A pilot study on the sexual side effects of finasteride as related to hand preference for men undergoing treatment of male pattern baldness
Ion G. Motofei, Department of Surgery and Urology, St Pantelimon Hospital, Carol Davila University of Medicine and Pharmacy, Cazangiilor Street, No. 10, Sect. 3, Bucharest 033063, Romania. e-mail: email@example.com
What's known on the subject? and What does the study add?
Cerebral lateralization/specialization is a neurophysiological feature that has been documented regarding somatic, psychological and sexual functioning and that may be manifested in differences in hand preference, cognitive style, gonadal hormonal effects and possibly even sexual orientation. In this study we investigated a possible cerebral lateralization effect on sexual response for dihydrotestosterone, using finasteride as a hormone-blocking compound.
The results of this study differ substantially from other studies examining the effects of finasteride on sexual response, presumably due to the greater restrictions we placed on defining relevant sexual activity, to our alerting patients to both positive and negative sexual effects and to the fact that we assessed the effects separately in right-handed vs left-handed patients. Handedness, as a proxy for cognitive style and possible lateralization of effect/function, appears to be a relevant factor when considering the sexual effects of specific gonadal hormones.
- • To investigate the relationships between pharmacologically induced deprivation of dihydrotestosterone, sexual arousal, libido and hand preference, by comparing the self-reported sexual response prior to and during reception of the anti-androgen finasteride in men undergoing treatment for male pattern baldness.
PATIENTS AND METHOD
- • In total, 33 sexually healthy Romanian men participated in this study.
- • Patients prospectively provided information regarding their sexual functioning (over 4 weeks), as measured by the International Index of Erectile Function (IIEF) prior to and after commencing treatment with 1 mg finasteride for male pattern baldness.
- • Overall IIEF scores as well as the erectile function, orgasmic function, sexual desire and overall satisfaction subscales showed group, treatment and group by treatment effects.
- • The intercourse satisfaction subscale showed group and group by treatment effects.
- • On most subscales, right-handed men showed no effect or lower sexual function whereas left-handed men reported no effect or improved sexual function, primarily.
- • These results suggest that the sexual effects of dihydrotestosterone deprivation may depend on handedness – a proxy variable that may represent cognitive style – which lends further support to the idea of two distinct neuroendocrine psychosexual axes.
- • They further suggest that detection of such sexual effects may be enhanced by using research methodologies and communication strategies that increase patients' sensitization to such effects.
International Index of Erectile Function
Sexual hormones, sexual orientation, cognitive style and handedness may all be interrelated. For example, sexual hormones may be related to an individual's sexual orientation , with androgens possibly operating in gay men and heterosexual women, and oestrogens operating in heterosexual men and lesbian women [2,3]. Sexual orientation may also, however, be linked to handedness. Left-handedness is more prevalent in heterosexual men and lesbian women while right-handedness is more prevalent in gay men and heterosexual women [4,5].
Handedness undoubtedly serves as a proxy for any number of interdependent prenatal endocrine and postnatal processes, as indicated by findings that the presence of older male siblings increases the odds of homosexuality in right-handed men [6,7]. Hand preference also appears to be related to other prenatally influenced variables, including the cognitive profile of the individual. In this respect, handedness, cognitive profile, gonadal hormones and sexual orientation all appear to be interrelated [8–11].
In support of these interrelationships, research has shown that homosexual men may have a cognitive pattern somewhat similar to heterosexual women, and this pattern differs from that of heterosexual men . Patients who have suffered cerebral infarct of the dominant hemisphere have been known to change their sexual orientation, suggesting that sexual orientation and handedness/cognitive profile are in some way correlated [13,14]. Other studies have shown that cerebral dominance for language and handedness share a common X-linkage, these functions being linked to the function of sex as well . The array of variables related to handedness and sexual orientation continues to expand – recently handedness and orientation have been related to the manner in which facial images are visually processed . What is lacking is the development of a unifying model that connects these many different processes.
The putative relationship between cognitive pattern and sexuality is also suggested by other findings. On the one hand, psychotropic drugs interfere not only with cognitive/affective processes but also with sexual function [17,18]. On the other hand, the anti-androgen finasteride (which decreases dihydrotestosterone) induces not only sexual dysfunction but also depression , while the administration of mesterolone (a dihydrotestosterone derivative) is sometimes used in the treatment of depression . In addition, a relationship between testosterone and spatial cognition, perhaps indicated by hand preference , has been reported. Finally, testosterone and oestradiol in right-handed men, but only oestradiol in right-handed women, have been inversely correlated with the degree of right-hand preference , prenatal exposure to testosterone being thought to promote right hemisphere development thereby increasing the incidence of left-handers [23–25]. Consistent with this pattern, left-handed persons of both sexes have lower salivary testosterone concentrations than their right-handed counterparts .
Previous research indicates that finasteride, a synthetic anti-androgen that acts by inhibiting type II 5α-reductase, the enzyme that converts testosterone to dihydrotestosterone, induces sexual side effects in some, but not all, patients, suggesting that dihydrotestosterone modulates sexual function in these men . However, given that cognitive styles, sexual orientation and propensity for handedness may be related to hormonal interactions, the effects of finasteride might well be mitigated, predicted or even altered by such factors. In this study, we aimed to verify if sexual side effects that occurred in men taking finasteride for male pattern baldness are correlated with hand preference – a proxy variable for other pre/postnatally hormonally influenced variables.
PATIENTS AND MATERIALS
Thirty-three Romanian men presenting to a general practitioner for treatment for baldness participated in this study. Selection criteria for participation included the absence of significant sexual dysfunction, as determined by the International Index of Erectile Function (IIEF) , free of general disease (patients with significant comorbidities being excluded) and having a stable pre-menopausal spouse as a sexual partner. Unmarried men were excluded, thus ensuring a fairly homogeneous group with respect to partner conditions and opportunity for sex.
Candidates for participation were further screened for participation based on their handedness. Specifically, 19 men were right handed (mean age 36.5 years, sem= 1.6) and 14 were left handed (mean age 37.4 years, sem= 2.1), as determined by the Edinburgh Handedness Inventory.
For 4 weeks prior to treatment, patients prospectively noted their sexual functioning, which was then assessed using the IIEF, the most commonly used instrument for assessing sexual and erectile function in clinical studies in men . This instrument, with demonstrated reliability and validity, was translated into Romanian and administered with the assistance of a bilingual (Romanian and English) clinician. The IIEF yields an overall score as well as subscale scores on the following dimensions: erectile function (EF), orgasmic function (OF), sexual desire (SD), intercourse satisfaction (IS) and overall satisfaction (OS). Only patients meeting the criteria of normal or near-normal sexual functioning on all subscales of the IIEF were included in this study.
Patients then began treatment for baldness with finasteride 1 mg/day. Finasteride is a synthetic anti-androgen that acts by inhibiting type II 5α-reductase, the enzyme that converts testosterone to dihydrotestosterone and has been used for the treatment of BPH and male pattern baldness. As part of this procedure, patients were alerted to the fact that finasteride treatment might impart possible stimulatory or inhibitory effects on sexual function. Two weeks into the treatment phase, patients were asked again to prospectively note their sexual functioning for the next 4 weeks; at the end of this 6-week period, sexual functioning was then again assessed using the IIEF, using the prior 4 weeks as the reference period. Although sexual functioning assessment ceased at this point, finasteride treatment for baldness continued uninterrupted.
Results on the overall IIEF score, as well as on each of the subscales, were analysed using a two-way analysis of variance (anova), with handedness as a between-subjects factor and pre- vs post-assessment as a within-subjects factor.
Means for the overall IIEF and each of the subscales are presented in Table 1. Prior to treatment, no patients scored below 22 on the EF scale, below 11 on the IS scale or below 7 on any of the other scales (OF, SD or OS), thereby verifying a reasonably high level of sexual functioning. Furthermore, prior to treatment, left-handed and right-handed men did not differ on overall functioning or on four of the five subscales (P> 0.05). On the OF subscale, left-handed men were marginally less functional than right-handed men (P< 0.10).
Table 1. Overall IIEF and subscale means and standard deviations (in parentheses) for participants
|Overall|| || |
| Left handed||61.9 (4.3)||67.4 (2.2)|
| Right handed||65.7 (3.0)||57.2 (5.2)|
|Erective function (EF)|| || |
| Left handed||25.1 (2.3)||28.1 (1.3)|
| Right handed||27.5 (1.7)||23.7 (3.1)|
|Intercourse satisfaction (IS)|| || |
| Left handed||12.7 (1.1)||12.8 (1.3)|
| Right handed||12.7 (1.2)||9.6 (2.0)|
|Orgasmic function (OF)|| || |
| Left handed||7.8 (1.1)||9.3 (0.7)|
| Right handed||9.1 (0.8)||7.7 (1.1)|
|Sexual desire (SD)|| || |
| Left handed||8.3 (0.8)||8.2 (1.1)|
| Right handed||8.6 (1.1)||8.4 (0.7)|
|Overall satisfaction (OS)|| || |
| Left handed||7.6 (0.9)||8.9 (1.0)|
| Right handed||8.2 (1.2)||8.1 (0.9)|
To determine the effect of finasteride on left- and right-handed participants, two-way ANOVAs, using handedness (right vs left) as a between-subjects factor and treatment (pretreatment vs during treatment) as a within-subjects factor, were carried out on the overall IIEF score as well as on each of the five subscales.
For the overall IIEF score, a main effect for handedness and an interaction effect were found. Right-handed participants had lower overall IIEF scores than left-handed participants (F(1, 62) = 10.5, P= 0.002); and left-handed men showed increased post-treatment scores whereas right-handed men showed decreased post-treatment scores (F(1, 62) = 50.7, P< 0.001). No overall main effect for treatment was found.
A main effect for handedness was found for the IS subscale (F(1, 62) = 18.1, P< 0.001), with left-handed men showing overall higher IS than right-handed men. A main effect for treatment was found on the IS and OS subscales (F(1, 62) ≥4.9, P≤ 0.030), with IS decreasing at post-treatment but OS increasing at post-treatment.
Interaction effects were found on five subscales – EF, IS, OF, SD and OS – such that left-handed men showed increased post-treatment scores and right-handed men showed decreased post-treatment scores (F(1, 62) ≥8.1; P≤ 0.001).
The results of this study differentiate the effects of the anti-androgen finasteride on the sexual functioning of right- vs left- handed patients, a finding that further suggests a possible link between sexuality and cognition. Specifically, we have found that the selective anti-androgen finasteride tends to decrease sexual function in right-handed men and to increase it in left-handed men, suggesting a relationship between sexual function, dihydrotestosterone and handedness. Given that EF, OF, SD, IS and OS represent interdependent aspects of sexual response (the last two representing omnibus measures of erectile and orgasmic functioning), it is not surprising that multiple subscales of the IIEF were affected in this study.
Although the prevalence of side effects of finasteride in our study differs from reports of minimal or no sexual side effects reported in some other studies, we attribute this to the fact that, in contrast with those studies, we alerted patients to possible stimulatory or inhibitory effects of this treatment. To this point, the content of communication with patients undoubtedly impacts the prevalence of side effects – the occurrence of sexual side effects for finasteride has reportedly varied from 2.1% to 38% in subjects with BPH . When patients with BPH are not advised about the possibility of sexual side effects of finasteride the prevalence is relatively low , whereas, not surprisingly, when patients are advised about such effects the prevalence is much higher . In the current study, because patients were advised about possible inhibitory or stimulatory effects on sexual function, a higher level was reported, but the direction of these effects appeared to be related to the patients' handedness.
So why might a drug that affects dihydrotestosterone act differently based on patients' handedness? In this study, we presumed that handedness served as a proxy for cognitive style, and that specific cognitive styles may result from two ‘opposing’ psycho-neuroendocrine axes such that those men affected in one manner by finasteride are likely to be under the influence of a different psycho-neuroendocrine sexual axis than those affected in another manner.
We hypothesize that, although men receive sexual input via the same somatic afferents, because they may function under different psycho-neuroendocrine sexual axes these same somatic afferents are directed towards one or the other neuroendocrine axis through different neuromodulators, such that a modulator that channels information towards one axis would not do so toward the other axis, a supposition that has now received empirical support from several studies [3,32,33]. This same type of selective channelling may function with respect to dihydrotestosterone which, according to our results, may be sexually activating only within the neuroendocrine axis of right-handed men (with finasteride decreasing sexual function in these men) and counteractive for the opposing neuroendocrine axis of left-handed men (with finasteride tending to favour sexual function in these men).
Regarding these sexual neuromodulators, specific sexual hormones presumably modulate distinct peripheral inputs (corresponding to visual images, sensations and haptic perception) [2,11], so that the impact on sexual functioning occurs at a higher level when hormonal drugs act on multiple neural receptor types. Thus, cyproterone acetate strongly interferes with the effects of the two classes of sexual hormones, blocking the androgenic receptors and decreasing the level of oestradiol. As a result, men taking cyproterone acetate experience significant negative sexual side effects . Bicalutamide exerts a selective anti-androgenic activity with no oestrogenic blockade (in fact, the level of oestradiol actually increases) such that it produces fewer sexual side effects on male subjects compared with cyproterone acetate . By contrast, finasteride exerts even more selective action, with anti-androgenic activity affecting only dihydrotestosterone; testosterone and the opposite class of hormones (namely oestrogens) are not affected. Accordingly, finasteride produces even fewer sexual side effects  and, according to our findings, presumably ones that are more selective depending on the individual's dominant psycho-neuroendocrine axis, as manifested through their hand preference.
Such thinking is supported by a recent paper indicating that 5α-reductase inhibitor therapy (with finasteride and dutasteride) induces persistent sexual side effects (diminished libido/erection, depression), but only in a subset of patients . Furthermore, these anti-androgens appear to induce significant psychological impairment (e.g. depression, which has both affective and cognitive dimensions), suggesting the close relationship between sexuality and cognition. This research is further supplemented by studies supporting the purported relationship between sexual hormones and psychological/cognitive function. For example, recent studies have demonstrated that premenstrual depression, postnatal depression, climacteric depression and cognitive changes are related to changes in ovarian hormone levels, conditions which may effectively be treated by hormone substitution. Unfortunately, oral contraception/hormonal replacement therapy (which influences cognitive performance) is a form of therapy that is not yet widely accepted .
Our study awaits replication with larger and more diverse samples, using measures of cognitive function that are more sophisticated and multidimensional. Although we did not have direct measures of hormone levels in these men, we are reasonably confident that finasteride was exerting comparable anti-androgen effects on right vs left-handed men, given that the anti-baldness effects do not differ across groups . On the other hand, if the metabolism of testosterone to dihydrotestosterone should decrease, then metabolism of testosterone towards other pathways (oestrogens) might well increase. Interference with progesterone and glucocorticoid pathways, as well as changes in luteinizing and follicle stimulating hormone levels, might also occur. Analysis of such endocrine changes (including the expected variation of dihydrotestosterone) will be necessary to specify a direct link between finasteride and the effects on sexual response observed in this study.
Finally, the need to control for placebo effects is critical only in studies designed to assess the effectiveness of one treatment against another. In contrast, our major study variable was the handedness of the men, not the drug treatment itself, and therefore a placebo condition was not warranted; in addition, because the effects of finasteride were bidirectional, any role of expectation (i.e. placebo) would have been distributed equally over both groups, yet results were quite different across the two groups.
Our results suggest a possible linkage between cognitive patterns, hormonal axes, sexual modulators and sexual function. Such relationships/lateralizations suggest that interdependences among these domains may be stronger and more complex than originally assumed.
To illustrate, a recently published paper suggests that the left visual field is more related to sexual experiences in women , while our own data (not presented here) suggest the right visual field may be more related to sexual experiences in men. From a physiological perspective, visually evoked sexual arousal is related to hormonal/neuroendocrine activation of autonomic brain regions . Thus, women and men appear to differ regarding the visual hemi-field (either left or right) underlying sexual activation, a process that ultimately may be modulated by the predominant active sexual hormones (either oestrogens or androgens). Yet, each visual hemi-field (right or left) supports a different mode of cognitive/mental processing (recognition, language, haptic perception/hand preference) , while the level of salivary testosterone is related to both handedness and degree of linguistic lateralization in normal women . Consequently, the relationship between cognitive pattern, sexual hormones and function seems to be more prominent than originally presumed.
CONFLICT OF INTEREST