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Original Studies |
Department of Medicine, Manchester Royal Infirmary, University of Manchester, United Kingdom M13 9WL; and the Medical Research and Development Unit, N.V. Organon, Oss, The Netherlands
Address all correspondence and requests for reprints to: Dr. F. C. W. Wu, Department of Endocrinology, Manchester Royal Infirmary, Oxford Road, Manchester, United Kingdom M13 9WL. E-mail: frederick.wu{at}man.ac.uk
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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3-Ketodesogestrel or etonogestrel (ENG; 13-ethyl-17-hydroxy-11-methylene-18,19-dinor-17
-pregn-4-en-20-en-3-
one) is a potent and highly selective synthetic progestogen (22)
that is considered to have less androgenic properties than other
19-nortestosterone-derived gonane progestogens, such as
levonorgestrel and norethisterone acetate (23). ENG does not lower
circulating HDL-C or apolipoprotein A1 when coadministered with
estrogens in women (24). Based on the results of steady state studies
and on excretion data, ENG (unlike MPA) does not accumulate in the body
(25). Desogestrel (DSG), which is converted by the liver
to ENG as the active metabolite, has been used widely in the combined
oral female contraceptive (Marvelon, N.V. Organon, Oss,
The Netherlands) since 1981. The effects of DSG or ENG in men have not
previously been investigated. We hypothesized that oral DSG combined
with T can reversibly suppress spermatogenesis in healthy men with
minimal metabolic effects.
Based on the knowledge that 150 µg DSG are used in the female oral contraceptive pill for ovulation suppression and that between 125–500 µg levonorgestrel daily with T enanthate can suppress spermatogenesis (19, 26), we selected DSG doses of 300 and 150 µg daily for the present study. In a pilot study we have shown that increasing the dose of DSG from 300 to 450 µg daily did not produce greater gonadotropin suppression in men (27). In the same study it was demonstrated that LH, FSH, and T were all suppressed to the nadir by DSG within 3 weeks. Thus, administering DSG alone for the initial 3 weeks and deferring the addition of T by 3 weeks should provide a unique opportunity to determine the individual contributions to the synergism between the two steroids.
We have conducted a downward dose-ranging study to investigate the impact of combining DSG with reducing physiological replacement doses of T on suppression of spermatogenesis and androgen-related nonreproductive effects. The aim of the study was to address the following specific questions. 1) How much DSG is required to be combined with low doses of T to suppress spermatogenesis? 2) What is the lowest dose of T (enanthate) compatible with maintaining secondary sexual and physiological functions as well as contributing to the contraceptive action of the combination? 3) To what extent do the two components contribute to the overall actions of the combination?
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Twenty-four healthy male Caucasian volunteers (mean age, 33.2 ± 0.9 yr) were recruited from the community. Of 289 respondents to our advertisements, 40 were suitable for screening. Twelve did not wish to proceed further after the initial interview and screening tests, three were excluded because of low sperm counts, and one was excluded because of a blood coagulation disorder.
Study design
Subjects who met the admission criteria after screening were randomized into three treatment groups (n = 8) to receive: 1) 300 µg DSG, orally, daily and 100 mg T enanthate, im, weekly; 2) 300 µg DSG, orally, daily and 50 mg T enanthate, im, weekly; 3) 150 µg DSG, orally, daily and 100 mg T enanthate, im, weekly for 24 weeks in a single blind, parallel group design. Each subject was studied in three phases: 1) control phase: a screening medical examination, two baseline semen analyses, and hormonal and biochemical assessments were carried out over 4 weeks; 2) treatment phase: each subject was randomly allocated to one of the three treatment groups [for all subjects, desogestrel was administered during the total treatment period (weeks 1–24), and T enanthate was given during weeks 4–24; subjects received the first dose of T enanthate on day 22 after starting DSG; a medical review, including physical examination, semen analyses, and blood sampling, was carried out every 4 weeks except during the first 6 weeks, when blood samples were obtained on days 3, 5, 7, 14, 21, 28, and 56]; and 3) recovery phase: all subjects were monitored every 4 weeks by medical review, semen analyses, and blood sampling until they attained the recovery criteria, i.e. when the 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 alternative forms of contraception during the study. The study was approved by the Central Manchester ethical committee for medical research.
Medications
DSG (150 µg) and matching placebo tablets were supplied by NV Organon. Each subject received one active and one placebo (150 µg group) or two active tablets (300 µg groups). T was administered weekly by the study personnel as deep im injections of 0.2 or 0.4 mL Testoviron Depot (250 mg T enanthate in 1 mL castor oil; Schering AG, Berlin, Germany), giving 50 or 100 mg T enanthate, respectively.
Clinical monitoring
Subjects were interviewed monthly and were examined at 3-month intervals throughout the study, with particular emphasis on eliciting any side-effects and monitoring sexual function, endocrine system, body weight, blood pressure, and testicular size (by orchidometer). A digital prostate examination was carried out pretreatment, at the end of treatment, and on recovery. Sexual function and moods were recorded by weekly diaries.
Semen analysis
Semen collection and analysis of semen volume, sperm density, motility, and morphology were carried out according to the WHO Laboratory Manual for the Examination of Human Semen and Semen-Cervical Mucus Interaction (28). Azoospermia was verified by centrifugation of the whole semen sample. Semen analyses were carried out twice during the control phase and at monthly intervals until recovery, as defined above, was achieved.
Blood tests
Blood samples were obtained twice pretreatment; on days 3, 5, 7, 14, 21, 28, and 56 in the treatment phase; and thereafter at 4-week intervals for hormone measurements [T, LH, FSH, and sex hormone-binding globulin (SHBG)]. Blood samples were also obtained immediately before the daily dose of DSG on days 7 and 28 and then at weeks 4, 8, 12, 16, 20, and 24 for measurement of ENG concentrations. Additional fasting blood samples were taken for hematological (hemoglobin, hematocrit, and white cell count), biochemical (urea, creatinine, electrolytes, albumin, liver enzymes, glucose, and hemoglobin A1c), and lipid profiles [total cholesterol, low density lipoprotein cholesterol (LDL-C), HDL-C, triglyceride, and apolipoprotein A1) at baseline and at weeks 3, 6, 12, 20, 24, 32, 40, and 48.
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, Turku, Finland) (29) with an assay sensitivity of 0.05 IU/L for both LH and FSH, T was determined by a previously described RIA (30) with an assay sensitivity of 0.3 nmol/L, SHBG was determined by an immunoradiometric assay (Farmos Diagnostica, Oulun Salo, Findland), and ENG was determined by an in-house RIA. All serial samples from one individual were assayed in a single batch to reduce variability.
Biochemical analyses
Full blood counts, glucose, hemoglobin A1c, lipids (total cholesterol, HDL-C, and triglyceride), and renal and liver functions were measured by routine autoanalyzer methods. LDL-C was derived from the other lipid measures using Friedwald’s formula.
Statistical analyses
The data were analyzed by repeated measure ANOVA, paired t tests, one-way ANOVA with Tukey’s post-hoc test for continuous variables, and contingency table (Fisher’s) test for categorical variables, with statistical significance set at P < 0.05. Data that were not normally distributed were log transformed before analysis. Values were expressed as the arithmetical mean ± SEM. LH and FSH concentrations below the sensitivity of the assay were allocated a value of 0.05 U/L, the lower limit of detection.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The mean sperm densities before, during, and after DSG and T
enanthate administration in the three treatment groups are shown in
Fig. 1
. The rates of suppression to
various target sperm densities during the 24-week treatment phase and
recovery after cessation of treatment are shown in Fig. 2 and Table 1. All three dose combinations suppressed
sperm production significantly by week 8. Eighteen (78%) of 23
subjects who completed the suppression phase achieved azoospermia, the
earliest by week 8 (n = 3) and the latest after 24 weeks (n =
1) of treatment. Some 91.7% (22 of 24) and 95.8% (23 of 24) of
subjects suppressed to less than 1 million/mL and less than 3
million/mL, respectively, after 24 weeks. The most effective regimen
was 300 µg DSG daily combined with 50 mg T enanthate weekly, under
which all eight subjects became azoospermic after 20 weeks of
treatment, although a statistically significant difference in the
number or percentage of subjects achieving any of the 3 targets
(azoospermia or <1 or <3 million/mL) among the three regimens could
not be detected (Table 1). However, the overall decline in sperm
densities with time in response to 300 µg DSG/50 mg T enanthate was
significantly greater (by ANOVA: F = 6.99; P <
0.02) than that observed with 300 µg DSG/100 mg T enanthate but not
that observed with 150 µg DSG/100 mg T enanthate (by ANOVA: F =
3.11; P = 0.1; Fig. 1). Sperm densities at any of the
individual times during treatment from weeks 4–24 (Fig. 1) were not
significantly different among the three treatment groups. One subject
in the 300 µg DSG/100 mg T enanthate group was relatively
unresponsive to treatment, with nadir sperm density remaining at 16.3
million/mL at week 24. His compliance with oral medication was
confirmed by the ENG concentrations during the treatment phase, which
were consistently above the 10th percentile of values for subjects
receiving 300 µg DSG daily. Exclusion of this single outlier did not
change the conclusions of the above analyses.
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). The average times taken to suppress sperm density to
azoospermia, less than 1 million/mL, and less than 3 million/mL were
13.1 ± 1.0, 10.0 ± 0.5, and 9.6 ± 0.5 weeks,
respectively.
Sperm density in all three groups started to recover within 4–8 weeks
after discontinuation of treatment, and all subjects achieved the
recovery criteria by week 44 (20 weeks after the end of treatment). The
slower rate of recovery in group 3 was due to one individual who did
not recover until 20 weeks after treatment. There was no significant
difference in the posttreatment sperm densities among the three
treatment groups (Fig. 1).
LH
All three dose combinations of DSG with T enanthate were highly
effective in suppressing LH secretion (Fig. 3). DSG treatment alone in the first 3
weeks suppressed LH significantly (P < 0.001; Fig. 3, inset) from a baseline of 3.53 ± 0.31 to 2.16 ±
0.46 U/L (group 1) and from 3.62 ± 0.30 to 2.0 ± 0.20
(group 2) with 300 µg DSG and from 4.29 ± 0.51 to 2.81 ±
0.56 in response to 150 µg DSG (group 3) at the end of 3 weeks of
treatment. Although the suppression of LH by 300 µg (groups 1 and 2)
was consistently greater than that by 150 µg (group 3) DSG daily
during the first 3 weeks, the difference did not reach statistical
significance. The suppression of LH by DSG alone was rapid, being
apparent by day 3 (P < 0.006 compared to day 0).
Indeed, there was no further decline in LH from days 3–21. Addition of
T enanthate to DSG from weeks 4–24 induced a further striking fall in
LH (P < 0.0001 compared with the first 3 weeks) in all
three treatment groups (Fig. 3). The decrease in LH continued until
week 6 (0.06 ± 0.01, 0.13 ± 0.03, and 0.11 ± 0.04
U/L, groups 1, 2, and 3, respectively), after which the LH
concentrations were maintained at or below the lower limit of assay
detection. From week 16 to the end of treatment, all subjects had
undetectable levels of LH, except for one man (LH, 0.2–0.6 U/L) in the
300 µg DSG/50 mg T enanthate group. LH recovered rapidly, so that
levels were not significantly different from baseline within 4 weeks
after the cessation of treatment in all three groups. There was no
significant difference in LH among the three treatment groups in the
baseline, treatment, or recovery phases of the study.
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All three dose combinations of DSG with T enanthate were highly
effective in suppressing FSH (Fig. 4).
DSG alone suppressed FSH significantly (P < 0.0001)
from the baseline of 3.58 ± 0.59 progressively to a nadir of
1.61 ± 0.32 U/L (group 1), from 3.15 ± 0.42 to 1.44 ±
0.26 U/L with 300 µg (group 2), and from 3.95 ± 0.45 to
2.10 ± 0.26 U/L with 150 µg DSG (group 3) at the end of week 2;
there was no further decline between weeks 2–3 (Fig. 4, inset). FSH was consistently suppressed to a lower level by
300 µg (groups 1 and 2) than by 150 µg (group 3) DSG daily during
the first 3 weeks; this difference reached statistical significance on
day 7 (1.7 ± 0.2 vs. 2.3 ± 0.2;
P < 0.05). Addition of T enanthate to DSG induced a
further decrease (P < 0.0001) in FSH from sweek 3–6.
Between weeks 8 and 24, FSH was maintained around the lower limit of
assay detection (0.07 ± 0.01, 0.18 ± 0.06, and 0.06 ±
0.01 U/L for groups 1, 2, and 3, respectively). Although there was no
significant difference in FSH concentrations among the three groups
during the combination treatment, the number of samples with detectable
FSH was significantly higher in the group receiving 300 µg DSG/50 mg
T enanthate (25 of 40) than in the other two groups receiving 300 µg
DSG/100 mg T enanthate (13 of 40; P < 0.02) and 150
µg DSG/100 mg T enanthate (9 of 40; P < 0.001).
After treatment, FSH recovered to baseline concentrations within 4
weeks similarly in the three groups.
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In response to DSG, T decreased from the baseline of 19.7 ±
1.0 to a nadir on day 14 of 6.6 ± 1.9 nmol/L with 300 µg (group
1; P < 0.0001), 19.5 ± 1.2 to 6.1 ± 0.6
nmol/L with 300 µg (group 2; P < 0.0001), and
21.2 ± 2.0 to 8.8 ± 1.4 nmol/L with 150 µg DSG (group 3;
P < 0.0001; Fig. 5, inset). A small, but significant, rise (P <
0.05) in T was observed between days 14 and 21. Lower T levels were
consistently observed during the first 3 weeks with the 300-µg DSG
dose in groups 1 and 2; this approached statistical significance on day
7 (7.8 ± 1.0 vs. 10.2 ± 1.7 nmol/L;
P = 0.074; Fig. 5, inset).
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). T levels
returned to baseline 4 weeks after treatment terminated in all three
groups. ENG levels
ENG concentrations increased within 1 week to stable levels that did not change subsequently during the 24-week treatment phase. The mean ENG concentrations were 1056 ± 103, 1176 ± 167, and 592 ± 107 pg/mL in the 300 µg DSG/100 mg T enanthate, 300 µg DSG/50 mg T enanthate, and 150 µg DSG/100 mg T enanthate groups, respectively. The 150-µg dose produced ENG concentrations significantly lower (P < 0.02) than the 300-µg dose.
SHBG
DSG alone decreased SHBG concentrations significantly
(P < 0.0001) from 28.2 ± 4.0 to 21.3 ±
3.7, 28.1 ± 3.9 to 20.7 ± 2.1, and 29.3 ± 4.5 to
21.7 ± 3.1 nmol/L in groups 1, 2, and 3, respectively, after 3
weeks of treatment (Table 2).
Addition of T enanthate at either 100 or 50 mg weekly further decreased
SHBG to 17.7 ± 3.0, 16.8 ± 1.9, and 17.0 ± 3.2 nmol/L
in groups 1, 2, and 3, respectively, at week 24 (P <
0.0001 compared to week 3). These recovered to the pretreatment levels
by 4 weeks after cessation of treatment. There was no significant
difference in SHBG concentrations among the three treatment groups in
the baseline, treatment, or recovery phases of the study. However, the
SHBG decline after introduction of T enanthate was apparent by weeks 6
and 12 in groups 1 (P < 0.03) and 3 (P
< 0.005), respectively, whereas in group 2, this only became
significant at week 24 (P < 0.02).
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The lipid results from the three treatment groups are shown in
Fig. 6 and Table 2. In the first 3 weeks,
DSG alone significantly suppressed total cholesterol (-9.3 ±
1.7%; P < 0.0001), HDL-C (-10.3 ± 2.6%;
P < 0.0001), and LDL-C (-7.7 ± 2.8%;
P < 0.005), with no difference between the daily doses
of 300 and 150 µg. However, with the addition of T enanthate at the
end of week 3, only HDL-C, but not total or LDL-C, decreased further
until week 12 (-18.8 ± 2.4%; P < 0.005). There
was no significant difference in the extent of suppression of HDL-C
among the three dose combinations compared to that at week 3 or
baseline. In particular, 50 and 100 mg T enanthate induced similar
degrees of HDL-C suppression when combined with DSG. The overall
decrease in HDL-C during treatment with DSG combined with T enanthate
(all three groups) was 22.6 ± 3.7% compared to baseline.
Triglyceride levels were unaffected by DSG alone or by DSG with T
enanthate. All lipid parameters returned to baseline after
treatment.
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). No changes in routine biochemistry
(data not shown) or liver function were observed (Table 2). Physical changes
No significant changes in body weight or blood pressure were
observed during treatment (Table 2). Testicular volume decreased
(P < 0.001) during treatment, but recovered by week 40
(Table 2).
Discontinuations and side-effects
There were four discontinuations, all at the end of week 16. One subject (group 2) discontinued because of headaches and sweating. Another subject (group 3) had to withdraw from the study because his 16-month-old son died from a congenital abnormality. One subject (group 3) withdrew for social reasons. The fourth subject (group 2) discontinued because his partner conceived (condom failure at a time when sperm densities were between 0.1–6.0 million/mL, but achieved azoospermia 4 weeks later) and subsequently miscarried at 6 weeks. There were no other pregnancies during this study. All prematurely discontinued subjects were followed until recovery was complete.
During the first 3 weeks of treatment (DSG without T), 5 subjects experienced side-effects, including decreased sex drive (n = 4), tiredness (n = 1), and feeling depressed (n = 1). Between weeks 4 and 24, side-effects reported included mild acne (10 subjects; but only 1 from group 2), short temper (n = 5), increased sexual interest (n = 3), emotional lability (n = 2), tiredness (n = 2), night sweat (n = 1), and headache (n = 1).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The most effective suppression of spermatogenesis was found in the
group receiving the lowest T enanthate dose of 50 mg weekly with 300
µg DSG daily, with which all subjects became azoospermic. In a study
complementary to ours (Anawalt, B. D., et al., 1998,
unpublished), men receiving 50 mg T enanthate with 150 µg DSG showed
suboptimal spermatogenesis suppression with 57% azoospermia, 75% with
less than 1 million/mL, and 78% with less than 3 million/mL, whereas
both LH and FSH remained detectable throughout treatment. Our results
show that an increase in dose of either DSG or T will achieve
significantly greater suppression. Thus, either 300 µg DSG daily with
50 mg T enanthate weekly or 150 µg DSG daily with 100 mg T enanthate
weekly suppressed spermatogenesis to less than 1 million/mL in all
subjects. However, increasing the dose of both agents, DSG to 300 µg
daily and T enanthate to 100 mg weekly, did not bring about any
additional suppression. Indeed, the suppression of spermatogenesis with
the highest doses (300 µg DSG and 100 mg T enanthate) was marginally
less effective. As gonadotropin suppression in groups 1 and 3 was
greater than that in group 2, it is possible that higher circulating
testosterone in groups 1 and 3 or its 5-reduced metabolites (33) may
prevent the achievement of azoospermia by direct stimulatory action of
the testis. This supports the use of the lowest possible doses of
testosterone in male contraception, provided gonadotropin suppression
is adequate and physiological androgen-dependent functions can be
maintained.
The efficacy of spermatogenesis suppression achieved by DSG and T
enanthate (78% azoospermia overall and 100% in group 2) is superior
to those obtained in earlier studies of progestogen/androgen
combinations that used suboptimal doses and longer dosing intervals of
T (2, 3, 4, 5). The efficacy and rate of spermatogenic suppression in the
present study also compared favorably with more recent work
investigating the oral progestogens levonorgestrel (500 µg daily;
67% azoospermic) and cyproterone acetate (100 mg daily; 100%
azoospermic) combined with 100 mg T enanthate weekly (19, 20) and 250
mg depot-MPA, im, combined with 800-mg T implants (90%
azoospermic) (21). The minimal effective doses of these combination
regimens are as yet unknown. The present results are also superior to
those obtained with androgen-only regimens, including 200 mg T
enanthate weekly alone (65% azoospermia), 1200-mg T implants (56%
azoospermia), and 1200 mg T buciclate (37.5% azoospermia) (11, 18, 34). The speed of suppression to azoospermia (13.1 ± 1.0
weeks) with DSG and T enanthate, however, was not faster. Apart from
using lower doses of T, the improved efficacy of progestogen-containing
regimens may be due to an antispermatogenic or antiandrogenic effect
(20, 35) or inhibition of 5-reductase activity (36).
DSG treatment alone decreased LH, FSH, and T within 3 days, and all subjects became profoundly hypogonadal by day 7, reaching a nadir on day 14. This dramatic and acute effect is similar to that observed with the Nal-Glu GnRH antagonist (37). DSG alone suppressed T to a greater extent than LH and FSH. This reflects the simultaneous decline in SHBG so that bioavailable T is proportionately higher than total T levels. The bioactivity of LH is not preferentially lowered during DSG treatment, and the bioactive/immunoactive ratio is unchanged (30). The greater suppression of LH, FSH, and T by 300 µg compared to 150 µg DSG during the first 3 weeks suggests that the latter is the first submaximal dose. However, oral DSG on its own, even at the maximal dose, suppressed the hypothalamic-pituitary-testicular axis only partially. T is therefore essential not only for maintenance of androgen-dependent physiological functions but also for the crucial additional suppression of gonadotropins.
By deferring the introduction of T enanthate after DSG, this study has provided the first demonstration of the individual action of an oral progestogen as well as the subsequent additive effects of T on the pituitary-testicular axis. It is clear that the addition of T to DSG was required to further suppress gonadotropins toward the limits of assay detection. This was achieved even at doses of T enanthate (50 or 100 mg weekly) that, when administered on their own, are relatively ineffective (19). Thus, combining two agents at doses that are submaximal when used individually produced a clear additive effect in suppressing gonadotropins to levels compatible with maximal abrogation of spermatogenesis. Although plasma T in group 2 (50 mg T enanthate weekly) was half that in groups 1 and 3 (100 mg T enanthate weekly), there was no difference in gonadotropin suppression. As the dose of 300 µg DSG daily was more effective in suppressing gonadotropins and T than 150 µg, this might have compensated for the lower dose of T in group 2. This is supported by the findings that increasing the dose of T to 100 mg T enanthate weekly allowed a reduction in the dose of DSG from 300 to 150 µg (i.e. group 3) without losing efficacy, whereas 150 µg DSG and 50 mg T enanthate were ineffective (Anawalt, B. D., et al., 1998, unpublished). These results not only show an additive effect, but also demonstrate an interchangeable action between T and DSG in inhibiting pituitary-testicular endocrine function and accord well with the results of spermatogenesis suppression (see above).
The present results show that a dose of 50 mg T enanthate weekly was sufficient for maintaining physiological circulating T (attaining a consistent predose trough level of 11 nmol/L) and normal sexual function during DSG treatment for 24 weeks. This has also been reported in normal men rendered hypogonadal by Nal-Glu GnRH antagonist treatment for 6 weeks (38). The higher dose of 100 mg T enanthate weekly raised preinjection trough plasma T above the pretreatment baseline and is therefore a supraphysiological dose (10.3 mg T daily). On its own, however, 100 mg T enanthate weekly was unable to induce maximal suppression of spermatogenesis (19), which required an even higher dose of 200 mg weekly. Our results therefore indicate that introducing a second gonadotropin-suppressing agent permitted a major (75%) reduction in the dose of T, which was not only sufficient to support secondary sexual functions but was also essential for suppression of spermatogenesis, with efficacy surpassing that obtained with higher dose androgen-only regimens. This is similar to using 300 mg depot-MPA monthly with a 800-mg T implant (6 mg T daily), which was suboptimal on its own, yet was fully effective when administered in combination (21). We have not extended the T dose range further downward because it is likely that lower doses than 50 mg T enanthate weekly would produce symptoms of androgen deficiency. The T production rate in young men determined by the stable isotope dilution technique is 3.7 ± 2.2 mg/day (39). Thus, 50 mg T enanthate weekly, or the equivalent of 5 mg of free T daily, is probably the minimally effective and optimal dose when combined with progestogens for male contraception. However, even these mandatory minimum replacement doses of T contribute substantially to the suppression of spermatogenesis, thereby permitting the use of the second antigonadotropic agent at relatively low or submaximal doses. This mutual dose-sparing effect and interchangeable additive action between T and progestogens are the key findings in the present study.
DSG treatment alone (either 150 or 300 µg daily) decreased HDL-C, apolipoprotein A1 lipoprotein, SHBG, and, to a lesser extent, total cholesterol and LDL-C. These metabolic effects on the liver had a rapid onset, being apparent within 3 weeks. It should be noted that at the time when these metabolic changes occurred, T was also declining into the hypogonadal range. When T is acutely lowered, as in men receiving GnRH antagonist (37), HDL-C and SHBG would be expected to rise. This anticipated increase in HDL-C or SHBG not only did not occur, but was actually reversed during oral DSG treatment in the first 3 weeks. Although DSG is a 19-nortestosterone-derived progestogen, it is noted for its low androgenic activity compared with other members of this family (40), and its relative binding affinity for the androgen receptor is only 0.12 compared to that of dihydroxytestosterone (23). It is therefore unlikely that the acute metabolic effects of oral DSG were mediated through its cross-reactivity with the androgen receptor. The simultaneous, albeit minor, suppression of total and LDL-C in addition to HDL-C was also uncharacteristic of an androgenic effect.
The addition of T enanthate in week 4 returned T into the normal range, but further decreases in HDL-C and SHBG were also induced that were similar whether 100 or 50 mg weekly was administered. As 100 mg T enanthate (and, by inference, 50 mg also) weekly did not alter lipids when administered in men rendered hypogonadal experimentally (37), but 200 mg T enanthate weekly decreased HDL-C only with no change in total cholesterol or LDL-C (16, 41, 42), the observed overall changes in lipid metabolism during weeks 4–24 (DSG plus T) were probably predominantly due to the effects of DSG rather than T. The magnitude of the fall of 22.6% in HDL-C during combined DSG and T enanthate treatment was greater than that observed with 200 mg T enanthate weekly alone (16, 41, 42) [it was typically 13–18%], similar to the 23% fall observed in men treated with 500 µg levonorgestrel daily plus 100 mg T enanthate weekly (19) and was much greater than that when DSG was coadministered with estrogen in the female pill (43).
It is accepted that 19-nortestosterone-derived progestogens such as DSG and levonorgestrel stimulate hepatic lipoprotein lipase and decrease HDL-C (44, 45). This is generally believed to be due to their inherent androgenic properties. However, supposedly nonandrogenic 17-hydroxyprogesterone-derived progestogens such as MPA also decreased HDL-C (46) even when administered parentally. This would be more in keeping with a class effect of progestogens rather than a reflection of androgenicity or route of administration. It is interesting to note that the antigonadotropic effects of 19-norprogesterone-derived progestogens are not mediated by the androgen receptor (47). Whether the metabolic effects of progestogens are mediated via the progesterone receptor or other alternative receptor pathways is currently unclear.
Side-effects were relatively uncommon, and oral DSG was well tolerated. Sexual function in particular was not significantly impaired even with the lowest dose of T enanthate combined with DSG. Subjects in groups 1 and 3 noticed a modest increase in acne and skin greasiness. This supports the view that 100 mg T enanthate weekly may give rise to a net increase in androgenic activity in normal men.
In summary, this study has clearly demonstrated the individual contributions to the additive actions of an oral progestogen combined with T on the hypothalamic-pituitary testicular axis. The downward dose-ranging showed that DSG at either 300 or 150 µg daily combined with low doses of T enanthate (50 or 100 mg weekly) can augment each other’s action interchangeably, thereby creating an extremely effective regimen for suppressing spermatogenesis with moderate doses of both steroid. The optimal combination that induced azoospermia in all subjects was 300 µg DSG daily with 50 mg T enanthate weekly. Oral DSG, however, exerts discernible metabolic effects, the clinical significance of which is currently unclear. We conclude that the use of an oral progestogen for male contraception allows a substantial reduction in the dose of T with greater efficacy than androgen only regimens. Combination of DSG with T is a promising approach for reversible male contraception that is worthy of further investigation.
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Acknowledgments |
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Footnotes |
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Received June 17, 1998.
Revised October 7, 1998.
Accepted October 12, 1998.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-reductase activity in
oligozoospermic responders during testosterone enanthate
administration. J Clin Endocrinol Metab. 81:902–908.[Abstract]
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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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M. J. Walton, R. A. L. Bayne, I. Wallace, D. T. Baird, and R. A. Anderson Direct Effect of Progestogen on Gene Expression in the Testis during Gonadotropin Withdrawal and Early Suppression of Spermatogenesis J. Clin. Endocrinol. Metab., July 1, 2006; 91(7): 2526 - 2533. [Abstract] [Full Text] [PDF]
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Y. Lue, C. Wang, Y.-X. Liu, A. P. S. Hikim, X.-S. Zhang, C.-M. Ng, Z.-Y. Hu, Y.-C. Li, A. Leung, and R. S. Swerdloff Transient Testicular Warming Enhances the Suppressive Effect of Testosterone on Spermatogenesis in Adult Cynomolgus Monkeys (Macaca fascicularis) J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 539 - 545. [Abstract] [Full Text] [PDF]
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K. L. Matthiesson, P. G. Stanton, L. O'Donnell, S. J. Meachem, J. K. Amory, R. Berger, W. J. Bremner, and R. I. McLachlan Effects of Testosterone and Levonorgestrel Combined with a 5{alpha}-Reductase Inhibitor or Gonadotropin-Releasing Hormone Antagonist on Spermatogenesis and Intratesticular Steroid Levels in Normal Men J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5647 - 5655. [Abstract] [Full Text] [PDF]
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C. J. Hay, B. M. Brady, M. Zitzmann, K. Osmanagaoglu, P. Pollanen, D. Apter, F. C. W. Wu, R. A. Anderson, E. Nieschlag, P. Devroey, et al. A Multicenter Phase IIb Study of a Novel Combination of Intramuscular Androgen (Testosterone Decanoate) and Oral Progestogen (Etonogestrel) for Male Hormonal Contraception J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2042 - 2049. [Abstract] [Full Text] [PDF]
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