1, H Shiina1, M Igawa2, M Fujime3, TF Lue4 and R Dahiya1* 1VA Medical Center and UCSF, Urology, San Francisco, California USA; 2Shimane Medical University, Izumo, Shimane, Japan; 3Juntendo University, Bunkyo-ku, Tokyo, Japan; and 4UCSF/Mt. Zion Medical Center, Department of Urology, San Francisco, California, USA We hypothesize that downregulation of sex hormone receptors (androgen, estrogen and progesterone receptors) is involved in aging-related erectile dysfunction. To test this hypothesis, we investigated the expression of sex hormone receptors in penile crura of aging rats. A total of 40 rats were divided into four groups based on age (6, 12, 18 and 24 months), and the erectile function was analyzed by the measurement of intracavernous pressure. Gene and protein expressions of sex hormone receptors were analyzed by RT-PCR and immunostaining, respectively. The mean intracavernous pressures of 6-, 12-, 18- and 24-month-old rats were 110.1, 89.6, 73.5 and 42.7 cmH2O, respectively. Gene and protein expressions for androgen receptor, estrogen receptor- beta and progesterone receptor were present in similar levels in 6-, 12- and 18-month-old rat crura, but significantly lower or absent in 24-month-old crura. This is the first study to demonstrate that downregulation of sex hormone receptors in aging rat crura is associated with erectile dysfunction. International Journal of Impotence Research (2003) 15, 391–396. doi:10.1038/sj.ijir.3901050 Keywords: steroid hormone receptor genes; erectile dysfunction; aging Introduction and progesterone are present in the circulation in men, and it may be possible that the altered balance between sex hormones and their receptors exerts an Erectile dysfunction (ED) is common in elderly influence on male sexual function. In the central 1,2 men. The Massachusetts Male Aging Study nervous system, progesterone could mediate male reported that the combined prevalence of minimal, sexual behavior by interacting with progesterone moderate and complete ED reached up to 52% in receptor (PR) located in the olfactory bulb.4 aging men. The prevalence of complete ED tripled Although male organs produce estrogens and pro- 1 from 5 to 15% in subjects aged 40–70 y old. Older gesterone, their effects on penis are not clear. In a men are more frequently affected by systemic previous study, we have demonstrated that the diseases and often take a lot of medication. estrogen receptor-beta (ER-b) gene expression was Although it might be possible that these factors are significantly reduced in diabetic rat penis as inter-related with the higher incidence of ED, the compared to controls.5 However, there have been aging process itself undoubtedly plays a significant few reports on the relationship of sex hormone role in the development of ED. receptors (SHR) with aging-related ED. We hypothe- Circulating androgen in serum is considered to be size that SHR (androgen receptor (AR), ER and PR) one of the principal factors that affect male sexual play a significant role in maintaining the male function. It has been shown in rats that an adequate sexual function and altered levels of SHR expression testosterone level is essential to maintain the are involved in the etiology of aging-related ED. To availability of nitric oxide in the cavernous test this hypothesis, we analyzed gene and protein compartment through stimulation of expression expressions of SHR in aging rat crura and correlated and activity of penile endothelial and neuronal them with erectile function. nitric oxide synthase (NOS) isoforms.3 Estrogens Materials and methods *Correspondence: R Dahiya, VA Medical Center and UCSF, Urology, 112F, 4150 Clement Street, San Francisco, Experimental animals CA 94121, USA. E-mail: [email protected] Received 26 October 2002; revised 7 March 2003; accepted A total of 40 male Fisher rats, divided into four 11 March 2003 groups (n ¼ 10) based on age (6, 12, 18 and 24 Downregulation of sex hormone receptor genes M Shirai et al 392 months) were used in this study. These rats Louis, MO, USA) and PCR reaction buffer provided were purchased from the National Institute of by the manufacturer. The primers used for rat AR, Aging, Washington, D.C. and/or Simonson, Gilroy, ER-a, ER-b, PR and glyceraldehyde 3-phosphate California. dehydrogenase (G3PDH) as a reference gene in RT-PCR were as follows: AR forward, 50-TGTTATC TAGTCTCAACGAGC-30; AR reverse, 50-CATCATTT CAGGAAAGTCC-30; ER-a forward, 50-GTCCAATTC Electrostimulation TGACAATCG-30; ER-a reverse, 50-CTTCAACATTC TCCCTCC-30; ER-b forward, 50-TGTACCATAGACA AGAACC-3; ER-b reverse, 50-GGAGTATCTCTGTGT After anesthetizing by intraperitoneal injection of 0 0 pentobarbital (40 mg/kg), a lower abdominal inci- GAAG-3 ; PR forward, 5 -CTCCTGGATGAGCCTGA TG-30; PR reverse, 50-CCCGAATATAGCTTGACCTC- sion was made and the cavernous nerve was 0 0 0 exposed. Electrostimulation was performed using a 3 , G3PDH forward, 5 -TCCCATCACCATCTTCCA-3 and G3PDH reverse, 50-CATCACGCCACAGTTTCC- delicate stainless-steel bipolar hook electrode. The 0 diameter of each pole was 0.2 mm and the two poles 3 . PCR reactions were performed in a PTC-200 were separated by 1-mm distance. Monophasic thermal cycler (MJ Research, Watertown, MA, USA) rectangular voltage pulses were generated by a at 941C for 3 min; 32 cycles at 941C for 1 min, 521C computer and converted to current pulses by a for 1 min, 721C for 1 min; followed by final extension computer-assisted stimulator. The stimulus para- at 721C for 5 min. For semiquantitative analysis, meters were 1.5 mA, 20 Hz frequency, pulse width three other dilution sets of each sample (original, 1/ 0.2 ms and duration 60 s. Each cavernous nerve was 2, 1/4 and 1/8 dilution) underwent PCR. Annealing stimulated. For monitoring intracavernous pressure temperature was 521C for all RT-PCR reactions. The (ICP), the skin overlying the penis was incised and PCR products were electrophoresed on 2.0% agarose the penile crura were exposed. A 25-gauge needle gel and the expression level of these genes was filled with heparin solution (1000 U/ml) was inserted evaluated by an ImageJ software (http://rsb.info. into the right crus and connected to a pressure nih.gov/ij), and the areas under the curves were monitor with polyethylene tubing.6 ICP was mea- calculated and analyzed. PCR cycles were adjusted sured and recorded using a computer with Lab View until these four preparations in each sample were 5.01 software (National Instruments, Austin, TX, within linear range. Between 28 and 32 cycles all USA). The ICP was defined as the maximum SHR PCR reactions were within linear range. The pressure obtained by the stimulation minus the expression of each gene was quantified relative to basal pressure before the stimulation. G3PDH expression and expressed as arbitrary units (AU). The expected sizes of PCR products were 587 base pair (bp), 346, 633, 293 and 380 bp in AR, ER-a, ER-b, PR and G3PDH, respectively. Tissue preparation Penile crura of each rat were collected immediately Immunohistochemistry after completing electrostimulation. Half of the sample was fixed in 10% buffered formalin (pH Tissue sections were cut (4 mm) and mounted on 7.0) and embedded in paraffin wax, and used for a slide. Tissue block sections were dewaxed, immunostaining. The remaining half of each sample rehydrated, incubated with 0.3%(v/v) hydrogen 1 was immediately frozen and stored at –80 C until peroxide for 20 min, and autoclaved at 1211C for analyzed. 15 min in 10 mM citrate buffer (pH 6.0). The samples were incubated with serum block (Santa Cruz Bio- technology, Inc., Santa Cruz, CA, USA) for 20 min at Reverse transcription-polymerase chain reaction room temperature followed by overnight at 41C with (RT-PCR) the following antibodies: 1:150 dilution of a mono- clonal antibody against mouse ER-a (Ab-10) (Lab Vision Corp., Fremont, CA, USA), 1:400 dilution of a Total RNA was extracted from the samples of penile polyclonal antibody against rabbit AR (C-19), 1:400 crura using Tri-Reagent (Molecular Research Center, dilution of a polyclonal antibody against rabbit ER-b Cincinnati, OH, USA). Complementary DNA (cDNA) (H-150) and 1:100 dilution of a polyclonal antibody was constructed by reverse transcription (Promega against rabbit PR (H-190) (Santa Cruz Biotechnology, Corp., Madison, WI, USA) using the total RNA as a Inc.). After the slides were washed, they were template. The samples then underwent PCR ampli- incubated with a biotinylated goat anti-mouse anti- fication, cDNA samples were diluted in 20 mlof body and streptavidin-peroxidase (Lab Vision Corp.) solution containing 200 mM of dNTP, 500 nM of each for ER-a; or biotinylated goat anti-rabbit antibody primer, 0.5 U of Red Taq DNA polymerase (Sigma, St and HRP-streptavidin (Santa Cruz Biotechnology, International Journal of Impotence Research Downregulation of sex hormone receptor genes M Shirai et al 393 Inc.) for AR, ER-b and PR at room temperature for Gene expression of AR, ER-a, ER-b and PR in aging 30 min. Following incubation with the avidin–biotin rat crura (Figures 1 and 2). complex, the antigen–antibody complexes were visualized with diaminobenzidine (Lab Vision Corp.). The sections were counterstained using Typical results and summarized data of each RT- hematoxylin. As a negative control, normal goat PCR are shown in Figures 1 and 2, respectively. IgG was substituted for the specific antibody at There was no significant difference in AR mRNA the same dilution.
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