Drugs 18: 206-2170979) 0012-6667 /79/0900-0206 /$03.00/0 C ADIS Pre ss Aust ralasia Pl y ltd. All right s reserved.

Drugs and Impaired Male Sexual Function John D. Horowitz and Alan J . Goble O inical Pha rmacology Unit a nd Department of Car diology . Austin Hospital. Heidelberg. Melboume

The recognised factors leading to impaired male sexual function have not changed significantly in recent years. However, there has been a tendency towards freer discussion of sexual matters and in particular greatly increased awareness of the woman's needs in a sexual relationship. This trend, together with changed general conceptions (and misconceptions) of sexual 'norms' has probably contributed to an increase in the willingness of males to present for treatment of inadequate sexual function. This review examines the role of drug therapy in producing sexual dysfunction in meres'. While some 1 It was initially in~nded that this review shou ld encompass drug· induced. suual dysfu nctio n affecting both sexes. How ever. While the re is little rel iable info rmation concerning the effects o f d rugs on selu.ality in males . there is virtuall y none relating to females, apan from the influence of oral oon\nlCeptives, In the absence ofsatisfaetory data . one cannot assu me anything about d rug effects in females by analogy w ith the male. Fo r eumple. a par ticular drug may give different effects o n active and passive components of fe ma le selual behaviour. and on a utoerotic behav iou r (Rose, Inn The decision to elclude effects of d rugs on female seluality from this review therefore highl ights a major need for future investigation of this important aspect o f drug use.

drugs induce relatively isolated effects on the components of male sexual function, such as libido, penile erection and ejaculation of seminal fluid, in general, changes are more complex.

J. Physiological Mechanisms Normal male sexual function depends on the complex interaction of a number of neurogenic, hormonal and vascular mechanisms. Knowledge concerning the exact nature and relative importance in man of these various factors remains incomplete.

1.1 Neurogenic/Psychogenic Mechanisms

1.1.1 Mechanisms Controlling Penile Erection These are summarised in figure I . Influences giving rise to penile erection may be classified as psychogenic or reflexogenic. The former are mediated by impulses descending from the cerebral cortex and the limbic system to eventually reach the thoraco-lumbar sympathetic ganglion and

207

8pe(:iBl SenSOl'YS tImu li (visual, aud,IOfY . et c)

Sympathetic

I

1

I

LimbicConu

I

Lumbar Spinal

Nerves

I

""'"

_.

p.,..ympathetlC

1

I

Vesoddll la llOn

I

I

Erection

I

.........

I

• I

Tacl", Slomuli

I

8owel/~ Oostensoon

I

\.-

$2-'

I

Vn Def...• nd ~l V. . . -

I

I

Y

Cont' lICtJon of

Stimu~

I

r--I I

'PsychlC'

(f antasy, .IC)

-~

I

Frg. I. N" urogen ic and psychogenic mecha nism. 01 penile erection and ejaculation.

I

Contrk_ of boA:>ar

-'"

I

Drugs and Im paorecl Ma le Se.ua1 Fuoclion

the sacr al parasympa thetic nerv es. Reflexogenic stimuli are initiated largely by tactile sti mulation of the genital regions. and are tra nsmitted via the puden dal nerves of the spinal cord. Efferent impulses transmitted via the parasympathetic fibres arising from the second, thi rd and fourth sacral segments initiate penile erection. These sacra l parasympathetic nerves also supply the distal colon. rectu m and the detrusor muscle of the bladder. However . incomplete anatomical lesion of these nerves or the effects of dru gs interfering w ith cholinergic neurotransm itter function tend to prod uce impote nce before clinically interfering with bladder or large bowel function (Boo; and Co merr. 197 1). 1.1.1 M« hanisms Controlling Emission a/Semen Emission of semen is largely controlled by sympathetic nerve fibres originating from the second and third lu mbar segments. Neurotransmission in these sympathetic nerve termi nals apparently activates a adrenoceptors. inducing contraction of the seminal vesjcies and vas defere ns, and triggers contracrons of the bulbar muscles, which induces ejaculation.

J.J.3 Interaction ofControl Mechanisms The possible influence of cortical (or 'psychogenic') impu lses on sexual arousal include inhibit ion of other (e.g. reflexogenic) stimuli, Thus drugs which depress the activity of cortical centres may. depend ing on circumsta nces and dosage . eithe r initiate or relieve sexual dysfuncti on. However . studies of patients with spinal cord lesions at various levels also show that penile erection may occur with purely psychogenic (Kuhn. 1950) or reflexogenic (Talbot. 1955) stim uli.

1.2 Vascular Mechanisms The actual process of penile erectio n involves a the two corpora cavemosa and the corpus spon giosum. This is bro ught about by the relaxat ion of valve-like structures called 'potsters' wh ich. at times of penile Ilac-

pooling of blood in the 'erectile' tissues -

cidity, limit entry of arteriolar blood to the vascular

spaces (Conti, 1952), These potsters are control led by both sympathetic and parasympathetic fibres (from the thoracolumbar and sacral centres , respectively).

1.3 Hor monal Mechanisms

W hile a number of endocrine disorder s may be associated with impai red male sexual function (vide infra), th e exact role of var ious horm ones in the maintenance of nor mal sexual function is subject to debate. This is well illustrated by the var ious studies related to the effects of testosterone and other sex steroids. Alth ough syndro mes of primary hypogonad ism are often associated with both decreased libido and erectile impotence, postpubertal reduction in testoster one levels tends to affect libido more often than potency; th is is also seen with the use of antiandrogens such as cyprotero ne in the treatment of male sexual offenders (Bancroft et al., 1974 ). Similar changes are produced by the use of exogenous oestrogens, for example, in the treatment of prostatic carcinoma. Controll ing mechanism s for testos terone secretion are complex. The major direct stimulus for secretion is luteinising horm one (LH); th is is secreted by the ante rior pitu itary under the influence of hypothalamic gonadotrophin releasing ho rmone (G nRH) and the feedback inhibition exerted by testosterone. Pro lactin. also secreted by the an terior pitu itary . appears to reduce end organ responsiveness to LH. and to reduce convers ion of testoste rone to its active metabolit e dihydrotestosterone. This regulating role of prolactin appears to be of considerable clinical signifkance (Franks et at, 1978). and since prolactin secretion is inhibited by dopamine, dru gs which affect cerebral mechanisms involving th is neurotransm itter may have profound effects on male libido. alth ough as may be expect ed . generally less marked effects on potency. Figure 2 summarises the major hormo nal mechanisms involved.

209

Drugs and Impaired Male Se ~ual Function

2. Classification ofImpaired Male Sexual Fun ction

ejaculation or a combination of these, by far the most common presenting symptom is impotence. The physiological control mechanisms for penile erection which have been discussed imply that impotence may result from a variety of psychogenic, neurogenic,

Wh ile impaired male sexual function may take the form of reduced libido, erectile impotence, failure of

Hypothalamus

I

Gonadotrophin Thyrotrophin releasing releasing hormone Dopamine hormone

o

o

Enkephalins ~ - E ndorphin

5- Hydr oxyt ryptamin e

LH

?Inhibition •

_

8

rorecte

Feedback inhibition

[l»

Stimulation

. . . Inhibition

Fig, 2. Major hormonal mec hanisms inlloilled in male sexual function.

Drugs and Impaired Male

Se ~ual

'"

Funct ion

vascular and hormonal causes, some of which may be induced by drug therapy. Wh ile erectile difficulty may therefore occur in the presence or absence of any significant change in sexual interest, it is obviously useful to look. closely at changes in libido in any patient experiencing erectile difficulty. Similarly, the fact that ejaculation is primarily controlled by the lumbar sympathetic nerves implies that anatomical or drug-induced impairment of local sympathetic nerve activity may result in im paired ejaculation, dissociated from any other sexual difficulties. On the other hand, there is often considerable overlap in causes and features of impaired sexual function, and therefore it must be appreciated that the subclassifications shown in table I represent an approximation.

Table I . Conditiorls' associated with im paired m ale sexcer f unction Primary mechanism

Conditions

1. Reduced libido

Psychogenic factors ChroniC lll Funclion

clinical evidence of an organic aetiology. This does not necessarily demonstrate a cause and effect relations hip, given the variable effects of testosterone deficiency and replacement on male sexual funct.Mln. Moreover , there is evidence to suggest (Kreuz et al ., 1972) that such decreases in serum testos terone levels are secondary to stress induced by the onset of impotence. The secondary psychiatric effects of chronic physical illness or of impotence itself furth er complicates the problems of assessing the aetiology of sexual dysfuncti on in any individual patient. The frequently encountered problem of sexual dysfunction in alcoholics illustrates the interplay of or ganic and psychiatric factors. The patient is often severely depressed . with considerable anxiety related to alcohol-induced problem s with employment and his domestic situa tion. However, the direct pharmacological effects of alcohol (vide infra), and the influence of alcohol-induced damage to brai n. liver or testes. may be equally important aetiologK:a1 factors .

3 . Methods ofAssess ment Dysfunction

0/ Male S exual

3. 1 Qinical AspectS of Drug-related Sexual Impairment

3././ Presentation The clinician should be aware of possible impaired sexual function in a patient presenting for any reason, but especially of its future development in patients who are at particular risk . Thus, enquiry about sexual difficulties sho uld be part of rou tine history -taking in alcoholics. diabetics. depressed individuals or patients receiving antihypertensive medication . It is most unl ikely that the patient will spontaneous ly volunteer this information. Self-initiated presentat ion in males with impaired sexual Iunction is relatively rare. It is most likely to be tr iggered by the onset of impote nce without significant reduction in libido. Those males who are urged to seck treatment by their spouses frequently find the problem so emotionally thr eatening that they

2 11

mention it only in passing, together with a number of anx iety-related symptoms. Many patients assume tha t a gradual reductio n in potency merely reflects the inevitable effects of aging and therefore do not seck treatment at an y stage. On the other hand . the sudden developme nt of impotence will rarel y be ignored, and the patient usually presents to his medical attendant with a stro ng suspicion of the factors precipitating his disability. In contr ast to males with an insidious onset of impotence. such patients are likely to ascribe their problem to physical illness (rarely psych iatric) or to the effects of recently ingested medication. Patients with cardiovascular disease present a dif· feren t problem. Impotence may develop after a myocardial infarction or cerebro-vascular accident as a result of fear that intercourse may induce a recur rence. The developm ent of angina pectoris du ring intercourse exerts a strong inhibitory influence on funher sexual activity (Goble , 1974), However . man y drugs which may be used to treat cardiac disease and hypertens ion are among those most frequently implicated in causing male sexual dysfunction . Thus. patients should be reassured that sexual intercourse is possible with safety, and informed of the poss ible side effects of their medication, even th ough this may increase the likelihood that impotence wiJl be incorrectly ascri bed to therapy . The patient's sexual partner should be present at discussions of his actual or potential sexual difficulties; it is desirable that both partners understand the nature of the problem involved and cooperate according ly. The possible effects of therapy on sexual function must always be considered both when a problem has been uncovered and also whe n a dru g is first prescribed. A history of relevant drug exposure must include information on the intake of alcoho l. sedatives and illicit dru gs. as well as currently prescri bed med ication .

3.1.2 Exam ination A complete pbysK:al examination shouk! be performed on all patients presenting with sexual ctysfuoaion in order to exclude contri buting organic

212

Drugs and lmoa ired Ma le Se ... uaf Func tion

factors . In particular, evidence of bypogonad ism. bypothalamic-pituitary or central nervous syste m disease sbould be sought. Examination may also reveal evidence of underlying alcoholic liver disease or diabetes mellitus .

residual penile erection occurring du ring REM sleep or the effect of bladder distension . and thus the absence of suc h erections implies a guarded prognosis for recovery of sexual function .

4. Drug -induced Sexual Dysfunction 3.2 Investigations

3.2. J General Th e range of investigations which s hould be undertak en in cases of male sexual dysfunction depends largely upon findings on physical examination . It is sometim es poss ible to identify a potential organic cause on exam ination , and investigations should be undertaken pr imarily to estab lish this dia,aoosis. On the other hand , s hould physical exam ination be unrewarding , a number of more specialised investiga tions are available to assist differentiation of psy chiatric from organic causes .

3.2.1 SpedaUS4!d £ ndocrinr I/!'Sts It is reasonabl e to measure seru m levels of testosterone. FSH . LH and prolactin in patients in whom impot ence of uncertain aetiology proves persistent. Franks et al. (J 978) demonstrated a close association between elevat ion of serum prolactin levels and impotence, and cases associated with such elevation may improve when prolactin levels are reduced by bromocriptine or rem oval of a pituitary adenoma. On th e other hand , as previously stated , the finding of reduced seru m testos terone levels does not definitely imply an organic cause , oor the potential for improve ment with hor monal supplements.

Penile plethysmography This is occasionally of value in the differentiation of organic from psychogenic causes of impotence . The presence of penile erections during REM sleep correlates well with the absence of detectable 'organic' causes. and a good long term prognosis (Fisher et al., 197 5). The 'morning erection' represents either a

The problem of impairment of male sexual dysfuncti on by dru gs is usually only cons idered when an individual patient presents wit h impotence or decreased libido possibly associated with medication . However. the clinician s hould consider the poss ible development of such problem s whenever a new dru g is prescribed. Th is is important in the pr ocess of initial clinical assess ment of recently developed drugs, and is a cr itical factor in determ ining the patient's compliance. Patients who cote decreasing potency anributable to medicat ion are unlikely to take it. whether or not they advise the clinician of this . The medical literat ure is fuU of case reports of drug-induced male sexual dysfunction . These are difficu lt to evaluate, because of the frequency of coer istanr factors of potential importance such as other illness and concomitan t exposure to othe r dru gs. Even a close temporal association between the symptom and the medication can be due to placebo effects. Nevertheless, such reports cannot be ignored . A theo retically more satis factory way of detecting dru g effects on sexuality is the dou ble-blind controlled trial aga inst placebo medication whenever possible. However , here again. difficulties are encounter ed. Th e frequency of repo rting of sexual fun ctional impairment will depend lar gely on the manner in which such information is sought, and gross under-reporting may result from adverse circumstances. For example, methy ldopa has been report edly associated with an incidence of impotence ranging from less than 0.1 96 (Lawson et 1978) to 25 96 (Newman and Salerno. 1974). depending on the method of obtaining information and the circumstances of the patients (e.g . hospitalised vs ou tpatients) at the time of questioning. A high incidence of sexual dysfu nction in the patients being treated - e.g. for ischaemic beart

a..

Drugs and Im paired Male Sexua l Functio l'l

Table II , Theoret ical mechara srns of drug-ind uced im _ paired male sexual f Ul'lctOO Mechal'lisms

Drugs possi~y il'lvo lved

1. Production of sedation and/or depression

Reserpine . clonidine . methyldopa Phenytoin, carbamazepme Alcohol ? Cannabis Phenot hiazlnes. bur vroobeno nes Barbiturates. bel'lzodia lepolism . S: 361-310 (19111. Co nti. G., L'erecuon du penis human et ses bases morphologrvescutaires. Actio AllIlOmica (Basel) 14: 2 11·262 (19S2). Ebringer. A., Doyle. A.E., Dawbom . J .K.; Johnston. CI. and Mashrord . M.L.: T he use of clon idine (Cat;lpres) in the u eat· menl or hypertension. Med ical Jou rnal or Australia I , SH-S26 ( 19101. Fm.er . C : Schiavi, R., Lear. H., Ed wards. A., Dav~ D.M. and W itikin. A.P.: Tbe assessment of nocturnal REM erectio n in the dilTtTential dllgnosis of SICll ual impollence. Jou rnal of Sel. and MV ila! Tbenpy I: 211-219 (I 91S1. Fr.anks. S.: JilCObs. H.5., Manin . N. and Sabarro. J .D.N .: Hyperpr-oa.ctinaentil. and irnpocrtlCC- ainical E.ndocfinoktgy I : 211· 211 (19111 Goble. AJ .: Sel.uaIil)' aDd COI'OlWY bean d~. Pabenl MIUI.I&Cmem )(No. 11 2S·3 1 tNovembeT 19"1. Greenblatt. D.1. and Koch-Weser. 1.: Gynam:>mastil and imp1enCe: Co mplKations of spironolActone ~y _lou.rna1 of !he America n Medical Association 22): 12 U 913 ). HalhtrOm. T. and Persson . T., L· Dopa and non-emi5.sion of ,..,men. ~1lCCl I: 123 1· 12) 2 (1910). Khan. A.; Camel. G . and Perry . H_MJ .: CIonidinc (Cata pres) A ncw anti -hypeTlell.'iive il8ent. Current Thenpeutic Research 12: 10-11 (1910). Kinsey. A ,C .: Pomeroy, W .B. and Martin. C.E.: in Selual Behaviou r in llle Human Male (Saunders, Phijadelphia 1941). Knarr, J .W .: Impotence Ite m prop ranolol? Anna ls or I n~rn.al Medicine I S, 682·6 83 (19161. Kolodn y. R.C.: M..,~~ W .H., Kolod ner . R.M. and Tor e , G .: Depression of plasma teslOs~rone levels afk r chronic in~n­ sive marihuana u.'iC. New England Jou rnal or Medicine 290 : 812 -8" 1I 9 14~ KTeu.z. LE.: Rose. R.M. and Jenn in&s. 1.R.: SuppreMions or plasma 1C:SlO5Iefone )cvels and psycholoP::al $U'C§$: A IonailUdinal study of YOUlli men in offICer candda~ school. Archives or General Psychiatry 26: 419·492 (19121

Kuhn. R.A., Functional eapaary of the i5oIa~ human spinal cord. Brain 13: I ·S11I9S01 Lawson, D.H.; G~. D. and J ick. H : Adwcn.e reactions 10 mcdIy~ with panicullr nferellC:e 10 hypotension. Amcricarl Heat! JoumaJ 96 : S72-S191197Bl. U W'SOD. D .M . and G.... R.R.: The innu~ or adrma-lic. dopami ners ic. cholinerllic and scrolOnerllic dro ll" on pla., ma prolactin levels in ovariectomized. CQtrogcn·trClted rats. EndocrillO!o&y 96: 3 1l ·318 (I91S1. Lei.ra.s. 1.1.: Pak m. M.; Servais. J . CI. ill.: B.a.....:J pitui!arY-IlOnadal function in impotency en luated by blood testos~rone and LH assays; in Horm ones and Brain Function. pp.S21· S29 (Plenum Press. New York 191 31. Lemere. F. and S mith. J.W .: Ak:ohol-induad scl.uill im po~llCC . A merican Journal or Psychiatry 1l 0, 212-21l (1973). Miller. R.A .: Propranolol and impote nce. Ann.als of I n~rnal Medicine 8S, 682 .613 (1916). Mintz. 1.: O·Hare . K.: O·Brien. C P. an d Goldsc hmidt. J.: Selual prob lems of heroin add icls. Arch ives or Gene ral Psychiatry 3 1: 700-703 (197 41 l'ewman. RJ . and Salerno. HR.: ScI.ua1 d~run