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From the * Clinic of Obstetrics and Gynecology and
Departments of Internal Medicine and
Gastroenterology, S. Orsola-Malpighi Hospital
and University of Bologna, 40138 Bologna, Italy; and
Department of Medicine, University of
Washington, Seattle, Washington.
| Correspondence to: M. Cristina Meriggiola, I Clinic of Obstetrics and Gynecology, S. Orsola-Malpighi Hospital and University of Bologna, Via Massarenti 13, 40138 Bologna, Italy (e-mail: crismeri{at}med.unibo.it). |
| Received for publication November 21, 2001; accepted for publication April 23, 2002. |
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Abstract |
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Key words: Spermatogenesis, cyproterone acetate, contraception, hormones
Regimens that combine androgens with different progestins such as levonorgestrel, desogestrel, medroxyprogesterone acetate, cyproterone acetate (CPA), or norethisterone enanthate have been shown to be most promising for achieving optimal spermatogenic suppression (Bebb et al, 1996; Handelsmann et al, 1996; Meriggiola et al, 1996, 1997, 1998; Anawalt et al, 1999, 2000; Kamischke et al, 2001; Kinniburgh et al, 2001). In preliminary pilot studies, the prototype regimen, based on combined administration of 100 mg/week of TE with CPA at 100, 50, 25, and 12.5 mg/day has been reported to suppress sperm production below 1 million/mL in all subjects, whereas 85% of subjects (17 of 20) became azoospermic. Suppression of spermatogenesis was dependent on the dose of CPA, and azoospermia was induced in all subjects with 100 and 50 mg/day of CPA, in 75% of subjects (4 of 5) with CPA at 25 mg/day, and in 60% of subjects (3 of 5) with 12.5 mg/day of CPA administered in combination with TE at 100 mg/week. A decrease in hemoglobin and hematocrit that could potentially blunt the acceptability of this contraceptive regimen was also reported. This decrease in hematological parameters was related to the dose of CPA because decreasing the antiandrogen dose also led to a reduction in hemoglobin and hematocrit (Meriggiola et al, 1996, 1998).
In this study we tested whether a further decrease in the dose of CPA to 5 mg/day combined with the same dose of TE (100 mg/week) used in previous studies could completely abolish the decrease in hematological parameters. However, because the combination of CPA at 12.5 mg/day with TE at 100 mg/week has already been shown to not induce azoospermia in all subjects, the dose of 5 mg/day of CPA was expected to result in even more incomplete spermatogenic suppression. Therefore, in another group of men, a higher dosage of TE (200 mg/week) was administered in combination with CPA at 5 mg/day to evaluate whether the increase in androgen dose could balance the decrease in progestin dose, and whether it could improve profound gonadotropin suppression and thus, sperm suppression.
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Materials and Methods |
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Study Design
Subjects underwent a 3-week control phase in which they provided at least 3
semen specimens, 3 blood draws, and underwent a physical examination. After
completing the control phase, subjects were randomly divided into 2 groups;
one received CPA 5 mg/day plus TE 100 mg/week (n = 9; group CPA-5-100),
whereas the other group received CPA 5 mg/day plus TE 200 mg/week (n = 9;
group CPA-5-200) for 16 weeks. During this treatment period, subjects
underwent monthly blood draws and biweekly semen analysis. Following the
treatment period, subjects entered the recovery phase, which included 3 blood
draws, physical examinations every 4 weeks, and biweekly sperm counts until
each subject had at least 2 sperm counts that were within his own baseline
values.
Measurements
Physical examinations included blood pressure, height and weight, and
testis volume measurement (with a Prader orchidometer). Sperm count was
performed according to WHO criteria
(1992). Azoospermia was
defined as no sperm found in a sample after centrifugation and analysis of the
pellet.
Measurements were performed in each blood sample for reproductive hormones (LH, FSH, and testosterone), clinical chemistry (total cholesterol, triglycerides, high-density lipoprotein [HDL]-cholesterol and low-density lipoprotein [LDL]-cholesterol, glucose, urea creatinine, total bilirubin, glutamic-oxaloacetic transaminase, and glutamic-pyruvic transaminase), and hematology (hemoglobin, hematocrit, and red blood cells).
Serum levels of LH and FSH were measured by a fluoroimmunoassay (Autodelfia; Wallac, Turku, Finland). The minimum sensitivity was 0.3 IU/L and 0.1 IU/L for FSH and LH assays, respectively. The interassay coefficient of variation (CV) in the high, medium, and low parts of the standard curve were 9.5%, 12.5%, and 11.2% for LH; and 6.2%, 6.1%, and 17.9% for FSH. The intraassay CV in the high, medium, and low parts of the curve for LH and FSH assays were 2.6%, 3.2%, and 7.6%; and 2.7%, 2.9%, and 6.8%, respectively. Serum testosterone levels were measured by radioimmunoassay using reagents from the WHO-matched reagent program by methods previously described (Matsumoto et al, 1983). The assay sensitivity was 0.017 nmol/L; the intraassay and interassay CVs were 5.1% and 9.8%, respectively. Samples from the CPA-5-100 and CPA-5-200 groups were measured in the same assay. Chemistries and hematological measurements were performed by routine assays according to previously described procedures (Meriggiola et al, 1996).
Statistics
Data are reported as mean values ± SEM. The normal distribution of
the data was tested by means of the Kolmogorov-Smirnov test
(Siegel, 1956) and, when
necessary, data were log-transformed before analysis. Azoospermic samples were
extrapolated using the linear regression observed between the log sperm counts
and their ranks. The frequency of azoospermia and the time for spermatogenesis
to return to baseline were compared between the 2 treatment groups by means of
the Fisher exact and the Mann-Whitney tests, respectively
(Siegel, 1956). Statistical
evaluations were performed by running the SPSS/PC+ package on a personal
computer (SPSS/PC+, 1992; Chicago, Ill). Two-tailed P values less
than .05 were considered statistically significant.
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Results |
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Spermatogenesis
No significant differences in sperm counts were detected between the 2
groups at baseline and among the 3 baseline samples
(Table 1 and
Figure 1).
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Both CPA-5-100 and CPA-5-200 regimens induced a profound suppression of spermatogenesis (Figure 1). In the CPA-5-100 group, sperm counts were significantly lower than baseline from week 4 to the end of hormone administration. In the CPA-5-200 group, sperm counts were significantly lower than baseline by week 2 and remained significantly lower until the end of hormone administration. At week 2, mean sperm counts were significantly higher in the CPA-5-100 group than in CPA-5-200 group (P = .020). From week 6 to week 16, sperm counts were significantly lower in the CPA-5-100 group than in the CPA-5-200 group. At week 16, 5 of 9 subjects in the CPA-5-100 group were azoospermic (55.6%). One subject in this group exhibited azoospermia at weeks 10, 12, and 14 and had a sperm count of 0.1 at week 16. The other 3 subjects had sperm counts less than 1 million/mL at week 16. In the CPA-5-200 group, at week 16, 4 subjects had sperm counts less than or equal to 1 million/mL, 2 subjects had sperm counts between 1 and 3 million/mL, and 1 subject had a sperm count of more than 3 million/mL. Significantly more subjects in the CPA-5-100 group achieved azoospermia (55.6%) than those in the CPA-5-200 group (none; P = .034). After stopping hormone administration, sperm counts returned to baseline levels in all subjects. The mean time to return to baseline was 11.1 ± 0.7 and 14.6 ± 1.0 weeks in the CPA-5-100 and CPA-5-200 groups, respectively (P = .017).
Hormones
No significant differences in LH, FSH, and testosterone were detected
between the 2 groups at baseline and among the 3 baseline samples
(Table 1 and
Figure 2).
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FSH and LH were significantly suppressed by week 4 of hormone administration in both groups and remained profoundly suppressed until the end of hormone administration (Figure 2). No significant difference in FSH and LH levels could be detected between the CPA-5-100 and CPA-5-200 groups at any time. In group CPA-5-100, serum testosterone levels did not change at any time throughout the study period. In the CPA-5-200 group, serum testosterone levels were significantly higher than baseline levels from week 4 to week 16 of hormone administration. During this period, testosterone levels were significantly higher in the CPA-5-200 group than in the CPA-5-100 group at all time points. In the recovery phase, FSH, LH, and testosterone returned to values that were not significantly different from baseline in both groups at weeks 4, 12, and 4, respectively.
Clinical Characteristics
No significant differences in baseline demographic and clinical
characteristics were found between the 2 groups at baseline
(Table 1). At week 16 of
hormone administration, HDL-cholesterol and total cholesterol in the CPA-5-100
group and HDL-cholesterol and triglycerides in the CPA-5-200 group showed a
significant decrease. All these changes returned to pretreatment levels 12
weeks after hormone administration had ceased. No significant changes were
found in any other laboratory tests performed. No significant change in
hematological parameters was found in any group at any time, although patients
in the CPA-5-200 group exhibited a trend toward higher hematocrit (3.8%
± 1.9% increase) that did not achieve significance at week 16 compared
to baseline (P = .101). In both groups, a significant decrease in
testis size was reported at the end of hormone administration
(Table 2). No significant
change in body weight was detected in either group at any time
(Table 2).
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Discussion |
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Our previous studies have suggested that the prototype regimen consisting of the combined administration of CPA (100, 50, and 25 mg/day) and TE (100 mg/week) results in profound and uniform sperm suppression (Meriggiola et al, 1996). In those studies, sperm reduction seemed to be dependent on the dose of CPA. We hypothesized that together with the induction of profound gonadotropin suppression, CPA may also act directly at the gonadal level by blocking the stimulatory effect of androgens on spermatogenesis. After hormone administration, intratesticular testosterone (ITT) has been reported to decrease to about 5% of normal (Morse et al, 1973). Whether these low testosterone levels are able to maintain some level of sperm production in some subjects is unclear. Because of the pharmacokinetic characteristics of TE, high supraphysiological serum testosterone levels can be measured soon after injection (Anderson et al, 1996). These high testosterone levels may contribute to maintaining ITT levels and thus sperm production in some subjects. The antiandrogenic effect of CPA within the testis may counteract ITT and thus result in a more profound and uniform sperm suppression.
Studies performed in animals have indicated that testosterone exerts a stimulatory effect on germ cells. In rats and in nonhuman primates, very low androgen concentrations are sufficient to maintain some level of sperm production in the absence of gonadotropins (Cunningham and Huckins, 1979; Sharpe et al, 1988; Weinbauer et al, 1988; Zirkin et al, 1989; Singh et al, 1995; Meachem et al, 1997; Handelsman et al, 1999). Although no direct evidence exists in humans, various observations suggest that testosterone can play a major role in the maintenance of sperm production in the presence of very low gonadotropin levels in men. Two independent studies showed that no difference in serum fluoroimmunoreactive or bioactive gonadotropins can be detected between men who achieved azoospermia and those who achieved oligozoospermia after weekly injections of 100, 200, or 300 mg of TE (Anderson et al, 1996; Amory et al, 2001). These findings may suggest that factors other than gonadotropin suppression may be involved in degree of sperm suppression induced by TE.
In recent studies, testosterone pellets, a zero-order kinetic androgen formulation, administered together with the progestin depot medroxyprogesterone acetate or with desogestrel, induced a more profound sperm suppression than occurred in studies in which each progestin was given together with TE (Wu and Aitken, 1989; Handelsman et al, 1996; Wu et al, 1999; Kinninburgh et al, 2001). The absence of supraphysiological testosterone levels when testosterone pellets were used may explain the more profound sperm suppression achieved with these regimens. After human chorionic gonadotropin and testosterone administration, qualitatively normal spermatogenesis could be maintained in men. In boys with Leydig cell tumors or with an activating mutation of the LH receptor, evidence of gonadal maturation and sperm development was reported (Matsumoto and Bremner, 1989; Shenker et al, 1993; Weinbauer and Nieschlag, 1996; Gromoll et al, 1998).
In the present study, the higher dose of TE given in combination with the same CPA dose led to an impairment of sperm suppression despite there being no difference in serum gonadotropin levels. It is not clear why increasing the hormonal load does not further suppress gonadotropin levels. It is possible that in the CPA-5-100 group, maximal gonadotropin suppression was already achieved, that the number of subjects was not enough to observe a difference, or that the assay we used was not sensitive enough in the low part of the curve to detect small differences. Regardless of the case, compared with men in the CPA-5-100 group, sperm counts in men in the CPA-5-200 group were not as suppressed and none of the subjects achieved azoospermia, whereas sperm counts in one subject were not suppressed to levels lower than 3 million/mL. In the CPA-5-100 group, sperm counts fell below 1 million/mL in all subjects and 5 of 9 subjects (56%) who completed the study achieved azoospermia. In the CPA-5-200 group, TE induced higher supraphysiological serum testosterone levels that resulted in androgen-related effects such as a 3.8% increase in hematocrit and a 9.6% decrease in HDL-cholesterol. We hypothesized that these higher serum testosterone levels may have also resulted in higher ITT concentrations that may have contributed to the maintenance of high sperm production in this group of men. These data represent the first direct evidence that in humans, testosterone can maintain spermatogenesis.
Both the increase of hematological parameters and decrease of HDL-cholesterol induced by the CPA-5-200 regimen seemed to be slightly lower than previously reported with the administration of 200 mg of TE alone. This observation is consistent with the concept that the addition of 5 mg of CPA may counteract some of the androgenic effects of TE (Bagatell et al, 1994; Anderson et al, 1995; Meriggiola et al, 1995). No significant changes in hematological parameters were found in the CPA-5-100 group, confirming previous data suggesting that the effects of CPA on hematological parameters are dose dependent.
In conclusion, results of the present study confirm and extend previous data that suggested that the prototype CPA/TE male contraceptive regimen induces profound sperm suppression. Increasing the dose of the androgen impairs sperm suppression without causing a noted change in gonadotropin suppression. These data may suggest that higher serum testosterone concentrations may result in higher intratesticular concentrations that can maintain qualitative sperm production in men. They also suggest that in future studies of hormonal male contraception, induction of supraphysiological testosterone levels should be avoided to improve sperm suppression and to avoid androgen-related side effects.
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Footnotes |
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) during baseline (weeks
-2, -1, and 0), 16 weeks of hormone administration, and 12 weeks after
stopping hormone administration.