Chronic myelogenous leukemia occurring in two brothers diagnosed 26 years apart

Chronic myelogenous leukemia (CML) is characterized by the presence of the chromosomal abnormality t(9;22)(q34;q11), which is detected in more than 90% of cases. Despite great strides in our understanding of this disease, few predisposing etiologic factors have been identified. We report on the case of a 45-year-old man with Philadelphia chromosome-positive, BCR-ABL fusion-positive chronic-phase CML, whose brother had succumbed to the same disease 22 years earlier. While a coincidental familial occurrence cannot be excluded in this case, we believe that this report underscores the need for further investigation of possible unknown environmental or heritable etiologic factors in this disease.     

Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T

Testosterone (T) therapy in older men with low serum T levels increases lean body mass and decreases fat mass. These changes might improve physical performance and strength; however, it has not been established whether T therapy improves functional outcome in older men. Moreover, concerns exist about the impact of T therapy on the prostate in older men. The administration of finasteride (F), which partially blocks the conversion of T to the more potent androgen, dihydrotestosterone, attenuates the impact of T replacement on prostate size and prostate-specific antigen. We hypothesized that T replacement in older, hypogonadal men would improve physical function and that the addition of F to this regimen would continue to provide the T-induced improvements in physical performance, strength, and body composition. Seventy men with low serum T (<350 ng/dl), age 65 yr and older, were randomly assigned to receive one of three regimens for 36 months: 1) T enanthate, 200 mg im every 2 wk, with placebo pills daily (T-only); 2) T enanthate, 200 mg every 2 wk, with 5 mg F daily (T + F); or 3) placebo injections and pills (placebo). We obtained serial measurements of timed physical performance, grip strength, lower extremity strength, body composition (by dual-energy x-ray absorptiometry), fasting cholesterol profiles, and hormones. Fifty men completed the 36-month protocol. After 36 months, T therapy significantly improved performance in a timed functional test when compared with baseline and placebo [4.3 +/- 1.6% (mean +/- sem, T-only) and 3.8 +/- 1.0% (T + F) vs. -5.6 +/- 1.9% for placebo (P < 0.002 for both T and T + F vs. placebo)] and increased handgrip strength compared with baseline and placebo (P < 0.05). T therapy increased lean body mass [3.77 +/- 0.55 kg (T-only) and 3.64 +/- 0.56 kg (T + F) vs. -0.21 +/- 0.55 kg for placebo (P < 0.0001)], decreased fat mass, and significantly decreased total cholesterol, low-density lipoprotein, and leptin, without affecting high-density lipoprotein, adiponectin, or fasting insulin levels. These results demonstrate that T therapy in older men with low serum T improves physical performance and strength over 36 months, when administered alone or when combined with F, and suggest that high serum levels of dihydrotestosterone are not essential for these beneficial effects of T in men.     

Elevated end-of-treatment serum INSL3 is associated with failure to completely suppress spermatogenesis in men receiving male hormonal contraception

The administration of testosterone plus a progestogen functions as a male contraceptive by inhibiting the release of pituitary gonadotropins. After 3 to 4 months of treatment, most men are azoospermic or severely oligospermic (< or =1 million sperm/mL). However, 10% to 20% of men have persistent sperm production despite profound gonadotropin suppression. Since insulin-like factor 3 (INSL3) has been shown to prevent germ cell apoptosis in mice, we hypothesized that INSL3 might be higher in men with persistent spermatogenesis during treatment with male hormonal contraceptives. In a retrospective analysis, we measured serum INSL3 in 107 men from 3 recent male hormonal contraceptive studies and determined the relationship between suppression of spermatogenesis and serum INSL3. At the end of treatment 63 men (59%) were azoospermic and 44 men (41%) had detectable sperm in their ejaculates. Baseline INSL3 did not predict azoospermia; however, end of treatment serum INSL3 was significantly higher in nonazoospermic men compared with those with azoospermia (median [interquartile range]: 95 [73-127] pg/mL vs 80 [67-101] pg/mL; P = .03). Furthermore, serum INSL3 was positively correlated with sperm concentration (r = .25; P = .009) at the end of treatment and was significantly associated with nonazoospermia by multivariate logistic regression (P = .03). After 6 months of treatment with a hormonal male contraceptive regimen, higher serum INSL3 concentrations were associated with persistent sperm production. INSL3 may play a role in preventing complete suppression of spermatogenesis in some men on hormonal contraceptive regimens. This finding suggests that INSL3 may be a potential target for male contraceptive development.     

Newer agents for hormonal contraception in the male.

Efforts to create a hormonal contraceptive for men use testosterone to suppress the production of pituitary gonadotropins and, hence, spermatogenesis. However, conventional testosterone must be administered by frequent injection, and when given alone, is not 100% effective. Therefore, newer androgens and agents that synergistically suppress gonadotropin production are being studied to create an effective and commercially viable contraceptive.     

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.     

Contraceptive developments for men

Efforts are underway to develop new methods of contraception for men. The most promising approach to male contraceptive development is hormonal and involves the administration of testosterone. When testosterone is administered to a man, it functions as a contraceptive by suppressing the secretion of luteinizing hormone and follicle-stimulating hormone from the pituitary gland, thereby depriving the testes of the signals required for spermatogenesis. After two to three months of treatment, low levels of gonadotropins lead to markedly decreased sperm counts and effective contraception in a majority of men. In many clinical trials, male hormonal contraception has proven to be free from serious adverse effects and is well-tolerated by men. In addition, sperm parameters uniformly normalize when treatment is discontinued. The main drawback to this approach is the observation that spermatogenesis is not suppressed to zero in all men, meaning that some potential for fertility persists. Because of this, recent studies have combined testosterone with progestogens and/or gonadotropin-releasing antagonists to synergistically suppress pituitary gonadotropins and improve suppression of spermatogenesis. Current combinations of testosterone and progestogens severely 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 testosterone, such as testosterone undecanoate, which can be administered every 8-10 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.     

Oral administration of the GnRH antagonist acyline, in a GIPET?-enhanced tablet form, acutely suppresses serum testosterone in normal men: single-dose pharmacokinetics and pharmacodynamics

Purpose  GnRH analogs are useful for the treatment of prostate cancer, but require parenteral administration. The peptide GnRH antagonist acyline potently suppresses luteinizing hormone (LH) and testosterone in man; however, its clinical utility is limited by the requirement for frequent injections. The use of a proprietary enhancer system called GIPET^?, which is based on medium-chain fatty acids, facilitates the oral bioavailability of peptides. We hypothesized that GIPET^? enhancement would allow for the safe oral dosing of acyline for the treatment of prostate cancer. Methods  We enrolled eight healthy young men in a pharmacokinetic and pharmacodynamic study of 10, 20 and 40 mg doses of GIPET^?-enhanced oral acyline. Blood for measurement of serum LH, FSH, testosterone and acyline was obtained prior to each dose of GIPET^?-enhanced oral acyline and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 48 h after dosing. Results  Serum LH, FSH and serum testosterone were significantly suppressed by all doses of GIPET^?-enhanced oral acyline after 6 h, with suppression reaching a nadir 12 h after dosing. In addition, the 20 and 40 mg doses demonstrated sustained suppression of testosterone for 12–24 h. All hormone concentrations returned to normal 48 h after administration. There were no treatment-related serious adverse events, and laboratory assessments, including liver function tests and creatinine, were unaffected by treatment. Conclusions  Oral administration of GIPET^?-enhanced acyline significantly suppresses testosterone and gonadotropins in normal men without untoward side effects and might have utility in the management of prostate cancer.