International Journal of Impotence Research (1997) 9, 17±26 ß 1997 Stockton Press All rights reserved 0955-9930/97 $12.00 The in¯uence of medication on erectile function W Meinhardt1, RF Kropman2, P Vermeij3, AAB Lycklama aÁ Nijeholt4 and J Zwartendijk4 1Department of Urology, Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; 2Department of Urology, Leyenburg Hospital, Leyweg 275, 2545 CH The Hague, The Netherlands; 3Pharmacy; and 4Department of Urology, Leiden University Hospital, P.O. Box 9600, 2300 RC Leiden, The Netherlands Keywords: impotence; side-effect; antipsychotic; antihypertensive; physiology; erectile function Introduction stopped their antihypertensive treatment over a ®ve year period, because of side-effects on sexual function.5 In the drug registration procedures sexual Several physiological mechanisms are involved in function is not a major issue. This means that erectile function. A negative in¯uence of prescrip- knowledge of the problem is mainly dependent on tion-drugs on these mechanisms will not always case reports and the lists from side effect registries.6±8 come to the attention of the clinician, whereas a Another way of looking at the problem is drug causing priapism will rarely escape the atten- combining available data on mechanisms of action tion. of drugs with the knowledge of the physiological When erectile function is in¯uenced in a negative mechanisms involved in erectile function. The way compensation may occur. For example, age- advantage of this approach is that remedies may related penile sensory disorders may be compen- evolve from it. sated for by extra stimulation.1 Diminished in¯ux of In this paper we will discuss the subject in the blood will lead to a slower onset of the erection, but following order: may be accepted. A mild `venous leak' can be compensated by extra in¯ow of blood2 and the Physiology: suboptimal rigidity may be accepted. Therefore a Penile erection negative in¯uence of medication on the erectile Control mechanisms function will not always lead to a complaint. hormonal system The problems themselves for which drugs are central nervous system prescribed, such as cardiovascular disease, psycho- peripheral nervous system sis, depression, diabetes mellitus may have a Cavernous tissue function negative effect on sexual and erectile function. In Prescription drugs: this situation the already compromised system is more vulnerable to adverse effects of medication. psychotropic drugs Erroneously the erectile dysfunction may be attrib- cardiovascular drugs uted to the disease, instead of the medication. In miscellaneous drugs geriatric patients, who often use several medicines drugs to treat erectile disorders at the same time, the issue is even further compli- Guidelines for clinical practice cated.3 Many patients will not discuss their sexual problems when not invited to do so. In clinical practice all this will result in an underestimation of Penile erection the drug factor in impotence. It has been estimated that the drug factor plays a role in 25% of patients An extensive review on the physiology of penile seeking advice for erectile dysfunction.4 Patient erection has been published by Andersson.9 The compliance concerning correct medication usage, initiation of an erection is a neurogenic event. The is, among other things, dependent on side-effects. In impulses may originate from the brain (as in REM a large follow-up program 8.3% of the male patients sleep erections) or derive from sacral re¯exes (as in some paraplegic patients). In normal circumstances Correspondence: Dr W Meinhardt. it will be a combination of both. Dilatation of the Received 25 July 1996; accepted 21 October 1996 arteria cavernosa and the helicine arteries is con- The in¯uence of medication on erectile function W Meinhardt et al 18 trolled by the well described neural regulation The negative effect of castration on erectile function mechanisms. This is however not suf®cient for the may be secondary to this. Erections during REM development of a rigid erection, since there are sleep are inhibited by castration, suggesting an shortcuts to the venous channels and the resistance in¯uence on the central nervous system.14,15 of the lacunar spaces in the corpora cavernosa The adult corpus cavernosum hardly has any depends on smooth muscle tone. Relaxation of the receptors for testosterone, while in children testos- smooth muscle cells is necessary for the expansion terone induces growth of the penis, rather than of the corpora, this is initiated by parasympathetic erections.16 It has been shown that the hormonal impulses. Sympathetic tone needs to be reduced, manipulation preceding gender reassignment (phar- since this causes contraction of the smooth muscle macological castration) lowers the amount of nitric cells. The search for non cholinergic, non adrenergic oxide synthase (NOS) in the corpus cavernosum (NANC) transmission of the impulses of the nervous tissue.17 In a rat model nitric oxide mediated erectile system to the smooth muscle cells has drawn activity was a testosterone dependent event, while attention to nitric oxide (NO) as an initiator of a in another rat model it was shown that dihydrotes- cascade of chemical events that results in relaxation tosterone levels positively correlate with the amount of all the smooth muscle cells of the corpora.10,11 of NOS in the corpus cavernosum.18,19 However, After the ®rst impulses, the scarcely innervated after castration the local mechanisms leading to network of endothelial cells and smooth muscle penile smooth muscle relaxation are not impaired, cells take care of their own coordination in order to possibly since compensation occurs by lowering of relax all at the same time. This is accomplished the sympathetic tone.20 through tight junctions and gap junctions. Free The testosterone serum level is mainly deter- in¯ow of blood is allowed in the lacunae, ®nally mined by the epiphyse/pituitary/testes feedback resulting in such a tumescence that out¯ow of blood system. Estrogens and steroid-antiandrogens in¯u- will be stopped by compression of the venous ence the testosterone serum level via this system. channels between the distended corporal tissue High prolactin levels also lower the testosterone and the tunica albuginea. This leads to rigidity of production. Hyperprolactinaemia may be drug in- the penis that may be further enhanced by contrac- duced. Cimetidine, estrogens, metoclopramide, a- tions of pelvic ¯oor muscles, compressing the crurae methyldopa, morphine and the phenothiazines are of the corpora cavernosa and building a pressure known for this. The elevation of prolactin serum that is higher than the systolic blood pressure.12 levels is usually mild and not accompanied by a In¯ow of blood to the corpora cavernosa is minimal decrease in serum testosterone levels. In absence of at that point. The erection comes to an end by a low testosterone serum level the relation of renewed contraction of the smooth muscle cells, hyperprolactinaemia and impotence is unclear and initiated by sympathetic impulses and by the withdrawal of the culprit drug maybe disappointing production of substances such as endotheline-1, because of other organic factors determining the prostaglandin F2a and tromboxane A2 by the erectile dysfunction.21 endothelial cells.9,13 This will allow venous out¯ow Some drugs have an unexpected anti-androgen by decompression of the subtunical venous plexus. effect such as H2-antagonists and some antifungal drugs. Effects on the testosterone levels have been described of beta blockers, spironolactone and digoxin, the practical value of these reports is Control mechanisms unclear.22±24 Several control mechanisms play a role in sexual behavior and erectile function. Many have effects on Central nervous system the central nervous system as well as on the cardiovascular system. There is an analogy in the responses of blood vessels to these regulation Emotional and cognitive factors in¯uencing sexual mechanisms and the responses of the tissue in the behavior and erectile function are beyond the scope corpora cavernosa. of this review. Several parts of the brain are involved in sexual function and already on this central level integration with autonomous regulation of other body functions is present. The brain may inhibit or Hormonal system facilitate the spinal mechanisms leading to an erection. Among others, the hypothalamic and limbic pathways are intensively studied. The medial The exact role of testosterone on erectile function is preoptic hypothalamic area, in contact with the not well de®ned. The negative in¯uence of castra- paraventricular nucleus of the hypothalamus is tion on libido is regularly seen in clinical practice. important for autonomic and neuroendocrine inte- The in¯uence of medication on erectile function W Meinhardt et al 19 gration.9 Dopaminergic systems and serotoninergic mechanisms of homotropic and heterotropic inter- systems play a major role in sexual behavior and action can be in¯uenced by drugs. The pelvic erectile function.25 For several psychopharmaca ganglions are also the site where neuromodulation these systems are the speci®c target.26 Apomor- takes place by various endogenous substances phine, a central dopamine agonist, is effective in (serotonin, adenosine, histamine, enkephalin and enhancing sexual behavior in the animal model as dopamine) at their speci®c receptors.29 At the well as in humans.27 For this effect testosterone peripheral