Combined nestorone-testosterone gel suppresses serum gonadotropins to concentrations associated with effective hormonal contraception in men.

BACKGROUND: Novel male-based contraceptives are needed to broaden family planning choices. A progestin, Nestorone® (Nes) gel, plus a testosterone (T) gel suppresses sperm concentrations to levels associated with effective contraception in normal men. However, administration of two gels on different parts of the body daily is impractical. OBJECTIVE: Compare the effectiveness of daily application of a single, combined 8.3 mg Nes-62.5 mg T gel (Nes-T) vs. 62.7 mg T gel to suppress serum FSH and LH concentrations to ≤1.0 IU/L (a threshold associated with suppression of sperm concentrations to ≤1 million and effective contraception) and to compare the pharmacokinetics of serum Nes and T concentrations between the gel groups. DESIGN: We conducted a 28-day, double-blind, controlled trial of 44 healthy men randomized to daily Nes-T or T gel with measurement of hormones at baseline, treatment, and recovery and during 24-h pharmacokinetic studies on days 1 and 28 of treatment. RESULTS: Of the subjects who met pre-defined inclusion criteria, 84% of the Nes-T group suppressed serum gonadotropin concentrations to ≤1.0 IU/L at days 21-28 vs. 16.7% in the T group (p < 0.001). On day 1, Nes concentrations rose significantly above baseline by 2 h and continued to rise up to 24 h after Nes-T gel application. Nes concentrations were not detectable in the T group. Serum total T concentrations rose and were significantly higher in the T gel group compared to the Nes-T group at 24 h on day 1 and days 11, 14, and 21 (p < 0.01). There were no serious adverse events in either group. About 80% of the subjects reported satisfaction with both gels. CONCLUSION: Daily Nes-T gel effectively and safely suppresses serum gonadotropins and is acceptable to most men. It should be studied further in efficacy trials of hormonal male contraception.

Isotretinoin administration improves sperm production in men with infertility from oligoasthenozoospermia: a pilot study.

There is currently no effective medical therapy for men with infertility due to oligoasthenozoospermia. As men with abnormal sperm production have lower concentrations of 13-cis-retinoic acid in their testes, we hypothesized that men with infertility from oligoasthenozoospermia might have improved sperm counts when treated with isotretinoin (13-cis-retinoic acid). We conducted a single-site, single-arm, pilot study to determine the effect of therapy with isotretinoin on sperm indices in 19 infertile men with oligoasthenozoospermia. Subjects were men between 21 and 60 years of age with infertility for longer than 12 months associated with sperm concentrations below 15 million sperm/mL. All men received isotretinoin 20 mg by mouth twice daily for 20 weeks. Subjects had semen analyses, physical examinations, and laboratory tests every 4 weeks during treatment. Nineteen men enrolled in the study. Median (25th, 75th) sperm concentration increased from 2.5 (0.1, 5.9) million/mL at baseline to 3.8 (2.1, 13.0) million/mL at the end of treatment (p = 0.006). No significant changes in sperm motility were observed. There was a trend toward improved sperm morphology (p = 0.056). Six pregnancies (three spontaneous and three from intracytoplasmic sperm injection) and five births occurred during the study. Four of the births, including all three of the spontaneous pregnancies, were observed in men with improvements in sperm counts with isotretinoin therapy. Treatment was well tolerated. Isotretinoin therapy improves sperm production in some men with oligoasthenozoospermia. Additional studies of isotretinoin in men with infertility from oligoasthenozoospermia are warranted.

Comparison of the single dose pharmacokinetics, pharmacodynamics, and safety of two novel oral formulations of dimethandrolone undecanoate (DMAU): a potential oral, male contraceptive.

Dimethandrolone (DMA, 7α,11ß-dimethyl-19-nortestosterone) has both androgenic and progestational activities, ideal properties for a male hormonal contraceptive. In vivo, dimethandrolone undecanoate (DMAU) is hydrolyzed to DMA. We showed previously that single oral doses of DMAU powder in capsule taken with food are well tolerated and effective at suppressing both LH and testosterone (T), but absorption was low. We compared the pharmacokinetics and pharmacodynamics of two new formulations of DMAU, in castor oil and in self-emulsifying drug delivery systems (SEDDS), with the previously tested powder formulation. DMAU was dosed orally in healthy adult male volunteers at two academic medical centers. For each formulation tested in this double-blind, placebo-controlled study, 10 men received single, escalating, oral doses of DMAU (100, 200, and 400 mg) and two subjects received placebo. All doses were evaluated for both fasting and with a high fat meal. All three formulations were well tolerated without clinically significant changes in vital signs, blood counts, or serum chemistries. For all formulations, DMA and DMAU showed higher maximum (p < 0.007) and average concentrations (p < 0.002) at the 400 mg dose, compared with the 200 mg dose. The powder formulation resulted in a lower conversion of DMAU to DMA (p = 0.027) compared with both castor oil and SEDDS formulations. DMAU in SEDDS given fasting resulted in higher serum DMA and DMAU concentrations compared to the other two formulations. Serum LH and sex hormone concentrations were suppressed by all formulations of 200 and 400 mg DMAU when administered with food, but only the SEDDS formulation was effectively suppressed serum T when given fasting. We conclude that while all three formulations of oral DMAU are effective and well tolerated when administered with food, DMAU in oil and SEDDS increased conversion to DMA, and SEDDS may have some effectiveness when given fasting. These properties might be advantageous for the application of DMAU as a male contraceptive.

Characteristics associated with suppression of spermatogenesis in a male hormonal contraceptive trial using testosterone and Nestorone(®) gels.

Development of a male hormonal contraceptive has been challenging ascribable to the failure to adequately suppress spermatogenesis in 5-10% of men. Methods to identify incomplete suppressors early in treatment might identify men most responsive to male hormonal contraceptives. We hypothesized that serum hormone and gonadotropin concentrations after 4 weeks of transdermal treatment with testosterone and Nestorone in a contraceptive trial would be associated with suppression of sperm concentrations to <1 million/mL after 24 weeks. Indeed, luteinizing hormone or follicle-stimulating hormone concentrations greater than 1 IU/L after 4 weeks of transdermal testosterone/nestorone treatment were 97% sensitive for predicting failure to suppress spermatogenesis after 24 weeks of treatment. Serum nestorone concentrations were significantly associated with suppression, but serum testosterone concentrations were not. Early suppression of gonadotropins is associated with, but does not ensure, adequate suppression of spermatogenesis. This information may allow for rapid identification of non-responders in male hormonal contraceptive trials.

Intratesticular 13-cis retinoic acid is lower in men with abnormal semen analyses: a pilot study.

Intratesticular retinoic acid is necessary for spermatogenesis, but the relationship between intratesticular retinoic acid and sperm quality in man has not been studied. We hypothesized that intratesticular concentrations of retinoic acid would be lower in men with abnormal semen analyses compared to men with normal semen analyses. We recruited men requiring scrotal or penile surgery in a pilot observational study examining the relationship between sperm quality and intratesticular and serum retinoic acid. Twenty-four men provided two pre-operative blood and semen samples, and underwent a testicular biopsy during surgery. Serum and tissue all-trans and 13-cis retinoic acid and reproductive hormones were measured by LC/MS/MS and radioimmunoassays, respectively. Seven men had abnormal semen analyses by at least one WHO criteria and 17 men were normal. In men with abnormal semen, the median (25th, 75th percentile) intratesticular 13-cis retinoic acid was 0.14 (0.08, 0.25) pmol/gram tissue compared with 0.26 (0.18, 0.38) pmol/gram tissue in men with normal semen (p = 0.04). There were no significant differences in intratesticular all-trans retinoic acid or serum reproductive hormones between men with normal and abnormal semen analyses. Intratesticular 13-cis retinoic acid is significantly lower in men with abnormal semen analyses compared to men with normal semen analyses. Lower intratesticular 13-cis retinoic acid concentrations may be due to decreased biosynthesis or increased metabolism in the testes. Further investigation of the relationship between intratesticular 13-cis retinoic acid and poor sperm quality is warranted to determine if this association is present in infertile men.

Androgen synthesis in the gonadotropin-suppressed human testes can be markedly suppressed by ketoconazole.

CONTEXT: The concentration of intratesticular testosterone (IT-T) required for human spermatogenesis is unknown because spermatogenesis can persist despite the markedly reduced IT-T concentrations observed with LH suppression. Methods to lower IT-T further are needed to determine the relationship between IT-T and spermatogenesis. OBJECTIVE: The objective of the study was to determine the effect of inhibiting the synthesis and metabolism of testosterone (T) on IT-T in gonadotropin-suppressed human testes. DESIGN/SETTING/PATIENTS: Forty normal men participated in a blinded, placebo-controlled, randomized trial at an academic center. INTERVENTION/OUTCOME MEASURES: All men were first administered the GnRH antagonist acyline to suppress LH. Forty-eight hours after acyline administration, subjects were randomly assigned to placebo, ketoconazole (to inhibit T synthesis) at 400 or 800 mg, dutasteride (to inhibit T metabolism) 2.5 mg, or anastrazole (to inhibit T metabolism) 1 mg, daily for 7 days (n = 8/group). Intratesticular steroid concentrations were measured 48 hours after acyline administration alone and again after 7 days of combination treatment. RESULTS: After 7 days of combination treatment, the median IT-T (25th, 75th percentile) in the placebo group was 14 (8.0, 21.2) ng/mL. IT-T was reduced to 3.7 (2.5, 7.1) ng/mL in the ketoconazole 400 mg group and 1.7 (0.8, 4.0) ng/mL in the ketoconazole 800 mg group (P < .001 vs placebo for both comparisons). IT-T concentrations in the dutasteride and anastrazole groups were similar to placebo. CONCLUSION: Combining inhibition of steroidogenesis with gonadotropin suppression lowers IT-T more than gonadotropin suppression alone. This combination might be useful to determine the minimum IT-T concentration necessary for human spermatogenesis, information essential for developing male hormonal contraceptives.

Acute testosterone deprivation reduces insulin sensitivity in men.

OBJECTIVE: In men with prostate cancer, androgen deprivation reduces insulin sensitivity; however, the relative roles played by testosterone and estradiol are unknown. To investigate the respective effects of these hormones on insulin sensitivity in men, we employed a model of experimental hypogonadism with or without hormone replacement. DESIGN: Placebo-controlled, randomized trial. PARTICIPANTS: Twenty-two healthy male volunteers, 18-55 years old. METHODS: Following screening, subjects received the gonadotrophin-releasing hormone antagonist acyline plus one of the following for 28 days: Group 1, placebo transdermal gel and placebo pills; Group 2, transdermal testosterone gel 10 g/day plus placebo pills; Group 3, transdermal testosterone gel 10 g/day plus the aromatase inhibitor anastrozole 1 mg/day to normalize testosterone while selectively reducing serum estradiol. Fasting insulin, glucose, adipokines and hormones were measured bi-weekly. RESULTS: With acyline administration, serum testosterone was reduced by >90% in all subjects in Group 1. In these men, mean fasting insulin concentrations were significantly increased compared with baseline (P = 0·02) at 28 days, despite stable body weight and no changes in fasting glucose concentrations. Decreased insulin sensitivity was also apparent in the insulin sensitivity indices homeostasis model of insulin resistance (P = 0·03) and quantitative insulin sensitivity check index (P = 0·04). In contrast, in Groups 2 and 3, testosterone concentrations remained in the physiologic range, despite significant reduction in mean estradiol in Group 3. In these groups, no significant changes in insulin sensitivity were observed. CONCLUSIONS: Acute testosterone withdrawal reduces insulin sensitivity in men independent of changes in body weight, whereas estradiol withdrawal has no effect. Testosterone appears to maintain insulin sensitivity in normal men.

The effect of gonadotropin withdrawal and stimulation with human chorionic gonadotropin on intratesticular androstenedione and DHEA in normal men.

INTRODUCTION: Concentrations of intratesticular (IT) testosterone (T) are known to be 100-200 times those of serum T; however, the IT concentrations of T's precursors, their testicular to serum gradients, gonadotropin dependence, and response to stimulation with human chorionic gonadotropin (hCG) have not been studied in detail. We hypothesized that serum and IT androstenedione (ADD) and IT dehydroepiandrosterone (DHEA) would be significantly suppressed by the administration of a GnRH antagonist and increased when stimulated by hCG, without a similar suppression of serum DHEA. METHODS: We suppressed gonadotropins in 23 normal men with the GnRH antagonist acyline and randomly assigned them to one of four doses of hCG, 0, 15, 60, or 125 IU sc every other day for 10 d. Blood and IT fluid for the measurement of serum and IT hormones were obtained at baseline and after 10 d of treatment. RESULTS: Baseline IT ADD [median (25th, 75th percentile)] was 629 (308, 860) nmol/liter, and IT DHEA was 564 (411, 879) nmol/liter, which were 175 and 27 times higher than their respective serum concentrations. IT ADD and IT DHEA were suppressed by 98 and 82%, respectively, by acyline and significantly increased with hCG administration. Likewise, serum ADD was suppressed by 50%, but serum DHEA was unchanged. DISCUSSION: ADD and DHEA are highly concentrated within the human testes compared with serum. Serum and IT ADD and IT DHEA are markedly suppressed with GnRH administration and stimulated by hCG, but serum DHEA is not, suggesting that most circulating DHEA is not of testicular origin.

Pharmacologic development of male hormonal contraceptive agents.

The world population continues to increase dramatically despite the existence of contraceptive technology. The use of male hormonal contraception may help in preventing un intended pregnancies and managing future population growth. Male hormonal contraception relies on the administration of exogenous hormones to suppress spermatogenesis. Clinical trials have tested several regimens using testosterone, alone or in combination with a progestin. These regimens were shown to be >90% effective in preventing conception and were not associated with serious adverse events.

Steady-state pharmacokinetics of oral testosterone undecanoate with concomitant inhibition of 5α-reductase by finasteride.

Oral testosterone undecanoate (TU) is used to treat testosterone deficiency; however, oral TU treatment elevates dihydrotestosterone (DHT), which may be associated with an increased risk of acne, male pattern baldness and prostate hyperplasia. Co-administration of 5α-reductase inhibitors with other formulations of oral testosterone suppresses DHT production and increases serum testosterone. We hypothesized that finasteride would increase serum testosterone and lower DHT during treatment with oral TU. Therefore, we studied the steady-state pharmacokinetics of oral TU, 200 mg equivalents of testosterone twice daily for 7 days, alone and with finasteride 0.5 and 1.0 mg po twice daily in an open-label, three-way crossover study in 11 young men with experimentally induced hypogonadism. On the seventh day of each dosing period, serum testosterone, DHT and oestradiol were measured at baseline and 1, 2, 4, 8, 12, 13, 14, 16, 20 and 24 h after the morning dose. Serum testosterone and DHT were significantly increased into and above their normal ranges similarly by all three treatments. Co-administration of finasteride at 0.5 and 1.0 mg po twice daily had no significant effect on either serum testosterone or DHT. Oral TU differs from other formulations of oral testosterone in its response to concomitant inhibition of 5α-reductase, perhaps because of its unique lymphatic route of absorption.

Dose-dependent increase in intratesticular testosterone by very low-dose human chorionic gonadotropin in normal men with experimental gonadotropin deficiency.

CONTEXT AND OBJECTIVE: In men with infertility secondary to gonadotropin deficiency, treatment with relatively high dosages of human chorionic gonadotropin (hCG) stimulates intratesticular testosterone (IT-T) biosynthesis and spermatogenesis. Previously we found that lower dosages of hCG stimulated IT-T to normal. However, the minimal dose of hCG needed to stimulate IT-T and the dose-response relationship between very low doses of hCG and IT-T and serum testosterone in normal men is unknown. DESIGN, SETTING, PATIENTS, AND INTERVENTION: We induced experimental gonadotropin deficiency in 37 normal men with the GnRH antagonist acyline and randomized them to receive one of four low doses of hCG: 0, 15, 60, or 125 IU sc every other day or 7.5 g daily testosterone gel for 10 d. Testicular fluid was obtained by percutaneous aspiration for steroid measurements at baseline and after 10 d of treatment and correlated with contemporaneous serum hormone measurements. RESULTS: Median (25th, 75th percentile) baseline IT-T was 2508 nmol/liter (1753, 3502 nmol/liter). IT-T concentrations increased in a dose-dependent manner with very low-dosage hCG administration from 77 nmol/liter (40, 122 nmol/liter) to 923 nmol/liter (894, 1017 nmol/liter) in the 0- and 125-IU groups, respectively (P<0.001). Moreover, serum hCG was significantly correlated with both IT-T and serum testosterone (P<0.01). CONCLUSION: Doses of hCG far lower than those used clinically increase IT-T concentrations in a dose-dependent manner in normal men with experimental gonadotropin deficiency. Assessment of IT-T provides a valuable tool to investigate the hormonal regulation of spermatogenesis in man.

Serum LH correlates highly with intratesticular steroid levels in normal men.

Sex steroids are essential for spermatogenesis; however, normal intratesticular concentrations of these hormones in man have not been extensively studied. To improve our understanding of intratesticular hormone concentrations, we performed bilateral testicular aspirations in a group of normal men, determined sex steroid concentrations within each testis, and compared these levels to serum hormone concentrations. Ten healthy human subjects aged 20-49 underwent bilateral testicular aspirations. Intratesticular hormone concentrations of testosterone, dihydrotestosterone (DHT), and estradiol were measured using liquid chromatography-tandem mass spectrometry. Intratesticular testosterone concentrations ranged from 119 to 1251 ng/mL, with a mean of 635 +/- 368 ng/mL. Intratesticular estradiol ranged from 0.41 to 3.9 ng/mL, with a mean of 2.4 +/- 1.3 ng/mL. Intratesticular DHT ranged from 1.1 to 7.9 ng/mL, with a mean of 3.5 +/- 3.2 ng/mL. Intratesticular testosterone and estradiol concentrations correlated highly with serum luteinizing hormone (LH; r = 0.87 and r = 0.70 respectively, P < .01). Intratesticular testosterone correlated highly with serum testosterone. Moreover, a significant correlation between the right and left testes was observed for testosterone (r = 0.82, P = .003), but not for estradiol or DHT. Intratesticular hormone concentrations can be safely assessed by testicular aspiration. Intratesticular testosterone and estradiol correlate highly with serum LH concentrations, and variation in serum LH accounts for most of the variation in intratesticular testosterone among men. In addition, intratesticular testosterone is highly correlated between testes in a given individual. Direct measurement of intratesticular testosterone will improve our understanding of the relationship between intratesticular sex steroids and spermatogenesis, and may have implications for the development of male hormonal contraception.

Characterization of verbal and spatial memory changes from moderate to supraphysiological increases in serum testosterone in healthy older men.

BACKGROUND: It has been suggested that cognitive changes in response to T supplementation may occur within an ideal range. The objective of this study was to compare the cognitive responses of older, eugonadal men in whom moderate or large increases in serum testosterone levels was induced by exogenous testosterone supplementation. DESIGN: Randomized, double-blind, placebo-controlled study with subsequent grouping of participants according to average increase in circulating T from baseline. SETTING: Community dwelling participants. PARTICIPANTS: Fifty-seven healthy, eugonadal, community dwelling male volunteers, mean age 67 years (+/-11 years). INTERVENTIONS: Participants were randomized to receive weekly intramuscular (i.m.) injections of either 50, 100 or 300 mg T enanthate or placebo (saline) injection for 6 weeks. Cognitive evaluations using a battery of neuropsychological tests were conducted at baseline, weeks 3 and 6 of treatment and after 6 weeks of wash-out. MAIN OUTCOME MEASURES: Performance on cognitive tests of verbal and spatial memory. RESULTS: Men with moderate increases in serum T and/or its metabolites demonstrated significant improvements in verbal and spatial memory. In contrast, men with large or low increases in circulating T levels, failed to demonstrate significant changes in memory. CONCLUSION: These results suggest that in healthy older men, beneficial changes in cognitive function induced by T supplementation are most evident with moderate changes in cognition from moderate to high T supplementation increases in T levels. Large or no to low increases in T levels do not appear to appreciably effect cognition.

Miglustat has no apparent effect on spermatogenesis in normal men.

BACKGROUND: In mice, administration of the glycosphingolipid biosynthesis inhibitor miglustat results in reversible infertility, characterized by impaired sperm motility and markedly abnormal sperm morphology. This observation suggested that miglustat might have utility for fertility control in man. To ascertain the impact of miglustat on human spermatogenesis, we conducted a pilot study of miglustat administration in normal men. METHODS: After a 2-week baseline period, seven normal men were administered miglustat 100 mg, orally, twice daily for 6 weeks. During treatment, subjects had frequent seminal fluid analyses to assess the impact of treatment on sperm concentration, motility and morphology and the ability to undergo the acrosome reaction by in vitro assays. RESULTS: Five subjects completed all aspects of the study. In these subjects, there was no apparent effect of miglustat on sperm concentration, motility or sperm morphology after 6 weeks of therapy. In addition, no changes in acrosome structure or function were observed with treatment, despite therapeutic concentrations of miglustat in the serum and seminal plasma. All subjects experienced gastrointestinal upset, diarrhoea and mild weight loss during treatment. No other abnormalities in blood counts, serum chemistries, vision or overall health were observed. CONCLUSION: In contrast to the observations in mice, the oral administration of miglustat does not appear to affect human spermatogenesis. Further elucidation of the mechanism underlying the species specificity of miglustat may improve our understanding of the role of glycosphingolipids in spermatogenesis and result in alternative approaches to male fertility control.

Male hormonal contraceptives.

Efforts are underway to develop additional forms of contraception for men. The most promising approach to male contraceptive development involves the administration of exogenous testosterone (T). When administered to a man, T functions as a contraceptive by suppressing the secretion of luteinizing hormone and follicle-stimulating hormone from the pituitary, thereby depriving the testes of the signals required for spermatogenesis. After 2-3 months of treatment, low levels of these gonadotropins lead to markedly decreased sperm counts and effective contraception in a majority of men. Hormonal contraception with exogenous T has proven to be free from serious adverse effects and is well tolerated by men. In addition, sperm counts uniformly normalize when the exogenous T is discontinued. Thus, male hormonal is safe, effective and reversible; however, spermatogenesis is not suppressed to zero in all men, meaning that some diminished potential for fertility persists. Because of this recent studies have combined T with progestogens and/or gonadotropin-releasing antagonists to further suppress pituitary gonadotropins and optimize contraceptive efficacy. Current combinations of T and progestogens completely suppress spermatogenesis without severe side effects in 80-90% of men, with significant suppression in the remainder of individuals. Recent trials with newer, long-acting forms of injectable T, which can be administered every 8 weeks, combined with progestogens, administered either orally or by long-acting implant, have yielded promising results and may soon result in the marketing of a safe, reversible and effective hormonal contraceptive for men.

A multicentre study investigating subcutaneous etonogestrel implants with injectable testosterone decanoate as a potential long-acting male contraceptive.

BACKGROUND: The combination of etonogestrel implants with injectable testosterone decanoate was investigated as a potential male contraceptive. METHODS: One hundred and thirty subjects were randomly assigned to three treatment groups, all receiving two etonogestrel rods (204 mg etonogestrel) and 400 mg testosterone decanoate either every 4 weeks (group I, n = 42), or every 6 weeks (group II, n = 51) or 600 mg testosterone decanoate every 6 weeks (group III, n = 37) for a treatment period of 48 weeks. RESULTS: One hundred and ten men completed 48 weeks of treatment. Sperm concentrations of <1 x 10(6)/ml were achieved in 90% (group I), 82% (group II) and 89% (group III) of subjects by week 24. Suppression was slower in group II, which also demonstrated more frequent escape from gonadotrophin suppression than groups I and III. Peak testosterone concentrations remained in the normal range throughout in all groups. Mean trough testosterone concentrations were initially subphysiological but increased into the normal range during treatment. Mean haemoglobin levels increased in group I, and a non-significant increase in weight and decline in high-density lipoprotein cholesterol was observed in all groups. Fourteen subjects discontinued treatment due to adverse events. CONCLUSIONS: Subcutaneous etonogestrel implants in combination with injectable testosterone decanoate resulted in profound suppression of spermatogenesis that could be maintained for up to 1 year. Efficacy of suppression was less in group II, probably due to inadequate testosterone dosage. This combination has potential as a long-acting male hormonal contraceptive.

Testosterone improves spatial memory in men with Alzheimer disease and mild cognitive impairment.

OBJECTIVE: To determine the efficacy of testosterone (T) supplementation on cognition in a sample of men with Alzheimer disease (AD) or mild cognitive impairment (MCI). METHODS: Fifteen patients with AD and 17 patients with MCI aged 63 to 85 years completed a randomized, double-blind, placebo-controlled study. Nineteen participants received weekly intramuscular (IM) injections of 100 mg T enanthate and 13 participants received weekly injections of placebo (saline) for 6 weeks. Cognitive evaluations using a battery of neuropsychological tests were conducted at baseline, week 3, and week 6 of treatment and again after 6 weeks of washout. RESULTS: Peak serum total T levels were raised from baseline an average of 295% in the active treatment group. Improvements in spatial memory (p < 0.05) and constructional abilities (p < 0.05) and verbal memory were evident in the T group. No changes were noted for selective and divided attention or language. Prostate specific antigen did not significantly change during this brief treatment. CONCLUSION: Testosterone supplementation may benefit selective cognitive functions in men with Alzheimer disease and mild cognitive impairment.

The role of aromatization in testosterone supplementation: effects on cognition in older men.

OBJECTIVE: To determine the contribution of conversion of testosterone (T) to estradiol on cognitive processing in a population of healthy older men who received T supplementation. METHODS: Sixty healthy, community-dwelling volunteers aged 50 to 90 years completed a randomized, double-blind, placebo-controlled study. Participants were randomized to receive weekly IM injections of 100 mg T enanthate plus daily oral placebo pill (T group, n = 20), 100 mg testosterone enanthate plus 1 mg daily of anastrozole, an aromatase inhibitor (oral pill), to block the conversion of T to estradiol (AT group, n = 19), or saline injection and placebo pill (placebo group, n = 21) for 6 weeks. Cognitive evaluations using a battery of neuropsychological tests were conducted at baseline, week 3 and week 6 of treatment, and after 6 weeks of washout. RESULTS: Circulating total T was increased from baseline an average of 238% in the T and AT treatment groups. Estradiol increased an average of 81% in the T group and decreased 50% in the AT group during treatment. Significant improvements in spatial memory were evident in the AT and T treatment groups. However, only the group with elevated estradiol levels (T group) demonstrated significant verbal memory improvement. CONCLUSION: In healthy older men, improvement in verbal memory induced by testosterone administration depends on aromatization of testosterone to estradiol, whereas improvement in spatial memory occurs in the absence of increases in estradiol.

Oral testosterone-triglyceride conjugate in rabbits: single-dose pharmacokinetics and comparison with oral testosterone undecanoate.

Development of a safe and effective oral form of testosterone has been inhibited by the rapid hepatic metabolism of nonalkylated androgens. Since triglycerides are absorbed via lymphatics and bypass the liver, we hypothesized that a testosterone-triglyceride conjugate (TTC) might allow for safe and effective oral testosterone therapy. Therefore, we studied the single-dose pharmacokinetics of oral administration of TTC in rabbits. Female New Zealand rabbits were administered 2, 4, or 8 mg/kg of TTC in sesame oil by gastric lavage. Testosterone undecanoate (TU) by gastric lavage was used as a positive control. Blood was sampled from a catheter in the auricular artery at 0, 15, 30, 60, 90, 120, 180, 240, 360, 480, and 600 minutes after drug administration. Samples were assayed for testosterone by a fluoroimmunoassay. Mean serum testosterone, area under the curve (AUC), and terminal half-life were calculated. Oral TTC administration resulted in rapid and marked increases in serum testosterone. Oral TTC resulted in higher maximum serum testosterone concentrations than oral TU at 8 mg/kg (TTC: 28.6 +/- 7.9 nmol/L vs TU: 11.9 +/- 2.1 nmol/L; P <.001) and 4 mg/kg (TTC: 11.5 +/- 4.2 nmol/L vs TU: 3.6 +/- 1.0 nmol/L; P <.001). In addition, the AUC was 1.8 to 2.6 times greater for TTC than TU at both doses (P <.05). The terminal half-life for both TU and TTC was between 3 and 5 hours and was not significantly different. We conclude that oral TTC is rapidly absorbed from the rabbit intestine and results in elevated concentrations of serum testosterone. The absorption of TTC appears to be superior to that of TU; however, the in vivo persistence of the 2 compounds is similar. TTC may offer an alternative to the use of TU for oral testosterone therapy. Further testing of this compound is warranted.

Cognitive effects of short-term manipulation of serum sex steroids in healthy young men.

We examined the effects of sex steroids on cognitive functioning by exogenously manipulating circulating T levels in a group of healthy young men. Thirty-two men were randomized to receive 8 wk of treatment including: 1) im T enanthate 100 mg/wk plus daily oral placebo (T); 2) im placebo/wk plus 125 microg daily oral levonorgestrel (LNG); 3) im T enanthate 100 mg/wk plus 125 microg daily oral LNG (T + LNG); 4) im placebo/wk plus daily oral placebo. Cognitive functions were assessed at baseline and twice during treatment. Serum T and E2 levels were significantly increased in the T and T + LNG groups compared with baseline (P < 0.01) and T levels were significantly decreased in the LNG group (P < 0.05). Verbal memory significantly decreased in the LNG group (P < 0.01) and was maintained by coadministration of T in the T + LNG group. Divided attention was unaffected in the LNG group but improved significantly in the T + LNG group. In summary, decreased serum T levels induced by LNG or direct effects of the progestin, LNG, adversely affects verbal memory in normal young men. These results suggest that short-term changes in sex steroid levels have effects on cognitive function in healthy young men.