This last article in our series on adverse drug reactions discusses the most frequently reported drug-induced sexual problems, including infertility
Other articles in this series:
The issue of sexual health, once regarded as a taboo subject, has been widely debated recently, provoked by the introduction of sildenafil, the first licensed oral treatment for male erectile dysfunction. It is now generally accepted that good sexual health is an important aspect of physical well-being and the possibility that drug therapy can cause sexual dysfunction is increasingly recognised. Although sexual dysfunction is not life threatening, it can have a major impact on personal relationships, quality of life and the ability to conceive. It is also an important factor in non-compliance; studies have confirmed that many patients with hypertension, depression and schizophrenia discontinue their medication because of sexual side effects.
Patient information leaflets may alert patients to the possibility that their sexual function may be affected. Pharmacists should have some knowledge of the types of problem that can occur in case questions arise. This article reviews the most frequently reported drug-induced sexual problems, including infertility.
The overall incidence of drug-induced sexual dysfunction is difficult to quantify. Patients are often unwilling to raise the issue of sexual health with health professionals, leading to under-reporting of problems. In addition, many diseases can affect sexual function, making it difficult to establish causality with a drug rather than concurrent illness. Antihypertensive medication, for example, is associated with erectile dysfunction and is often prescribed for hypertension in patients with diabetes, which itself may cause impotence. Other factors that can influence sexual function in men and women are age, alcohol consumption, smoking, drugs of abuse, over-the-counter medicines, and exposure to environmental or occupational toxins. Most of the published literature relates to the adverse effects of drugs on male sexual function. It is more difficult to assess these effects in women and this aspect of drug safety has seldom been considered in clinical studies. The effects of environmental exposures and drugs of abuse will not be considered here.
Sexual dysfunction as a consequence of drug therapy has been reported with a range of drugs, notably antihypertensives, antipsychotics and antidepressants. Yellow card reports to the Committee on Safety of Medicines (CSM) involving reproductive dysfunction constitute a small proportion (generally less than 5 per cent) of the total received. Serious reactions in this category include infertility, congenital abnormalities and some pregnancy complications.
Case StudyDr M, a consultant psychiatrist, contacts the drug information centre about one of his patients. Mr J is a 42-year-old man with depression. He showed a good response to fluoxetine during a previous episode about three years ago. However, he stopped treatment abruptly when he noticed that he had difficulties with erection and ejaculation. Mr J has now told the psychiatrist that he would rather be depressed than take another drug that will ruin his sex life. Dr M is aware that problems like this have been described with most antidepressants. He would like to know if there is any evidence that another SSRI or one of the newer antidepressants would be less likely than fluoxetine to cause these problems. How common is sexual dysfunction with SSRIs? Are both men and women affected? The exact incidence of these problems is unknown. The reported frequency ranges between 2 and 75 per cent but data from controlled clinical studies are lacking. It is likely that at least 20 per cent of patients will experience problems. The reported frequency is usually higher in men, who complain of decreased libido, delayed ejaculation, erectile difficulty or anorgasmia. There is also evidence that women may experience loss of libido or orgasm dysfunction. Would another SSRI or a newer antidepressant be less likely than fluoxetine to cause problems? Of the SSRIs, there are limited data to suggest that paroxetine may be associated with an increased rate of sexual difficulties compared with fluoxetine, fluvoxamine and sertraline. It has been suggested that nefazodone and mirtazapine are associated with a low incidence of sexual side effects but this requires confirmation. If problems do develop might they remit during continued treatment? There have been reports of tolerance to sexual side effects developing, sometimes after months of treatment. If the antidepressant is effective it may be worth continuing it for a period of time to see whether the problem resolves, if this is acceptable to the patient and their partner. Some patients may find that the effect diminishes but does not disappear entirely. How else could this problem be managed? Would sildenafil be of benefit? The preferred approach is to find a medication that is effective without causing sexual adverse effects. These problems are generally dose related so it is important to ensure that the minimum effective dose is given. In a patient who experiences problems it is not clear whether switching from one SSRI to another is helpful but it may be tried. There are reports of a “drug holiday” being used to allow patients to time sexual intercourse with a medication-free period. However, this is not a very practical option and can only be tried with short half-life drugs. Sildenafil is of benefit in erectile failure but there is limited evidence of efficacy in drug-induced sexual dysfunction. A number of specific treatment strategies have been reported to be effective in reversing SSRI-induced sexual dysfunction, including cyproheptadine (an antihistamine with serotonin blocking properties), yohimbine (a pre-synaptic alpha-blocker), amantadine, buspirone, granisetron and gingko biloba. Adding a medication to treat the adverse effect of another should always be avoided if possible because of the potential for additional adverse effects and drug interactions. |
INFERTILITY
Infertility is one element of a spectrum of reproductive disorders that includes miscarriage, congenital abnormality, premature delivery and stillbirth. Infertility — defined as the failure to conceive after two years of unprotected intercourse — is fairly common, affecting about 15 per cent of all couples at some time during their reproductive lives. It is generally only detected when a couple is actively trying to conceive. It can be difficult to draw firm conclusions about trends in infertility rates but the high number of patients currently attending fertility clinics suggests a growing problem.
Causes of infertility in women include failure of ovulation, tubal damage, endometriosis and hostile cervical mucus. In men, sperm defects, coital factors such as impotence or retrograde ejaculation, and hypogonadism may be implicated. In as many as 30 per cent of cases, a cause cannot be found. Drugs and other toxins may be responsible in a small proportion of cases, but, in general, the effects of drugs on fertility have been poorly studied.
The activity of the gonads (testes or ovaries) is regulated by the pituitary gonadotrophins, follicle stimulating hormone (FSH) and luteinising hormone (LH). Secretion of both hormones is controlled by gonadotrophin-releasing hormone (GnRH) from the hypothalamus. FSH regulates the development of Sertoli cells (which are involved in sperm maturation) in the testes, and the Graafian follicle in females. LH controls formation of the corpus luteum in females and testosterone production by the Leydig cells in males. Both FSH and LH regulate oestrogen production and ovulation. Decreased amounts of FSH and/or LH reaching the testes can inhibit spermatogenesis.
Primary drug-induced infertility results from a direct toxic effect of the drug on the gonads or an indirect effect on pituitary go
| PANEL 1: SOME DRUGS THAT MAY CAUSE PRIMARY INFERTILITY
Alkylating agents (eg, chlorambucil,cyclophosphamide, melphalan) Anabolic steroids Colchicine Diethylstilbestrol Methotrexate NSAIDs (females) Procarbazine Sulphasalazine (males) Vincristine |
Anovulation and amenorrhoea About 30 per cent of infertile women have anovulatory infertility. They may present with amenorrhoea (primary or secondary), oligomenorrhoea (infrequent or irregular periods ) or occasionally with regular menstrual cycles but low or undetectable serum progesterone concentrations in the putative luteal phase. Secondary amenorrhoea is defined as the absence of menstruation for at least six months in a woman with previously normal and regular menses. Hyperprolactinaemia is a common finding in women with amenorrhoea or oligomenorrhoea; occasionally this is drug-induced (see previous article on drug-induced endocrine disorders [PJ 1998;260:17-21]).
Drugs known to increase prolactin include methyldopa, metoclopramide, cimetidine, phenothiazines and oestrogens. Amenorrhoea is also associated with high dose corticosteroids, danazol and isoniazid.
There has in the past been concern about a high incidence of amenorrhoea shortly after stopping combined oral contraceptives. However, studies have shown that the incidence of amenorrhoea is no greater than in the general population and that subsequent fertility is probably not impaired by previous use of oral contraceptives.
Spironolactone has been reported to cause amenorrhoea at daily doses of 100-200mg. Normal menstrual periods usually return within two months of spironolactone being stopped. The mechanism is believed to involve inhibition of dihydrotestosterone binding to androgen receptors.
Evidence is accumulating that non-steroidal anti-inflammatory drugs (NSAIDs) taken in the middle of the menstrual cycle may inhibit ovulation. It has been suggested that the NSAID prevents rupture of the ovarian follicle which has developed normally. Progesterone levels measured in the second half of the menstrual cycle may be compatible with ovulation having occurred, which can obscure the diagnosis.
This problem has been reported with indomethacin, diclofenac and naproxen. NSAIDs should preferably be avoided around the time of ovulation in women trying to conceive and should be withdrawn in women undergoing investigation of infertility.
SEXUAL DYSFUNCTION
Sexual function may be divided into three categories reflecting the sexual response cycle: (1) libido or sexual desire; (2) arousal, including erectile function in men and lubrication in women; and (3) release (orgasm in women and ejaculation in men). Drugs can affect one or more areas of the response cycle.
Understanding of the sexual response remains incomplete but there is evidence of dopaminergic, adrenergic, muscarinic and serotonergic involvement. In general, dopamine increases sexual behaviour and serotonin inhibits it. Libido is influenced by reproductive hormones and the emotional and physical health of the individual. Testosterone is necessary for normal sexual arousal, probably in both men and women, and in men testosterone deficiency is associated with impotence.
ERECTILE DYSFUNCTION AND EJACULATORY DISORDERS
Erectile dysfunction, or impotence, is the inability to achieve or maintain an erection sufficient for satisfactory sexual performance. It is the most common form of male sexual dysfunction with a prevalence of up to 10 per cent across all ages, rising to over 50 per cent in men between 50 and 70 years old. The aetiology is often vascular but other contributory factors include drug therapy, endocrine disease and neurological dysfunction.
Erectile dysfunction often occurs with diabetes, heart disease, hypertension and peripheral vascular disease. It may also be a consequence of spinal cord injuries and pelvic or perineal radiotherapy or surgery. Smoking and alcohol intake are important contributing factors.
| PANEL 2: SOME DRUGS THAT MAY CAUSE ERECTILE DYSFUNCTION
Anti-androgens (eg, finasteride) Anticholinergics Antidepressants (tricyclics, MAOIs, selective serotonin reuptake inhibitors) Benzodiazepines Beta-blockers Carbamazepine Cimetidine Digoxin Finasteride Methyldopa Metoclopramide Omeprazole Phenothiazines Phenytoin Prazosin Spironolactone Thiazide diuretics |
Antihypertensives The prevalence of both erectile dysfunction and ejaculatory disorders is significantly greater in untreated hypertensive men than in matched normotensive controls, so caution is needed when assessing whether medication is likely to be the cause of such problems. Most epidemiological studies addressing this issue were carried out over 10 years ago when the types of drugs used did not reflect those in use today. More recent studies confirm that the rate of erectile dysfunction depends on the class of antihypertensive. The effects of treatment on quality of life are particularly important in the management of hypertension, which can require lifelong therapy despite being asymptomatic. Evidence suggests that many hypertensive patients experiencing sexual side effects will stop taking their medication.
High rates of erectile dysfunction and ejaculatory failure are associated with the older adrenergic blockers reserpine and guanethidine, which are no longer used. Clonidine and methyldopa have also caused loss of libido, erectile dysfunction and ejaculatory failure. The alpha-adrenergic blockers indoramin and prazosin can cause ejaculatory failure and retrograde ejaculation.
The incidence of sexual dysfunction in men taking diuretics is between two and six times higher than in men taking placebo. Thiazides may cause reduced libido, erectile dysfunction and problems with ejaculation. The underlying mechanism is unclear as thiazides lack significant hormonal, autonomic or central nervous system effects but a direct effect on smooth muscle is thought to be responsible.
Erectile dysfunction is well documented with propranolol and can occur with other beta-blockers. The problem is more likely with lipid soluble beta-blockers but has also been reported with atenolol and with ophthalmic timolol. Reduced perfusion pressure caused by a drop in blood pressure or a direct effect on smooth muscle may be responsible.
Calcium channel blockers seem to cause fewer problems with sexual function than diuretics or beta-blockers although there are several published case reports of erectile dysfunction.
Erectile dysfunction does not seem to be a problem with angiotensin converting enzyme (ACE) inhibitors.
Psychotropic drugss As sexual dysfunction is a common feature of psychiatric illness, particularly depression, it can be difficult to assess the relative contribution of the disease and drug therapy. Both antidepressants and antipsychotics have recognised adverse effects on sexual function in men and women.
Erectile dysfunction has been described with all classes of antidepressant. Numerous case reports have implicated tricyclic antidepressants (TCAs) but the association has not been confirmed in the few published controlled trials.
There is consistent evidence that serotonergic antidepressants (eg, selective serotonin reuptake inhibitors [SSRIs], monoamine oxidase inhibitors [MAOIs] and clomipramine) are associated with high rates of decreased libido, ejaculatory disturbance, delayed orgasm and anorgasmia. Serotonin appears to have a mainly inhibitory effect on sexual function. The mechanism of orgasm has not been confirmed but it is thought to be regulated by a balance of cholinergic and adrenergic influences and that serotonin receptor stimulation inhibits adrenergically mediated ejaculation.
Evidence that SSRIs cause sexual dysfunction is accumulating as their use increases. The reported incidence varies widely, mainly because of differences in methodology between studies, but is probably at least 20 per cent. Problems may occur with all SSRIs. Delayed orgasm or ejaculation appears to be the most frequent problem and this has been observed in controlled studies. As a consequence of this effect, the SSRIs are now used in the treatment of premature ejaculation.
MAOIs can also cause delayed ejaculation. The phenothiazines, particularly thioridazine, have caused changes in ejaculation (no ejaculate or a reduced volume) and pain on orgasm. Chlorpromazine is also associated with dose-related ejaculatory failure. Newer antipsychotics, such as olanzapine, may be less likely to cause these problems.
Priapism Priapism is a prolonged penile erection which is usually unrelated to sexual stimulation. The problem occurs when the regulatory mechanisms which initiate and maintain penile flaccidity are disturbed and venous drainage from the corpora cavernosa is obstructed. It is a medical emergency requiring immediate treatment to prevent fibrosis or even gangrene. Management involves the aspiration of blood and administration of a vasoconstrictor sympathomimetic such as phenylephrine.
| PANEL 3: SOME DRUGS THAT MAY CAUSE PRIAPISM
Anticoagulants Haloperidol Hydralazine Nifedipine Papaverine Phenothiazines Phentolamine Prazosin Risperidone Trazodone |
FEMAL ORGASM DYSFUNCTION
In women, sexual dysfunction has not been thoroughly investigated and the underlying mechanisms are not fully understood. Most reported problems relate to orgasm dysfunction, reduced vaginal lubrication or loss of libido. Female orgasm involves involuntary rhythmic vaginal and pelvic muscle contractions; it can be assumed that the neurovascular control is similar to that in males. Thioridazine has been known since 1961 to inhibit ejaculation in men but it was not until 20 years later that the first report of inhibition of female orgasm was published.
Failure to achieve orgasm (anorgasmia) is one of the most common sexual adverse effects of psychotropic drugs in women. This problem has been described with SSRIs. Delayed orgasm or anorgasmia has been reported with MAOIs, TCAs, clozapine and risperidone. The antihypertensives clonidine and methyldopa have also been linked with anorgasmia (see Panel 4). Multiple spontaneous orgasms have been described in women treated with fluoxetine. There have also been occasional case reports of spontaneous orgasm induced by yawning caused by clomipramine and by fluoxetine.
| PANEL 4: SOME DRUGS THAT MAY AFFECT FEMALE SEXUAL FUNCTION
Antidepressants (tricyclics, MAOIs,selective serotonin reuptake inhibitors) Benzodiazepines Cimetidine Clonidine Gonadorelin analogues Methyldopa Oestrogens Propranolol Spironolactone Thiazide diuretics Trazodone |
ALTERED LIBIDO
Loss of libido or sexual desire is frequently attributed to medication in both men and women. For example, all drugs causing central nervous system depression can potentially decrease libido. In women, loss of libido is the commonest reported form of sexual dysfunction; it is extremely difficult to quantify and manage. Changes in desire may be due to illness (eg, gynaecological disorders causing pain on intercourse), stress or fatigue, or may be drug-induced. In controlled studies women have rarely been questioned about the effect of medication on sexual function and therefore most reports of altered libido are anecdotal or case reports.
Several antihypertensives, including clonidine and methyldopa, reduce female libido. Studies of both men and women taking methyldopa report an incidence of decreased libido ranging from 7 to 14 per cent. Spironolactone has anti-androgenic effects and is clearly linked with decreased libido. Propranolol, thiazide diuretics and calcium antagonists are believed to have mild effects (if any) while captopril appears to have no effect.
Psychotropic drugs affect sexual desire in men and women by several possible mechanisms, including sedation, effects on central or peripheral neurotransmitters, or effects on hormones (eg, prolactin). Antidepressants have been reported to decrease sexual desire. MAOIs, particularly phenelzine, are frequently implicated. The SSRIs have all been reported to decrease libido, possibly as a consequence of an indirect effect on dopamine; the incidence in men and women may be as high as 40 per cent.
In general, rates of sexual dysfunction appear to be greatest with the SSRIs, followed by MAOIs then TCAs. Rates of sexual dysfunction appear to be similar for all the SSRIs and it is not known if switching between them will diminish sexual side effects.
Case reports of decreased libido with anxiolytics have been published; centrally-mediated sedation and muscle relaxation are thought to be responsible.
Cimetidine has been reported to cause loss of libido, possibly because of its anti-androgen activity. This is likely to be dose-related. The problem is not seen with ranitidine.
The influence of testosterone on libido is well recognised and any drug that reduces serum testosterone may lead to a loss of sexual desire. In men, this includes drugs such as oestrogens, antiandrogens and gonadorelin analogues.
There are preliminary data linking protease inhibitors with loss of libido and also with erectile dysfunction and problems with ejaculation.
Increased sexual desire is a rare adverse effect. Trazodone has been reported to increase libido in both men and women, possibly by decreasing prolactin levels or by increasing dopamine. Levodopa has caused hypersexuality in men with Parkinson’s disease. The reversible inhibitor of mono-amine oxidase A, moclobemide, has been reported to increase sexual desire in some patients.
MANAGEMENT
The management of drug-induced sexual dysfunction can be difficult. Occasionally these problems may remit spontaneously over time. In some situations it may be possible to change therapy to a drug in another class which is less likely to cause problems, eg, changing from a thiazide to an ACE inhibitor in hypertension. There may not always be an effective or tolerated alternative, however. Other possible options may include dose reduction, delaying dosing until after sexual intercourse, or advocating “drug holidays.” Pharmacological management of drug-induced sexual dysfunction with agents such as cyproheptadine or sildenafil is seldom indicated (see case study, p781).
Sexual dysfunction due to medication is relatively uncommon and probably not an issue that the pharmacist will be consulted about very often. If approached by a patient or partner about the possibility that a sexual problem may be drug related, a sympathetic and non-judgmental attitude should be adopted. The pharmacist may be able to give some general guidance about the likelihood that a particular drug therapy is involved. However, there are complex and sensitive issues surrounding sexual dysfunction and in most cases, if not every case, the individual should be advised to discuss the matter with his or her GP.
ACKNOWLEDGMENT: The authors would like to thank Susanna Gilmour-White (principal pharmacist, Guy’s hospital, London) for her helpful comments.
A fully referenced copy of this article is available on request. Please send an A4 stamped and addressed envelope to: The Pharmaceutical Journal, 1 Lambeth High Street, London SE1 7JN.
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FURTHER READING 1. Bateman DN. Drug-induced sexual dysfunction and infertility. In: Davies DM, Ferner RE, de Glanville H, editors. Textbook of Adverse Drug Reactions. 5th ed. London: Lipincott-Raven Publishers, 1998. 2. Forman R, Gilmour-White S, Forman N. Drug-induced infertility and sexual dysfunction. Cambridge: Cambridge University Press, 1996. 3. Thompson JW, Ware MR, Blashfield RK. Psychotropic medication and priapism: a comprehensive review. J Clin Psychiatry 1990;51:430-3. 4. Clayton DO, Shen WW. Psychotropic drug-induced sexual dysfunction. Diagnosis, incidence and management. Drug Safety 1998;19:299-312. 5. Wagner G, Saenz de Tejada I. Update on male erectile dysfunction. BMJ 1998;316;678-8 |
Miss MacLean is senior pharmacist, oncology, Western General hospital, Edinburgh, and Mrs Lee is principal pharmacist, area drug information centre, Glasgow Royal Infirmary