Antidepressant-Induced Sexual Dysfunction Associated with Low Serum Free Testosterone

Presented by Alan J. Cohen, M.D.,
Private Practice and Assistant Clinic Professor of Psychiatry, UCSF

SUMMARY

In the course of an evaluation for treatment of antidepressant induced sexual dysfunction (ASD) with a new agent, an unforeseen pattern emerged in the pre-treatment laboratory assessment. Free serum testosterone levels in both men and women study subjects were found to be below the normal ranges in 75 percent of subjects in this small study. There were no other consistent laboratory findings that could account for such a high percentage correlation. Further inquiries into the possible causes for decreased serum testosterone and its association with ASD seems warranted.

INTRODUCTION

Antidepressant induced sexual dysfunction (ASD) is a well recognized complication of treatment for mood and anxiety disorders (Gitlin 1997). Recent discoveries have helped to provide effective remedies for this significant obstacle to patient compliance and successful treatment outcome (Cohen 1997, Gitlin 1997, Bartlik 1995). However, no remedy is 100% effective. In addition, there is no fully satisfactory theory that explains the physiologic mechanisms responsible for the varied aspects of sexual dysfunction observed (Sussman 1998). In the course of an evaluation of treatment for ASD in a community office based research setting, a striking pattern emerged in the laboratory screening protocol. Free testosterone levels were found to be subnormal in 15 of 20 patients. No other consistent laboratory value nor physical examination finding could account for this observation. Causes for reduced free testosterone and its effect on sexual function are discussed with implications for future research and treatment strategies.

METHODS AND AIMS

Twenty subjects, ages 35 to 74 years, were evaluated for a double blind placebo controlled trial of a dietary supplement combination for the treatment of ASD. All of the subjects were using medication for the treatment of mood disorder (DSM IV Criteria) included SSRI's, SNRI's, Bupropion, Trazodone and Mirtazipine. Screening physical exams and laboratory studies including CBC, TSH, Prolactin, serum free Testosterone, Serum Chemistries, and Urinalysis were done. The Arizona Sexual Experiences Scale (ASEX) was used as part of the clinical assessment of ASD. In the course of the evaluation process, low serum free testosterone was noted in 15 patients.

RESULTS 

Twelve men and eight women were evaluated. Eight men had subnormal free testosterone levels, two additional men had borderline low levels. Six women had subnormal levels of free testosterone. The average age of male subjects was 50.5 years. The male ASEX mean score was 20 with a mean free Testosterone of 13.5 pg/ml. The laboratory range of free Testosterone was 16-33 pg/ml. The average age of female subjects 39.6 years; female ASEX score was 20, and the mean free Testosterone level was 0.8 pg/ml. (normal range 0.8 - 3.0 pg/ml). (Laboratory ranges were modified according to standardized norms for age; average free testosterone levels decline slightly with increasing age.) Table #1 summarizes the data on all of the subjects in the study. Prolactin levels were above normal in only two subjects (one male, one female), both of whom were also found to have sub-normal levels of free testosterone. All of the other subjects had normal Prolactin levels. Thyroid stimulating hormone was found to be normal in all subjects.

Table 1.

SexAgeMedicationASEX Scorefree T
(pg./ml.)M35venlafaxine1623.4M36sertraline215.2 *M43paroxetine1813.5
*M45venlafaxine1716.3 #M46venlafaxine2013.2
*M46paroxetine/mirtazepine2013.4 *M47citalopram1929.0M47fluoxetine2217.6
#M50sertraline176.2 *M53nefazodone2511.1 *M54bupropion217.4
*M74venlafaxine245.6 *F20citalopram291.7F31venlafaxine210.50
*F37paroxetine230.70 *F41paroxetine191.5F44sertraline160.40
*F45bupropion/trazodone160.50 *F47fluoxetine200.50 *F52bupropion160.40 *
(* denotes subnormal fT levels, # denotes borderline low free T levels)
ASEX score range is 5-30, 5 is maximal sexual function, 30 is minimal
score.

DISCUSSION

This report is the first known documentation of reduced free testosterone levels associated with ASD. Prior reports have mentioned SSRI-induced prolactin elevations but none have described effects on testosterone levels (Amsterdam 1997).

Certainly, drugs can play a role in decreasing testosterone levels. Ketoconazole, megestrol, cimetadine, and spironolactone have all been reported to lower testosterone levels (De Coster 1985, Griffin and Wilson 1998). Methadone and other opiates can suppress testosterone by reducing LH levels centrally (Griffin and Wilson 1998). Anticonvulsants It is generally thought to be related to an increased metabolic clearance of testosterone or reduced LH levels. However, a 1991 report postulated that primary hypogonadism was the likely cause . (The P-450/ CYP3A3/4 system is the subgroup of chemical detoxifying liver enzymes involved in the metabolism of testosterone). Many antidepressants are substrates of these isoenzymes. Nevertheless, enzyme-induction is unlikely to account for lowered free Test. levels. Changes in sex hormone binding globulin levels can influence the quantity of circulating free testosterone. Estrogen supplements will increase the levels of SHBG and thereby reduce levels of free testosterone.

Testosterone can also bind with albumin, so changes in albumin levels could also be a factor. Certain medical conditions have been associated with lower levels of testosterone. Low testosterone levels have been described in HIV-infected males; proposed explanations include Leydig cell failure or concurrent medication effects.

Studies investigating testosterone levels and mood disorders have shown conflicting results. Levels of testosterone in 12 depressed males were compared to age-matched normal controls by Levitt and Joffe in 1988. No significant differences were noted between the patient and control groups. In 1991, Steiger et al. evaluated nocturnal testosterone secretion in 12 patients with major endogenous depression and found that blunted testosterone and elevated cortisol secretion were markers of acute depression prior to treatment. Testosterone concentration increased after remission from the depression, following drug cessation. Lower testosterone levels were also observed in an evaluation of healthy male internal medicine residents; suggesting that chronic stress and sleep deprivation may play a role in testosterone levels. Clearly, more research is needed to elucidate the role of testosterone in the evaluation and treatment of antidepressant induced sexual dysfunction. Further studies should take into account diurnal variations in hormone level, total and free levels of hormone, and pre- and post-antidepressant levels of hormone. Studies on women must also consider menstrual cycle fluctuations in hormones, and the responses that may be noted in post-menopausal women. Low testosterone levels have been described in HIV-infected males. However, enzyme-induction is unlikely to account for these observations. Changes in SHBG affinity may be relevant in this case, as enhanced binding would reduce free testosterone levels. Additionally, increased synthesis of SHBG would allow greater proportion of total testosterone to be bound, thereby reducing the free component. Limited by small number of subjects, lack of control group. Furthermore, we have no information on the testosterone level of subjects prior to onset of antidepressant use. Further studies should also include measurement of total testosterone levels, with its implications regarding SHBG levels.

This brief report raises more questions than it answers. However, it is the first description of an association between low free testosterone levels and antidepressant induced sexual dysfunction. Further research is needed to evaluate this relationship for cause and effect factors, as well as avenues to explore regarding treatment of ASD involving hormone replacement.

REFERENCES

Amsterdam J. et al (1997) Breast enlargement during chronic antidepressant therapy J Affective Disorders Nov.; 46(2);151-156.  

Bartlik B et al (1995) Psychostimulants apparently reverse sexual dysfunction secondary to select serotonin reuptake inhibitors. J Sex Marital Ther. 21, (4):264-271  

Bernhardt PC et al (1998) Testosterone changes during vicarious experiences of winning and losing among fans at sporting events. Physiol. Behav Aug.; 65(1):59-62.  

Cohen AJ and Bartlik B (1998) Ginkgo biloba for antidepressant-induced sexual dysfunction J Sex Marital Ther Apr-Jun 24:2 139-143.  

De Coster R et al (1985) Effect of a single administration of ketoconazole on total and physiologically free plasma testosterone and 17 beta-oestradiol levels in healthy male volunteers. Eur J Clin Pharmacol 29(4):489-493.  

Gitlin M. (1997) Sexual side-effects of psychotropic medications, in Psychiatric Clinics of North America: Annual of Drug Therapy, pp. 61-90.  

Griffin J and Wilson J (1998) Disorders of the testes and the male reproductive tract in: Williams Textbook of Endocrinology 9th ed. W.B. Saunders Co. pp. 845-861. 

Herzog AG (1995) Hormonal changes in epilepsy Epilepsia Apr; 36(4):323-326  

Levitt A and Joffe R (1988) Total and free testosterone in depressed men Acta Psychiatr Scand Mar;77(3)346-348. 

Sternbach H (1998) Age-associated testosterone decline in men: clinical issues for psychiatry Am J Psychiatry Oct, 155:10, 1310-1318. 

Seidman S and Rabkin J (1998) Testosterone replacement therapy for hypogonadal men with SSRI-refractory depression. J Affect. Disord Mar; 48(2-3):157-161

The author wishes to thank Laura Stachel, M.D. for her assistance in the preparation of this report.

Psychiatry On-Line 1999 
revised 10/3/2000

Courtesy of Alan J. Cohen M.D. http://www.doccohen.com