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Clinical Trial of Transdermal Testosterone and Oral Levonorgestrel for Male Contraception¹

Institute of Reproductive Medicine and Institute of Clinical Chemistry (A.v.E.), University of Münster, D-48149 Münster, Germany

Address all correspondence and requests for reprints to: Prof. Dr. E. Nieschlag, F.R.C.P., Institute of Reproductive Medicine of the University, Domagkstrasse 11, D-48149 Münster, Germany.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Approaches to hormonal male contraception are predominantly based on injectable testosterone (T) application. As most users would prefer an injection-independent modality, this study was designed to develop a self-applicable hormonal male contraceptive regimen by combining transdermal T with an oral gestagen. Eleven healthy men (23–40 yr old) were treated with oral levonorgestrel and transdermal T for 24 weeks. T was applied daily as a transdermal patch to be worn on the trunk. Levonorgestrel was taken orally at a dose of 250 µg daily up to week 12, followed by 500 µg to week 24 in those volunteers who had not become azoospermic by that time. Within 24 weeks, 2 of 11 volunteers had become azoospermic, and 3 of 11 showed sperm concentrations below 3 million/mL. The sperm concentrations of the remaining volunteers declined, but failed to reach the limit considered compatible with contraception by WHO. Treatment resulted in suppression of LH, FSH, and sex hormone-binding globulin, whereby the volunteers with lower sperm concentrations showed more pronounced suppression than the others. Mean T concentrations remained within the lower limit of normal and on occasions were below this level. There were no complaints of hypoandrogenism. Although mean levels of low density lipoprotein cholesterol, apolipoprotein B, as well as basal and postprandial insulin increased, high density lipoprotein cholesterol and apolipoprotein A-I decreased during the treatment phase. Changes in lipid parameters were normalized within 3 weeks after cessation of medication. Although only 5 of 11 volunteers reached the target sperm counts (<3 million/mL), the study shows that a self-applicable hormonal male contraceptive could be developed.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
ATTEMPTS to develop hormonal male contraception have focussed on T because of its simultaneous gonadotropin-suppressing and androgenizing effects. T has been combined with other gonadotropin-suppressing agents such as GnRH antagonists or gestagens in contraceptive trials to achieve a more profound suppression of spermatogenesis with higher contraceptive efficacy (for review, see Ref. 1). Recently, Bebb et al. (2) continued earlier studies by Fogh et al. (3) and reported satisfying results combining im testosterone (T) enanthate with the oral gestagen levonorgestrel. Widespread application of such a modality would be impeded by the need for frequent injections. As most users would prefer an injection-independent modality, this study was designed to develop a self-applicable hormonal male contraceptive by combining oral levonorgestrel with transdermal T.

	Subjects and Methods

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Subjects

The study was approved by the ethics committee of the University and the State Medical Board (Münster. Germany). Healthy men, aged 18–45 yr, were recruited by newspaper advertisements using the same inclusion/exclusion criteria as previously described (4). Blood samples were drawn for routine chemistry, lipids, hematology, and hormone measurements. Sonography of scrotum and prostate was performed, and two semen samples (each after at least 48 h of abstinence) were analyzed. Of 34 men examined, 12 fulfilled the inclusion criteria and gave informed consent. One subject dropped out after several weeks for personal reasons.

Study design

After screening, treatment was initiated consisting of a combination of oral levonorgestrel and transdermal T over a period of 24 weeks. Transdermal T was applied daily in the morning as a transdermal patch, 60 cm² in size, to be worn on the trunk containing 328 mg T and delivering 5 mg T to the circulation over 24 h (Alza Corp., Palo Alto, CA). In addition, levonorgestrel (Jenapharm, Jena, Germany) was administered orally in a dose of 250 µg daily up to week 12, followed by 500 µg to week 24 in those volunteers who did not become azoospermic by week 12.

During the course of treatment, examinations were performed every 3 weeks and after week 36 every 6 weeks, consisting of general and genital examination, blood chemistry, lipid profile, hematology, prostate-specific antigen, and hormone measurements [FSH, LH, estradiol (E₂), T, dihydrotestosterone, sex hormone-binding globulin (SHBG), inhibin B, and leptin]. Basal and augmented glucose and insulin (oral challenge with 75 g glucose) were determined once before treatment and during weeks 12 and 36. At every visit all volunteers reported on possible side-effects or skin reactions, answered a questionnaire about their condition and sexual behavior, and provided a semen sample after abstinence for at least 48 h. Sonography of scrotal contents and the prostate were performed once before treatment and repeated in weeks 12, 24, and 54. The recovery period lasted until the volunteers had provided at least one semen sample with normal sperm concentration and motility.

Blood measurements

Venous blood samples were taken between 0800–1200 h after a 12-h fasting period. Samples were separated at 800 x g and stored at -20 C for endocrine determinations and at -80 C for lipid parameters or glucose/insulin measurement. Serum levels of LH, FSH, E₂, SHBG, and prostate-specific antigen were determined by highly specific time-resolved fluoroimmunoassays (DELFIA, Pharmacia, Freiburg, Germany). Serum T was determined using a commercial RIA (DSL-4100, Diagnostic Systems Laboratories, Sinsheim, Germany). The normal serum level for T is above 12 nmol/L. Serum inhibin B levels were determined by solid phase enzyme-linked immunosorbent assay (MCA1312 KZZ, Serotec, Oxford, UK), serum leptin levels were determined by RIA (Linco Research, Inc., St. Louis, MO), and serum insulin levels were determined by immunoassay (Dako Corp., Copenhagen, Denmark).

A Hitachi 917 autoanalyzer (Hitachi, Hialeah, FL) was used to quantify serum concentrations of glucose, cholesterol, and triglycerides with enzymatic tests (Boehringer Mannheim, Mannheim, Germany), high density lipoprotein (HDL), cholesterol with a homogeneous enzymatic assay (Boehringer Mannheim), and apolipoprotein A-I (apoA-I) and apoB (Boehringer Mannheim) as well as lipoprotein(a) [Lp(a); Immuno, Vienna, Austria) with immunoturbidimetric tests. Samples from every volunteer were analyzed within one series to minimize the effects of interassay variation.

Semen analysis

Semen analysis was performed according to the WHO Laboratory Manual (5). The volunteers were requested to abstain from sexual activity for 48 h to 7 days before the investigation. In cases of extremely low sperm counts or azoospermia, the ejaculates were centrifuged, and analysis was performed on the sediment. Severe oligozoospermia was defined as a sperm count of 3 million/mL or less.

Evaluation of well-being and sexual function

For evaluation of psychosexual effects of the treatment, a questionnaire on sexual thoughts and fantasies, interest and desire, satisfaction with sexuality, frequency of erections and ejaculations, and number of morning erections was completed by the volunteers at every visit (6).

Ultrasonography of testicular volume/transrectal ultrasonography of the prostate

At one pretreatment examination, in weeks 12, 24, and 54, testicular and prostate volumes were determined objectively, applying a high frequency 7.5-megahertz sector scanner (Sonoline Versa Pro, Siemens, Erlangen, Germany) (7). Total testicular volume was calculated by adding right and left testicular volumes. Prostate size was measured using transrectal ultrasonography with a 7.5-megahertz sector scanner (Endo-P, Siemens), applying the ellipsoid method.

Statistics

All variables were checked for normal distribution in the Kolmogorov-Smirnov one-sample test for goodness of fit. Two-sided P values of 0.05 were considered significant. Variations over time within the whole study group were evaluated by factorial ANOVA for repeated measurements of clinical chemistry, lipids, and data from sexual questions. In the case of an overall P < 0.05 in the ANOVA, differences between baseline values and the following time points were tested by Dunnett’s post-hoc test. A paired t test was used for the statistical analysis of changes in glucose, insulin, and leptin, because only baseline data and data from one visit during treatment were compared. Differences between responders and nonresponders were analyzed by t test for independent samples at the various time points. No correction was made for multiple comparisons. All analyses were performed using the statistical software GraphPadPrism for Windows version 2.01 (GraphPad Software, Inc., San Diego, CA). In general, results are given as the mean ± SEM.

	Results

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Semen parameters

The 11 volunteers who completed the trial showed no significant change in ejaculate volume throughout the study period. Treatment resulted in a significant suppression of sperm counts in all participants. Two of 11 volunteers showed azoospermia after 6 and 18 weeks, respectively, which was maintained until week 24. Three additional volunteers showed severe oligozoospermia (sperm counts, 3 mill/mL) in week 24; others showed a decline in sperm concentration without reaching this limit (Fig. 1). Before treatment, the median sperm concentration of all volunteers was 63.8 million/mL (range, 29.4–157 mill/mL), the percentage of forward motility (WHO grades a and b) was 63 ± 2%, and the percentage of normally formed sperm was 29 ± 2%. When the volunteers were separated retrospectively into those suppressing sperm concentrations below 3 million/mL (responders) and those with less suppression (nonresponders), the nonresponders had higher pretreatment sperm concentrations and retained higher levels throughout, including the recovery phase. Except for one subject, all volunteers regained normal sperm concentrations, motility, and morphology by week 54. One responder experienced a genital infection during week 50 and was treated with tetracyclins; his sperm counts were 6.9 million/mL at week 54 and had returned to normal at the next investigation 12 weeks later.

View larger version (19K): [in this window] [in a new window]   Figure 1. Sperm concentrations (mean and SEM) in volunteers undergoing transdermal T and oral levonorgestrel treatment divided into responders (closed circles; n = 5) and nonresponders (open diamonds; n = 6). Stars indicate significant differences between the two groups (P < 0.05). A and B indicate basal values.

Serum concentrations of FSH and LH were significantly suppressed by treatment (Fig. 2), with volunteers with azoospermia or severe oligozoospermia showing a more pronounced suppression than the others. On one pretreatment occasion, T serum levels were higher in the nonresponders than in the responders. During treatment serum T levels were decreased in all volunteers from weeks 3–24. Three weeks after stopping medication, T levels returned to normal (Fig. 2). There was a slight decrease in estradiol that did not reach significance. SHBG decreased significantly during treatment and returned to pretreatment levels within 3 weeks after cessation of treatment (Fig. 2). Once in the pretreatment phase and at the end of treatment, SHBG was significantly lower in the responders. Inhibin B levels were not significantly affected by treatment.

View larger version (34K): [in this window] [in a new window]   Figure 2. LH, FSH, T, and SHBG (mean and SEM) in the responders (closed circles) and nonresponders (open diamonds). Stars indicate significant differences between groups (P < 0.05).

Values from routine clinical chemistry and hematology did not show any significant change during the study period. Treatment was associated with changes in serum levels of low density lipoprotein (LDL) cholesterol, HDL cholesterol, apoA-I, apoB, and Lp(a) that were aggravated by the increase in levonorgestrel after week 12 (Table 1). Mean levels of LDL cholesterol and apoB increased steadily up to 13% and 19% during the 24 weeks, respectively. Mean levels of HDL cholesterol and apoA-I steadily decreased during treatment by up to 28% and 20%, respectively. As a result the atherogenic index of LDL cholesterol/HDL cholesterol increased by up to 54%. The changes in medians of Lp(a) were not significant but were consistent and reversible. The changes in lipid parameters were normalized within 3 weeks after cessation of medication. Both basal and postprandial insulin levels as well as basal and postprandial insulin/glucose ratios were significantly higher after 12 weeks contraceptive hormone therapy (Table 2). These changes were reversed 12 weeks after the end of treatment. Leptin levels were slightly higher in week 12 compared to baseline or posttreatment levels (Table 2).

Volunteers frequently complained about insufficient adhesiveness of the patches, especially when sweating. One patient changed the site of application and applied his T patches to the upper outer arm. Two of 11 volunteers showed no skin reaction. One reacted with strong erythema and itching. Another volunteer showed only strong erythema with itching after direct sun exposure on the application site. Seven volunteers occasionally showed erythema or moderate itching with no reduction of well-being.

Testicular volume

Total testicular volume (right plus left side) was 52.9 ± 4.4 mL before treatment in all volunteers and decreased more strongly in the responders than in the nonresponders. After treatment, testicular volumes increased, but had not returned to baseline by week 54 (Fig. 3).

View larger version (31K): [in this window] [in a new window]   Figure 3. Total testicular volumes, prostate volumes, and ejaculations per week (mean and SEM) in responders (closed circles) and nonresponders (open diamonds). Stars indicate significant differences between groups (P < 0.05).

Prostate volume did not change significantly during therapy. Prostate volumes were 18.8 ± 1.6 mL before treatment and 19.7 ± 1.6 mL after 24 weeks of treatment (Fig. 3). PSA serum levels did not change under treatment.

Sexual function

No significant changes in mood ratings, individual well-being, or in frequency of erections, ejaculations (Fig. 3), and sexual intercourse were reported, except in week 21 when the responders had fewer ejaculations per week than the nonresponders.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In trials for hormonal male contraception, injectable T esters or implants led to azoospermia in about two thirds of Caucasian and almost all Chinese volunteers (8, 9, 10). However, application of these preparations could not avoid supraphysiological T serum levels. Furthermore, weekly im injections of T enanthate, most widely used in contraceptive trials, render this regimen impractical for general use. Moreover, an azoospermia rate of 67% achieved in Caucasian men remains suboptimal, as contraceptive protection in the remaining 33% of users would not be better than under condom use.

To increase the efficacy of sperm suppression, T was combined with other gonadotropin-suppressing agents. Although combination with GnRH agonists could not induce effective suppression of spermatogenesis (6), GnRH antagonists combined with T were highly effective (11, 12). T enanthate combined with oral cyproterone acetate resulted in suppression of spermatogenesis in all volunteers (13). However, the antiandrogenic effects of cyproterone acetate as revealed by decreased hematopoiesis are not desirable. Previously Fogh et al. (3) and more recently Bebb et al. (2) had suggested that the addition of oral levonorgestrel to injected T esters would increase the spermatogenesis-suppressing effect. Their findings encouraged us to initiate the current study using levonorgestrel in addition to transdermal T.

With this combined regimen we achieved severe oligozoospermia or azoospermia in 5 of 11 of the volunteers (46%). One reason for the relatively low efficacy could be the dose of levonorgestrel in our study. Bebb et al. (2) had used 500 µg. However, meanwhile another study indicated that 250 µg might be as effective as 500 µg (14). Therefore, we started with 250 µg and increased the dose to 500 µg only in those volunteers who had not achieved azoospermia by week 12. It is also likely that the transdermal patches might not have delivered enough T into circulation to exert an additive effect to the gonadotropin suppression by the gestagen. Indeed, serum T levels, although still in the low normal range, were significantly below pretreatment values in all volunteers. However, the patches had been shown to be sufficient for substitution of hypogonadal men (15), and our volunteers showed no signs of hypoandrogenemia. As levonorgestrel is known to suppress SHBG and bind strongly to this binding protein (for review, see Ref. 16), it is likely that the low total serum T levels were accompanied by normal free T levels sufficient to maintain androgenicity but insufficient to cause further gonadotropin suppression. The unaffected inhibin B levels would further support this idea, as a previous contraceptive study based on T enanthate injections alone demonstrated a decline in inhibin B levels (17).

At first glance, the low azoospermia rate is disappointing and demonstrates the difficulties of developing a noninjectable and self-applicable hormonal male contraceptive. In an earlier study based on oral T undecanoate alone only 1 of 7 volunteers became azoospermic (18), and in a recent study adding cyproterone acetate to oral T undecanoate, only 1 of 11 volunteers showed azoospermia (19). Although not much better than these previous studies, the current trial provides useful clues for further investigation, as responders and nonresponders showed differences in hormone levels before and during treatment. Although the number of subjects is small, the findings show that men with higher T and SHBG levels as well as higher sperm counts may be less likely to suppress sperm. This phenomenon has been observed in another trial for male contraception using the long acting T buciclate (4), and future research for effective male contraception has to aim at the highest possible degree of gonadotropin suppression.

Treatment with levonorgestrel and T was associated with significant increases in the proatherogenic risk markers LDL cholesterol and apoB as well as with significant decreases in the antiatherogenic parameters HDL cholesterol and apoA-I. As a result, the atherogenic index of LDL cholesterol/HDL cholesterol increased. In view of the lowered serum concentrations of T, these changes are surprising at first sight, because it had been previously demonstrated that suppression of T raises HDL cholesterol, apoA-I, and Lp(a) and does not alter LDL cholesterol and apoB levels (20, 21). As gestagens are known to raise LDL cholesterol and to decrease HDL cholesterol and Lp(a) (22, 23), levonorgestrel appears to override the effects of low serum T levels.

The increase in basal and postprandial insulin levels as well as in insulin/glucose ratios suggests that treatment with levonorgestrel and transdermal T increases insulin resistance, which would imply another adverse cardiovascular risk. Both low T levels (24) and exogenous gestagens (23) have been associated with insulin resistance and obesity, so that both suppression of endogenous T and the treatment with levonorgestrel may be responsible for the reversible increases in insulin observed in our study.

Because of these metabolic effects and as the combination of transdermal T and oral levonorgestrel did not result in a high rate of azoospermia, oral levonorgestrel does not appear to be a useful component of a male contraceptive regimen, and other compounds enhancing gonadotropin suppression by T might be preferred.

	Acknowledgments

 
We are grateful to Alza Corp. (Palo Alto, CA) for providing the transdermal T patches, and to Jenapharm (Jena, Germany) for providing levonorgestrel. We thank Nicole Terwort, Martina Niemeier, Heidi Beering, Kathrin Wardecki, Sabine Rehrs, Raphele Kürten, Elke Börger, and Karin Fehmer for technical assistance, and Susan Nieschlag, M.A., for language editing of the manuscript.

	Footnotes

 
¹ This work was supported by the Deutsche Forschungsgemeinschaft Confocal Research Group, "The Male Gamete: Production, Maturation, Function" (Ni 130/15), and the Medical Faculty Münster (IKF, Project A3).

Received October 1, 1998.

Revised December 14, 1998.

Accepted December 18, 1998.

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