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Original Studies |
Division of Endocrinology, Departments of Medicine and Pediatrics, Harbor-University of California Los Angeles Medical Center (R.S.S., C.W., N.B., B.S.), Torrance, California 90509; and Division of Endocrinology, Department of Medicine, Veterans Administration Puget Sound Health Care System (C.J.B., B.D.A., W.J.B.), Seattle, Washington 98108
Address all correspondence and requests for reprints to: R. S. Swerdloff, Division of Endocrinology, Harbor-University of California Los Angeles Medical Center, 1000 West Carson Street, Torrance, California 90509. E-mail: Swerdloff{at}gcrc.humc.edu
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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GnRH antagonists, when administered to man, inhibited gonadotropin secretion rapidly and without the initial stimulation of gonadotropins observed with the GnRH agonists. GnRH antagonists were shown to profoundly suppress serum FSH and T levels and to inhibit spermatogenesis, resulting in azoospermia or severe oligozoospermia in over 90% of men studied (10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22). Because T levels were suppressed, various replacement doses of T (TE 25–200 mg/week im) were used (13, 16, 19, 23). Though effective, GnRH antagonists were expensive to synthesize, had to be administered daily by SC injections, and produced local skin irritation in most of the subjects.
The present study was designed to test the hypothesis that when suppression of spermatogenesis to severe oligo- or azoospermia was induced by the combined administration of GnRH antagonist and T, this suppression would be maintained by T administration in a dose inadequate to induce maximal suppression of spermatogenesis if used alone. In previous studies, TE 100 mg/week im administered alone for 6 months resulted in azoospermia in only 33% and severe oligozoospermia in 61% of normal volunteers in the United States (mainly Caucasians) (24). This dose of TE, previously shown to reverse symptoms of hypogonadism in androgen-deficient men, was chosen to be the replacement dose for the induction of suppression of spermatogenesis with the regimen GnRH antagonist plus T, and subsequently as a single agent during the maintenance phase of the study. If this hypothesis is proven to be true, then other combination regimens such as a nonpeptide GnRH antagonist or a progestagen plus T (24) could also rapidly induce severe spermatogenic suppression that would be maintained by a lower, more physiological dose of T. Such a combination might be a practical and more effective method of male contraception.
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Subjects and Methods |
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Fifteen healthy male volunteers between 21–41 yr of age were recruited from the community via radio and newspaper advertisements. They were studied either at the Harbor-UCLA Medical Center (n = 8) or the VA Puget Sound Health Care System (n = 7). Twelve of the subjects were non-Hispanic whites, two were Hispanics, and one was East Asian. The subjects were in good health as determined by medical history, physical examination, and screening laboratory tests including blood counts, renal and liver function tests, serum lipid panel, and serum T, FSH, and LH levels. All subjects had normal semen analyses as defined by the WHO guidelines (25) i.e. semen volume over 2.0 mL, sperm concentration over 20 x 106/mL, motility over 50% (includes all motile spermatozoa) and normal morphology over 20% by strict criteria. (The percent normal morphology threshold was set at 20% based on data generated in our laboratory from semen analyses of 61 normal, healthy volunteers). All subjects were within plus or minus 20% of ideal body weight. Other methods of contraception were used by the subjects or their partners throughout the study period. All subjects signed an informed consent form, and the study was approved by the Institution Review Board of each institution.
Study design
The study was divided into four phases (Fig. 1
): pretreatment phase of a minimum of 6
weeks duration, induction phase of 12 weeks, maintenance phase of 20
weeks, and posttreatment phase of a minimum of 12 weeks. During the
pretreatment phase at least four semen samples were obtained from each
volunteer, and a skin test for GnRH antagonist was performed. Skin
tests were performed with intradermal injection of 10 µg GnRH
antagonist. Only volunteers with a wheal of equal to or less than 0.5
cm with no pseudopods were admitted to the study. During the induction
phase, the volunteers administered Nal-Glu GnRH antagonist 10 mg sc
daily by self-administration and TE 100 mg im weekly by the study
coordinators. On occasions when the volunteers could not return to the
clinic, TE injections were administered by the volunteers after careful
instructions from the medical staff. At the end of 12 weeks, volunteers
who had attained azoospermia or a sperm concentration equal to or less
than 3 x 106/mL on two consecutive semen analyses
entered into a 20-week maintenance period during which they received TE
100 mg/week im alone. If at the end of the induction period the
volunteer did not suppress to severe oligozoospermia (defined as sperm
count 
3 x 106/mL) or azoospermia on two consecutive
semen analyses, he entered recovery phase. During the entire
maintenance phase, TE im injections 100 mg/week were administered for
another 20 weeks. Volunteers were discontinued from the maintenance
period and entered into recovery phase if sperm concentrations reached
more than 3 x 106/mL in two consecutive semen samples
at any time. The recovery phase lasted for a minimum of 12 weeks or
until two consecutive semen analyses showed sperm concentration of over
20 x 106/mL. Semen samples were collected at
2-week intervals throughout the study. Blood samples for
hormones were collected at 2-week intervals before and during
the induction phase and then at 4-week intervals during
treatment and recovery phase. Complete blood counts, clinical
chemistry, and lipid panel were done during and at the end of
induction, maintenance, and recovery phases. In addition, psychosexual
diary data for 7 consecutive days were collected by volunteers at
monthly intervals throughout the study period (26, 27).
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The Nal-Glu GnRH antagonist was obtained from J. Rivier, Ph.D. (Salk Institute, La Jolla, CA) and was made available through the Contraceptive Development Branch, Center for Population Research, National Institute of Child Health and Human Development. Nal-Glu antagonist was supplied as a lyophilized powder that was dissolved in bacteriostatic water containing 4 g/L mannitol and then diluted to a concentration of 10 mg/mL. The preparation was passed through a 0.2-µm filter into sterile vials under sterile conditions by the research pharmacist at the Harbor-UCLA Medical Center. Each batch of vials was tested for pyrogenicity and sterility before use. Volunteers self-administered Nal-Glu GnRH antagonist sc in the abdominal area each day. The volunteers were asked to record the local reaction caused by the GnRH antagonist. TE was a gift from BioTechnology General (Iselin, NJ) in 5-mL vials of 200 mg TE/mL sesame oil. TE was administered to the volunteers by the nurse coordinator, or volunteers were taught how to self-administer the injections.
Methods
Serum FSH and LH were measured by highly sensitive and specific immunofluorometric assays with reagents provided by Delfia (Wallac, Inc., Gaithersburg, MD) (16). The sensitivities of these assays was 0.1 IU/L, and lower limit of quantitation was 0.2 IU/L for both LH and FSH. The intra- and interassay coefficients of variation were 4.3 and 11.0%, respectively, for serum LH and 5.2 and 12.0%, respectively, for serum FSH. Adult normal range for serum LH was 0.7–6.0 IU/L, and FSH was 0.5–7 IU/L. Serum T was measured by RIA after an extraction procedure with hexane and ethyl-acetate. The reagents for the RIA were obtained from ICN Pharmaceuticals, Inc. (Costa Mesa, CA). The lower limit of quantitation of serum T in the assay was 0.87 nmol/L (25 ng/dL) and the intra- and interassay coefficients of variation were 7.3 and 11.1, respectively, for the adult male range, which in our laboratory was 10.1–36.1 nmol/L (290–1042 ng/dL) (28). All samples from each subject were measured in the same assay. Complete blood counts, clinical chemistry, and lipid panels were measured by the hospital laboratory of each center. Semen analyses (semen volume, sperm concentration, and total sperm concentration) were performed according to the methods described in the WHO Laboratory Manual for Semen Analyses and Sperm-Cervical Mucus Interaction (25).
Statistical analyses
Descriptive statistics were calculated for each variable at each time point. Continuous variables were transformed, if necessary, to meet the requirements of ANOVA. Outcome variables including sperm concentration, serum hormone levels, clinical biochemistry, and scores from psychosexual diaries were analyzed using repeated measured ANOVA. Time in treatment (including baseline values obtained during the pretreatment period) was used as the repeated (within subject factor). Post test contrasts were used to compare subsequent values to baseline.
There was no significant difference in the baseline or response to treatment in any of the outcome variables between the two centers. The results, expressed as mean ± SEM, represented data from both centers.
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Results |
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The combination of Nal-Glu GnRH antagonist (10 ng/day sc) and TE
(100 mg/week im) induced a rapid and progressive suppression of sperm
concentration in all subjects during the induction phase (Fig. 2). The mean sperm concentration of all
subjects was suppressed to a very low level during the maintenance
phase with TE alone in all subjects. Upon withdrawal of TE injections,
sperm concentrations rose gradually, and by 12 weeks all subjects
reached their pretreatment levels. The semen volume was not
significantly changed during the study, and total sperm count
paralleled the decrease in the sperm concentration (defined as semen
volume x sperm concentration x 106 per
ejaculate).
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. By 10 weeks of the induction phase, 10
of the 15 subjects suppressed to azoospermia and another 4 to severe
oligozoospermia. In only 1 (subject 122) did the sperm concentration
fail to suppress to severe oligozoospermia. This subject had wheals at
the injection sites that lasted for 2 weeks after each injection. His
serum FSH and LH failed to suppress to nondetectable levels. He entered
recovery without going through the maintenance phase. During the
maintenance phase of 20 weeks, 12 out of 14 subjects reached
azoospermia, which was persistent in 8 subjects. Two subjects each had
a sperm concentration of 0.1 x 106/mL once during the
20 weeks of maintenance. Another 2 out of the 14 subjects remained
persistently severely oligozoospermic with sperm concentrations less
than 3 x 106/mL. Thus 13/14 subjects (93%) remained
suppressed to severe oligozoo- or azoospermia throughout the 20-week
maintenance phase with TE alone. A single (subject 105) escaped
suppression while on TE maintenance alone. His sperm concentration was
0.03 x 106/mL at the end of induction and reached
azoospermia at week 2 of maintenance, but by week 8 it rose to 1.6
x 106/mL. At weeks 10 and 12 his sperm concentration rose
to 11.8 and 22.3 x 106/mL, respectively. He entered
the recovery phase at this time point.
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Serum LH and FSH levels (Fig. 4)
showed a dramatic decrease with GnRH antagonist plus TE treatment. Mean
serum LH and FSH levels were suppressed to 0.4 ± 0.2 IU/L and
0.5 ± 0.2 IU/L, respectively (P < 0.0001 when
compared with pretreatment levels for both hormones), by week 4 of
induction and remained suppressed throughout the induction and
maintenance periods. In subject 122, whose sperm concentration failed
to decrease below 3 x 106/mL during induction, serum
LH and FSH levels were 0.3 and 0.5 IU/L, respectively, at week
12 of GnRH antagonist plus TE treatment. In subject 105 who escaped
during maintenance, serum LH and FSH levels were 1.0 and 0.2 IU/L,
respectively, at the end of induction. Both levels gradually rose, and
by the time his sperm concentration at week 10 was above 3 x
106/mL, his serum gonadotropins were 1.6 IU/L for LH and
2.1 IU/L for FSH. Mean serum T concentration for the group
was 15.0 ± 0.9 nmol/L at baseline (week 0) and remained within
the normal range in all subjects throughout induction, treatment, and
recovery phases (Fig. 4).
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As shown in Fig. 5, sexual
motivation (including average scores of sexual desire, sexual dreams,
anticipation of sex, and flirting) and sexual performance (including
average scores of intercourse, masturbation, orgasm, ejaculation, and
erection) remained unchanged throughout the study. Positive and
negative mood summary scores also remained unchanged throughout the
treatment and recovery phase.
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In all subjects, Nal-Glu GnRH antagonist administered sc in the abdominal area caused local irritation. The redness and itchiness lasted for 2–3 days, but in some subjects the wheal lasted up to 2 weeks. Despite the presence of local irritation, none of the 15 subjects withdrew from the study for this reason. There was no untoward effect reported with the TE injections. Complete blood counts, clinical chemistry, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides were not significantly changed throughout the treatment period.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We also demonstrated that when severe oligozoo- or azoospermia was achieved by hormonal treatment, this level of suppression of human spermatogenesis could be maintained by T alone. Serum FSH and LH levels showed that the only subject who failed suppression and the subject who had rebound of sperm counts during maintenance had gonadotropin levels above the lower limit detectability even at the end of induction. Failure to suppress or maintain severe oligozoospermia appeared to be related to the degree of suppression of both gonadotropins. Previous studies demonstrated that this dose of TE administered to normal men alone would suppress spermatogenesis to azoospermia in about 50% and to severe oligozoospermia in about 75% of non-Asian men. Thus, we showed for the first time that if gonadotropin secretion and spermatogenesis were severely suppressed, absent or very low sperm counts could be sustained with a dose of TE that on its own was suboptimal in achieving a similar degree of inhibition of spermatogenesis. In this study, the maintenance period with androgens alone was continued for 20 weeks. Although longer maintenance data are not yet available, it is logical to assume that spermatogenesis should remain suppressed as long as the gonadotropin secretion remains inhibited. The GnRH antagonist used in the present study frequently produced local skin irritability at the injection site. It is likely that if spermatogenesis were inhibited by low dose T (e.g. 100 mg/week im) plus a nonpeptide GnRH antagonist without local side effects, then low dose TE given alone would maintain suppression with fewer side effects than the supraphysiological dose of TE (200 mg/week im) used in prior studies (1, 2). Moreover, it is likely that other hormonal regimens, such as progestagens plus androgens or high dose androgens alone could induce marked inhibition of sperm production, which could be maintained by lower doses of the steroid hormone combinations or androgens alone.
In the non-human primate, Weinbauer et al. (31) administered GnRH antagonist (Cetrorelix, Asta Medica, Frankfurt am Main, Germany) daily for 18 weeks with or without T replacement (T buciclate 200 mg/animal). The results were compared with a third group who received cetrorelix for 7 weeks followed by T buciclate maintenance for 12 weeks. The azoospermia induced by the GnRH antagonist was not maintained when T buciclate was administered. During the reappearance of germ cells in the ejaculate, serum LH levels were suppressed, whereas serum inhibin levels rose, suggesting FSH escape.
The previous reported study of Behre et al. (32) used an induction regimen with GnRH antagonist (cetrorelix 10 mg/day sc for 5 days, then 2 mg/day for 12 weeks) plus 19 nor-T (19 NT) im (400 mg 19 NT followed by 200 mg 19 NT once every 3 weeks for 26 weeks) to induce severe suppression of spermatogenesis in all 6 normal male volunteers within 12 weeks. When the GnRH antagonist was withdrawn after 12 weeks, rebound of gonadotropins occurred, and significant amounts of spermatozoa reappeared in the ejaculate in 5 out of 6 subjects despite the continuation of 19 NT treatment. Their conclusion was that GnRH antagonist plus 19 NT led to azoospermia that could not be maintained by continued 19 NT injections. Their data were different from the current study in which only 1 out of 14 subjects escaped from gonadotropin suppression when GnRH antagonist treatment was withdrawn, and the subjects were continued on TE injections. The interval of 19 NT administration was 3 weeks, which could be insufficient to maintain the suppression of gonadotropins and spermatogenesis to very low levels observed during the androgen alone maintenance phase of the current study.
GnRH antagonist in the current formulation would not be a feasible agent for male contraceptive development because of its route of administration (daily sc), local skin irritation (wheals, itchiness, and discomfort), and high cost of production. Long-acting formulation of an GnRH antagonist as microsphere injections or gel implants might be developed. New nonpeptide GnRH analogs developed by molecular drug modeling methods would permit the development of orally active or long- acting products that might have the gonadotropin suppressive potency of the currently available GnRH antagonists but devoid of the local histamine-like effects. It should be noted that the dose of TE tested (100 mg/week im injections) produced no apparent adverse effects. The levels of serum T were unchanged from the observed pretreatment levels both during the induction as well as the maintenance phases. The serum T levels measured were obtained before the next injections, and higher serum T might be present during the first few days following each TE administration. However, this dose of TE did not induce similar side effects as reported with TE 200 mg/week in the multicenter contraceptive efficacy study (1, 2). Furthermore, serum hemoglobin, hematocrit, and high-density lipoprotein cholesterol levels were not significantly altered, and normal sexual function was maintained during both induction and maintenance. New long-acting injectable T preparations such as TE buciclate (33, 34) and T microspheres (35) or even T implants (36) might serve as acceptable maintenance regimens once almost complete suppression of spermatogenesis was attained by combination methods.
We conclude that this paradigm of complete gonadotropin suppression by GnRH antagonist or other gonadotropin suppressive agents followed by maintenance with a near physiological dose of T could be used in the development of new, long-acting, sustained release hormonal methods of male contraception.
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Acknowledgments |
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Footnotes |
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Received April 27, 1998.
Revised June 25, 1998.
Accepted July 6, 1998.
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References |
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