Constitutive LH receptor activity impairs NO-mediated penile smooth muscle relaxation

in Reproduction
View More View Less
  • 1 Department of Physiology, Southern Illinois School of Medicine, Carbondale, Illinois, USA
  • 2 Cardiovascular Translational Research Center and Department of Cell Biology and Anatomy University of South Carolina, Columbia, South Carolina, USA
  • 3 Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA

Correspondence should be addressed to P Narayan; Email: pnarayan@siu.edu
Restricted access

Timely activation of the luteinizing hormone receptor (LHCGR) is critical for fertility. Activating mutations in LHCGR cause familial male-limited precocious puberty (FMPP) due to premature synthesis of testosterone. A mouse model of FMPP (KiLHRD582G), expressing a constitutively activating mutation in LHCGR, was previously developed in our laboratory. KiLHRD582G mice became progressively infertile due to sexual dysfunction and exhibited smooth muscle loss and chondrocyte accumulation in the penis. In this study, we tested the hypothesis that KiLHRD582G mice had erectile dysfunction due to impaired smooth muscle function. Apomorphine-induced erection studies determined that KiLHRD582G mice had erectile dysfunction. Penile smooth muscle and endothelial function were assessed using penile cavernosal strips. Penile endothelial cell content was not changed in KiLHRD582G mice. The maximal relaxation response to acetylcholine and the nitric oxide donor, sodium nitroprusside, was significantly reduced in KiLHRD582G mice indicating an impairment in the nitric oxide (NO)-mediated signaling. Cyclic GMP (cGMP) levels were significantly reduced in KiLHRD582G mice in response to acetylcholine, sodium nitroprusside and the soluble guanylate cyclase stimulator, BAY 41-2272. Expression of NOS1, NOS3 and PKRG1 were unchanged. The Rho-kinase signaling pathway for smooth muscle contraction was not altered. Together, these data indicate that KiLHRD582G mice have erectile dysfunction due to impaired NO-mediated activation of soluble guanylate cyclase resulting in decreased levels of cGMP and penile smooth muscle relaxation. These studies in the KiLHRD582G mice demonstrate that activating mutations in the mouse LHCGR cause erectile dysfunction due to impairment of the NO-mediated signaling pathway in the penile smooth muscle.

 

     An official journal of

    Society for Reproduction and Fertility

 

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 732 732 49
Full Text Views 60 60 1
PDF Downloads 34 34 1
  • Ahn GJ, Sohn YS, Kang KK, Ahn BO, Kwon JW, Kang SK, Lee BC & Hwang WS 2005 The effect of PDE5 inhibition on the erectile function in streptozotocin-induced diabetic rats. International Journal of Impotence Research 17 134141. (https://doi.org/10.1038/sj.ijir.3901295)

    • Search Google Scholar
    • Export Citation
  • Akingba AG & Burnett AL 2001 Endothelial nitric oxide synthase protein expression, localization, and activity in the penis of the alloxan-induced diabetic rat. Molecular Urology 5 189197. (https://doi.org/10.1089/10915360152745885)

    • Search Google Scholar
    • Export Citation
  • Andersson KE 2011 Mechanisms of penile erection and basis for pharmacological treatment of erectile dysfunction. Pharmacological Reviews 63 811859. (https://doi.org/10.1124/pr.111.004515)

    • Search Google Scholar
    • Export Citation
  • Ascoli M, Fanelli F & Segaloff DL 2002 The lutropin/choriogonadotropin receptor, a 2002 perspective. Endocrine Reviews 23 141174. (https://doi.org/10.1210/edrv.23.2.0462)

    • Search Google Scholar
    • Export Citation
  • Azadzoi KM & Tejada ISD 1991 Hypercholesterolemia impairs endothelium-dependent relaxation of rabbit corpus cavernosum smooth muscle. Journal of Urology 146 238240. (https://doi.org/10.1016/s0022-5347(17)37759-5)

    • Search Google Scholar
    • Export Citation
  • Behr-Roussel D, Bernabe J, Compagnie S, Rupin A, Verbeuren TJ, Alexandre L & Giuliano F 2002 Distinct mechanisms implicated in atherosclerosis-induced erectile dysfunction in rabbits. Atherosclerosis 162 355362. (https://doi.org/10.1016/s0021-9150(01)00740-7)

    • Search Google Scholar
    • Export Citation
  • Bernabé J, Rampin O, Sachs BD & Giuliano F 1999 Intracavernous pressure during erection in rats: an integrative approach based on telemetric recording. American Journal of Physiology 276 R441R449. (https://doi.org/10.1152/ajpregu.1999.276.2.R441)

    • Search Google Scholar
    • Export Citation
  • Bivalacqua TJ, Champion HC, Usta MF, Cellek S, Chitaley K, Webb RC, Lewis RL, Mills TM, Hellstrom WJ & Kadowitz PJ 2004 RhoA/Rho-kinase suppresses endothelial nitric oxide synthase in the penis: a mechanism for diabetes-associated erectile dysfunction. PNAS 101 91219126. (https://doi.org/10.1073/pnas.0400520101)

    • Search Google Scholar
    • Export Citation
  • Bivalacqua TJ, Liu T, Musicki B, Champion HC & Burnett AL 2007 Endothelial nitric oxide synthase keeps erection regulatory function balance in the penis. European Urology 51 17321740. (https://doi.org/10.1016/j.eururo.2006.10.061)

    • Search Google Scholar
    • Export Citation
  • Boot AM, Lumbroso S, Verhoef-Post M, Richter-Unruh A, Looijenga LH, Funaro A, Beishuizen A, Van Marle A, Drop SL & Themmen AP 2011 Mutation analysis of the LH receptor gene in Leydig cell adenoma and hyperplasia and functional and biochemical studies of activating mutations of the LH receptor gene. Journal of Clinical Endocrinology and Metabolism 96 E1197E1205. (https://doi.org/10.1210/jc.2010-3031)

    • Search Google Scholar
    • Export Citation
  • Burchardt T, Burchardt M, Karden J, Buttyan R, Shabsigh A, De La Taille A, Ng PY, Anastasiadis AG & Shabsigh R 2000 Reduction of endothelial and smooth muscle density in the corpora cavernosa of the streptozotocin induced diabetic rat. Journal of Urology 164 18071 81 1. (https://doi.org/10.1016/S0022-5347(05)67111-X)

    • Search Google Scholar
    • Export Citation
  • Burnett AL 2006 The role of nitric oxide in erectile dysfunction: implications for medical therapy. Journal of Clinical Hypertension 8 (Supplement 4) 5362. (https://doi.org/10.1111/j.1524-6175.2006.06026.x)

    • Search Google Scholar
    • Export Citation
  • Cartledge JJ, Eardley I & Morrison JFB 2001 Nitric oxide‐mediated corpus cavernosal smooth muscle relaxation is impaired in ageing and diabetes. BJU International 87 402407. (https://doi.org/10.1046/j.1464-410x.2001.00067.x)

    • Search Google Scholar
    • Export Citation
  • Chang S, Hypolite JA, Changolkar A, Wein AJ, Chacko S & Disanto ME 2003 Increased contractility of diabetic rabbit corpora smooth muscle in response to endothelin is mediated via Rho-kinase β. International Journal of Impotence Research 15 5362. (https://doi.org/10.1038/sj.ijir.3900947)

    • Search Google Scholar
    • Export Citation
  • Chiou WF, Liu HK & Juan CW 2010 Abnormal protein expression in the corpus cavernosum impairs erectile function in type 2 diabetes. BJU International 105 674680. (https://doi.org/10.1111/j.1464-410X.2009.08852.x)

    • Search Google Scholar
    • Export Citation
  • Chitaley K 2009 Type 1 and Type 2 diabetic‐erectile dysfunction: same diagnosis (ICD‐9), different disease? Journal of Sexual Medicine 6 (Supplement 3) 262268. (https://doi.org/10.1111/j.1743-6109.2008.01183.x)

    • Search Google Scholar
    • Export Citation
  • Costa WS, Carrerete FB, Horta WG & Sampaio FJ 2006 Comparative analysis of the penis corpora cavernosa in controls and patients with erectile dysfunction. BJU International 97 567569. (https://doi.org/10.1111/j.1464-410X.2005.05917.x)

    • Search Google Scholar
    • Export Citation
  • Dean RC & Lue TF 2005 Physiology of penile erection and pathophysiology of erectile dysfunction. Urologic Clinics of North America 32 37939 5, v. (https://doi.org/10.1016/j.ucl.2005.08.007)

    • Search Google Scholar
    • Export Citation
  • Ferrini MG, Kovanecz I, Sanchez S, Vernet D, Davila HH, Rajfer J & Gonzalez-Cadavid NF 2007 Long-term continuous treatment with sildenafil ameliorates aging-related erectile dysfunction and the underlying corporal fibrosis in the rat. Biology of Reproduction 76 9159 23. (https://doi.org/10.1095/biolreprod.106.059642)

    • Search Google Scholar
    • Export Citation
  • Gajbhiye SV, Jadhav KS, Marathe PA & Pawar DB 2015 Animal models of erectile dysfunction. Indian Journal of Urology 31 15–21. (https://doi.org/10.4103/0970-1591.128496)

    • Search Google Scholar
    • Export Citation
  • Gholami SS, Rogers R, Chang J, Ho HC, Grazziottin T, Lin CS & Lue TF 2003 The effect of vascular endothelial growth factor and adeno-associated virus mediated brain derived neurotrophic factor on neurogenic and vasculogenic erectile dysfunction induced by hyperlipidemia. Journal of Urology 169 15771581. (https://doi.org/10.1097/01.ju.0000055120.73261.76)

    • Search Google Scholar
    • Export Citation
  • Giuliano F & Allard J 2001 Dopamine and sexual function. International Journal of Impotence Research 13 ( Supplement 3) S18S28. (https://doi.org/10.1038/sj.ijir.3900719)

    • Search Google Scholar
    • Export Citation
  • Giuliano F, Allard J, Rampin O, Droupy S, Benoit G, Alexandre L & Bernabe J 2002 Pro-erectile effect of systemic apomorphine: existence of a spinal site of action. Journal of Urology 167 402406. (https://doi.org/10.1016/S0022-5347(05)65476-6)

    • Search Google Scholar
    • Export Citation
  • Hai L, Hiremath DS, Paquet M & Narayan P 2017 Constitutive luteinizing hormone receptor signaling causes sexual dysfunction and Leydig cell adenomas in male mice. Biology of Reproduction 96 10071018. (https://doi.org/10.1095/biolreprod.116.146605)

    • Search Google Scholar
    • Export Citation
  • Hedlund P, Aszódi A, Pfeifer A, Alm P, Hofmann F, Ahmad M, Fässler R & Andersson KE 2000 Erectile dysfunction in cyclic GMP-dependent kinase I-deficient mice. PNAS 97 23492354. (https://doi.org/10.1073/pnas.030419997)

    • Search Google Scholar
    • Export Citation
  • Hiremath DS, Geerling EC, Hai L & Narayan P 2020 High levels of androgens cause chondrocyte accumulation and loss of smooth muscle in the mouse penile body. Biology of Reproduction 102 12251233. (https://doi.org/10.1093/biolre/ioaa023)

    • Search Google Scholar
    • Export Citation
  • Jiang X & Chitaley K 2012 The promise of inhibition of smooth muscle tone as a treatment for erectile dysfunction: where are we now? International Journal of Impotence Research 24 4960. (https://doi.org/10.1038/ijir.2011.49)

    • Search Google Scholar
    • Export Citation
  • Laufs U & Liao JK 1998 Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. Journal of Biological Chemistry 273 2426624271. (https://doi.org/10.1074/jbc.273.37.24266)

    • Search Google Scholar
    • Export Citation
  • Liu G, Duranteau L, Carel JC, Monroe J, Doyle DA & Shenker A 1999 Leydig-cell tumors caused by an activating mutation of the gene encoding the luteinizing hormone receptor. New England Journal of Medicine 341 17311736. (https://doi.org/10.1056/NEJM199912023412304)

    • Search Google Scholar
    • Export Citation
  • Liu G, Sun X, Bian J, Wu R, Guan X, Ouyang B, Huang Y, Xiao H, Luo D & Atala A et al. 2013 Correction of diabetic erectile dysfunction with adipose derived stem cells modified with the vascular endothelial growth factor gene in a rodent diabetic model. PLoS ONE 8 e72790. (https://doi.org/10.1371/journal.pone.0072790)

    • Search Google Scholar
    • Export Citation
  • Lombo C, Morgado C, Tavares I & Neves D 2016 Effects of prolonged ingestion of epigallocatechin gallate on diabetes type 1-induced vascular modifications in the erectile tissue of rats. International Journal of Impotence Research 28 133138. (https://doi.org/10.1038/ijir.2016.19)

    • Search Google Scholar
    • Export Citation
  • Luttrell IP, Swee M, Starcher B, Parks WC & Chitaley K 2008 Erectile dysfunction in the type II diabetic db/db mouse: impaired venoocclusion with altered cavernosal vasoreactivity and matrix. American Journal of Physiology: Heart and Circulatory Physiology 294 H2204H2211. (https://doi.org/10.1152/ajpheart.00027.2008)

    • Search Google Scholar
    • Export Citation
  • Marin R, Escrig A, Abreu P & Mas M 1999 Androgen-dependent nitric oxide release in rat penis correlates with levels of constitutive nitric oxide synthase isoenzymes. Biology of Reproduction 61 10121016. (https://doi.org/10.1095/biolreprod61.4.1012)

    • Search Google Scholar
    • Export Citation
  • Matsumoto K, Yoshida M, Andersson KE & Hedlund P 2005 Effects in vitro and in vivo by apomorphine in the rat corpus cavernosum. British Journal of Pharmacology 146 259267. (https://doi.org/10.1038/sj.bjp.0706317)

    • Search Google Scholar
    • Export Citation
  • McGee SR & Narayan P 2013 Precocious puberty and Leydig cell hyperplasia in male mice with a gain of function mutation in the LH receptor gene. Endocrinology 154 39003913. (https://doi.org/10.1210/en.2012-2179)

    • Search Google Scholar
    • Export Citation
  • Mita S-I, Kobayashi N, Yoshida K, Nakano S & Matsuoka H 2005 Cardioprotective mechanisms of Rho-kinase inhibition associated with eNOS and oxidative stress-LOX-1 pathway in Dahl salt-sensitive hypertensive rats. Journal of Hypertension 23 8796. (https://doi.org/10.1097/00004872-200501000-00017)

    • Search Google Scholar
    • Export Citation
  • Moreland RB, Traish A, Mcmillin MA, Smith B, Goldstein I & De Tejada Saenz I 1995 PGE1 suppresses the induction of collagen synthesis by transforming growth factor-beta 1 in human corpus cavernosum smooth muscle. Journal of Urology 153 826834. (https://doi.org/10.1016/S0022-5347(01)67730-9)

    • Search Google Scholar
    • Export Citation
  • Morelli A, Filippi S, Vignozzi L, Mancina R & Maggi M 2006 Physiology of erectile function: an update on intracellular molecular processes. EAU-EBU Update Series 4 96108. (https://doi.org/10.1016/j.eeus.2006.03.003)

    • Search Google Scholar
    • Export Citation
  • Mostafa ME, Senbel AM & Mostafa T 2013 Effect of chronic low-dose tadalafil on penile cavernous tissues in diabetic rats. Urology 81 12531259. (https://doi.org/10.1016/j.urology.2012.12.068)

    • Search Google Scholar
    • Export Citation
  • Narayan P, Ulloa-Aguirre A & Dias JA 2019 Gonadotropin hormones and their receptors. In Yen and Jaffe’s Reproductive Endocrinology, 8th ed. , pp. 2557. Eds Strauss RL Barbieri JLPhiladelphia, PA: Elsevier.

    • Search Google Scholar
    • Export Citation
  • Nehra A, Azadzoi KM, Moreland RB, Pabby A, Siroky MB, Krane RJ, Goldstein I & Udelson D 1998 Cavernosal expandability is an erectile tissue mechanical property which predicts trabecular histology in an animal model of vasculogenic erectile dysfunction. Journal of Urology 159 22292236. (https://doi.org/10.1016/S0022-5347(01)63311-1)

    • Search Google Scholar
    • Export Citation
  • Nunes KP & Webb RC 2012 Mechanisms in erectile function and dysfunction: an overview. In Erectile Dysfunction-Disease-Associated Mechanisms and Novel Insights into Therapy. IntechOpen.

    • Search Google Scholar
    • Export Citation
  • Okumu LA, Braden TD, Vail K, Simon L & Goyal HO 2014 Low androgen induced penile maldevelopment involves altered gene expression of biomarkers of smooth muscle differentiation and a key enzyme regulating cavernous smooth muscle cell tone. Journal of Urology 192 267273. (https://doi.org/10.1016/j.juro.2013.11.101)

    • Search Google Scholar
    • Export Citation
  • Park KH, Kim SW, Kim KD & Paick JS 1999 Effects of androgens on the expression of nitric oxide synthase mRNAs in rat corpus cavernosum. BJU International 83 327333. (https://doi.org/10.1046/j.1464-410x.1999.00913.x)

    • Search Google Scholar
    • Export Citation
  • Penson DF, Ng C, Cai L, Rajfer J & Gonzalez-Cadavid NF 1996 Androgen and pituitary control of penile nitric oxide synthase and erectile function in the rat. Biology of Reproduction 55 5675 74. (https://doi.org/10.1095/biolreprod55.3.567)

    • Search Google Scholar
    • Export Citation
  • Rampin O, Jérôme N & Suaudeau C 2003 Proerectile effects of apomorphine in mice. Life Sciences 72 23292336. (https://doi.org/10.1016/s0024-3205(03)00122-x)

    • Search Google Scholar
    • Export Citation
  • Raviv G, Kiss R, Vanegas JP, Petein M, Danguy A, Schulman C & Wespes E 1997 Objective measurement of the different collagen types in the corpus cavernosum of potent and impotent men: an immunohistochemical staining with computerized-image analysis. World Journal of Urology 15 5055. (https://doi.org/10.1007/BF01275157)

    • Search Google Scholar
    • Export Citation
  • Sattar AA, Wespes E & Schulman CC 1994 Computerized measurement of penile elastic fibres in potent and impotent men. European Urology 25 142144. (https://doi.org/10.1159/000475269)

    • Search Google Scholar
    • Export Citation
  • Seo SI, Kim SW & Paick JS 1999 The effects of androgen on penile reflex, erectile response to electrical stimulation and penile NOS activity in the rat. Asian Journal of Andrology 1 1691 74.

    • Search Google Scholar
    • Export Citation
  • Shenker A, Laue L, Kosugi S, Merendino JJ Jr, Minegishi T & Cutler Jr GB 1993 A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty. Nature 365 652–654. (https://doi.org/10.1038/365652a0)

    • Search Google Scholar
    • Export Citation
  • Simonsen U, Comerma‐Steffensen S & Andersson KE 2016 Modulation of dopaminergic pathways to treat erectile dysfunction. Basic and Clinical Pharmacology and Toxicology 119 (Supplement 3) 6374. (https://doi.org/10.1111/bcpt.12653)

    • Search Google Scholar
    • Export Citation
  • Sopko NA, Hannan JL & Bivalacqua TJ 2014 Understanding and targeting the Rho kinase pathway in erectile dysfunction. Nature Reviews: Urology 11 622–628. (https://doi.org/10.1038/nrurol.2014.278)

    • Search Google Scholar
    • Export Citation
  • Sugimoto M, Nakayama M, Goto TM, Amano M, Komori K & Kaibuchi K 2007 Rho-kinase phosphorylates eNOS at threonine 495 in endothelial cells. Biochemical and Biophysical Research Communications 361 462467. (https://doi.org/10.1016/j.bbrc.2007.07.030)

    • Search Google Scholar
    • Export Citation
  • Themmen APN & Huhtaniemi IT 2000 Mutations of gonadotropins and gonadotropin receptors: elucidating the physiology and pathophysiology of pituitary-gonadal function. Endocrine Reviews 21 551583. (https://doi.org/10.1210/edrv.21.5.0409)

    • Search Google Scholar
    • Export Citation
  • Toque HA, Nunes KP, Yao L, Liao JK, Webb RC, Caldwell RB & Caldwell RW 2013 Activated Rho kinase mediates diabetes‐induced elevation of vascular arginase activation and contributes to impaired corpora cavernosa relaxation: possible involvement of p38 MAPK activation. Journal of Sexual Medicine 10 15021515. (https://doi.org/10.1111/jsm.12134)

    • Search Google Scholar
    • Export Citation
  • Traish AM 2009 Androgens play a pivotal role in maintaining penile tissue architecture and erection: a review. Journal of Andrology 30 363369. (https://doi.org/10.2164/jandrol.108.006007)

    • Search Google Scholar
    • Export Citation
  • Traish AM, Park K, Dhir V, Kim NN, Moreland RB & Goldstein I 1999 Effects of castration and androgen replacement on erectile function in a rabbit model. Endocrinology 140 18611868. (https://doi.org/10.1210/endo.140.4.6655)

    • Search Google Scholar
    • Export Citation
  • Traish A, Kim NN, Moreland RB & Goldstein I 2000 Role of alpha adrenergic receptors in erectile function. International Journal of Impotence Research 12 (Supplement48) S48S63. (https://doi.org/10.1038/sj.ijir.3900506)

    • Search Google Scholar
    • Export Citation
  • Traish AM, Munarriz R, O'connell L, Choi S, Kim SW, Kim NN, Huang YH & Goldstein I 2003 Effects of medical or surgical castration on erectile function in an animal model. Journal of Andrology 24 381387. (https://doi.org/10.1002/j.1939-4640.2003.tb02686.x)

    • Search Google Scholar
    • Export Citation
  • Traish AM, Toselli P, Jeong SJ & Kim NN 2005 Adipocyte accumulation in penile corpus cavernosum of the orchiectomized rabbit: a potential mechanism for veno‐occlusive dysfunction in androgen deficiency. Journal of Andrology 26 242248. (https://doi.org/10.1002/j.1939-4640.2005.tb01091.x)

    • Search Google Scholar
    • Export Citation
  • Ulloa-Aguirre A, Reiter E, Bousfield G, Dias JA & Huhtaniemi I 2014 Constitutive activity in gonadotropin receptors. Advances in Pharmacology 70 3780. (https://doi.org/10.1016/B978-0-12-417197-8.00002-X)

    • Search Google Scholar
    • Export Citation
  • Waldkirch E, Uckert S, Sigl K, Imkamp F, Langnaese K, Richter K, Jonas U, Sohn M, Stief C & Wolf G et al. 2008 Expression and distribution of cyclic GMP-dependent protein kinase-1 isoforms in human penile erectile tissue. Journal of Sexual Medicine 5 5365 43. (https://doi.org/10.1111/j.1743-6109.2007.00735.x)

    • Search Google Scholar
    • Export Citation
  • Wang XJ, Xu TY, Xia LL, Zhong S, Zhang XH, Zhu ZW, Chen DR, Liu Y, Fan Y & Xu C et al. 2015 Castration impairs erectile organ structure and function by inhibiting autophagy and promoting apoptosis of corpus cavernosum smooth muscle cells in rats. International Urology and Nephrology 47 11051115. (https://doi.org/10.1007/s11255-015-1011-3)

    • Search Google Scholar
    • Export Citation
  • Way KJ & Reid JJ 1999 The effects of diabetes on nitric oxide-mediated responses in rat corpus cavernosum. European Journal of Pharmacology 376 7382. (https://doi.org/10.1016/s0014-2999(99)00347-7)

    • Search Google Scholar
    • Export Citation
  • Xie D, Odronic SI, Wu F, Pippen A, Donatucci CF & Annex BH 2007 Mouse model of erectile dysfunction due to diet-induced diabetes mellitus. Urology 70 196201. (https://doi.org/10.1016/j.urology.2007.02.060)

    • Search Google Scholar
    • Export Citation
  • Yang R, Huang YC, Lin G, Wang G, Hung S, Dai YT, Sun ZY, Lue TF & Lin CS 2009 Lack of direct androgen regulation of PDE5 expression. Biochemical and Biophysical Research Communications 380 758762. (https://doi.org/10.1016/j.bbrc.2009.01.144)

    • Search Google Scholar
    • Export Citation
  • Yeşilli C, Yaman O & Anafarta K 2001 Effect of experimental hypercholesterolemia on cavernosal structures. Urology 57 11841188. (https://doi.org/10.1016/s0090-4295(01)00974-8)

    • Search Google Scholar
    • Export Citation
  • Zvara P, Sioufi R, Schipper HM, Begin LR & Brock GB 1995 Nitric oxide mediated erectile activity is a testosterone dependent event: a rat erection model. International Journal of Impotence Research 7 209219.

    • Search Google Scholar
    • Export Citation