Effects of psychotropic drugs on human sperm motility*

FERTILITY AND 8TEIuLITY Copyright

0

Vol. 36, No.4, October 1981 Prinf£d in U.S.A.

1981 The American Fertility Society

EFFECTS OF PSYCHOTROPIC DRUGS ON HUMAN SPERM MOTILITY·

ROBERT M. LEVIN, PH.D.t§~ JAY D. AMSTERDAM, M.D.:j:§ ANDREW WINOKUR, M.D.:j: ALAN J. WEIN, M.D.t

Division of Urology, Department of Surgery, and Depression Research Unit, Department of Psychiatry, University of Pennsylvania School of Medicine, and Veterans Administration Hospital, Philadelphia, Pennsylvania 19104

Imipramine has been shown to have a potent inhibitory effect on sperm motility in vitro. Because of the frequent chronic use of antidepressants in treatment of depression, we investigated the in vivo effects of desmethylimipramine and lithium carbonate on sperm function in patients suffering from clinical depression. We also studied the in vitro effects of a series of neurotropic agents on sperm motility. There were no significant differences in sperm count, viability, or motility between a group of patients diagnosed as having clinical depression and a group of semen donors with normal sperm characteristics. Three weeks of continuous therapy with desmethylimipramine or lithium carbonate resulted in a significant decrease in sperm viability but no significant change in sperm count or motility. The in vitro drug studies demonstrated that imipramine hydrochloride, desmethylimipramine, chlorpromazine, trifluoperazine, and nortriptyline hydrochloride were all potent inhibitors of sperm motility, whereas lithium carbonate had no effect on motility. Fertil Steril36:503; 1981

There is increasing evidence of a relationship between affective illness and specific endocrine and metabolic alterations. 1-3 Although the physiologic consequences of these changes are unknown, many depressed and manic patients demonstrate significant alterations in their sex drive. 4 Since spermatogenesis and the development of sperm motility are in part hormone-dependent,5, 6 it is possible that spermatogenesis and sperm function are altered in affective dis-

orders. In addition, previous studies performed in our laboratory7 had demonstrated that the antidepressant imipramine hydrochloride is a potent in vitro inhibitor of sperm motility. Because of the frequent use of antidepressants in the treatment of affective disorders, we investigated the effects of acute treatment of depressed patients with desmethylimipramine or lithium carbonate on sperm function. In addition, we studied the direct in vitro effects of a variety of neurotropic agents on sperm motility.

Received March 6, 1981; revised and accepted June 3, 1981. *Supported in part by the McCabe Fund, by NIMH Grant MH-32702 (Dr. Amsterdam), by NIMH Research Scientist Development Award MH-0044 (Dr. Winokur), by research funds from the Veterans Administration, and by the Michael R. Babitts Fund for Psychoneuroendocrinology. tDivision of Urology, Department of Surgery. :j:Depression Research Unit, Department of Psychiatry. §Veterans Administration Hospital. ~print requests: Robert M. Levin, Ph.D., Division ofUrology, 3010 Ravdin Courtyard Bldg., Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, Pennsyl. vania 19104.

MATERIALS AND METHODS

Measurement of Sperm Characteristics. Fresh ejaculates obtained by masturbation were allowed to liquefy for 30 minutes at room temperature. The sperm count and viability (percentage of motile spermatozoa) were determined by routine microscopic analysis, with the mean of four determinations being used as the final value. Sperm motility was quantitated by the turbidimetric method,7,8 in which semen (100 JJ.l) is 503

504

October 1981

LEVINETAL.

layered on the bottom of a specially constructed cuvette containing 0.6 ml of modified Lopata's medium (pH 7.6). Sperm motility is measured spectrophotometrically as an increase in absorbance (at 545 nm) as the sperm swim upward into the light path. Optical density (absorbance) was measured with a Hitachi Model 100-40 spectrophotometer equipped with a constant-temperature housing that was maintained at 37° C. Sperm motility was expressed by a "motility index" (MI), 9 which is independent of both sperm count and viability. This index was determined for each sample by the following formula: MI = _ _ _ _ _S_lo_p_e_(_ID_O_D_/ID_i_n_)_ _ _ _ x 100 Sperm Count (l06/IDD x Viability (%)

In Vitro Drug Studies. The effects of various neurotropic agents on sperm motility were studied. The test drug was added to the Lopata's medium before the semen was introciuced so that the immediate effect of the drug'- could be measured. Each experiment included a pair of assays. A control assay was run immediately before or after an assay with the drug, and the effect of the drug was quantitated by measurement of the difference between the initial slopes of the two absorbance curves. For each drug a minimum of three experiments were performed at each of five or six drug concentrations. The following drugs were tested: chlorpromazine, trifluoperazine, promethazine hydrochloride, nortriptyline hydrochloride, imipramine hydrochloride, desmethylimipramine, lithium carbonate, and barbital. Clinical Studies. Twenty-four psychiatric patients agreed to participate in a study of sperm characteristics in clinical depression. Both inpatients and outpatients, ranging in age from 21 to 55 years (mean age, 40 ± 9 years), were included. All were physically healthy and had had normal physical examinations and laboratory tests (complete blood count, SMA-12, Ta uptake, T4 , and urinalysis). None had a history of significant medical illness, endocrinopathy, drug or alcohol dependence, steroid use, testicular surgery, varicocele, or genitourinary disease. None had previously had problems with sexual performance unrelated to an affective episode. The patients had been diagnosed as having an affective illness according to Research Diagnostic Criteria10 and had a depression rating of at least 16 on the 17-item Hamilton Depression ScaleY They complained of mild to severe changes in libido and sexual performance, and each charac-

terized his libido as normal prior to the present affective episode. All patients had been drug-free for at least seven days and had been sexually abstinent for at least two days prior to producing a semen specimen for analysis. Prior to participating in our study, some of the patients had been taking aspirin, Valium as required, or low doses of antidepressants « 50 mg/day). Previous studies had demonstrated that plasma concentrations of desmethylimipramine and lithium carbonate were below detectable levels after seven days; the half-life is approximately 18 hours (unpublished data). Thirty-six volunteer semen donors (mean age, 29 ± 3 years) served as control subjects. Since they had been chosen because their semen quality was within normal limits (i.e., the sperm count was above 40 million/ml, the viability was at least 60%, and the motility index was above 6.0), they did not represent a cross-section of the general male population. However, their semen quality was, by design, equal to or better than that of the general population. Nine of the depressed patients participated in a study of the effects of desmethy limipramine and lithium carbonate on sperm motility, providing semen specimens before and after 3 weeks of continuous therapy with either desmethylimipramine (200 mg daily) or lithium carbonate (at a dosage sufficient to maintain a plasma concentration of 0.6 to 1.4 mEq/liter). Nine of the control subjects also produced semen samples three weeks apart for comparison. 70

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FIG. 1. The effect ofdesmethylimipramine (DMI) on sperm motility. Typical tracings of a pair of assays performed in the presence and absence .of DMI (25 IJ.M)are shown.

PSYCHOTROPIC DRUGS AND HUMAN SPERM MOTILITY

Vol. 36, No.4

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istics changed significantly when measured 3 weeks apart in the nine control subjects. DISCUSSION

o

25 DESMETHYLlMIPRAMINE

("M)

FI.G: 2. The. ~ffect of desmet~ylimipramine (DMI) on sperm motIhty. MotIhty was determmed at different concentrations of DMI (12.5 to 100 IJ.M). Motility is presented as the percentage of control motility (motility in the absence of DMI) determined by division of the initial slope of the absorbanc~ curve ob~aine~ in the presence of the drug by the initial slope obtamed m the absence of the drug and multiplication by 100. Each point is the mean of four to six determinations' the vertical brackets represent the standard error of the me~n.

RESULTS

In Vitro Drug Studies. The effect of desmethylimipramine on sperm motility is shown in Figures 1 and 2. Figure 1 gives a representative turbidimetric tracing obtained in the presence and absence of desmethylimipramine (25 jJ.M). Figure 2 shows the dose-dependent inhibitory effect of the drug on sperm motility. The effects of a variety of neurotropic agents on sperm motility are presented in Table 1. The I50's were calculatedJrom dose-response curves (similar to that presented in· Table 2) based on at least five drug concentrations for each semen specimen. Three to five dose-response curves were generated for each drug. All agents tested except lithium carbonate and barbital produced a dose-dependent inhibition of sperm motility. Clinical Studies. A comparison of the sperm characteristics ofthe total (drug-free) patient and donor populations showed no significant difference (using Student's t-test) between the two groups in sperm count, viability, or motility index (data not shown). . The effects of 3 weeks of continuous therapy with either desmethylimipramine or lithium carbonate on sperm count, viability, motility, and seminal pH in nine depressed patients are given in Table 2. Treatment with desmethylimipramine produced no significant change in the sperm count or mean sperm motility, but it produced a significant reduction in sperm viability. Lithium carbonate therapy also produced a significant reduction in sperm viability but no change in sperm count or motility. None of these sperm character-

Although the biochemical basis for clinical depression is unknown, there is increasing evidence of endocrine involvement in affective illnesses. In light of the fact that spermatogenesis and sperm function can be altered by hormonal changes, we compared a variety of characteristics of sperm isolated from patients suffering from clinical depression with those of sperm isolated from a donor population. It is interesting to note that, although the mean age ofthe patient population was significantly greater than that of the donor population, sperm count, viability, motility, and seminal pH were similar in the two groups. The acute drug studies provided preliminary evidence that 3 weeks of continuous therapy with either desmethylimipramine or lithium carbonate may decrease sperm viability without affecting either sperm count or motility. However, it is possible that the sperm of older men are more fragile and therefore more susceptible to the effects of drugs. Since these were acute experiments, our results were not related to changes in spermatogenesis. However, antidepressants are routinely given over extended periods of time. Some men who receive trichloroacetic acid (a tricyclic antidepressant) complain of decreased libido or sexual impotence, and there is some evidence that this class of drugs can cause alterations in spermatogenesis. 12 Tricyclics affect both the central and peripheral catecholamine and indoleamine systems, which may alter the normal functioning of the hypothaTABLE 1. Effects of Neurotropic Agents on Sperm Motility

,.M

Trifluoperazine (6.25--100 IJ.M) Desmethylimipramine (12.5--100 IJ.M) Promethazine hydrochloride (12.5--150 IJ.M) Nortriptyline hydrochloride (25--100 IJ.M) Chlorpromazine (25--125 IJ.M) Imipramine hydrochloride (12.5 -250 IJ.M) Barbital (25--500 IJ.M) Lithium carbonate (3.9 -10,000 IJ.M)

25 ± 4 27 ± 0.8 50 ± 7 51 ± 0.5 53 ± 0.5 65 ± 4 (500 IJ.M)b (10,000 IJ.M)b

aDose-response curves were performed as described in Methods. A minimum of three curves were generated for each drug. The Iso (drug concentration that will produce a 50% decrease in sperm motility) was determined for each curve by graphic analysis. Mean ± standard error of the mean. bFifty percent inhibition was not obtained up to the concentration given.

LEVIN ET AL.

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October 1981

TABLE 2. Effects of Acute Therapy with Desmethylimipramine or Lithium Carbonate on Sperm Count, Viability, and Motility Patients Controls

Characteristic

Initial

Sperm count (l06/m n Viability (%) Motility index pH of semen

90 68 8.8 8.0

± ± ± ±

13a 4 0.8 0.3

(n =

9)

Desmethylimipramine

3 Weeks

82 71 8.4 8.0

± ± ± ±

13 4 1.0 0.2

Pretreatment

71 71 12 8.1

± ± ± ±

14 7 3.0 0.3

(n =

5)

3 Weeks

55 49 12 8.0

± ± ± ±

12 2c 4.8 0.3

Lithium carbonate Pretreatment

45 70 12 8.0

± ± ± ±

7b 4 2.0 0.2

(n =

4)

3 Weeks

46 55 14 8.0

± ± ± ±

7 4C 2.8 0.2

aMean ± standard error of the mean. b Although the mean' sperm count of the four patients was 45 ± 7, the mean sperm count of the total population of depressed patients studied (n = 24) was 76 ± 22. cThe difference between the pretreatment and posttreatment values is statistically significant (P < 0.01, Student's t-test).

lamie-gonadal-spermatogenic axis, thereby affecting the process of spermatogenesis. Studies to determine the effects of chronic antidepressant therapy on sperm function are in progress. The in vitro studies of the effects of desmethylimipramine, lithium carbonate, and a series of other centrally acting agents demonstrated that all of the drugs except lithium carbonate and barbital were potent inhibitors of sperm motility. It is interesting to note that promethazine hydrochloride, a non-centrally acting phenothiazine, was as potent an inhibitor as chlorpromazine, a centrally acting phenothiazine. Thus, the direct inhibition of sperm motility is probably not a function of the neurotropic nature of these compounds but may be related to other biologic and biochemical effects.

REFERENCES 1. Rubin RT, Kendler KS: Psychoneuroendocrinology: fun· damental concepts correlated in depression. In Depression: Clinical, Biological, and Psychological Perspectives, Edited by E Usdin. New York, Brunner/Mazel, 1977, p 122 2. Benkert 0: Effects of hypothalamic releasing hormones in depression and sexual impotence. In Neuropsychopharmacology, Edited by JR Boissier, H Hippius, P Pichot. Amsterdam, Excerpta Medica, 1975, p 663

3. Brambilla F, Smeraldi E, Sacchetti E, Negri F, Cocchi D, Muller EE: Anterior pituitary responsiveness to hypothalamic hormones in depressed patients. Arch Gen Psychiatry 35:1231, 1978 4. Petrie WM: Sexual effects of antidepressants and psychomotor stimulant drugs. Mod Prohl Pharmacopsychiatry 15:77,1980 5. Hansson V, Calandra R, Purvis K, Ritzen M, French F: Hormonal regulation of spermatogenesis. Vitam Horm 34:187, 197u 6. Lostroh AJ: Hormonal control of spermatogenesis. In Regulating Mechanisms of Male Reproductive Physiology, Edited by LH Spelman. Amsterdam, Excerpta Medica, 1976, p 13 7. Levin RM, Shofer J, Greenberg SH: A quantitative method for determining the effects of drugs on spermatozoal motility. Fertil Steril 33:631, 1980 8. Sokoloski JE, Blasco L, Storey BT, Wolf DP: Turbidimetric analysis of human sperm motility. Fertil Steril 28: 1337, 1977 9. Levin RM, Greenberg SH, Wein AJ: Clinical use of the turbidimetric analysis of sperm motility: comparison with visual techniques. Fertil Steril 35:332, 1981 10. Spitzer RL, Endicott J, Robins E: Preliminary report of the reliability of research diagnostic criteria applied to psychiatric case records. In Predictability in Psychopharmacology: Preclinical and Clinical Correlations, Edited by A Sudilovsky, S Gershon, B Beer. New York, Raven Press, 1975, p 1 11. Hamilton M: A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56, 1960 12. Kurland AA, Pinto A, Destounis N, Babikow PW: Effects of trimipramine (Surmontil) on spermatogenesis and mood in normal volunteers. Curr Ther Res 12:186, 1970