7Alpha-methyl-19-nortestosterone maintains sexual behavior and mood in hypogonadal men.

The synthetic steroid 7alpha-methyl-19-nortestosterone (MENT) is a potent androgen that is resistant to 5alpha-reductase. It thus has decreased activity at the prostate and may have advantages over testosterone-based regimens in long term treatment or as part of a male contraceptive. Administration to eugonadal men results in suppression of gonadotropins, but its ability to support androgen-dependent behavior has not been investigated. For sustained release administration, MENT acetate was used, because its diffusion characteristics were more suitable for use in implants. However, upon release the acetate is rapidly hydrolyzed, and MENT is the biologically active moiety in circulation. We studied the effects of MENT on sexual interest and activity, spontaneous erection, and mood states in comparison with testosterone enanthate (TE) in 20 Caucasian and Chinese hypogonadal men recruited in Edinburgh and Hong Kong (n = 10 in each center). Outcomes were measured using a combination of daily diaries, semistructured interviews, and questionnaires. Nocturnal penile tumescence (NPT) was also recorded in the Edinburgh group. After withdrawal of androgen replacement treatment (wash-out phase) for a minimum of 6 weeks, subjects were randomized to two groups in a cross-over design. Drug treatment regimens were of 6-week duration and consisted of two implants, each containing 115 mg MENT acetate, inserted s.c. into the upper arm and removed after 6 weeks and two injections of TE (200 mg, i.m.) 3 weeks apart. MENT treatment resulted in stable plasma MENT concentrations of 1.4 +/- 0.1 nmol/L after 3 weeks and 1.3 +/- 0.1 nmol/L after 6 weeks (mean +/- SEM; all men). Nadir testosterone concentrations were 3.6 +/- 0.6 nmol/L at the end of the wash-out phase and 9.4 +/- 0.6 nmol/L 3 weeks after each injection. There were no differences in hormone concentrations between centers. There were no adverse toxicological effects. There were only minor differences between the two treatments. Both MENT and TE treatment resulted in significant increases in sexual interest and activity, spontaneous erection (both by self-report and NPT measurement), and increases in positive moods, with decreases in negative moods in the Edinburgh group. In the Hong Kong group, both treatments increased waking erection, with a trend toward increased sexual interest and activity. Mood states appeared to be less affected during the wash-out phase than in Edinburgh men and showed no significant response to either treatment. These results demonstrate that MENT has similar effects on sexual activity and mood states as testosterone in hypogonadal men. As NPT is a physiological androgen-dependant outcome, these data provide further evidence for the androgenicity of MENT. The lack of detected effect of either androgen in Hong Kong men other than on waking erection illustrates the importance of the cultural context of symptomatology and its measurement. The appropriate dose of MENT remains to be determined, but these results support its development as a potential androgen replacement therapy.     

A clinical trial of 7 alpha-methyl-19-nortestosterone implants for possible use as a long-acting contraceptive for men

Several preparations of testosterone and its esters are being investigated alone or in combination with other gonadotropin-suppressing agents as possible antifertility agents for men. We studied the effectiveness of 7 alpha-methyl-19-nortestosterone (MENT) as an antispermatogenic agent in men. MENT has been shown to be more potent than testosterone and to be resistant to 5 alpha-reduction. For sustained delivery of MENT, we used a system consisting of ethylene vinyl acetate implants containing MENT acetate (Ac), administered subdermally. Thirty-five normal volunteers were recruited in 3 clinics and were randomly assigned to 1 of 3 doses: 1 (12 men), 2 (11 men), or 4 (12 men) MENT Ac implants. The initial average in vitro release rate of MENT Ac from each implant was approximately 400 micro g/day. Implants were inserted subdermally in the medial aspect of the upper arm under local anesthesia. The duration of treatment was initially designed to be 6 months. However, in 2 clinics the duration of treatment was extended to 9 months for the 2-implant group and to 12 months for the 4-implant group. Dose-related increases in serum MENT levels and decreases in testosterone, LH, and FSH levels were observed. Effects on sperm counts were also dose related. None of the subjects in the 1-implant group exhibited oligozoospermia (sperm count, <3 million/ml). Four subjects in the 2-implant group became oligozoospermic, 2 of whom reached azoospermia. Eight subjects in the 4-implant group reached azoospermia, with 1 exhibiting oligozoospermia, whereas 2 were nonresponders. Side effects generally seen with androgen administration, such as increases in erythrocyte count, hematocrit, and hemoglobin and a decrease in SHBG, were also seen in this study and were reversible. Changes in lipid parameters were moderate and transient. Liver enzymes showed small changes. This study demonstrates that MENT Ac, when administered in a sustained release fashion via subdermal implants, can inhibit spermatogenesis over a prolonged period after a single administration and has the potential to be used as a male contraceptive.     

In vitro metabolism of 7 alpha-methyl-19-nortestosterone by rat liver, prostate, and epididymis

The in vitro metabolism of 7 alpha-methyl-19-nortestosterone (7 alpha-methyl-3-oxo-estr-4-ene-17 beta-ol) was investigated in male rat liver, ventral prostate, and epididymis. Three metabolites were recovered from the liver incubation: 7 alpha-methyl-estr-4-ene-3,17-dione, 7 alpha-methyl-5 beta-estrane-3,17 beta-diol, and 7 alpha-methyl-3-oxo-estr-4-ene-16,17 beta-diol, whereas prostate and epididymis did not perceptibly metabolize the steroid. The kinetics of metabolism in liver differed significantly from those of testosterone or 19-nortestosterone. About 85% of the 7 alpha-methyl-19-nortestosterone added was recovered at the end of 30 min of incubation. We conclude that the androgenic potency of 7-alpha-methyl-19-nortestosterone is not dependent on its further conversion to 5 alpha-dihydro-metabolites.     

Effects of androgen on sexual behavior in hypogonadal men.

Despite the widespread use of androgen in the treatment of hypogonadal men, its efficacy in restoring sexual behavior to hypogonadal patients has not been established in appropriately controlled behavioral studies. Accordingly, testosterone enanthate or vehicle was injected once every 4 weeks im in a double blind experiment. The subjects were six adult males, aged 32-65 yr, two with gonadal failure and four with secondary hypogonadism. Two doses of testosterone (100 and 400 mg) were administered for approximately 5 months, with the treatments varied at random within and among subjects. Details of sexual activity and experience were followed by the use of daily logs. Frequencies of erections, including nocturnal erections and coitus, showed significant dose-related responses to androgen treatment which closely followed the fluctuations in the circulating testosterone level. As indicated by the Profile of Mood States test, behavioral responses did not appear to be mediated by changes in mood. We concluded that the stimulatory effects of testosterone on sexual activity are rapid, reliable, and not due to a placebo effect. To maintain plasma testosterone and adequate sexual function within normal levels, even high doses of testosterone enanthate should be given no less frequency than once every 3 weeks.     

Vascular reactivity in hypogonadal men is reduced by androgen substitution

The effect of testosterone (T) substitution therapy on blood vessel functions in relation to cardiovascular disease has not been fully elucidated. In 36 newly diagnosed nonsmoking hypogonadal men (37.5 +/- 12.7 yr) endothelium-dependent flow-mediated vasodilatation (FMD; decreased in atherosclerosis) of the brachial artery was assessed before treatment and after 3 months of T substitution therapy (250 mg testosterone enanthate im every 2 wk in 19 men, human chorionic gonadotropin sc twice per week in 17 men). Twenty nonsmoking controls matched for age, low-density lipoprotein cholesterol (LDL-C), body height, and baseline diameter of the artery were selected for repeated measurements from a larger eugonadal control group (n = 113). In hypogonadal men, basal FMD (17.9 +/- 4.5%) was significantly higher than in the large (11.9 +/- 6.4%) and matched control (11.8 +/- 7.1%, both P < 0.001) groups. Grouped multiple linear regression analysis revealed a significant negative association of T levels with FMD within the hypogonadal range, but no significant association was seen within the eugonadal range. During substitution therapy, T levels increased from 5.8 +/- 2.3 to 17.2 +/- 5.1 nmol/liter and FMD decreased significantly to 8.6 +/- 3.1% (P < 0.001, analysis for covariance for repeated measurements including matched controls). LDL-C and advanced age contributed significantly to decrease FMD (P = 0.01, P = 0.04, respectively). Because T substitution adversely affects this important predictor of atherosclerosis, other contributing factors (such as smoking, high blood glucose, and LDL-C) should be eliminated or strictly controlled during treatment of hypogonadal men.     

The biological activity of 7 alpha-methyl-19-nortestosterone is not amplified in male reproductive tract as is that of testosterone.

Based on the premise that testosterone, but not 7 alpha-methyl-androgens, is reduced at the 5 alpha-position in the prostate and seminal vesicles, the differential bioactivities of these androgens were investigated in castrated rats. The ability of 7 alpha-methyl-19-nortestosterone acetate (MENT) to increase the weights of ventral prostate and seminal vesicles of castrated rats was four times higher than that of testosterone, while its effect on the weights of bulbocavernosus plus levator ani muscles (muscle), was 10 times that of testosterone. MENT was also approximately 12 times more potent than testosterone in the suppression of serum gonadotropin levels. A dose of testosterone that maintains serum gonadotropin levels and muscle mass also maintains prostate and seminal vesicle weights in castrated rats. By contrast, a dose of MENT that maintains muscle and gonadotropins does not maintain prostate and seminal vesicles. The action of other 7 alpha-methylated androgens were similar to that of MENT. The importance of 5 alpha reductase in the differential action of testosterone and MENT on prostate was confirmed by using a 5 alpha-reductase inhibitor. The activity of testosterone was significantly suppressed in the ventral prostate and seminal vesicles but not on muscle by the 5 alpha-reductase inhibitor (N,N-diethyl-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta-carboxamide). The enzyme inhibitor, however, had no influence on the activity of MENT on either tissue. In contrast, cyproterone acetate, an antiandrogen that competitively binds to the androgen receptors, inhibited the action of MENT and of testosterone on the prostate as well as on the muscle. In conclusion, these observations show that 7 alpha-methylated androgens can maintain muscle mass and normal gonadotropin levels in androgen deficient rats without hyperstimulating the prostate. These findings suggest that 7 alpha-methylated androgens may offer some health benefits to men who require androgen treatment.     

Effect of aromatizable and unaromatizable androgen replacement in hypogonadal men on GH responsiveness

Objectives  Although studies have clearly demonstrated that oestrogen replacement affects GH responsiveness by causing relative GH resistance, the effect of androgen replacement is unknown. Circumstantial evidence only suggests that androgen replacement may increase GH sensitivity and/or responsiveness. To examine the impact of androgens on GH responsiveness, hypogonadal men underwent the IGF-1 generation test in the unreplaced state, replaced with testosterone (T) and also replaced with dihydrotestosterone (DHT), its nonaromatizable metabolite.
Design and patients  Twelve hypogonadal men with a normal GH axis were recruited. Each subject in random order had 4 weeks off T (NoRx), 4 weeks on T gel (TG) and 4 weeks on DHT gel (DHTG) applied daily, with 1 week washout between each preparation. An IGF-1 generation test using a subcutaneous injection of 7 mg of GH was performed at the end of each of these 4-week phases.
Measurements  Serum GHBP, total and free IGF-1, IGFBP-3 and acid-labile subunit (ALS) levels were measured at baseline and 24 h (peak) after GH administration.
Results  Despite a decrease in GHBP during the TG and DHTG phases, there were no observed differences in baseline, peak or increment (peak – baseline) total or free IGF-1 between the NoRx, TG or DHTG phases.
Conclusions  There is no evidence of fluctuation in GH responsiveness in hypogonadal men, untreated or replaced with T or DHT alone. This implies that the increased level of oestradiol as a consequence of T replacement in hypogonadal men does not impact significantly on GH responsiveness, nor is there evidence of an androgen effect with elevated DHT levels as a consequence of either T or DHT replacement.     

Sublingual administration of testosterone-hydroxypropyl-beta-cyclodextrin inclusion complex simulates episodic androgen release in hypogonadal men

In search of a more physiological testosterone (T) replacement therapy for hypogonadal states, we evaluated an inclusion complex of T with 2-hydroxypropyl-beta-cyclodextrin (HPBCD). HPBCD enhances T solubility and absorption, but HPBCD is not absorbed. Five hypogonadal men (mean age, 32.4 +/- 2.3 yr) with serum T levels below the normal range were treated in two separate experimental phases with either a 2.5- or 5.0-mg tablet of sublingual (SL) T-HPBCD three times daily for 7 days. Acute pharmacodynamic changes were monitored at baseline and 10, 20, and 40 min and 1, 1.5, 2, 3, 4, and 8 h after administration of the first dose. At the 5-mg dose, a maximal concentration (Cmax) of T (85.4 +/- 11.0 nmol/L) was achieved in 20 min (63 +/- 24-fold increase), followed by a rapid decline to below the normal range (less than 12 nmol/L) at 2 h, with an estimated half-life of decline of 1.87 +/- 0.19 h. The dihydrotestosterone (DHT) Cmax (4.1 +/- 0.5 nmol/L) occurred at 32 +/- 5 min (8.9 +/- 1.3-fold increase) and declined to below the normal range (less than 1.2 nmol/L) after 3 h. The integrated 8 h value for the ratio of T/DHT was 10.0 +/- 1.1, which fell within the normal range. The increment in androstenedione paralleled that in T, and the Cmax (6.8 +/- 0.9 nmol/L) was reached in 24 +/- 4 min (2.3 +/- 0.6-fold increase). Compared to baseline, the Cmax was significantly greater for T (P less than 0.005), DHT (P less than 0.0005), and androstenedione (P less than 0.005). Both estradiol (E2) and estrone (E1) remained in the normal range (less than 200 pmol/L), although the Cmax for E1 was significantly greater than baseline (P less than 0.05). Serum LH levels were suppressed (19.0 +/- 2.6%) at 2 h (P less than 0.05), without a significant change in FSH. During 7 days of treatment, there was no cumulative increase in basal T, DHT, and E2 levels or further decline in LH or FSH levels. There was no change in sex hormone-binding globulin levels. Similar results were observed with the 2.5-mg dose, suggesting that the capacity of SL absorption may be limited to a certain dose of T-HPBCD. The fluctuations in T after SL administration of T-HPBCD resemble endogenous episodic secretion. We conclude that T, complexed with HPBCD, is rapidly absorbed by the SL route and quickly metabolized without sustained elevations of DHT or E2.     

Evidence for the presence of endogenous 19-nortestosterone in the cow peripartum and in the neonatal calf.

Urine samples were collected from five Brown Swiss cows during the 18 days prior to and 11 days after parturition and were analysed for 19-nortestosterone using an enzyme immunoassay. Nortestosterone concentrations ranged from 70 to 130 nmol/l in all samples taken before parturition. The levels declined within two days, and 11 days post partum no nortestosterone was detectable. In urine from newborn calves, maximal nortestosterone concentrations were determined during the first day of life (10.9-120 nmol/l), declining below 7.3 nmol/l until day 3 in most animals and remaining below the detection limit (less than 3.6 nmol/l) after day 8 in all animals. There was no obvious difference between cows carrying a male or a female calf nor between newborn male or female calves. Using the combined methods high performance liquid chromatography/enzyme immunoassay and high performance liquid chromatography/gas chromatography-mass spectrometry, the immunoreactivity in urine was identified to be 19-nortestosterone-17 alpha. Although there is unequivocal evidence for the endogenous production of nortestosterone in pregnant cows, its function for placenta physiology, pregnancy anabolism and parturition remains unclear. However, new threshold levels for residue control of nortestosterone need to be fixed in accordance with the endocrine status of the animals.     

Experience with 19-nortestosterone in the therapy of systemic lupus erythematosus: worsened disease after treatment with 19-nortestosterone in men and lack of improvement in women.

Three men and 4 women with systemic lupus erythematosus (SLE) received 100 mg of 19-nortestosterone decanoate in weekly intramuscular injections over a period of 3 to 24 months. During therapy in the men plasma luteotrophic hormone and free testosterone levels decreased while estrogen levels increased. Anti-DNA antibodies also increased for unknown reasons. Serological changes in two men coincided with an overall increase in the clinical activity of SLE and the appearance of new onset Raynaud's phenomenon and pleuropericardial disease. In contrast, women treated with 19-nortestosterone showed clinical stability despite the persistence of high titer antibodies to DNA, and were able to continue therapy for as long as 16 months in one case. These data indicate that men and women with SLE respond differently to synthetic androgen therapy. Additionally, dissociation of clinical signs and symptoms from serological variables seems possible.     

Binding of 7 alpha, 17 alpha-dimethyl-19-nortestosterone (mibolerone) to androgen and progesterone receptors in human and animal tissues

In rat uterus and prostate, 7 alpha, 17 alpha-dimethyl-19-nortestosterone (DMNT) binds to the androgen receptor specifically and with high affinity. However, this steroid does not bind to glucocorticoid receptors, since it does not displace binding of [3H]triamcinolone acetonide in calf thymus cytosol. In calf uterine and human breast tumor cytosols DMNT binds to the androgen and progesterone receptors, since binding of [3H] DMNT is displaced by unlabeled 16 alpha-ethyl-21-hydroxy-19-nor-4-pregnene-3, 20-dione triamcinolone acetonide, and 5 alpha-dihydrotestosterone (DHT). Conversely, binding of [3H]16 alpha-ethyl-21-hydroxy-19-nor-4-pregnene-3,20-dione is effectively competed for by unlabeled DMNT but not by DHT. The observed differences in binding of [3H]DMNT to rat and calf uterine cytosols suggest the species specificity of progesterone receptors. Unlike DHT, DMNT has no appreciable binding to human sex-steroid binding globulin. These findings suggest DMNT as a suitable ligand for measurement and characterization of androgen receptors in rat and human prostate.     

Influence of various modes of androgen substitution on serum lipids and lipoproteins in hypogonadal men.

We investigated whether the androgen type or application mode or testosterone (T) serum levels influence serum lipids and lipoprotein levels differentially in 55 hypogonadal men randomly assigned to the following treatment groups: mesterolone 100 mg orally daily ([MES] n = 12), testosterone undecanoate 160 mg orally daily ([TU] n = 13), testosterone enanthate 250 mg intramuscularly every 21 days ([TE] n = 15), or a single subcutaneous implantation of crystalline T 1,200 mg ([TPEL] n = 15). The dosages were based on standard treatment regimens. Previous androgen substitution was suspended for at least 3 months. Only metabolically healthy men with serum T less than 3.6 nmol/L and total cholesterol (TC) and triglyceride (TG) less than 200 mg/dL were included. After a screening period of 2 weeks, the study medication was taken from days 0 to 189, with follow-up visits on days 246 and 300. Before substitution, all men were clearly hypogonadal, with mean serum T less than 3 nmol/L in all groups. Androgen substitution led to no significant increase of serum T in the MES group, subnormal T in the TU group (5.7 +/- 0.3 nmol/L), normal T in the TE group (13.5 +/- 0.7 nmol/L), and high-normal T in the TPEL group (23.2 +/- 1.1 nmol/L). 5 alpha-Dihydrotestosterone significantly increased in all treatment groups compared with baseline. Compared with presubstitution levels, a significant increase of TC was observed in all treatment groups (TU, 14.4% +/- 3.0%; MES, 18.8% +/- 2.5%; TE, 20.4% +/- 3.0%; TPEL, 20.2% +/- 2.6%). Low-density lipoprotein cholesterol (LDL-C) also increased significantly by 34.3% +/- 5.5% (TU), 46.4% +/- 4.1% (MES), 65.2% +/- 5.7% (TE), and 47.5% +/- 4.3% (TPEL). High-density lipoprotein cholesterol (HDL-C) showed a significant decrease by -30.9% +/- 2.8% (TU), -34.9% +/- 2.5% (MES), -35.7% +/- 2.6% (TE), and -32.5% +/- 3.5% (TPEL). Serum TG significantly increased by 37.3% +/- 11.3% (TU), 46.4% +/- 10.3% (MES), 29.4% +/- 6.5% (TE), and 22.9% +/- 6.7% (TPEL). TU caused a smaller increase of TC than TE and TPEL, whereas the parenteral treatment modes showed a lower increase of TG. There was no correlation between serum T and lipid concentrations. Despite the return of serum T to pretreatment levels, serum lipid and lipoprotein levels did not return to baseline during follow-up evaluation. In summary, androgen substitution in hypogonadal men increases TC, LDL-C, and TG and decreases HDL-C independently of the androgen type and application made and the serum androgen levels achieved. Due to the extended washout period for previous androgen medication and the exclusion of men with preexisting hyperlipidemia, this investigation demonstrates more clearly than previous studies the impact of androgen effects on serum lipids and lipoproteins. It is concluded that preexisting low serum androgens induce a "male-type" serum lipid profile, and increasing serum androgens further within the male normal range does not exert any additional effects. The threshold appears to be above the normal female androgen serum levels and far below the lower limit of normal serum T levels in adult men. These findings may have considerable implications for the use of androgens as a male contraceptive and for androgen therapy in elderly men.     

The relationship of androgen to the thyrotropin and prolactin responses to thyrotropin-releasing hormone in hypogonadal and normal men

Fluoxymesterone, an androgen not converted to estrogen, caused a significant decrease in the TSH response to TRH in 11 men with primary hypogonadism [maximum change in TSH: before treatment, 11.3 +/- microU/ml (mean +/- SE); 8.9 +/- 1.0 after 2 weeks (P less than 0.001); 8.2 +/- 1.1 after 6 weeks (P less than 0.01)]. There was a significant fall in serum T4-binding globulin (TBG) (measured directly by RIA) without a change in the free T4 or free T3 index. Fluoxymesterone had no effect on the PRL response to TRH in hypogonadal men. The results suggest that 1) androgen per se is at least partly responsible for the lower TSH response to TRH in men compared to women and 2) androgen is not a cause of the lower PRL response to TRH in men.     

Effects of testosterone replacement in hypogonadal men

Treatment of hypogonadal men with testosterone has been shown to ameliorate the effects of testosterone deficiency on bone, muscle, erythropoiesis, and the prostate. Most previous studies, however, have employed somewhat pharmacological doses of testosterone esters, which could result in exaggerated effects, and/or have been of relatively short duration or employed previously treated men, which could result in dampened effects. The goal of this study was to determine the magnitude and time course of the effects of physiological testosterone replacement for 3 yr on bone density, muscle mass and strength, erythropoiesis, prostate volume, energy, sexual function, and lipids in previously untreated hypogonadal men. We selected 18 men who were hypogonadal (mean serum testosterone +/- SD, 78 +/- 77 ng/dL; 2.7 +/- 2.7 nmol/L) due to organic disease and had never previously been treated for hypogonadism. We treated them with testosterone transdermally for 3 yr. Sixteen men completed 12 months of the protocol, and 14 men completed 36 months. The mean serum testosterone concentration reached the normal range by 3 months of treatment and remained there for the duration of treatment. Bone mineral density of the lumbar spine (L2-L4) increased by 7.7 +/- 7.6% (P < 0.001), and that of the femoral trochanter increased by 4.0 +/- 5.4% (P = 0.02); both reached maximum values by 24 months. Fat-free mass increased 3.1 kg (P = 0.004), and fat-free mass of the arms and legs individually increased, principally within the first 6 months. The decrease in fat mass was not statistically significant. Strength of knee flexion and extension did not change. Hematocrit increased dramatically, from mildly anemic (38.0 +/- 3.0%) to midnormal (43.1 +/- 4.0%; P = 0.002) within 3 months, and remained at that level for the duration of treatment. Prostate volume also increased dramatically, from subnormal (12.0 +/- 6.0 mL) before treatment to normal (22.4 +/- 8.4 mL; P = 0.004), principally during the first 6 months. Self-reported sense of energy (49 +/- 19% to 66 +/- 24%; P = 0.01) and sexual function (24 +/- 20% to 66 +/- 24%; P < 0.001) also increased, principally within the first 3 months. Lipids did not change. We conclude from this study that replacing testosterone in hypogonadal men increases bone mineral density of the spine and hip, fat-free mass, prostate volume, erythropoiesis, energy, and sexual function. The full effect of testosterone on bone mineral density took 24 months, but the full effects on the other tissues took only 3-6 months. These results provide the basis for monitoring the magnitude and the time course of the effects of testosterone replacement in hypogonadal men.     

Deterioration of trabecular architecture in hypogonadal men

Bone strength depends on trabecular architecture, characterized by interconnected plates and rods. In osteoporosis, the plates become fenestrated, resulting in more rods that deteriorate and become disconnected. In men, hypogonadism is a common cause of osteoporosis. To determine whether male hypogonadism affects trabecular architecture, we selected 10 men with severe, untreated hypogonadism, and for each hypogonadal man, we selected a eugonadal man matched for race and age. Trabecular architecture in the distal tibia was assessed by magnetic resonance microimaging. Two composite topological indices were determined: the ratio of surface voxels (representing plates) to curve voxels (representing rods), which is higher when architecture is more intact; and the erosion index, a ratio of parameters expected to increase upon architectural deterioration to those expected to decrease, which is higher when deterioration is greater. The surface/curve ratio was 36% lower (P = 0.004), and the erosion index was 36% higher (P = 0.003) in the hypogonadal men than in the eugonadal men. In contrast, bone mineral density of the spine and hip were not significantly different between the two groups. We conclude that male hypogonadism is associated with marked deterioration of trabecular architecture and to a greater degree than bone densitometry of the spine and hip suggests.     

Molecular heterogeneity of serum follicle-stimulating hormone in hypogonadal patients before and during androgen replacement therapy and in normal men

OBJECTIVE The present study was performed to characterize the molecular heterogeneity of serum FSH in normal males and to investigate the possible influence of testosterone on serum FSH in androgen-deficient men before and during testosterone administration. DESIGN AND PATIENTS Serum samples were taken at 10-minute intervals between 0730 and 0830 h from nine healthy, eugonadal men and from eight men with primary hypogonadism (Klinefelter's syndrome). In the hypogonadal patients, sampling was performed before treatment (n= 8), 4-5 days after the first and the third injection of 250 mg testosterone enanthate given intramuscularly at three-weekly intervals (n= 6), as well as 3 months after the onset of therapy (n= 3). Sampling was repeated 7 days apart in two of the nine healthy volunteers. MEASUREMENTS Aliquots from the individual serum samples were pooled and fractionated by chromatofocusing in the pH range 6-3. Immunoreactive FSH was measured by immunofluorimetric assay (IFMA) in each fraction and the individual serum samples. In each serum pool, bioactive FSH was determined by in-vitro bioassay (rat Sertoli cell aromatase bioassay), testosterone by RIA and LH by IFMA. RESULTS After grouping the percentage of immunoreactive FSH recovered in the individual fractions into intervals of 0 5 pH units, significant differences between controls and patients were observed in the pH regions 4-4.5, 5.5-6 and 6-6.5. No statistically significant changes in the isoform distribution of FSH were detected during therapy in the Klinefelter patients. A high degree of variability, which did not follow a common pattern, was observed in the isoform distribution of FSH within the same individuals, both in the hypogonadal patients during treatment and in the two normal men whose blood samples were taken on two different occasions. CONCLUSIONS Serum FSH is highly heterogeneous in normal and hypogonadal men. There is a spontaneous intra-individual variability in the relative abundance of the different FSH isoforms in serum that may most probably be related to metabolic deglycosylation of FSH. Minor but significant differences in the molecular heterogeneity of serum FSH could be demonstrated in Klinefelter patients compared to normal men. These differences are not modified by administration of testosterone enanthate at doses achieving normal androgenization, suggesting that factors different from testosterone may modulate FSH pleomorphism.     

Testosterone buciclate (20 Aet-1) in hypogonadal men: pharmacokinetics and pharmacodynamics of the new long-acting androgen ester.

Due to unfavorable pharmacokinetics of the available androgen esters for substitution therapy of male hypogonadism, there is a demand for new testosterone (T) preparations producing constant serum levels in the physiological range. To assess the pharmacokinetics and pharmacodynamics of the new ester testosterone buciclate (TB) [20 Aet-1] in hypogonadal men a clinical phase I-study was performed. After two control examinations 8 male patients with primary hypogonadism were randomly assigned to 2 treatment groups (n = 2 x 4) given single doses of either 200 (group I) or 600 mg (group II) TB im. Blood samples were obtained 1, 2, 3, 5, and 7 days post injection and then weekly in the course of 4 months. In group I serum androgen levels did not rise to normal values. However, in group II androgens increased significantly and were maintained in the normal range up to 12 weeks with maximal serum levels of 13.1 +/- 0.9 nmol/L (mean +/- SE) in study week 6. No initial peak release of T was observed in either study group. Pharmacokinetic analysis revealed a terminal elimination t1/2 beta of 29.5 +/- 3.9 days and a mean residence time of 65.0 +/- 9.9 days in group II. In one patient in group II dihydrotestosterone levels slightly exceeded the upper normal limit during the study course. Sex hormone-binding globulin remained unchanged and estradiol serum levels never exceeded the normal range in any patient. In group II gonadotropins were significantly suppressed, whereas no change was seen in group I. A significant increase in body weight, hematological parameters, and libido/potency was observed after TB injection which was more pronounced in the higher dose group. Regardless of the dose administered, no significant change was seen in uroflow, prostate volume measured by transrectal ultrasonography, or prostate specific antigen. No adverse side-effects including changes in clinical chemistry were observed. In conclusion, single injections of 600 mg TB in hypogonadal patients show favorable pharmacokinetics and pharmacodynamics. This new long-acting T ester is a promising new agent for substitution therapy of male hypogonadism and for male contraception.