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Department of Medicine (S.T.P., J.K.A., B.D.A., M.S.I., A.T.B., A.M.M., W.J.B.), University of Washington, Seattle, Washington 98195; and Geriatric Research, Education and Clinical Center (A.M.M.), and Department of Medicine (B.D.A., A.M.M.), Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108
Address all correspondence and requests for reprints to: Stephanie T. Page, M.D., Ph.D., P.O. Box 357138, 1959 NE Pacific, Seattle, Washington 98195. E-mail: page{at}u.washington.edu.
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Abstract |
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Objectives: The objectives of the study were: 1) to determine the rate of severe oligospermia (
1 million sperm/ml) using T gel+DMPA; and 2) to determine whether the addition of acyline to T gel+DMPA during the first 12 wk of the regimen would accelerate and improve suppression of spermatogenesis.
Methods: Forty-four healthy men, ages 18–55 yr, were randomized to T gel (100 mg daily)+DMPA (300 mg/3 months) or acyline (300 µg/kg·2 wk x 12 wk)+T gel+DMPA. Thirty-eight men completed the 24-wk treatment protocol.
Results: All men had dramatic suppression of spermatogenesis; 90% of the subjects became severely oligospermic, a rate comparable to implantable and injectable T+progestin combinations. The addition of acyline did not significantly accelerate spermatogenic suppression or improve rates of severe oligospermia. There were no serious adverse events, and there were minimal changes in weight, serum lipids, and prostate-specific antigen.
Conclusions: The combination of T gel+DMPA is a promising new regimen in male contraception. The addition of the GnRH antagonist acyline, as part of an induction phase in a male contraception regimen, has limited clinical utility. Additional studies using T gel for male contraception are warranted.
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Introduction |
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GnRH antagonists may have a role in the induction of azoospermia, increasing the rapidity or efficacy of obtaining azoospermia. The combination of weekly T enanthate (TE) and daily Nal-Glu injections for 12 wk effectively induced azoospermia in 10 of 15 subjects, whereas 14 of 15 achieved oligospermia (<3 million/ml) that was maintained for an additional 20 wk with TE alone in 13 of 14 subjects (5). Acyline is a more potent, longer-lasting GnRH antagonist that suppresses gonadotropins and T production for 2 wk after a single injection (6). In a small pilot study, acyline, in combination with weekly im TE or TE plus an oral progestin, rapidly and effectively suppressed gonadotropins for 8 wk (7); however, its effectiveness in a male hormonal contraceptive regimen has not been tested.
The development of a satisfactory male hormonal contraception has also been hampered by the need to use injectable T. Most oral androgens, which have been alkylated at the 17-carbon position to increase their serum half-life, are associated with hepatic toxicity (8, 9); therefore, injectable and implantable formulations of T have been employed. Injectable T formulations are associated with peaks and troughs, even after a number of serum half-lives (10). Implantable T pellets provide constant serum T levels but require an office procedure for insertion and occasionally extrude (11). Transdermal patches for male contraception have resulted in poor rates of sperm suppression, probably due to suboptimal serum T levels (12, 13, 14). Recently, transdermal gels have become available for the treatment of male hypogonadism (15, 16). These products are associated with a high level of patient satisfaction (17). However, their use as part of a male hormonal contraceptive regimen has not been tested.
The goal of our group is to develop a safe, acceptable, reversible, and efficacious male hormonal contraceptive. To this end, we conducted a randomized trial to answer the following questions. First, does daily T gel plus a potent, long-acting progestin provide a degree of spermatogenic suppression likely to be effective as a contraceptive [1 million/ml (18)]? Second, does the addition of the potent GnRH antagonist acyline to the combination of T gel plus a progestin increase the rapidity or efficacy of sperm suppression in normal, healthy men?
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Subjects and Methods |
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All procedures involving human subjects were approved by the Institutional Review Board at the University of Washington. Written, informed consent was obtained before screening. Forty-four healthy men, ages 18–55 yr, were recruited by newspaper advertisement and posted flyers. Inclusion criteria included the following: general good health; normal medical history; absence of routine medication use; normal physical examination including testicular volume by Prader orchidometer and prostate size by digital rectal exam; normal serum laboratory tests including complete blood count, liver function tests, gonadotropins, total T, and prostate-specific antigen (PSA) < 4.0 ng/ml; and two normal seminal fluid analyses as defined by World Health Organization (WHO) criteria (19) (sperm count > 20 million/ml, motility > 50%, morphology > 15% normal oval forms). Exclusion criteria included sleep apnea, skin conditions that might interfere with T gel absorption, significant chronic or acute psychiatric illness, history of alcohol or anabolic steroid abuse, and participation in another hormonal contraceptive study within the preceding 3 months.
Acyline
Acyline, a 10-amino-acid peptide, was originally synthesized by Jean Rivier at the Salk Institute and was distributed by the National Institute of Child Health and Human Development. Lyophilized acyline powder synthesized by NeoMDS (San Diego, CA) was suspended in bacteriostatic water to a final concentration of 2 mg/ml. In all cases, 300 µg/kg of acyline was administered by sc injection.
Study design
This was an open-label, two-arm randomized study consisting of a 1- to 2-month control period, 24 wk of treatment, and a recovery period. After screening, subjects were randomly assigned by the research pharmacist using a random number sequence to one of two treatment groups: 1) T+DMPA (depomedroxyprogesterone acetate) group: T gel 100 mg topically, daily Testim 1% (Auxilium Pharmaceuticals, Norristown, PA) plus DMPA (300 mg im every 3 months; Upjohn Pharmaceuticals, Kalamazoo, MI); or 2) Acy+T+DMPA group: acyline 300 µg/kg sc every 2 wk for 12 wk plus T gel+DMPA as in group 1. All injections were given by either a study nurse or an investigator. DMPA was given as a single injection in the gluteus muscle, and acyline was injected sc in the abdomen, requiring two to five injections depending on the weight of the subject. No subject missed an injection. Recovery was defined as normalization of LH, FSH, and T levels and achieving one sperm count higher than 20 million/ml (20).
Throughout the drug exposure and recovery periods, subjects were asked to provide a semen sample obtained by masturbation every 2 wk after at least 48 h of ejaculatory abstinence, and blood was collected monthly. Subjects underwent a physical examination monthly through the first 36 wk of the study (through recovery month 3) and monthly thereafter if any abnormalities were noted. All serum samples were centrifuged and stored at –70 C until the end of study analyses. Complete blood counts and serum chemistries including liver function tests, LH, FSH, T, and SHBG were measured monthly. Fasting serum lipids were measured on d 0, and wk 12, 24, and 36. Thirty-eight men completed the protocol, 21 in the T+DMPA group and 17 in the Acy+T+DMPA group.
Serum hormone, SHBG, and insulin-like factor 3 (INSL3) measurements
In all cases, samples from a given individual were run in a single assay. FSH and LH levels were measured by immunofluorometric assay (Delfia; Wallac Oy, Turku, Finland). The sensitivity of the assay for FSH and LH was 0.016 and 0.019 IU/liter, respectively. For low-, mid-, and high-pooled values of 0.05, 1.0, and 21 IU/liter of FSH, the intraassay coefficients of variation were 5.9, 3.0, and 3.0%; and the interassay coefficients of variation were 20.7, 5.0, and 6.2%, respectively. For low-, mid-, and high-pooled values of 0.06, 1, and 16 IU/liter of LH, the intraassay coefficients of variation were 12.6, 5.6, and 4.1%; and the interassay coefficients of variation were 16.5, 13.9, and 10.5%, respectively.
T and SHBG were measured by RIA (Diagnostic Products Corporation, Los Angeles, CA, for T; Delfia, Wallac Oy, for SHBG). Free T was calculated as described by Södergard et al. (21) and validated by Vermeulen et al. (22). The assay sensitivity for T was 0.5 nmol/liter. For low-, mid-, and high-pooled values of 3.8, 10.6, and 24.4 nmol/liter of T, the intraassay coefficients of variation were 4.4, 5.1, and 6.0%; and the interassay coefficients of variation were 17.5, 11.8, and 12.9%, respectively. For SHBG, the intraassay coefficients of variation were 3.1, 6.0, and 5.6%; and the interassay coefficients of variation were 37, 8.1, and 9.4% for low-, mid-, and high-pooled values, respectively.
INSL3 is a circulating protein of testicular origin that is a marker of Leydig cell function (23) and is postulated to be a more sensitive marker than serum T (24, 25). INSL3 was measured by RIA (Phoenix Pharmaceuticals, Inc., Belmont, CA). The normal range was 291-1132 pg/ml. The intraassay coefficients of variation were 7.6, 5.2, and 5.7%; and the interassay coefficients of variation were 30, 13, and 8.1% for low-, mid-, and high-pooled values, respectively.
Lipid analyses, clinical chemistries, and PSA
Screening and monitoring labs for complete blood count, electrolytes and glucose (chemistry 7), PSA, and liver function tests were measured in the clinical laboratory in the Department of Laboratory Medicine, University of Washington. Lipid panels, consisting of total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides, were performed at the Northwest Lipid Research Center (Seattle, Washington) as described previously (26). LDL was calculated using the Friedewald equation (27).
Seminal fluid analyses
Screening semen samples were examined within 60 min of collection and assessed for volume, sperm count, motility, and morphology according to WHO criteria (19). Thereafter, sperm counts were measured manually after centrifugation and confirmed using the IVOS-Hamilton counter (Hamilton Thorne, Los Angeles, CA).
Statistical analyses
The study was designed to have an 80% power to find a greater than 25% difference between the study groups for achievement of the primary end point (sperm concentration 1 million/ml). The proportion of subjects in each group suppressing sperm concentration to no greater than 1 million/ml after 6 months of treatment (the primary study end point) and other sperm thresholds were compared using Fisher’s exact test. Repeated measures ANOVA were used to compare hormone levels, serum chemistries (including lipids and PSA), and sperm concentrations between groups (i.e. T+DMPA vs. Acy+T+DMPA) over time. Paired t tests were used to identify which measurements were significantly different from baseline. Multiplicity was taken into account by regarding a result as statistically significant if P < 0.005. Comparisons of serum hormones and chemistries between responders (1 million sperm/ml) and nonresponders were made using a two-sample t test with unequal variance. Statistical analyses were performed using STATA (College Park, TX). For all comparisons, except the paired t tests, an 
< 0.05 was considered significant.
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Results |
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Of 54 men screened for the study, 48 met inclusion criteria. Four subjects dropped out before starting drug treatment for personal reasons or failure to return for follow-up appointments, and 44 were randomized. Six men discontinued the study during the treatment period: one moved from the state, one developed a significant rash from the T gel, four were noncompliant with study procedures (three missed gel application more than 3 d in a row, and one refused his second DMPA injection and digital rectal exam). These subjects were not included in the analyses.
Baseline characteristics of the study subjects are shown in Table 1
. There were no significant differences between subjects in the two groups in any parameter measured.
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Sperm concentration fell significantly from baseline by treatment wk 4 in the T+DMPA group and by treatment wk 2 with addition of acyline (P < 0.001; Fig. 1). The average time to reach a sperm concentration of no greater than 1 million/ml was equivalent for both groups (8.9 ± 1.0 wk for T+DMPA and 8.0 ± 1.0 for Acy+T+DMPA; P = 0.5). Similarly, the percentage of men who achieved sperm concentrations of no greater than 1 million/ml was not significantly different between groups at any point during treatment (Table 2). We did note, however, that two subjects treated with Acy+T+DMPA, while achieving sperm counts no greater than 1 million/ml at wk 12, increased above this threshold during wk 12–24 (Table 2).
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). By wk 42, 18 wk into recovery, 20 of 21 subjects receiving T+DMPA (95%) and 16 of 17 subjects receiving Acy+T+DMPA (94%) had achieved normal sperm counts. The remaining subjects recovered by wk 44 (T+DMPA) and 56 (Acy+T+DMPA). Of note, the subject in the Acy+T+DMPA group with the prolonged recovery time had received an incorrect dose of acyline for his first two injections (372 µg/kg instead of the 300 µg/kg as prescribed in the protocol) as a result of pharmacy error. Total T, free T, and SHBG
Serum T and free T significantly increased, whereas SHBG decreased, with treatment in both groups (P < 0.001), and there were no significant differences between the two treatment groups in these measures throughout the study (Fig. 2, A, B, and E). For total T, this increase was statistically significant at treatment wk 12 for the T+DMPA group and wk 24 for the Acy+T+DMPA group. For free T, levels were significantly increased above baseline for the T+DMPA group for wk 8–20 and for the Acy+T+DMPA group for wk 4–24.
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For both groups, LH, FSH, and INSL3 significantly declined with treatment (P < 0.001), and there were no significant differences between treatment groups. LH, FSH, and INSL3 decreased from baseline by wk 4 of treatment, and gonadotropins were no longer significantly lower than baseline 4 wk into recovery (Fig. 2, C, D, and F). INSL3 levels remained below baseline until wk 8 and 12 of recovery in the T+DMPA and Acy+T+DMPA groups, respectively.
Parameters predictive of achieving sperm count no greater than 1 million/ml
The data were grouped on the basis of whether subjects achieved a sperm count of no greater than 1 million/ml by treatment wk 24 (n = 33) or not (n = 5). Differences between groups were sought among serum LH, FSH, T, and INSL3; body mass index; weight; testicular size; and age at baseline and wk 12 and 24. None of these variables predicted achievement of severe oligospermia (data not shown).
Weight, lipids, PSA, and serum biochemistries
There was a modest increase in weight with treatment in both groups, and weight gain was slightly greater in the T+DMPA group compared with the Acy+T+DMPA group (Table 3). Weight returned to baseline during recovery in both groups. Fasting lipids were performed at baseline, wk 12 and 24 of treatment, and wk 36 (Table 3). Total cholesterol and HDL decreased significantly in both groups with treatment, whereas LDL and triglycerides were not significantly different with treatment over time. Total cholesterol and HDL had declined by wk 12 of treatment but returned to baseline during recovery (wk 36) in both groups. Only total cholesterol was affected differently between groups, with a slightly greater impact in the T+DMPA group compared with the Acy+T+DMPA group.
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). Similarly, hematocrit and liver function tests were unaffected by treatment in either group. There were no significant differences between groups in serum PSA, hematocrit, or liver function tests at any time point. Adverse events
As in previous studies (6), subjects who received acyline experienced erythema, tenderness, and occasional bruising at the injection site that resolved within 24–48 h. DMPA injections were well tolerated. In both groups, there was an equivalent, small reduction in testicular volume during treatment, which reversed completely during recovery (data not shown). There was no clinically significant gynecomastia. Twenty-seven subjects experienced mild exacerbations of acne with treatment, 26 of which returned to baseline during recovery. Eleven subjects noted skin reactions thought to be associated with the gel. Of these, one subject was treated with low-dose topical corticosteroid cream but continued with the study, and one subject dropped from the study.
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Discussion |
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1 million sperm/ml) in 80–90% of subjects. These rates are comparable to those reported for T pellets plus DMPA (11) as well as long-acting im T undecanoate or T decanoate plus progestin regimens (28, 29, 30). In addition, T gel+DMPA resulted in few side effects. Together, these data demonstrate that the combination of T gel+DMPA is a promising new regimen for male hormonal contraception. Second, we have demonstrated that the addition of a potent GnRH antagonist, acyline, does not significantly enhance the rapidity and effectiveness of sperm suppression when combined with an efficacious T+progestin regimen. We found no demonstrable improvement in any measure of sperm suppression with the addition of acyline to T+DMPA in this randomized trial. Previous small studies including GnRH antagonists as part of a male hormonal contraceptive regimen have reported mixed results, and the clinical utility of these early antagonists was further limited by short serum half-lives. When combined with weekly TE injections (100 mg/wk), daily injections of Nal-Glu suppressed sperm concentrations to below 3 million/ml in 14 of 15 subjects after 12 wk, 12 of whom remained at that level with TE alone (5). In contrast, Bagatell et al. (4) found no improvement in rates of azoospermia achieved with the combination of Nal-Glu and higher doses of im TE (200 mg/wk) compared with TE alone. This suggests that the addition of a GnRH antagonist does little to improve rates or rapidity of sperm suppression when combined with a "maximally effective" regimen of high-dose TE or TE+progestin. Our study was powered to find a greater than 25% difference in the achievement of severe oligospermia; therefore, we cannot exclude the possibility that acyline might have some small benefit in inducing sperm counts of no greater than 1 million/ml with more subjects. However, this randomized trial suggests that the clinical benefit of acyline in a male hormonal contraceptive regimen is limited and likely does not outweigh the cost, inconvenience, and potential side effects of this GnRH antagonist.
To our knowledge, this is the first study of a commercially available T gel in a male hormonal contraceptive study, although a pilot study of six subjects combining an experimental T gel with oral medroxyprogesterone acetate appeared promising (31). Previous studies including transdermal T administration via patches (12, 13, 14) or dihydrotestosterone delivery via gels (32, 33) as part of a male hormonal contraceptive regimen have been disappointing. There are a number of possible explanations for these different results. First, different progestins were used in combination with the patch that we employed here, although the dose of levonorgestrel used in two of these trials is clearly efficacious when combined with im TE (34). More likely, the different levels of serum T achieved with each preparation may be critical to achieving adequate sperm suppression. Indeed, we were surprised at the increases in serum T achieved in our study with 10 mg/d of T gel, which were higher than those reported for older, hypogonadal men (15). Although this may reflect differences in the younger population used in our study compared with a series of T gel used in older, hypogonadal men, it is possible the addition of DMPA to T gel alters T metabolism. This was recently suggested by Zhang et al. (35), who found that medroxyprogesterone acetate inhibits cytochrome P450 enzymes involved in T metabolism in vitro in human liver microsomes. The high levels of free T we observed may be the result of this phenomenon in addition to decreased levels of SHBG (Fig. 2E), possibly related to DMPA (36), although also noted in a recent study of etonogestrel plus im T decanoate (28). On the other hand, it is possible that with longer dosing periods, serum levels of T could be lowered due to interactions with DMPA, as observed in studies with T pellets plus DMPA (11). Future studies of T gel+DMPA for longer treatment periods should be done to determine the minimal dosage of exogenous T required to optimize sperm suppression.
The combination of T gel+DMPA was well tolerated. Subjects who received T+DMPA alone experienced mild increases in weight and decreases in total cholesterol and HDL, all of which were reversible, whereas hematocrit, PSA, and liver function tests were unaffected by treatment. This side effect profile is comparable to other regimens currently undergoing efficacy evaluation (11, 28). It is possible that decreases in HDL might be minimized by reduced doses of T gel in future studies of this regimen because T is known to decrease HDL, likely via regulation of hepatic lipase activity (37). In addition, T gel administration does not require an office procedure or have the potential for painful extrusions, and it can be self-administered, giving it a potential advantage over T pellets as a form of T delivery. Regarding reversibility, recovery of spermatogenesis after T gel+DMPA is similar to that reported in a recent meta-analysis of other male hormonal contraceptive regimens (20).
As in other trials of male hormonal contraception, a few men failed to suppress their sperm counts to levels associated with effective contraception. We were unable to determine a mechanism for this nonuniform suppression. Serum hormone levels, the degree of gonadotropin suppression, age, and body composition did not account for these differences. We, and others (1, 38), have suggested that these nonresponders may have differences in the intratesticular milieu, a hypothesis that requires further testing. We did not, however, see any differences in INSL3 levels, either before or during treatment, between responders and nonresponders. INSL3 is a circulating protein of testicular origin that appears to be a marker of mature Leydig cell function (23), regulated by both LH-dependent and LH-independent mechanisms (24, 25). These results suggest that perhaps intrinsic differences in Leydig cell function, as reflected by INSL3 production, do not account for differences between responders and nonresponders to male hormonal contraception, a hypothesis that requires further evaluation in larger trials.
In conclusion, this study demonstrates that the addition of a potent, long-lasting GnRH antagonist to an effective male hormonal contraceptive regimen of T+DMPA does not increase the rapidity or the degree of sperm suppression in normal men. However, unlike previous studies of transdermal T delivery via patches, our data show that transdermal T delivery via a currently available gel formulation, plus a long-lasting injectable progestin, results in effective sperm suppression with minimal side effects. The combination of T gel+DMPA is a valuable alternative to implants, and this approach may lead to the development of a safe, effective, and reversible male hormonal contraceptive.
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Footnotes |
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This work was supported by the Department of Veterans Affairs Special Fellowship in Advanced Geriatrics (to S.T.P.), the Endocrine Society Solvay Clinical Research Award (to S.T.P.), and the National Institute of Child Health and Human Development (NICHD) through cooperative agreements U54-HD-12629 and U54 HD-42454 as part of the specialized Cooperative Centers Program in Reproductive Research and the Cooperative Contraceptive Research Centers Program (to W.J.B.).
Disclosure Summary: S.T.P., J.K.A., B.D.A., M.S.I., and A.T.B. have nothing to disclose. W.J.B. and A.M.M. have consulted for GlaxoSmithKline and Quatrx. A.M.M. has consulted for Solvay, Amgen, Threshold, GTx, and Mattern Pharmaceuticals and received grant support from GlaxoSmithKline, Ascend Therapeutics, and Solvay Pharmaceuticals.
First Published Online August 29, 2006
Abbreviations: DMPA, Depomedroxyprogesterone acetate; HDL, high-density lipoprotein; INSL3, insulin-like factor 3; LDL, low-density lipoprotein; PSA, prostate-specific antigen; T, testosterone; TE, T enanthate.
Received July 3, 2006.
Accepted August 18, 2006.
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References |
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-reductase inhibitor or gonadotropin-releasing hormone antagonist. J Clin Endocrinol Metab 90:91–97-alkylated androgens. Br Med J (Clin Res Ed) 291:637This article has been cited by other articles:
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  P. Y. Liu, R. S. Swerdloff, B. D. Anawalt, R. A. Anderson, W. J. Bremner, J. Elliesen, Y.-Q. Gu, W. M. Kersemaekers, Robert. I. McLachlan, M. C. Meriggiola, et al. Determinants of the Rate and Extent of Spermatogenic Suppression during Hormonal Male Contraception: An Integrated Analysis J. Clin. Endocrinol. Metab., May 1, 2008; 93(5): 1774 - 1783. [Abstract] [Full Text] [PDF]
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S. T. Page, T. F. Kalhorn, W. J. Bremner, B. D. Anawalt, A. M. Matsumoto, and J. K. Amory Intratesticular Androgens and Spermatogenesis During Severe Gonadotropin Suppression Induced by Male Hormonal Contraceptive Treatment J Androl, September 1, 2007; 28(5): 734 - 741. [Abstract] [Full Text] [PDF]
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J. K. Amory, S. T. Page, B. D. Anawalt, A. D. Coviello, A. M. Matsumoto, and W. J. Bremner Elevated End-of-Treatment Serum INSL3 Is Associated With Failure to Completely Suppress Spermatogenesis in Men Receiving Male Hormonal Contraception J Androl, July 1, 2007; 28(4): 548 - 554. [Abstract] [Full Text] [PDF]
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, T+DMPA; 
, Acy+T+DMPA.