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Endocrine Care |
Department of Endocrinology, Manchester Royal Infirmary, University of Manchester, Manchester, United Kingdom M13 9WL
Address all correspondence and requests for reprints to: Dr. Frederick C. W. Wu, Department of Endocrinology, Manchester Royal Infirmary, Oxford Road, Manchester, United Kingdom M13 9WL.
Abstract
This study investigated the effect of transdermal T and oral desogestrel on the reproductive axis of healthy men. Twenty-three men were randomized to 1 of 3 treatment groups and received a daily transdermal T patch plus oral desogestrel at a dose of 75, 150, or 300 µg/d for 24 wk. Baseline blood and semen samples were obtained and then every 4 wk thereafter for 32 wk. The outcome measures were sperm density and plasma levels of FSH, LH, total and free T. The results show a dose-dependent suppression of spermatogenesis and gonadotropins. Seven of the 17 subjects became azoospermic. Desogestrel (300 µg daily) in combination with 5 mg daily transdermal T was the most effective (57% azoospermic), whereas a dose of 75 µg was ineffective (0% azoospermic). Total and free plasma T were reduced by approximately 30%. High density lipoprotein cholesterol was significantly reduced. No serious side-effects were encountered. We conclude that daily self-administered desogestrel with transdermal T is capable of suppressing the male reproductive axis, although the efficacy was less marked and less consistent than injectable regimens. The lower efficacy is likely to be due to failure of the transdermal T system to maintain circulating T levels consistently in the required range.
THE PRINCIPLE THAT exogenous sex steroid-induced oligo- and azoospermia can confer effective, reversible contraceptive protection in men was established in two multicenter trials employing an androgen-only prototype regimen of im injections of T enanthate (1, 2). The pharmacokinetics of T enanthate are such that a relatively high dose (200 mg), administered at weekly intervals, is required to ensure maximum suppression of gonadotropins and spermatogenesis (3). This regimen produced repeated supraphysiological peaks and markedly fluctuating levels of T (4) which induced significant extra-gonadal androgenic effects on lipid metabolism, skin, muscle, liver and hemopoiesis (5). These unwanted effects coupled with the impracticality of uncomfortable weekly im injections underline the need to use lower doses of T with more stable delivery in hormonal male contraception.
Spermatogenesis can be effectively suppressed by combining a reduced dose of T with a second antigonadotropic agent such as a progestagen (6) or GnRH antagonist (7). We previously reported that im T enanthate at the relatively low doses of only 100 or 50 mg weekly, if combined with a 19-nortestosterone-derived oral synthetic progestin, desogestrel (DSG), can suppress spermatogenesis very effectively in men; the best dose combination, 300 µg DSG daily with 50 mg T enanthate weekly, induced consistent azoospermia in all subjects (8). This study also showed that DSG and T both contributed additively and interchangeably to the reproductive as well as the nonreproductive metabolic effects, e.g. reduction of high density lipoprotein cholesterol (HDL-C) and SHBG levels. T enanthate (50 mg, im, weekly), delivering 5 mg free T daily, is regarded as the minimal effective dose and also the minimal dose required to maintain androgen sufficiency. Although it can be surmised that lower doses of DSG or alternate formulations of T, which can reproduce stable physiological (rather than sharply fluctuating) levels, may reduce these unwanted actions, the minimally effective dose combination is currently unknown.
Transdermal T delivery systems have been recently developed for use as a noninvasive method of androgen replacement therapy in hypogonadal men (9, 10). Daily self-application of these systems offers the potential of maintaining stable levels of T within the normal range with a small diurnal fluctuation that closely mimics the physiological pattern.
To date, few male contraceptive studies have employed an entirely subject-administered regimen. As this is likely to be preferred by the majority of potential users, it is important to determine whether daily self-administration, independent of provider or research personnel, can still be effective. This will give important clues about the tolerance or margin of safety in hormonal male contraceptive regimens against a backdrop of the varying levels of compliance that will inevitably be encountered with preventative medications across any population.
We have conducted a study that employs a novel, noninvasive, daily, self-administered treatment regimen to effect reversible suppression of spermatogenesis in healthy male volunteers. The specific aims of the study were 1) to evaluate the effects of oral DSG combined with a nonscrotal transdermal T delivery on gonadotropin secretion and spermatogenesis; 2) to compare the effects of reducing doses of DSG combined with a fixed dose of T designed for physiological androgen replacement; 3) to determine the minimally effective contraceptive combination and the tolerance for breakthrough of suppression in this self-administered regimen; and 4) to assess the nonreproductive effects of these combinations in men.
Subjects and Methods
Subjects
Of 101 respondents to our advertisements, 33 were suitable for screening. After the initial interview and screening tests, 10 were excluded because of low sperm counts (n = 5) or high cholesterol (n = 5), leaving 23 Caucasian men (mean age, 34.2 ± 7.0 yr; range, 20–43 yr) to take part in the study.
Study design
Subjects who met the admission criteria similar to our previous study (8) were randomized into one of three treatment groups to receive 1) oral DSG (300 µg daily) and transdermal T (5 mg daily; n = 7), 2) oral DSG (150 µg daily) and transdermal T (5 mg daily; n = 6), or 3) oral DSG (75 µg daily) and transdermal T (5 mg daily; n = 4) for 24 wk in a single blind, parallel group design.
Subjects were studied in three phases. 1) In the control phase medical screening examination, two baseline semen analyses, and hormonal and biochemical assessments were carried out over 4 wk. 2) In the treatment phase each subject was randomly allocated to one of the three treatment groups described above. Both transdermal T and DSG were administered for 24 wk. Medical review, including physical examination, blood sampling, and semen analyses, were performed every 4 wk. 3) In the recovery phase all subjects were monitored every 4 wk by medical review, semen analysis, and blood sampling until recovery criteria were satisfied; namely, geometric mean pretreatment sperm density was reached or two consecutive specimens showed sperm density greater than 20 million/ml.
All subjects provided informed written consent and were advised to continue with their existing forms of contraception during the study. The study was approved by the Central Manchester Healthcare Trust ethical committee for medical research.
Medications
Desogestrel (75- and 150-µg tablets) were supplied by NV Organon (Oss, The Netherlands). Each subject received one tablet per d in the case of the 75- and 150-µg tablets or two 150-µg tablets in the case of the 300 µg/d group. Tablets were taken in the evening before bed. T was administered by the volunteers as two transdermal delivery systems (Andropatch, SKB, Welwyn Garden City, UK) applied to skin of the upper back, legs, or flanks and changed daily at bedtime, employing a different site at each application.
Clinical monitoring
Subjects were interviewed monthly, with particular emphasis on eliciting any side-effects, monitoring sexual function, and checking medication compliance. The latter consisted of direct questioning and counting tablets and patches remaining in returned containers. Each subject was also asked to record the occasions they missed their medications in writing. Body weight, pulse, and blood pressure were measured monthly, and testicular size (by orchidometer) was measured every 3 months. A digital prostate examination was carried out before treatment and on recovery.
Semen analysis
Semen collection and analysis of semen volume, sperm density, and motility were carried out according to the WHO Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction. The suppression targets are defined as: azoospermia, complete absence of spermatozoa in the ejaculate verified by centrifugation of a whole semen sample; severe oligospermia, sperm concentration of less than 1 million/ml; and oligospermia, sperm concentration of less than 3 million/ml in one sample.
Blood tests
Blood samples were obtained twice before treatment and at 4-wk intervals thereafter for hormone measurements (T, LH, FSH, and SHBG) and hematological (hemoglobin, hematocrit, and white cell count), biochemical (urea, electrolytes, liver enzymes, glucose, and hemoglobin A1c), and lipid profiles [total cholesterol, low density lipoprotein cholesterol (LDL-C), HDL-C, triglycerides, and apolipoprotein A1].
Hormone assays
All plasma samples were stored at -20 C until assay. Plasma gonadotropins were assayed by previously reported highly sensitive immunofluorometric assays (Delfia, Pharmacia-Wallac, Inc., Turku, Finland) (10) with an assay sensitivity of 0.05 IU/ml for both LH and FSH. T was determined by previously described RIA with an assay sensitivity of 0.3 nmol/liter (11). SHBG was determined by an immunoradiometric assay (Farmos Diagnostica, Oulun Salo, Finland). Free T was determined using an established equilibrium dialysis technique (12). All serial samples from one individual were assayed in a single batch to reduce variability.
Biochemical analyses
Full blood count, glucose, hemoglobin A1c, lipids (total cholesterol, HDL-C, and triglyceride), and renal and liver function was measured by routine autoanalyzer methods. LDL-C was derived from the other lipid indices using Friedwald’s formula.
Statistical analyses
The data were analyzed by repeated measures ANOVA, paired t tests, and one-way ANOVA with Tukey’s post-hoc test for continuous variables with statistical significance set at P < 0.05. Values were expressed as the arithmetical mean ± SEM. LH and FSH levels below the sensitivity of the assay were allocated a value of 0.05 U/liter, the lower limit of detection.
Results
Spermatogenesis
Seventeen subjects completed the suppression phase, and 6 subjects
were discontinued (see below). The mean sperm densities before, during,
and after DSG and transdermal T administration in each of the 3
treatment groups are shown in Fig. 1A
.
The rates of suppression to three target sperm densities,
i.e. azoospermia (no sperm), severe oligospermia (<1
million/ml), and oligospermia (<3 million/ml), are shown in Fig. 1B.
Sperm density was significantly (P < 0.05) reduced in
all treatment groups with respect to baseline showing a clear dose
dependence, although the differences between treatment groups failed to
achieve significance. Seven (41%) of the 17 subjects who completed the
suppression phase achieved azoospermia. Nine (53%) of the 17 achieved
suppression to less than 1 million/ml, with no additional subjects
achieving suppression to less than 3 million/ml. The most effective
drug regimen was 300 µg DSG and 5 mg transdermal T daily in which 4
(57%) of the 7 subjects achieved azoospermia, the earliest by wk 8 and
the remainder by wk 16. One additional subject suppressed to less than
1 million/ml by wk 12, giving a total of 71% for this group. In the
150 µg DSG group, 3 (50%) of the 6 subjects achieved azoospermia,
the earliest by wk 8, and the others by wk 12, while the remainder
failed to suppress to oligospermia. In the 75 µg DSG group none of
the 4 subjects achieved azoospermia, although 1 became severely
oligospermic (<1 million/ml) by wk 12, whereas the others (75%)
remained outside the oligospermic range, with sperm densities above 10
M/ml throughout treatment. Pretreatment sperm
densities were not significantly different between the azoospermic or
oligozoospermic responders and the nonsuppressors.
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). In 4 of the 7 subjects who achieved azoospermia there was
escape from suppression before the end of the treatment period; the
others remained fully suppressed until treatment ended. This phenomenon
was also observed in 1 of the 2 subjects who became severely
oligospermic. Sperm density values began to recover within 4 wk of
cessation of therapy. All but 1 of the subjects achieved the recovery
criteria by wk 48 (i.e. 24 wk after the end of treatment).
One subject, despite normal gonadotropin levels, did not recover until
wk 64. His T levels were also subnormal over a similar time course,
although his gonadotropin levels were normal. LH
LH levels were significantly (P < 0.05)
suppressed during the treatment phase in all treatment groups from wk 4
onward. Suppression was dose dependent, the most effective being in the
300 µg DSG group, although the difference between treatment groups
did not achieve statistical significance (Fig. 2). In the 300 µg DSG group, LH was
significantly (P < 0.05) suppressed from a baseline
mean of 4.5 ± 0.7 U/liter to a nadir of 0.2 ± 0.1 U/liter
(wk 8), whereas in the 150 µg DSG group mean levels fell from
4.5 ± 1.0 U/liter to a nadir of 0.8 ± 0.3 U/liter (wk 4).
In the 75 µg DSG group LH levels were suppressed from a baseline mean
of 4.6 ± 1.5 to 0.9 ± 0.7 U/liter (wk 12). Suppression of
LH was not fully maintained during continued treatment. In the 300 µg
DSG group, LH decreased to below the assay detection limit initially in
four subjects and to less than 0.3 U/liter by wk 8 in the other three
subjects. Between wk 8 and the end of treatment, all subjects in this
group showed some degree of escape, mostly transient and below 0.8
U/liter, except for one which broke through to 1.6 U/liter at wk 16
having had undetectable LH 4 wk earlier. In the 150 µg DSG group, LH
suppressed to below assay detection in four of the six subjects, two of
whom escaped while the other two maintained undetectable LH until the
end of treatment. In the 75 µg DSG group, suppression was variable,
and no subject had detectable levels.
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FSH
FSH levels were significantly (P < 0.05)
suppressed during the treatment phase in all treatment groups.
Suppression was dose dependent, the most effective being in the 300
µg DSG group, although the difference between treatment groups did
not achieve statistical significance (Fig. 2). In the 300 µg DSG
group, FSH was significantly suppressed from a baseline mean of
2.7 ± 0.3 U/liter to a nadir of 0.4 ± 0.2 U/liter (wk 8),
whereas in the 150 µg DSG group, mean levels fell from a baseline of
4.2 ± 0.5 U/liter to a nadir of 0.5 ± 0.3 U/liter (wk 4).
In the 75 µg group mean FSH levels fell from a baseline of 3.4
± 0.4 to a nadir of 0.9 ± 0.4 (wk 8). There was a consistent
pattern of gradual escape from suppression after wk 8 in all three
groups.
In both the 300 and 150 µg DSG groups, FSH suppressed to below assay detection limits in three subjects, but only one in each group maintained the suppression until the end of treatment. In the 75 µg DSG group, FSH suppressed to less than 1.0 U/liter in two subjects, but only transiently.
There was no difference in pretreatment FSH levels in subjects who suppressed to azoospermia and oligozoospermia (<3 M/ml) compared with those who did not. The mean FSH level during treatment was significantly lower in azoopermic and oligozoospermic responders compared with nonresponders. FSH recovered rapidly on cessation of treatment, reaching normal levels by wk 28, i.e. the first posttreatment assessment. There was no significant difference in the rate of recovery in the three treatment groups.
T
Mean total T levels were significantly (P < 0.05) decreased during the treatment phase compared with baseline in all three groups, although they remained within the normal physiological range throughout the study. There was no significant difference in total T between the three groups. In the 300 µg DSG group, T levels fell from a baseline of 22.0 ± 2.7 nmol/liter to treatment mean of 14.2 ± 2.5 (64.5% of basal) and a nadir of 12.5 ± 2.2 nmol/liter (wk 20), whereas in the 150 µg DSG group, levels fell from a baseline of 25.2 ± 3.1 nmol/liter to a mean of 17.8 ± 2.7 (70.6% of basal) and a nadir of 15.5 ± 3.1 nmol/liter (wk 24). In the 75 µg DSG group T levels decreased from a baseline of 21.3 ± 1.8 nmol/liter to a mean of 16.4 ± 2.4 (76.8% of basal) and a nadir of 11.4 ± 2.8 nmol/liter (wk 8).
Free T levels also decreased significantly (P < 0.05) during the treatment phase. In the 300 µg DSG group levels fell from baseline mean of 0.28 ± 0.03 nmol/liter to a treatment period mean of 0.17 ± 0.01 nmol/liter (61.6% of basal). In the 150 µg DSG group free T levels fell from 0.31 ± 0.03 to 0.24 ± 0.04 nmol/liter (78.4%) and in the DSG 75 µg group T levels fell from 0.30 ± 0.01 to 0.20 ± 0.03 nmol/liter (66.3% of basal).
There was no difference in pretreatment total T levels in subjects who suppressed to azoospermia and oligozoospermia (<3 M/ml) compared with those who did not. The mean T during treatment was not significantly different in azoopermic and oligozoospermic responders compared with nonresponders. Total and free T levels returned to pretreatment levels by the end of the recovery period in all groups.
SHBG
SHBG levels were significantly reduced (P < 0.05) in all treatment groups during the treatment phase, although there was no significant difference between treatment groups in this regard. In the 300 µg DSG group, mean levels fell from a baseline of 31.3 ± 4.8 nmol/liter to a nadir of 20.7 ± 3.9 (wk 12), whereas in the 150 µg DSG group levels fell from baseline mean of 30.2 ± 6.7 nmol/liter to a nadir of 22.5 ± 5.5 nmol/liter (wk 24). In the 75 µg DSG group, levels fell from a baseline mean of 35 ± 8.92 nmol/liter to a nadir of 27.8 ± 6.3 nmol/liter (wk 12). SHBG levels returned to pretreatment levels by the end of the recovery period in all groups.
Biochemical and hematological parameters
There were no significant changes in plasma urea, creatinine,
sodium, potassium, calcium, alkaline phosphatase, aspartase amino
transferase, alanine amino transferase, 
-glutamyl
transpeptidase, bilirubin, glucose, HbA1c,
hemoglobin, hematocrit, white cell count, or platelets during treatment
(data not shown).
Lipids
HDL-C was significantly decreased (P < 0.05) with respect to baseline during treatment in all groups. In the 300 µg DSG group, HDL-C fell from a baseline of 1.34 ± 0.10 mmol/liter to a nadir of 1.11 ± 0.06 mmol/liter (wk 24), a fall of 17%. In the 150 µg DSG group, HDL-C fell from a baseline of 1.29 ± 0.15 mmol/liter to a nadir of 0.86 ± 0.06 mmol/liter (wk 16), representing a fall of 33%. In the 75 µg DSG group, HDL-C fell from a baseline of 1.18 ± 0.17 mmol/liter to a nadir of 0.90 ± 0.02 mmol/liter (wk 12), a fall of 24%. The differences in HDL-C suppression between treatment groups did not achieve statistical significance. Overall, the mean decrease in HDL-C levels at the end of the treatment period was 12 ± 3.2%.
There were no significant changes in total cholesterol, LDL-C, triglycerides, or apolipoprotein A1. Total cholesterol was significantly increased in the recovery period compared with baseline; this significance disappeared on removing one outlier from the analysis. All other lipid parameters returned to pretreatment levels by the end of the recovery phase in all treatment groups.
Physical changes
There was a small, but significant (P < 0.001), increase of 1.94 ± 0.56 kg (range, -4 to +7kg) in body weight by the end of the treatment phase. This gain persisted; the average weight gain at the end of the recovery period was 2.53 ± 0.67 kg (range, -3 to +9.5kg). There was no significant difference between treatment groups in this regard. Testicular volume decreased by an average of 3.3 ± 1.1 ml (range, 0–7.25 ml) during treatment and returned to pretreatment values by the end of the recovery phase. There were no significant changes in systolic or diastolic blood pressure throughout the study.
Discontinuations, side-effects, and compliance
There were 6 discontinuations; 2 were due to marked and persistent skin reaction to the T patches, and the remaining 4 subjects were either lost to follow-up before completion of the study (n = 2) or withdrew for nontreatment-related reasons, i.e. job relocation or marital discord (n = 2). During the treatment phase 11 subjects reported side-effects, namely increased sex drive (n = 4), decreased sex drive (n = 7), emotional lability (n = 2), irritability (n = 5), and tiredness (n = 2), although these were transient in nature and unrelated to treatment groupings. In addition, 15 (65%) of the subjects reported skin reactions of varying degree to the T patches. In 3 subjects the reaction was classified as mild (transient erythema), whereas in an additional 8 subjects the reaction was classified as moderate (marked erythema and itch requiring treatment with topical hydrocortisone). The remaining 4 subjects were classified as having severe reactions, manifest as marked skin erythema and blistering.
Most of our subjects reported full compliance with the drug regimen. Closer questioning, however, revealed problems with the transdermal patches other than the significant skin reaction. These included patch removal to swim, play sports, or participate in lovemaking; patch detachment with excess perspiration or showering; and poor patch adhesion to hirsute skin and in hot weather. It was therefore difficult to accurately assess the degree of noncompliance with the T patch. As daily oral DSG administration was not subject to the same problems as transdermal application and skin reaction, there was no reason to doubt the high degree of compliance reported, and this was confirmed by the tablet counts. This showed that compliance with oral medication was 90–95%.
Discussion
Previous studies in hormonal male contraception have overwhelmingly employed im injections of T (enanthate in particular) in doses (200 mg weekly) that generated supraphysiological levels in the circulation (13). Consequently, not only have side-effects been observed, but the minimal effective dose for spermatogenesis suppression has remained undefined. In the development of new therapies, it is important to demonstrate the extent of the safety margin for breakthrough and the tolerance to variable/suboptimal compliance. This can only be revealed by systematically investigating the effects of reducing doses and establishing the minimally effective dose level. In our previous study (8) we showed that spermatogenesis suppression could be effectively achieved even when im T enanthate was reduced to the lowest physiological maintenance dose of 50 mg weekly (equivalent to 5 mg unesterified T daily) when combined with the synthetic oral progestin, DSG. However, despite substantially reducing the total dose, the suboptimal pharmacokinetics of T enanthate inevitably produced sharp fluctuations with supraphysiological postinjection peak T levels (14). This contributed to demonstrable nonreproductive effects and rendered interpretation of minimal effective doses of drug combinations difficult. At the equivalent dose of 5 mg T daily, transdermal systems can maintain stable physiological levels of T and offer the opportunity to investigate the minimal dose combination of progestin required to suppress spermatogenesis effectively.
In the present study a downward dose-ranging design was employed to determine the threshold dose of DSG combined with a fixed daily amount of 5 mg transdermally delivered T for suppression of spermatogenesis. We have demonstrated a trend of progressively declining efficacy in achieving the three target levels of sperm density with reducing doses of DSG. Three hundred and 150 µg DSG daily induced azoospermia in 57% and 50% of subjects, respectively. This is approaching the range of azoospermic suppression observed with 500 µg levonorgestrel with 100 mg T enanthate weekly (67%) (15), 200 mg T enanthate weekly (1) (65%), and 1200 mg T implants (16) (56%) in Caucasian men. Suppression to oligozoospermia (either <1 or <3 M/ml) in the present study (71% and 50% with 300 and 150 µg DSG, respectively), however, was clearly inferior to the other regimens (8, 17, 18), which can achieve the less than 3 M/ml target in 94–100% of subjects. Below 150 µg/d DSG, there was a marked drop in effectiveness, with none of the subjects achieving azoospermia. Nevertheless, even at this suboptimal dose, one of the four subjects suppressed to less than 1 million/ml consistently, whereas the other three failed to reach sperm densities less than 10 M/ml. This divergence in responsiveness was also observed in the 150 µg, but not the 300 µg, DSG group. Thus, in contrast to previous studies that emphasized the resistance to achieving azoospermia in a minority of men receiving maximal doses (19), we have demonstrated a marked between-subject variation in sensitivity to hormonal suppression by exploring threshold (150 µg DSG daily) to subthreshold (75 µg DSG daily) doses of treatment. This heterogeneity in suppression suggests that a substantial proportion, perhaps up to 50%, of healthy men are able to respond to much lower doses of exogenous sex steroids than customarily used in attaining effective contraception in previous studies. In common with others (20) we have not been able to identify these susceptible individuals by any baseline characteristics, such as sperm density, gonadotropins, T levels, or body mass index, but they tend to show a more precipitous decline in sperm density within the first 8 wk after starting treatment.
Suppression of spermatogenesis with daily oral DSG and transdermal T
was also less effective than with similar doses of DSG combined with
weekly im injections of T enanthate (Table 1), although the speed of decline in
sperm density was not different (8, 21). This was
particularly true for the oligospermic targets. In the previous studies
using DSG (8, 21) the least effective combination
employing 150 µg DSG daily with 50 mg T enanthate weekly produced
suppression rates similar to the best results obtained in the group
receiving 300 mg DSG with 5 mg transdermal T. Furthermore, the
breakthrough of suppression in three of the seven men who reached
azoospermia and the partial recovery or escape before the end of the
treatment period in most subjects was not observed previously with DSG
and T enanthate or T enanthate alone. It appears that substituting
transdermal T for im T enanthate has resulted in a loss of efficacy in
spermatogenesis suppression.
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The torso transdermal T delivery system has been shown to produce
physiological circulating T levels in hypogonadal men (9, 10, 22). In eugonadal men rendered hypogonadal by exogenous sex
steroid in the present study, however, total T decreased from baseline
by about 30% during treatment, but mean levels at 16.1 ± 2.4
nmol/liter (all three groups combined; normal, 10–35 nmol/liter)
remained within the physiological range. Equilibrium dialysis-measured
free T levels also decreased significantly by similar extents as total
T. A lower SHBG concentration, associated with DSG and other oral
synthetic progestin treatment, therefore did not correct for the low
total T, and an absolute decline in circulating bioavailable T levels
was extant during treatment. Insufficient T may therefore be one
explanation for the lower efficacy in gonadotropin and spermatogenesis
suppression compared with other studies using the same doses of oral
DSG (Tables 1 and 2). Nevertheless, this study showed that improved
suppression of spermatogenesis can be obtained with DSG and transdermal
T compared with levonorgestrel combined with a similar dose but a
different transdermal T preparation (23) and also compared
with cyproterone acetate and oral T undecanoate
(24) (Table 2). This may be
related to the varying biopotencies and efficiencies of the different
progestins and/or preparations of noninjection T. Our results suggest
that self-administration of male hormonal contraceptive steroids is
potentially viable, particularly in more responsive individuals.
However, the transdermal systems are clearly less reliable than
injectable T regimens (see below). The loss of efficacy when weekly im
injections of T enanthate is substituted by daily self-administered
noninjection preparations of T is a consistent finding across all three
paired comparisons (Table 2). This highlights the critical role of T in
male hormonal contraception.
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), we deliberately targeted comparisons
with a lower, yet effective, dose of 50 mg T enanthate weekly, im,
which delivers 5 mg unesterified T daily, an amount equivalent to the
daily delivery rates of the transdermal system studied. The mean T
levels, therefore, should not be very different. The fluctuating T
levels giving high postinjection peaks with T enanthate are probably
not required for maximal gonadotropin suppression, as relatively stable
T levels generated by 800-mg T implants combined with depo
medroxyprogesterone acetate was highly effective
(25). Scrutiny of individual profiles showed that many
subjects in our study had transient decreases in total and free T
levels to the hypogonadal range with concomitant or subsequent escape
in gonadotropins and sperm density (Table 3, subject 1). In contrast, the few
individuals whose T levels were maintained in the normal range
throughout the treatment phase were able to sustain suppression of
gonadotropins and spermatogenesis throughout treatment (Table 3,
subject 2). Analogously, the short half-life of oral T undecanoate and
its unpredictable absorption (26) make it unlikely that
twice daily administration can maintain stable T levels within the
physiological range (27). These observations suggest that
the common thread that links the low efficacy in the three studies
using noninjectable T preparations is likely to be nonmaintenance of
adequate T levels, which may have resulted from pharmacokinetic and
delivery problems or noncompliance. The consequence of these
intermittent troughs in circulating T may not be important or
clinically evident in hypogonadal replacement, but is likely to be of
critical importance in the maintenance of spermatogenesis suppression
for contraception. The cumulative effects of repeated falls in T
(probably underestimated by monthly monitoring) provide the most likely
explanation not only for the lower initial efficacy, but also the
subsequent breakthrough and progressive escape seen across all three
studies using noninjectable T preparations.
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We have previously shown that DSG alone decreased levels of HDL-C as well as apolipoprotein A1, an effect augmented by coadministration of T enanthate. In the present study with transdermal T, HDL-C was reduced significantly in all treatment groups. This confirms that in the absence of high peak T levels, reduction of HDL-C is due to the action of oral DSG on hepatic lipid metabolism.
Side-effects during this study were relatively uncommon apart from skin irritation. Symptoms that may be attributable to androgen deficiency were encountered in seven subjects. However, these were transient in nature, and temporal correlation with changes in T levels was inconsistent.
In conclusion, we have shown that oral DSG combined with a nonscrotal transdermal T delivery system produces suppression of gonadotropins and spermatogenesis, but is less effective than regimens incorporating injectable T. The minimally effective dose of DSG is 150 µg. Escape from suppression is seen at all dose levels of DSG, particularly in those subjects in whom T replacement is not well maintained. These findings serve to further emphasize the critical role of T delivery and highlight some important practical issues concerning daily self-administered regimens for hormonal male contraception. In the current state of patch technology, the transdermal route of delivery may not be optimal for male contraception.
Acknowledgments
We are grateful to Dr. C. Wang, Dr. R. S. Swerdloff, and Mr. Andrew Leung for performing the equilibrium dialysis assay for free T, and NV Organon (The Netherlands) and SmithKline Beechams (UK) for donating the medications. We thank the Contraceptive Research and Development Program, University of East Virginia, for their support.
Footnotes
This work was supported by the Contraceptive Research and Development Program, University of East Virginia (CSA-95-164). This work was presented at 24th Annual Meeting of the American Society of Andrology, Louisville, Kentucky, April 10–13, 1999.
Abbreviations: DSG, Desogestrel; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol.
Received December 14, 2000.
Accepted July 16, 2001.
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S. T. Page, J. K. Amory, B. D. Anawalt, M. S. Irwig, A. T. Brockenbrough, A. M. Matsumoto, and W. J. Bremner Testosterone Gel Combined with Depomedroxyprogesterone Acetate Is an Effective Male Hormonal Contraceptive Regimen and Is Not Enhanced by the Addition of a GnRH Antagonist J. Clin. Endocrinol. Metab., November 1, 2006; 91(11): 4374 - 4380. [Abstract] [Full Text] [PDF]
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 K. L. Matthiesson and R. I. McLachlan Male hormonal contraception: concept proven, product in sight? Hum. Reprod. Update, July 1, 2006; 12(4): 463 - 482. [Abstract] [Full Text] [PDF]
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 J. Chen, J. Kim, and J. T. Dalton Discovery and Therapeutic Promise of Selective Androgen Receptor Modulators Mol. Interv., June 1, 2005; 5(3): 173 - 188. [Abstract] [Full Text] [PDF]
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D. B. O'Connor, J. Archer, and F. C. W. Wu Effects of Testosterone on Mood, Aggression, and Sexual Behavior in Young Men: A Double-Blind, Placebo-Controlled, Cross-Over Study J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2837 - 2845. [Abstract] [Full Text] [PDF]
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 M. C. Meriggiola, T. M.M. Farley, and M. T. Mbizvo A Review of Androgen-Progestin Regimens for Male Contraception J Androl, July 1, 2003; 24(4): 466 - 483. [Full Text] [PDF]
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R. A. Anderson and D. T. Baird Male Contraception Endocr. Rev., December 1, 2002; 23(6): 735 - 762. [Abstract] [Full Text] [PDF]
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 R.A. Anderson, Z.M. van der Spuy, O.A. Dada, S.K. Tregoning, P.M. Zinn, O.A. Adeniji, T.A. Fakoya, K.B. Smith, and D.T. Baird Investigation of hormonal male contraception in African men: suppression of spermatogenesis by oral desogestrel with depot testosterone Hum. Reprod., November 1, 2002; 17(11): 2869 - 2877. [Abstract] [Full Text] [PDF]
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R. A. Anderson, D. Kinniburgh, and D. T. Baird Suppression of Spermatogenesis by Etonogestrel Implants with Depot Testosterone: Potential for Long-Acting Male Contraception J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3640 - 3649. [Abstract] [Full Text] [PDF]
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) or oligozoospermia below 1 million/ml (
)
and below 3 million/ml (
) over the same time course. Subjects
received transdermal T (5 mg/d) plus daily oral DSG at a dose of 300,
150, or 75 µg.