528 II.4 Therapeutic Options DM (1998) Metastatic prostatic carcinoma in a male-to- vanKesterenP,LipsP,GoorenLJ,AsschemanH,MegensJ female transsexual. Br J Urol 81:776 (1998) Long-term follow-up of bone mineral density and van Kesteren PJ, Asscheman H, Megens JA, Gooren LJ (1997) bone metabolism in transsexuals treated with cross-sex hor- Mortality and morbidity in transsexual subjects treated with mones. Clin Endocrinol (Oxf) 48:347–354 cross-sex hormones. Clin Endocrinol (Oxf) 47:337–342 II.4.9 Treatment of Sexual Dysfunction L.J.G. Gooren Summary function does not necessarily imply restoration of a The introduction of the phosphodiesterase type 5 happy sex life (Montorsi and Althof 2004). Neverthe- inhibitors (PDE inhibitors) has been a major step less, the introduction of the phosphodiesterase type 5 forward in the treatment of erectile dysfunction inhibitors has substantially improved the therapeutic (ED). Though efficacious and safe, 50% of men options for ED. discontinue treatment, largely because other sexo- logical issues have not been properly addressed. To II.4.9.1.1 predict onset and duration of action, insight into Phosphodiesterase Type 5 Inhibitors the pharmacokinetics of the PDE inhibitors is re- quired. The identification of pathways in the physiology of erection and the discovery of the importance of nitric ■ In men whose testosterone levels are low, oxide (NO) and its downstream effects lie at the basis of testosterone substitution may booster the effi- the development of the phosphodiesterase type 5 in- cacy of PDE inhibitors. hibitors (PDE inhibitors). Subsequent to sexual stimu- ■ Before receiving PDE inhibitor the cardiovas- lation, NO arising from the nerve endings of non-ad- cular status of a patient must be assessed. renergic non-cholinergic innervation of the corpus ca- Themainactionoftestosteroneisonthecentral vernosum activates guanylyl cyclase, an enzyme that nervous system. It improves libido and mood. catalyses the conversion of GTP to cGMP.At the cellular Levels in the low-normal range suffice. level cGMP is broken down to 5-GMP by phosphodies- Hyperprolactinaemia impairs sexual interest terase type 5. Via a molecular cascade cGMP lowers in- and leads to secondary ED. Dopamine agonists are tracellular calcium and vascular smooth muscle of the the treatment of choice. corpus cavernosum relaxes, resulting in an increased Men with paraphilias may be treated with drugs penile blood flow thus facilitating the initiation and that lower androgen action if the desire to act out maintenance of an erection. their paraphilia is high. The pharmacological action of PDE inhibitors man- ifests itself only when a person is sexually aroused, which distinguishes this class of drugs from intracaver- II.4.9.1 nosal injections. This is also important information for the user (Seftel 2004). Erectile Dysfunction The efficacy and relative safety of PDE inhibitors is The availability of a highly efficacious and relatively well documented now. They have a common mode of safe compound such as the phosphodiesterase type 5 action, the inhibition of PDE 5. Selectivity and tissue inhibitor sildenafil has had a profound impact on diag- localization of the PDE inhibitors determine the side- nosis and treatment of erectile dysfunction (ED). Once effect profiles and safety. the domain of the urologist attempting to define the There are presently three PDE inhibitors available precise aetiology, ED is now largely treated by first-line for prescription: sildenafil, vardenafil and tadalafil. All physicians, without much of a diagnostic work-up. De- are efficacious, but there are differences in pharmaco- spite the simplicity and safety of the present therapy of kinetic profile, interactions with food and drugs, and ED, approximately 50% of patients discontinue treat- possible side-effects. Taking nitrate medications is an ment. The reasons for discontinuations lie mostly in an absolute contraindication to the use of PDE inhibitors incomplete evaluation of the sexual problem. Hypo- since PDE inhibitors increase the potential for exces- gonadism, ejaculatory dysfunction, lower urinary tract sively low blood pressure. Low blood pressure, though symptoms, depression, and last but not least partner is- to a lesser degree, has also been observed with PDE in- II.4 sues may all be components of the sexual dysfunction hibitors in men taking alpha adrenoreceptor antago- of the patient, and apparently restoration of erectile nists, such as doxazosin, prazosin, terazosin, alfuzosin II.4.9 Treatment of Sexual Dysfunction 529 ortamsulosin,whichareusedasantihypertensive It is not rare for patients to wish to “experiment” agents or for symptomatic relief of lower urinary tract with the available PDE inhibitors to find the drug that symptoms (LUTS). The latter is relevant since sexual suits them best. Patients do have distinctly different dysfunction is not rare in men with LUTS, both signifi- sexual habits with regard to timing of sexual activity. cantly increasing with age, and possibly sharing aetio- Another consideration is the “readiness” of the patients logical factors (Rosen et al. 2003). Drugs such as eryth- when sexual activity is initiated by the partner. romycin, ketoconazole and itraconazole, and protease The above information on dose–response effects inhibitors used in HIV treatment such as saquinavir, (sildenafil and tadalafil), the interaction with (particu- indinavirandritovirmayslowlivermetabolismofPDE larly fat-rich) food in slowing absorption, and the inhibitors and may increase plasma levels and the effect pharmacokinetic profiles may provide guidance. Pa- of PDE inhibitors. Grapefruit juice may have a similar tients who, in a series of at least four attempts to have effect on liver metabolism. Lower doses must be used in intercourse, do not respond to the maximum dose of patients with liver and/or kidney disease. one of the PDE inhibitors are unlikely to respond to the Sildenafil and vardenafil work best if no (fatty) food others. has been taken within the previous 2 h, while tadalafil Naturally, patients starting treatment with a PDE in- can be used without regard to food. hibitor will experience some anxiety about whether the Common adverse effects attributable to vasodilato- new drug will indeed induce an erection. Anxiety may ry effects include headache, flushing, stuffy nose, stom- reduce sexual arousal, which is a necessary condition ach pain, back pain (tadalafil) and indigestion. Visual for the desired pharmacological action of PDE inhibi- problems (for example, blurred vision, increased sensi- tors. Therefore, in case the patient recognizes this as a tivity to light, bluish haze, or temporary difficulty dis- potential problem, testing the efficacy of the drug first tinguishing between blue and green) may occur, more with masturbation may be recommended. often with sildenafil since the latter is less selective in At least 50% of patients suffering from ED have en- inhibiting phosphodiesterase 6 in the retina. dothelial dysfunction, and there are early indications Theprescribedtabletstrengthisswallowed that chronic treatment with PDE inhibitors might im- 30–60 min before sexual activity. Tadalafil has a longer prove their vascular function (Jackson 2003; Reffel- duration of increased sensitivity for developing an mann and Kloner 2003). At the same time chronic use erection (up to 24–36 h) compared with sildenafil and would obviate the need to take a PDE inhibitor before vardenafil (up to 4–12 h). engaging in sexual activity. There is no convincing evidence that the three avail- able PDE inhibitors differ significantly in their clinical II.4.9.1.2 efficacy. For sildenafil (50 and 100 mg) and tadalafil PDE Inhibitors and the Cardiovascular System (10 and 20 mg) there is a dose–response relationship, whichisnotsomuchthecaseforvardenafil(10and When the first PDE inhibitor sildenafil was introduced 20 mg) (Carson et al. 2004). In general starting with the there was great concern about the cardiovascular safety lowest dose of PDE inhibitors is recommended. of this class of drugs. In many a patient the aetiology of The feature that distinguishes the three PDE inhibi- ED is (also) based on vascular disease. The availability tors is their pharmacokinetic profile, which impacts on ofthedrugpromptedpatientstoresumesexualactivity their clinical use, in terms of the initiation of optimal after prolonged periods of inactivity. The pharmaco- pharmacological effect and duration of pharmacologi- logical action of PDE inhibitors is vasodilatory. Fears cal action [for review see Porst (2004)]. The time to arose that these elements would lead to myocardial is- maximal plasma concentration (in minutes) is on aver- chaemia or infarction when intercourse was attempted. age 60 (variation 30–120) for sildenafil, 120 (variation Fortunately,theseconcernshaveremainedunsubstan- 30–720!) for tadalafil and 60 (variation 30–120) for tiated. Placebo-controlled studies fail to show a higher vardenafil. These are statistical data and individual pa- cardiovascular morbidity/mortality in patients using tients may experience a faster onset of action. This in- PDE inhibitors (Hutter 2004; Kloner 2004). Naturally, formation lets patients plan prospective sexual action. before starting PDE inhibitors, the cardiovascular risks Another significant pharmacokinetic variable is the of the patient must be assessed. Factors such as hyper- half-life of the drug, which provides an indication of tension, biochemical risk markers, angina pectoris, ar- how long the