How Medications Impact Libido

Author: Dawn Knudsen, PharmD, CGP


Female sexual dysfunction (FSD) is a multifaceted and poorly understood condition. Female sexual function requires the harmony of the physical, emotional, and social aspects of the patient. A woman’s “sexual self and self-image, intimate relationships, family, society, and culture” and “the complexities of her environment, sexual and partner history, past relationships, mental health status, current medical problems, and hormonal status” all impact female sexual function.1 In men, “the pathways that lead to arousal and orgasm have been mapped,”2 but this information is lacking for the female body. FSD was categorized into 4 types by the 1994 Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition: those affecting desire, arousal, and orgasm and a type associated with sexual pain.3

Loss of libido or decreased sexual desire can be a serious adverse effect that impacts both men and women and can lead to decreased quality of life or relationship dysfunction. “Libido problems may be related to hypogonadism, hyperprolactinemia, depression, fear of sexual failure, certain medications, or systemic illness.”4

Many medications can be a cause of decreased or loss of libido. Loss of libido is inherently connected with all other aspects of sexual dysfunction, although it cannot be assumed that all medications that list sexual dysfunction as an adverse effect include specifically loss of libido. Patients can have orgasm dysfunction (anorgasmia) or erectile dysfunction without loss of libido, and some medications can affect just libido, just erectile function, or just orgasm function, whereas others can affect any combination. It can be difficult when reading evidence-based literature to discern if the term sexual dysfunction addresses the physical forms of sexual dysfunction (eg, ejaculation, erectile function) or the mental forms of sexual dysfunction (eg, loss of libido).

Libido is dependent on both psychogenic (mind) and somatogenic (body) stimuli and hormonal factors.5 The male body relies primarily on androgens, like testosterone, for sexual desire. Both men and women depend on the androgen dehydroepiandrosterone (DHEA; a precursor to testosterone), estrogen, and pheromones for arousal, and both sexes can have decreased libido6 from increased estrogen or an increased estrogen:testosterone ratio.5

Medications that affect libido often have mechanisms that affect the biologic or hormonal mediators of libido. Prolactin,4 testosterone,4 DHEA,6 and serotonin type 1 (5-HT1), 2 (5-HT2), and 4 (5-HT4) receptors7 are involved in arousal and sexual function.8 Increased prolactin— known as hyperprolactinemia—is one of the most commonly cited underlying causes of medication-induced loss of libido. Hyperprolactinemia can be caused by medications such as methyldopa, spironolactone, digoxin, and metoclopramide.4 DHEA can be decreased by carbamazepine, phenytoin, cytochrome P450 3A4 inhibitors, and alcohol.6 Ketoconazole and aminoglutethimide actually reduce the production of testosterone.

Medication-induced libido loss can be divided into 3 main categories: neurologic/ psychiatric agents, cardiovascular agents, and miscellaneous agents.6 Almost all of the medications that fall into these categories have a mechanism of action related to prolactin, testosterone, and/or serotonin.

NEUROLOGY/PSYCHIATRY
A commonly reported consequence of depression is loss of libido.7 Unfortunately, the most common class of medications that treat depression, selective serotonin reuptake inhibitors (SSRIs), can cause the same problem. Tricyclic antidepressants like amitriptyline, nortriptyline, and imipramine have adverse sexual effects due to their anticholinergic effects and inhibitory affect on prolactin levels.6 Selective norepinephrine reuptake inhibitors, like duloxetine and venlafaxine, and monoamine oxidase inhibitors, like phenelzine, increase serotonin activity, thereby causing libido problems.6

Fortunately, some antidepressants do not affect libido to the same extent as SSRIs. Medications that promote dopamine activity can reverse the loss of libido. These types of antidepressants, which include nefazodone, bupropion, and mirtazapine, block 5-HT2 receptors and encourage dopamine activity.6-9 Bupropion and mirtazapine, unlike the majority of antidepressants, have no significant effect on serotonin and are mild dopamine agonists; therefore, bupropion can actually have a positive influence on sexual desire.8,9

It can be beneficial for a patient with pretreatment complaints of decreased libido to start on a medication that clinical studies support as having little to no effect on libido. Michels et al states that because sexual impairment can be both a depressive symptom and adverse effect of depression treatment, it is important for practitioners and patients to evaluate preand posttreatment libido intensity.10

Unfortunately, this does not guide treatment options in one specific direction. Sexual dysfunction associated with 5-HT2 activity is completely dose-related.6 The increase, decrease, and static state of the libido can be due to underdosing of the SSRI, overdosing of the SSRI, or the need to change agents. Each of these therapy options has advantages and disadvantages. Increasing the dose of the SSRI to compensate for lack of depression symptom resolution may lead to further sexual dysfunction, as SSRI-induced libido loss is dose-related; as the dose increases, so does the severity of the adverse effect. Decreasing the dose of the SSRI may decrease the severity of libido loss, but depression symptoms may return, and libido will be once again be affected by the disease state. All antidepressants require adequate trials—at least 6 weeks of treatment—before medication or dose is considered treatment failure and doses or medications are changed.

Other possible options for improving libido include drug holidays or waiting for tolerance to develop. Waiting for tolerance to develop is the least viable option, whereas most experts agree that this does not occur.11 Practitioners should weigh the benefits and risks, such as withdrawal syndrome. The best pharmaceutical care plan is to switch depressed patients who complain of decreased libido to bupropion, nefazodone, or mirtazapine.

Antipsychotics, anticonvulsants, and lithium also contribute to loss of libido. It is estimated that 30% to 60% of men and women who take a typical antipsychotic drug with potent dopamine-blocking activity (chlorpromazine, thioridazine, haloperidol, fluphenazine, thiothixene) experience adverse sexual effects due to increased prolactin levels with decreased libido as the most common symptom.5 Due to this and other troubling side effects, atypical antipsychotics are the superior antipsychotic medication choice. Aripiprazole, clozapine, and quetiapine do not elevate prolactin levels12; therefore, they would not cause loss of libido. Olanzapine, paliperidone, risperidone, and ziprasidone are atypical antipsychotics that do increase prolactin, but to a much lesser extent than typical antipsychotics. Risperidone’s effect on libido is doserelated, and doses above 6 mg/day correlate to significant and consistent prolactin elevation.6 Ziprasidone and olanzapine may cause transient hyperprolactinemia, but it is not as prominent or clinically significant as with risperidone.13 Although this condition is dose-related, decreasing the dose can cause uncontrolled disease, and the best option is to switch a patient to aripiprazole, clozapine, or quetiapine.

Anticonvulsants, like phenytoin, carbamazepine, phenobarbital, and primidone, have been associated with sexual dysfunction due to increased prolactin levels, decreased DHEA level, and altered sex hormone metabolism.6 Valproate has the best sexual side effect profile among the anticonvulsants, due to the fact that it lacks effect on prolactin and DHEA levels.5

The best recommendation for patients suffering from loss of libido from neurologic and psychiatric medications is to switch to an agent that does not cause this problem.

CARDIOVASCULAR
Similar to depression, uncontrolled hypertension can cause erectile dysfunction, but medications used to treat hypertension can cause loss of libido. Beta-blockers, alpha2-adrenergic agonists, and thiazide diuretics are associated with libido changes. Nonselective beta-blockers, like propranolol, are associated with more severe dysfunction compared with selective betablockers, like atenolol, metoprolol, or nebivolol.6 An academically affiliated tertiary care Veterans Affairs medical center study found that atenolol-induced loss of libido could be reversed with lowering of the dose.14 This is true for all beta-blockers and alpha2-adrenergic agonists.6 Loss of libido is less likely with angiotensinconverting enzyme inhibitors, angiotensin receptor blockers, alpha blockers, and calcium channel blockers, making them good options for the treatment of cardiovascular conditions when patients complain of lack of libido.6 Spironolactone and thiazide diuretics can be switched to loop diuretics to decrease the risk of loss of libido.6

OTHER
Testosterone is the main hormonal mediator of a man’s libido. As testosterone levels decline, sexual desire decreases; therefore medications that affect testosterone can alter the libido. Finasteride and dutasteride, 5-alpha reductase inhibitors for the treatment of benign prostate hyperplasia (BPH), decrease dihydrotestosterone levels, the active metabolite of testosterone. Opioids and antiandrogens, like cyproterone and flutamide, decrease testosterone levels.6

Alpha agonists, the other class of medications used to treat BPH, can also cause sexual dysfunction but not to the extent of 5-alpha reductase inhibitors. When comparing tamsulosin and alfuzosin for sexual dysfunction—which groups libido, ejaculation, and potency dysfunction together—tamsulosin has a higher rate compared with alfuzosin, and at the lowest doses, alfuzosin has no reports of dysfunction.15 Cimetidine also has antiandrogenic effects and increases prolactin levels. The literature recommends switching to another H2 blocker like famotidine, but even high doses of ranitidine can increase prolactin secretion.6 Timolol maleate and acetazolamide, agents for glaucoma, list loss of libido as an adverse effect as well.16

CONCLUSION
In conclusion, when a patient is suffering from medication-induced loss of libido, the best option is to switch to a medication that will control their disease state and not affect their libido.



Dr. Knudsen is an assistant professor at Midwestern University College of Pharmacy, in Glendale, Arizona.



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