La disfunción sexual masculina , podría ser un efecto del uso de interferón
El Día - España
La pérdida de la libido y la disfunción eréctil en los hombres son dos efectos adversos asociados con la toma de muchas medicaciones. En relación con los antirretrovirales (ARV), los trastornos sexuales en varones se empezaron a reportar en cuanto se generalizó el uso de los inhibidores de la proteasa (IP), con los que se relacionó en primera instancia.
El asunto apenas se había investigado, puesto que los cuestionarios más utilizados para determinar la calidad de vida en pacientes crónicos (MOS, por ejemplo, y más en concreto el MOS-HIV) simplemente tienden a ignorar el componente sexual, cuando la comercialización del sildenafilo (ViagraÂ®) primero y otros derivados después solucionaron la parte más tangible del asunto: la disfunción eréctil. Desde entonces, como si el único problema fuese querer y no poder, apenas hay más estudios que pudieran abordar al menos la pérdida de libido tanto en hombres como en mujeres con VIH o hepatitis.
Los ARV comparten este efecto adverso con el tratamiento para el virus de la hepatitis C (VHC), por lo que las personas coinfectadas pueden ver su función sexual particularmente alterada.
Pese a que hombres que toman la terapia anti-VHC han informado de la reducción de la libido (apetito sexual) y la disfunción eréctil, hasta ahora los factores subyacentes relacionados con la terapia y la disfunción sexual no se habían definido con claridad. El interrogante es si estos fenómenos son el resultado de la depresión y otros síntomas neuropsiquiátricos típicos de la terapia con interferón o bien tienen otro origen.
Para intentar dilucidar esta cuestión, un grupo de investigadores de la Universidad de Wúrburg (Alemania) han analizado las contribuciones putativas de los cambios hormonales sexuales en la disfunción sexual. El Dr. Kraus y su equipo evaluaron de forma prospectiva los cambios en la testosterona libre, la testosterona total, la dehidroepiandrosterona sulfato (DHEAS), la prolactina, la globulina transportadora de hormonas sexuales (SHBG), los niveles de FSH y LH y unas escalas de autodeterminación psicométrica en 34 hombres tratados con interferón alfa-2b (5 MIU tres veces a la semana) más ribavirina (n=15) durante 6-12 meses. (A notar que la actualmente estándar es la formulación pegilada del interferón que supone una sola inyección semanal.)
La depresión se midió con la Escala Hospitalaria de Depresión y Ansiedad, y la disfunción sexual se evaluó con el Symptom Checklist 90 Item Revised y una escala de cinco puntos para determinar el trastorno de excitación sexual. Es importante añadir que ninguno de estos hombres con VHC estaba tomando medicación antidepresiva.
Los resultados arrojaron que la testosterona libre y la total descendieron de forma significativa durante la terapia antiviral en estrecha relación con la función libidinal/sexual. Las escalas de depresión aumentaron durante la terapia y también se relacionaron de modo significativo con la disfunción sexual. No obstante, los niveles de andrógenos no tuvieron una correlación significativa con la depresión.
En resumen, los autores descubrieron que el tratamiento con interferón recombinante alfa-2b en hombres con hepatitis C crónica se asocia con una deficiencia funcional de andrógenos. Este descenso en la testosterona está relacionado en parte con los síntomas de pérdida de libido inducidos por la terapia y puede deberse a los efectos directos del interferón en las gónadas o efectos en los centros reguladores del hipotálamo. Sin embargo, existe una cada vez mayor correlación entre los síntomas de trastorno de excitación sexual y la depresión inducida por el interferón en estos individuos.
En la práctica clínica, durante la preparación de los pacientes con hepatitis C crónica podría ser útil llevar a cabo una evaluación hormonal basal previa a la iniciación de la terapia con interferón. De esta manera los posibles síntomas de pérdida de libido asociados con interferón y la consecuente reducción de la calidad de vida podrían ponerse en contexto durante el período de tratamiento.
Referencia: M. R. Kraus et al. Sexual dysfunction in males with chronic hepatitis C and antiviral therapy: interferon-induced functional androgen deficiency or depression? Journal of Endocrinology (2005) 185, 345-352.
Nota Originál de natap:
Sexual dysfunction in males with chronic hepatitis C and antiviral therapy: interferon-induced functional androgen deficiency or depression?
ED NOTE from Jules Levin: my experience was that sexual function and drive declined on HCV therapy, particularly in the latter stages of my 18 months course of therapy, but shortly after completion of therapy my sex drive and function completely returned.
Journal of Endocrinology (May 2005) 185, 345-352
M R Kraus, A SchÃ¤fer, T Bentink, M Scheurlen, B Weissbrich2, O Al-Taie and J Seufert1
Department of Gastroenterology and Hepatology, Medizinische Poliklinik, University of Wurzburg, Klinikstrasse 6-8, D-97070 Wurzburg, Germany 1 Division of Metabolism, Endocrinology and Molecular Medicine, Medizinische Poliklinik, University of Wurzburg, Wurzburg, Germany 2 Institute for Virology and Immunobiology, University of Wurzburg, Versbacher Strasse 7, D-97078 Wurzburg, Germany
".....In summary, we found that treatment with recombinant interferon alfa-2b in male patients with chronic hepatitis C is associated with functional androgen deficiency. This decline in testosterone is partially linked to therapy-induced symptoms of libido loss and may be due to direct effects of interferon on the gonads or effects on hypothalamic regulatory centers. However, there is an even stronger correlation between symptoms of sexual arousal disorder and interferon-induced depression in these patients.....
.....In clinical practice, during the workup of patients with chronic hepatitis C it could be helpful to perform baseline hormone screening prior to the initiation of interferon therapy. Potential interferon-associated symptoms of libido loss and therefore reduced quality of life could hence be better put into context during treatment period (depression vs hormonal changes).....anti-depresstion medications were not used by patients in this study..."
Decrease of libido and erectile dysfunction are reported by male patients during antiviral therapy of chronic hepatitis C, but therapy-associated underlying factors for sexual dysfunction are not well defined.
To assess putative contributions of interferon-induced sex hormone changes to sexual dysfunction, we prospectively investigated changes in free testosterone, total testosterone, dehydroepiandrosterone sulfate, prolactin, sex hormone-binding globulin, FSH and LH levels and psychometric self-assessment scores in 34 male patients treated with interferon alfa-2b (5 MIU three times weekly) (n=19)+ ribavirin (n=15) for 6-12 months.
Depression was measured by the Hospital Anxiety and Depression Scale. Sexual dysfunction was evaluated by the Symptom Checklist 90 Item Revised and a five-point rating scale assessing sexual arousal disorder.
It is important to add that none of the hepatitis C patients in our study received antidepressant medication.
Free and total testosterone decreased significantly during antiviral therapy in close correlation with libido/sexual function. Depression scores increased during therapy and were also significantly associated with sexual dysfunction. However, androgen levels displayed no significant correlation with depression.
These results suggest that interferon-induced decrease in sexual function is associated - but not causally related -with both androgen reduction and increased depressive symptoms. These findings may affect care for male hepatitis C patients during interferon therapy.
Interferon alfa is therapeutically used, e.g. in malignant diseases and chronic viral hepatitis. Recombinant human interferon alfa has proven its antiviral effect in several licensing trials (McHutchison et al. 1998, Manns et al. 2001, Fried et al. 2002, McHutchison & Fried 2003) representing currently the standard treatment of chronic hepatitis C. Sustained virological response is achieved at present in about 50% of patients treated with a combination of peginterferon alfa and ribavirin for up to 12 months (Manns et al. 2001, Fried et al. 2002).
However, interferon alfa treatment is still unsatisfactory with respect to its profile of side-effects. Psychiatric side-effects (especially depression) are frequently seen in systemic therapy with human recombinant interferon alfa (Kraus et al. 2003). There are known hormonal effects of interferon alfa (e.g. on thyroid hormone metabolism (Corssmit et al. 1995)) - however, the extent of hormonal changes during interferon alfa therapy of chronic hepatitis C for up to 1 year is still not clear.
In addition, potential associations of hormonal changes with psychiatric symptoms such as depression or sexual dysfunction especially in male patients have yet to be documented. Occasionally, male hepatitis C patients on interferon alfa therapy report on noticeable symptoms such as sexual dysfunction or libido loss (Soto Alvarez et al. 1991). This may indicate a specific side-effect of interferon therapy, which possibly reduces quality of life and additionally adherence to antiviral therapy. Until now, it is not clear whether this is solely due to increased depression or whether this can be partially explained by hormonal changes.
Therefore, we prospectively investigated timing and intensity of psychiatric symptoms (especially depression), sexual satisfaction and hormonal changes (especially serum androgen levels) induced by therapy with recombinant human interferon alfa-2b in male patients with chronic hepatitis C.
In addition to previously described psychiatric side-effects (Kraus et al. 2003, 2005a,Kraus et al. b, Loftis & Hauser 2004), we focused in this study on the assessment of symptoms of sexual arousal disorder (APA 1994) and sexual dysfunction in response to interferon alfa-2b administration in antiviral treatment of male patients with chronic hepatitis C. In addition, we were particularly interested in androgen changes, alterations of the pituitary-testicular axis and adrenal gland function that may occur during interferon treatment of patients with chronic hepatitis C.
The patients in our study showed significantly increased depression scores during the treatment period, and we could also confirm previous patients' reports on interferon-associated libido loss (Soto Alvarez et al. 1991).
The assessment of interferon-induced changes in sex hormone serum levels has been so far limited to small studies (Barreca et al. 1993, Kauppila et al. 1997, Corssmit et al. 2000, Weidinger et al. 2002), case reports or animal models (Hibi et al. 1997, Montor et al. 1998).
In accord with Barreca et al.(1993) and Corssmit et al.(2000), we observed a significant decline of free and total testosterone serum concentrations within the normal range over time. As testicular function is known to be controlled by gonadotropins (LH, FSH) and is affected by prolactin, we evaluated the time course and concentrations of gonadotropins and prolactin. LH levels (as well as FSH serum concentrations) were not significantly affected during interferon alfa-2b treatment. Therefore, we assume that the observed testosterone decrease is not mediated by alteration of the pituitary-testicular axis. This, however, cannot be entirely excluded as gonadotropin secretion pulsatility was not analyzed.
An explanation for the apparent discrepancy between total and free testosterone levels at t4 remains open. We confirmed, however, that differences are not due to changes in SHBG levels. This is consistent with the findings of Corssmit et al.(2000). We are aware that the best measures for bioavailable testosterone are represented by either concentrations of free testosterone measured by equilibration dialysis assays or free testosterone calculated from albumin and SHBG levels (Christ-Crain et al. 2004a). However, we believe that in this particular study, direct measurement of free testosterone is equally representative (of male androgen status) because it has been demonstrated that within the physiological range of 40-50 g/l (5.8-7.2 x 10-4 mol/l) of albumin binding protein concentrations do not significantly affect free testosterone levels (Vermeulen et al. 1999). As indicated, in our study the patients' albumin levels stayed within the normal range throughout the whole evaluation time.
Elevated levels of prolactin are associated with sexual dysfunction, such as reduced libido, erectile dysfunction, diminished ejaculate volume and oligospermia (Spollen et al. 2004). In our study, mean serum prolactin levels were significantly increased during interferon therapy. As it has been demonstrated that the duration and frequency of prolactin secretory bursts from the pituitary are independent from gonadal steroid plasma levels in women and in men (Genazzani et al. 1994), we assume that the observed increase in mean serum prolactin values is not secondary to alterations in gonadal steroid concentrations. Rather we may speculate that interferon therapy either directly affected lactotrope cells in the pituitary, or hypothalamic factors which control prolactin secretion, or both. Elevated serum levels of prolactin during interferon therapy, however, did not significantly correlate with reductions in free testosterone serum concentrations. Therefore, we conclude that prolactin elevation did not contribute to reduced testosterone concentrations and impairment of libido.
In this context, it is important to add that none of the hepatitis C patients in our study received antidepressant medication known to exert dopaminergic effects as a confounding factor in the evaluation and interpretation of increased prolactin levels during interferon alfa-2b medication.
A marked association between the androgen-precursor DHEA and libido has been demonstrated in females (Arlt et al. 1999). Therefore, we monitored DHEAS levels before, during and after interferon therapy. The reversible decline of DHEAS serum concentrations during antiviral treatment may be explained either by direct effects on the adrenal cortex or by indirect mechanisms involving the adrenocorticotropic hypothalamic-hypophyseal-adrenal axis via corticotropin-releasing hormone/adrenocorticotropin. Alternatively, the decline of serum DHEAS in parallel with the observed reductions in total and free testosterone values during interferon therapy may be due to direct affects on the testes in the male patients.
The sexual arousal disorder in our study population was linked to both interferon-induced depressive symptoms and serum free testosterone decline (confirming the results of studies that did not find a significant correlation between total testosterone and symptoms of hypogonadism (Christ-Crain et al. 2004b)). However, we found no direct link between sex hormone changes and depression. This implies that both factors (interferon-induced depression and functional androgen deficiency) may independently affect the extent of male sexual dysfunction in patients with chronic hepatitis C and therapy with interferon alfa-2b. It is important to note that we do not postulate a causative relationship for each single factor (depression, androgen deficiency) - in contrast we propose that both may be permissive with respect to symptoms of sexual dysfunction.
As it is known that relatively low androgen levels generally suffice for normal sexual function, the results of the study do not allow us to define low testosterone serum concentrations as the main cause for sexual dysfunction in the study population. These may, however, represent among others, such as depression, a permissive factor for libido loss.
There are several limitations in our study that have to be kept in mind when drawing conclusions from the findings. Hormonal changes associated with interferon alfa-2b therapy were within the normal ranges throughout the evaluation period and therefore have to be interpreted with care. Sample size in our study does not exceed 34 male patients, although the sample population was quite homogeneous and target variables are clear. Therefore, from a statistical point of view this specific sample size provides enough power to detect relevant changes of target variables. Further limitations include the fact that conventional interferon alfa-2b has been used (as opposed to pegylated forms representing the current therapy standard) and that information on sexual dysfunction was obtained by a psychometric instrument that is not validated or referenced with larger study populations.
In summary, we found that treatment with recombinant interferon alfa-2b in male patients with chronic hepatitis C is associated with functional androgen deficiency. This decline in testosterone is partially linked to therapy-induced symptoms of libido loss and may be due to direct effects of interferon on the gonads or effects on hypothalamic regulatory centers. However, there is an even stronger correlation between symptoms of sexual arousal disorder and interferon-induced depression in these patients.
Subsequent studies should include larger sample sizes (anticipated alfa-level adjustment and corresponding sample size calculations) as well as specific hypothesis-driven analyses based on the presented findings.
In clinical practice, during the workup of patients with chronic hepatitis C it could be helpful to perform baseline hormone screening prior to the initiation of interferon therapy. Potential interferon-associated symptoms of libido loss and therefore reduced quality of life could hence be better put into context during treatment period (depression vs hormonal changes).
There were no significant differences in sociodemographic or biomedical parameters between both subgroups (treatment with interferon alfa monotherapy or combination therapy with interferon alfa-2b and ribavirin). The (low) mean age of less than 40 years (36.9 ± 1.4; range: 19-52 years) in our study sample is remarkable, because it is known that usually symptoms of male sexual dysfunction/arousal disorder are age-related (Martin 1979). Thus, advanced age as a possible confounding factor in the evaluation of libido loss can be considered negligible in this study.
Clinical features Clinical side-effects of interferon alfa - especially with respect to psychiatric symptoms - have previously been reported (Kraus et al. 2003). In accord with these results, HADS depression scores increased significantly (and reversibly after therapy) during treatment with interferon alfa-2b.
The SCL-90-R depression subscale confirmed these findings.
Self-assessment of sexual dysfunction and libido loss
Scores for libido self-assessment declined significantly during the course of interferon alfa therapy. Both SCL-90-R (item 5:loss of sexual interest or pleasure'; P<0.001) and the five-point Likert scale (P<0.001) increased significantly over time during therapy with interferon alfa-2b (and ribavirin).
Both items (SCL-90-R item 5 and the self-developed Likert rating scale) displayed high correlation at t3, after 3-4 months of antiviral therapy (Pearson correlation coefficient r=0.793; P<0.001).
Additionally, we performed a subgroup analysis to get insight into whether the observed loss of sexual interest was common in our study sample or restricted to a subgroup of male patients.
There were 15 out of 34 patients (44.11%) indicating a decline in sexual interest/satisfaction in both administered scales and 22 out of 34 male hepatitis C patients (64.71%) confirmed libido loss on at least one of the psychometric scales (comparison between evaluation time points t1 and t3).
The type of interferon therapy administered (monotherapy vs combination therapy with additional ribavirin) had no significant effect on the incidence rate of symptoms of libido loss during antiviral therapy (chi square test; P>0.350).