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,
From the * Department of Medicine,
Geriatric Research, Education and Clinical
Center, University of Washington School of Medicine, Seattle, Washington; the
Veterans Affairs Puget Sound Health Care
System; and the Department of Medicine,
Charles R Drew University, Los Angeles, California.
| Correspondence to: Dr Bradley D. Anawalt, VA Puget Sound S-111-CHF, 1660 S Columbian Way, Seattle, WA 98108 (e-mail: bradley.anawalt{at}med.va.gov). |
| Received for publication August 18, 2004; accepted for publication January 7, 2005. |
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Abstract |
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Key words: Contraception, gonadotropins, azoospermia, oligospermia, oligoazoospermia, free testosterone
It has long been recognized that progesterone and synthetic progestogens suppress spermatogenesis (Heller et al, 1958). Because the administration of progestogens alone suppresses endogenous testosterone secretion and results in iatrogenic hypogonadism, progestogens are not viable as single agents for male contraception. However, the combination of androgens plus progestogens may act additively to uniformly suppress spermatogenesis. The additive effect of the progestogen might allow a lower dosage of the androgen and result in less androgenic-induced weight gain or HDL suppression. Several androgen plus progestogen regimens have been studied as potential male contraceptive regimens (Meriggiola et al, 2003). The most extensively studied progestogens for male hormonal contraception include medroxyprogesterone acetate, cyproterone acetate, norethisterone acetate, desogestrel and its active metabolite etonogestrel, and levonorgestrel (LNG) (Anderson and Baird, 2002).
We have previously demonstrated that 6 months of T enanthate (100 mg intramuscularly [IM] weekly) plus LNG (125, 250, or 500 µg per os [PO] daily) induced oligoazoospermia (fewer than 3 x 106 spermatozoa/mL) in healthy American men significantly more than the same dosage of T enanthate alone (89%-94% vs 61%; P < .05) (Bebb et al, 1996; Anawalt et al, 1999). Although there were no significant differences in suppression of circulating gonadotropins or achievement of azoospermia or oligoazoospermia between the 3 regimens of T enanthate plus levonorgestrel, there was a dosage-dependent effect of LNG on weight gain and serum HDL suppression.
We hypothesized that intramuscular T enanthate plus a very low dosage of oral LNG would effectively suppress circulating gonadotropins and spermatogenesis without causing weight gain or HDL suppression. We therefore compared the effects of 6 months of T enanthate (100 mg IM weekly) plus LNG (31.25 or 62.5 µg PO daily) in healthy men.
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Materials and Methods |
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Sixty-six men were screened for the study. Eighteen of the 66 men were excluded from the study before entering the treatment phase. Ten men were excluded for medical reasons (8 men for low sperm counts, 1 man for abnormal liver function tests, and 1 man for newly diagnosed Klinefelter syndrome). Prior to the treatment phase of the study, 6 men were removed from the study because they did not keep their follow-up appointments, and 2 men opted to discontinue the study for personal reasons.
Experimental Design
After meeting the screening criteria, subjects were entered into a 3-month
control period. During this control period, monthly baseline hormone levels
and biweekly seminal fluid analyses were performed. At the end of the control
period, 48 subjects were assigned to 1 of 2 groups: 6 months of T+LNG 31 (T
enanthate [Schein Pharmaceuticals, Florham Park, NJ] 100 mg IM weekly plus LNG
31.25 µg PO daily; n = 24) or T+LNG 62 (T enanthate 100 mg IM weekly plus
LNG 62.5 µg PO daily; n = 24). To ensure unbiased balance between the 2
intervention groups, the subjects were allocated in a restricted randomization
using the minimization method (ie, "randomization with a balanced
design") with a random-number generator computer program
(Altman et al, 2001). A
statistician created the randomization list, which was then distributed to the
research coordinator and pharmacist. The allocation was concealed from the
subjects and investigators until the end of treatment. The LNG (Wyeth Ayerst,
Philadelphia, Pa) was formulated in identical capsules that ensured that the
dosage was concealed from the subjects and researchers. A research nurse or
one of the investigators administered all of the T injections. We recorded
weekly pill counts and injections. Subjects who missed more than 1 weekly
injection or more than 10% of pills in any month were counted as protocol
violations and were discontinued from the treatment phase. Following the
6-month treatment period, all subjects entered a recovery period that extended
until 2 consecutive sperm concentrations were within the individual's baseline
(pretreatment) range.
The University of Washington Human Subjects Review Committee and the Veterans Affairs Puget Sound Health Care System Research and Development Committee reviewed and approved our study. All subjects signed a consent form reviewing potential side effects before enrollment in the study.
Measurements
Physicians interviewed and examined all subjects monthly throughout the
study. Seminal fluid analysis was performed every 2 weeks on samples obtained
by masturbation after 48 hours of ejaculatory abstinence. Throughout the
study, monthly blood samples were obtained for measurement of serum total and
calculated free T, sex hormone binding globulin (SHBG), FSH, and LH levels.
During the treatment phase, blood samples were drawn immediately before the
administration of intramuscular T enanthate. During the treatment phase,
additional blood samples were drawn monthly immediately before and 1 hour
after ingestion of LNG to measure nadir and peak LNG levels. During control,
months 3 and 6 of treatment, and during recovery, we measured complete blood
counts, serum electrolytes, creatinine, and albumin and administered liver
function tests and a fasting lipid panel. The fasting lipid panel was
performed on serum obtained after a 12-hour fast. The lipid panel included
measurement of serum total, HDL, HDL2, HDL3, and
low-density lipoprotein (LDL) cholesterol levels and serum triglyceride
levels.
Hormone and Lipid Assays
We measured serum SHBG, total T, FSH, and LH levels by immunofluorometric
assay (Delfia, Wallac Inc, Turku, Finland). The lower limit of quantification
of SHBG was determined to be 0.2 nmol/L for SHBG; the intra-assay and
interassay coefficients of variation (CV) were 1.7% and 10.6% for midrange
pooled values, respectively. The lower limit of quantification of total T was
0.35 nmol/L; intra-assay and interassay coefficient of variation were 4.5% and
9.5% for midrange pools, respectively. The lower limit of quantification of
FSH was 0.016 IU/L; the intra-assay and interassay coefficient of variation
were 12% and 22.3%, respectively, for a low-range pooled value of 0.045 IU/L,
and these coefficients were 2.9% and 6.1% for a midrange pooled value of 0.96
IU/L. Free T was calculated based on serum total T, SHBG, and albumin levels
(Vermeulen et al, 1999). The
lower limit of quantification of LH was 0.019 IU/L; the intra-assay and
interassay coefficient of variation were 6.5% and 17.7% for a low-range pooled
LH value of 0.074 IU/L, and these coefficients were 3.2% and 12.5% for a
midrange pooled value of 1.15 IU/L. LNG levels were determined by
radioimmunoassay at the California Regional Primate Center (courtesy of Dr
Lisa Laughlin, University of California, Davis)
(Ahsan et al, 1988). Samples
from each participant were run in duplicate in the same assay to avoid
interassay variability. We determined the lower limit of quantification of
hormone assays by the first point discernible from zero on standard
curves.
Lipid analyses were performed on freshly prepared (never frozen) plasma samples that were processed within hours of collection. Total plasma cholesterol and triglycerides were measured enzymatically at the Northwest Lipid Research Clinic (Seattle, Wash) on the Roche Hitachi 917 (Roche Laboratories, Indianapolis, Ind). Cholesterol was measured by a Trinder-type method, and triglycerides were measured by an ultraviolet light method (Warnick, 1986). Total HDL and HDL2 cholesterol was measured directly after separation from plasma by precipitation with a modified dextran-sulfate technique (Warnick et al, 1982). HDL3 cholesterol and LDL cholesterol levels were calculated (Warnick et al, 1982).
Seminal Fluid Analysis
We determined sperm counts by Coulter counter (Coulter Electronics Inc,
Hialeah, Fla), and concentrations below 15 million/mL were confirmed by direct
determination using a hemocytometer
(Gordon et al, 1965;
Bremner et al, 1981). Sperm
motility assessment was performed according to the WHO laboratory manual for
the examination of human semen and sperm-cervical mucus interaction
(WHO, 1999). We defined
azoospermia, severe oligoazoospermia, and oligoazoospermia as 2 or more
consecutive sperm counts of zero, fewer than 1 million/mL, and fewer than 3
million/mL, respectively. We defined sperm recovery as the first of 3 normal
sperm counts (more than 20 million/mL) with at least 1 value greater than or
equal to the subject's mean baseline concentration.
Statistical Analysis
Our primary outcomes were comparing the effects of the 2 regimens on
effectiveness of spermatogenic suppression, weight gain, and HDL suppression.
Secondary outcomes included change in serum hormones, change in hematocrit,
and the incidence of gynecomastia or acne. The study was powered to detect a
significant difference between the 2 groups if 60% of 1 group and 90% of the
other became azoospermic or oligospermic. Comparisons between groups at the
end of control, treatment, and recovery were made with paired t
tests. Comparison within groups over time was analyzed by ANOVA with a Duncan
post hoc test. For the total cholesterol data where there were baseline
differences between the 2 groups, we performed a comparison by analysis of
covariance (ANCOVA). Two-sided P values of less than .05 were
considered significant. All results are expressed as mean values ±
SEM.
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Results |
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Response to Treatment
Sperm Counts—
By 4 weeks of therapy, sperm concentrations were suppressed significantly
in both groups (Figure 1).
There were no significant differences in overall rates or rapidity of onset of
azoospermia, severe oligoazoospermia, or oligoazoospermia between the T+LNG 31
and T+LNG 62 groups (Table 2).
There was no significant difference in the rate of recovery between the 2
groups. Sperm counts returned to baseline during the recovery period in 40 out
of 41 men. The 1 subject whose sperm counts did not return to baseline
suffered testicular trauma (unrelated to the study) during the recovery period
and underwent unilateral orchidectomy. His sperm concentration peaked at 40
million/mL during recovery compared with a pretreatment baseline range of
50-120 million/mL.
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Hormones— During treatment, serum total and calculated free T rose significantly in both groups while SHBG levels declined significantly (Figure 2). In both groups, serum FSH and LH levels were significantly suppressed by the end of the first month of treatment and remained suppressed throughout the treatment period (Figure 3). During treatment, serum LH levels were suppressed to or below the lower limit of quantification in the majority of subjects in both groups, but FSH levels were detectable in all but 5 subjects (2 in the T+LNG 31 group and 3 in the T+LNG 62 group) at the end of the treatment period. Serum total and calculated free T and serum FSH and LH levels were not significantly different between T+LNG 31 and 62 groups during control, treatment, or recovery (P = NS).
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Nadir and peak LNG levels were significantly higher in the T+LNG 62 group than the T+LNG 31 group at month 6 of treatment (T+LNG 62 vs T+LNG 31 nadir and peak at treatment month 6: 0.08 ± 0.02 and 0.25 ± 0.04 µg/L vs 0.06 ± 0.08 and 0.13 ± 0.14 µg/L; P < .05).
We compared men who became azoospermic vs those who did not during treatment with either regimen and found no significant differences in total and free T, SHBG, FSH, and LH levels at baseline, end of treatment, or percentage change from baseline.
Lipids— During treatment and recovery, there were no significant differences in lipid parameters between the T+LNG 31 and 62 groups. Total cholesterol declined significantly by 8%-9% during treatment in both groups (percentage decline month 6 of treatment vs control: 9.1% ± 2.6% and 8.4% ± 2.9%; P < .05 for T+LNG 31 and 62 respectively). More than half of the absolute decrease in total cholesterol was due to a decline in LDL cholesterol (Table 3); LDL declined by 6%-7% in both groups (percentage decline month 6 of treatment vs control: 6.9% ± 3.9% and 6.0% ± 4.1%; P < .05 for T+LNG 31 and P = NS for T+LNG 62). HDL cholesterol declined significantly by 12%-15% during treatment in both groups (percentage decline month 6 of treatment vs control: 12.0% ± 2.6% and 15.1% ± 3.0%; P < .05 for T+LNG 31 and 62). Most of the absolute decrease in HDL cholesterol was due to a decline in HDL3 (Table 3). Although HDL2 was unchanged in the T+LNG 31 group and tended to decline in the T+LNG 62 group (percentage decline month 6 of treatment vs control: 0.1% ± 8.9% and 13.6% ± 6.6%; P = NS for T+LNG 31 and P = .06 for T+LNG 62), HDL3 levels decreased significantly in both groups (percentage decline month 6 of treatment vs control: 12.7% ± 2.9% and 13.1% ± 2.7%; P < .05 for T+LNG 31 and T+LNG 62). Apoprotein A-1 levels declined significantly in both groups (percentage decline month 6 of treatment vs control: 11.0% ± 2.5% and 13.8% ± 2.5%; P < .05 for T+LNG 31 and T+LNG 62), but serum triglyceride levels were unchanged in both groups (percentage increase month 6 of treatment vs control: 7.3% ± 13.2% and 19.1% ± 11.6%; P = NS for T+LNG 31 and T+LNG 62). All lipid parameters normalized within 3 months during the recovery period.
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Hematological and Chemistry Profiles— Hematological and chemistry profiles including liver function tests did not change significantly from baseline during the treatment and recovery periods.
Weight, Testicular Size, Digital Rectal Prostate Exam, Gynecomastia, and Acne— Although subjects in the T+LNG 62 group gained a significant amount of weight during treatment (2.50 kg ± 0.77; P < .05), subjects in the T+LNG 31 group did not (0.25 ± 1.08 kg; P = NS). By the end of the recovery phase, mean weights were not significantly different from baseline for either group. Testicular size shrank significantly in both groups, but shrank more in the T+LNG 62 group (percentage decrease month 6 of treatment vs control: T+LNG 31; left testis 15.6% ± 4.4% and right testis 23.4% ± 3.0% vs T+LNG 62 left testis 29.0% ± 2.9% and right testis 32.1% ± 2.6%; P < .05 vs baseline and between groups). None of the subjects spontaneously commented on or complained about testicular shrinkage during the study.
We found no significant abnormalities in the digital rectal examination at baseline, the end of treatment, or control periods. There was no clear relationship between the study drugs and development of acne. Four subjects in the T+LNG 31 group, and 6 subjects in the T+LNG 62 group developed acne during the treatment phase. Three subjects in the T+LNG 31 and 5 subjects in the T+LNG 62 had mild baseline acne that resolved during the treatment phase. No subjects requested or received treatment for acne during the study. As previously noted, 1 subject discontinued early in the study due to very mild acne. No subjects complained of sleep disturbances during the study. No subjects developed symptomatic gynecomastia during the study; 1 subject in the T+LNG 62 group developed asymptomatic gynecomastia (defined as an increase of breast tissue diameter greater than 2 cm) that was detected by one of the investigators, but the subject had not noticed any abnormalities.
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Discussion |
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In the current study, we reduced the dosage of levonorgestrel to a dosage equal to or less than those used in common female oral combination contraceptives (Boonstra et al, 2000; Audet et al, 2001), but still induced oligoazoospermia (fewer than 3 million/mL) in 90%-95% of normal healthy young men. Our data showing spermatogenic suppression that is greater than the same dosage of T enanthate alone and equivalent to spermatogenic suppression with twice the dosage of T enanthate demonstrate the potent synergistic effect of intramuscular T plus oral LNG in suppressing spermatogenesis with very low dosages of oral LNG (31.25 or 62.5 µg of LNG daily) being equally effective as dosages more than 10-fold greater (125-500 µg of LNG daily).
Although there was no difference in spermatogenic suppression between the 2 groups, the T+LNG 62 group gained 2.5 kg (P < .05 compared with baseline) while the T+LNG 31 did not gain weight during the 6-month treatment period. This dose-dependent effect of oral LNG on weight gain in a LNG-T contraceptive regimen is consistent with our earlier findings (Anawalt et al, 1999). Most male hormonal contraceptive regimens have been associated with adverse metabolic effects on weight and lipid profiles (Anderson and Baird, 2002). Our findings showing that the combination of T plus very low dosage of LNG is as effective as T plus higher dosages of LNG while causing less weight gain may apply to other androgen-progestogen combinations. Our study highlights the importance of careful dose-finding studies of promising androgen-progestogen male contraceptive regimens to ensure the safest dosage while maintaining effective spermatogenic suppression.
Both intramuscular T enanthate plus 31.25 µg and 62.5 µg oral LNG regimens suppressed serum HDL cholesterol significantly by 12%-15% (P = NS between groups). Most of the suppression of serum HDL cholesterol was due to a decline in HDL3. Both serum HDL2 and HDL3 cholesterol levels are inversely associated with atherosclerotic disease, but HDL3 cholesterol may be particularly important for reverse cholesterol transport (Salter and Brindley, 1988; Stampfer et al, 1991). The potentially unfavorable suppression of serum HDL levels was at least partially offset by a decline in LDL cholesterol. Both dosages of oral daily LNG plus intramuscular T enanthate were otherwise well tolerated. No clinically significant hematological or biochemical abnormalities occurred during treatment. No subjects developed symptomatic sleep disturbance or sleep apnea. There were no adverse effects on prostate or skin, and only 1 subject developed mild, asymptomatic gynecomastia.
The route of administration of testosterone significantly affects the degree of spermatogenic suppression induced by T+LNG regimens. A study of a transdermal testosterone patch system plus a higher dosage of oral LNG (250-500 µg daily) yielded much lower rates of oligoazoospermia (44%) than our study (Buchter et al, 1999). It is likely that this difference in spermatogenic suppression is due to the greater amount of testosterone delivered by intramuscular T enanthate with higher peak and more sustained total and free T levels. Another male contraceptive study that included a comparison of intramuscular T or T patch plus LNG implants confirmed that intramuscular T+LNG more effectively induces azoospermia (93% vs 35%) and oligoazoospermia (100% vs 50%) compared with T patch plus LNG (Gonzalo et al, 2002). Finally, a study of a long-acting formulation of intramuscular T undecanoate plus oral LNG 250 µg daily caused oligoazoospermia in 14 out of 14 men (Kamischke et al, 2000). Thus, sustained high or high-normal levels of T achieved by intramuscular T esters such as T enanthate or T undecanoate are superior to T patch systems for spermatogenic suppression.
It is less clear that the route of administration of LNG has important effects on the degree of spermatogenic suppression achieved by T+LNG regimens although oral administration of LNG might cause more HDL suppression by a first-pass hepatic effect. A study of monthly intramuscular T undecanoate plus levonorgestrel implants (Sino-implant) at a dosage of 150 mg for 3 months yielded disappointing results with less than 50% (7/16) of the Chinese subjects becoming oligoazoospermic (Gao et al, 1999). There were no significant changes in serum lipid parameters including HDL cholesterol in the Sino-implant study. However, the study was very short and the dosage of intramuscular T undecanoate (250 mg monthly) was probably suboptimal. In a study by Gonzalo et al, T enanthate 100 mg IM weekly plus subcutaneous LNG (Norplant II) implants 300 mg for 6 months caused severe oligoazoospermia (less than 1 million sperm/mL) in 14 out of 14 men (Gonzalo et al, 2002). As with our results with intramuscular T enanthate plus very low dosage oral LNG, there was no weight gain, but there was approximately 12% suppression of serum HDL cholesterol in subjects administered intramuscular T enanthate plus Norplant II. The LNG levels (approximately 0.4 µg/L) were much higher in the study of men administered subcutaneous Norplant II than the LNG levels (peak approximately 0.13 µg/L and nadir approximately 0.06 µg/L) in the group of men receiving 31.25 µg of daily oral LNG in our study. In summary, the data from our studies and others suggest that there is a dosage-dependent effect of LNG on weight and to a lesser degree on HDL suppression, but there is also likely to be an important first-pass hepatic effect of oral LNG on HDL suppression. In our study, we have shown that this first-pass hepatic effect of HDL suppression occurs at very low dosages of oral LNG. It is possible that a lower dosage of LNG implant plus intramuscular testosterone ester could result in less HDL suppression (because of lower levels of intrahepatic LNG) while still effectively inducing uniform suppression of spermatogenesis and no weight gain.
There are several potential explanations for nonuniform suppression of spermatogenesis in our study. In 1 study of men administered transdermal T by patch plus oral LNG, men with higher baseline T and SHBG levels and higher sperm counts appeared to be less likely to develop oligoazoospermia (Buchter et al, 1999). In another study of men administered intramuscular T undecanoate plus LNG implant (Sino-implant), men who suppressed to severe oligoazoospermia had higher baseline LH levels and lower FSH levels than nonresponders (Liu et al, 2004). However, we did not find any differences in total or calculated free T, SHBG, FSH, or LH at baseline or treatment between those men who suppressed to azoospermia or oligoazoospermia and those who did not. One likely explanation of nonuniform achievement of azoospermia in our study of intramuscular T enanthate plus oral LNG is inadequate suppression of serum FSH (McLachlan et al, 2004). While treatment serum LH levels were suppressed to or below the lower limit of quantification in the majority of subjects, treatment FSH levels were detectable in all but 5 subjects.
Several studies have demonstrated the synergistic effects of androgens plus progestogens for the suppression of circulating gonadotropins and spermatogenesis. Many androgen-progestogen regimens have been shown to achieve very high rates of severe oligoazoospermia or azoospermia in small, short trials, and these combination regimens could provide safe, effective, and reversible male hormonal contraception. These regimens include the combination of subcutaneous T pellets plus either depot medroxyprogesterone, depot etonogestrel, or oral desogestrel or the combinations of intramuscular T undecanoate plus oral cyproterone acetate or norethindrone (oral or injectable) (Anderson et al, 2002a,b; Kamischke et al, 2002; Meriggiola et al, 2003b; Turner et al, 2003). Testosterone enanthate, the injectable T formulation used in our study, is an unattractive androgen formulation because it requires weekly injections. However, injectable T undecanoate, a long-acting T ester formulation that was not available in the United States when we initiated our study, may be injected intramuscularly at intervals as long as every 6-12 weeks and is thus convenient enough to be feasible in an androgen-based male hormonal contraceptive. Long-acting injectable formulations of an androgen plus a progestogen are attractive first candidates for a male hormonal contraceptive in part because these formulations are more likely to ensure greater compliance and greater contraceptive efficacy. The data from our study and the previous study of Norplant plus T enanthate suggest that a long-acting T formulation such as subcutaneous T pellets or intramuscular T undecanoate plus a lower dosage of LNG implant (eg, 150 mg q 6 months) might provide safe and effective contraception.
Although long-acting depot formulations of T plus progestogens appear to be the most likely male hormonal contraceptive regimens to be available soon, depot implantable formulations such as T pellets, Norplant II, or Sino-implant require a trained operator to implant. Therefore, regimens that could be self-administered or administered without special training will also be desirable. Like the combinations of long-acting intramuscular T undecanoate plus oral desogestrel, norethindrone, or cyproterone acetate, long-acting intramuscular T undecanoate plus very low dosage oral LNG appears to be an attractive contraceptive option that could be easily self-administered.
Although androgen-progestogen combinations show promise as safe, effective, and reversible contraceptive regimens, the only androgen-progestogen combination to be studied in a male contraceptive efficacy trial is implantable, long-acting T pellets plus depot medroxyprogesterone. This combination has recently been shown to provide safe and effective short-term contraception but is associated with weight gain (Turner et al, 2003). Women currently have many hormonal contraceptive options that offer them freedom of choice, convenience, and alternative when 1 option causes intolerable side effects. The time has come for men to have a similar broad range of hormonal contraceptive choices. Large, long-term clinical contraceptive efficacy trials should be conducted with a variety of androgen-progestogen combinations including long-acting T formulations such as depot T pellets or intramuscular T undecanoate plus depot LNG or very low dosage oral LNG.
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Acknowledgments |
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Footnotes |
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References |
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|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Altman DG, Schulz KF, Moher D, Egger M, Davidoff F, Elbourne D,
Gøtzsche PC, Lang T. The revised CONSORT statement for reporting
randomized trials: explanation and elaboration. Ann Intern
Med. 2001;134: 663
-694.
Anawalt BD, Bebb RA, Bremner WJ, Matsumoto AM. A lower dosage
levonorgestrel and testosterone combination effectively suppresses
spermatogenesis and circulating gonadotropin levels with fewer metabolic
effects than higher dosage combinations. J Androl. 1999; 20: 407
-414.
Anderson RA, Baird DT. Male contraception. Endocrine
Rev. 2002;23: 735
-762.
Anderson RA, Kinniburgh D, Baird DT. Suppression of spermatogenesis
by etonogestrel implants with depot testosterone: potential for long-acting
contraception. J Clin Endocrinol Metab. 2002a; 87: 3640
-3649.
Anderson RA, Van Der Spuy ZM, Dada OA, Tregoning SK, Zinn PM,
Adenjii OA, Fakoya TA, Smith KB, Baird DT. Investigation of hormonal male
contraception in African men: suppression of spermatogenesis by oral
desogestrel with depot testosterone. Hum Reprod. 2002b; 17: 2869
-2877.
Audet MC, Moreau M, Kotun WD, Waldbaum AS, Shangold G, Fisher AC,
Creasy GW. Evaluation of contraceptive efficacy and cycle control of a
transdermal contraceptive patch vs an oral contraceptive.
JAMA. 2001;285: 2347
-2354.
Bebb RA, Anawalt BD, Christensen RB, Paulsen CA, Bremner WJ, Matsumoto AM. Combined administration of levonorgestrel and testosterone induces more rapid and effective suppression of spermatogenesis than testosterone alone: a promising male contraceptive approach. J Clin Endocrinol Metab. 1996;81: 757 -762.[Abstract]
Boonstra H, Duran V, Northington Gamble V, Blumenthal P, Dominguez L, Pies C. The "Boom or Bust Phenomenon": the hopes, dreams and broken promises of the contraceptive revolution. Contraception. 2000; 61: 9 -25.[CrossRef][Medline]
Bremner WJ, Matsumoto AM, Sussman AM, Paulsen CA. Follicle-stimulating hormone and human spermatogenesis. J Clin Invest. 1981;68: 1044 -1052.
Buchter D, von Eckardstein S, von Eckardstein A, Kamischke A,
Simoni M, Behre H, Nieschlag E. Clinical trial of transdermal testosterone and
oral levonorgestrel for male contraception. J Clin Endocrinol
Metab. 1999;84: 1244
-1249.
Gao E, Lin C, Gui Y, Li L, He C. Inhibiting effects of Sino-implant plus testosterone undecanoate on spermatogenesis in Chinese men. Reprod Contracep. 1999; 10: 98 -105.
Gonzalo IT, Swerdloff RS, Nelson AL, Clevenger B, Garcia R, Berman
N, Wang C. Levonorgestrel implants (Norplant II) for male contraception
clinical trials: combination with transdermal and injectable testosterone.
J Clin Endocrinol Metab. 2002; 87: 3562
-3572.
Gordon DL, Moore DL, Thorslund T, Paulsen CA. The determination of size and concentration of human sperm with an electronic particle counter. J Lab Clin Med. 1965; 65: 506 -512.[Medline]
Gu Y-Q, Wang X-H, Xu D, Peng L, Cheng L-F, Huang M-K, Huang Z-J,
Zhang G-Y. A multicenter contraceptive efficacy study of injectable
testosterone undecanoate in healthy Chinese men. J Clin Endocrinol
Metab. 2003;88: 562
-568.
Heller CG, Laidlaw WM, Harvey HT, Nelson WO. Effects of progestational compounds on the reproductive processes of the human male. Ann NY Acad Sci. 1958; 71: 649 -665.
Kamischke A, Heuermann T, Krüger K, von Eckardstein S,
Schellschmidt I, Rübig A, Nieschlag E. An effective hormonal male
contraceptive using testosterone undecanoate with oral or injectable
norethisterone preparations. J Clin Endocrinol Metab. 2002; 87: 530
-539.
Kamischke A, Plöger D, Venherm S, von Eckardstein S, von Eckardstein A, Nieschlag E. Im testosterone undecanoate with or without oral levonorgestrel: a randomized placebo-controlled feasibility study for male contraception. Clin Endocrinol. 2000; 53: 43 -52.[CrossRef][Medline]
Liu ST, Gui YL, Lin CH, He CH. Hormonal contraception in Chinese men: variations in suppression of spermatogenesis with injectable testosterone undecanoate and levonorgestrel implants. Asian J Androl. 2004;6: 41 -46.[Medline]
McLachlan RI, Robertson DM, Pruysers E, Ugoni A, Matsumoto AM,
Anawalt BD, Bremner WJ, Meriggiola C. Relationship between serum gonadotropins
and spermatogenic suppression in men undergoing steroidal contraceptive
treatment. J Clin Endocrinol Metab. 2004; 89: 142
-149.
Meriggiola MC, Farley TMM, Mbizvo MT. A review of
androgen-progestin regimens for male contraception. J
Androl. 2003a;24: 466
-482.
Meriggiola MC, Costantino A, Cerpolini S, et al. Testosterone
undecanoate maintains spermatogenic suppression induced by cyproterone acetate
plus testosterone undecanoate in normal men. J Clin Endocrinol
Metab. 2003b;88: 5818
-5826.
Salter AM, Brindley DN. The biochemistry of lipoproteins. J Inherit Metab Dis. 1988; 11(suppl 1): 4 -17.
Stampfer MJ, Sacks FM, Salvini S, Willett WC, Hennekens CH. A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction. N Engl J Med. 1991; 325: 373 -381.[Abstract]
Turner L, Conway AJ, Jimenez M, Liu PY, Forbes E, McLachlan RI,
Handelsman DJ. Contraceptive efficacy of a depot progestin and androgen
combination in men. J Clin Endocrinol Metab. 2003; 88: 4659
-4667.
Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of
simple methods for the estimation of free testosterone in serum. J
Clin Endocrinol Metab. 1999; 84: 3666
-3672.
Warnick GR. Enzymatic methods for the quantification of lipoprotein lipids. Methods Enzymol. 1986; 129: 101 -123.[Medline]
Warnick GR, Benderson J, Albers JJ. Dextran sulfate Mg2+
precipitation procedure for quantification of high-density lipoprotein
cholesterol. Clin Chem. 1982; 28: 1379
-1388.
World Health Organization. WHO Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction. 4th ed. Cambridge, United Kingdom: Cambridge University Press; 1999 .
World Health Organization Task Force on Methods for the Regulation of Male Fertility. Contraceptive efficacy of testosterone-induced azoospermia in normal men. Lancet. 1990; 336: 955 -959.[CrossRef][Medline]
World Health Organization Task Force on Methods for the Regulation of Male Fertility. Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men. Fertil Steril. 1996; 65: 821 -829.[Medline]
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