Dose-Dependent Increase in Intratesticular Testosterone by Very Low-Dose Human Chorionic Gonadotropin in Normal Men with Experimental Gonadotropin Deficiency-(this one is new, 2010, newer than all the studies using massive doses)
M. Y. Roth,
S. T. Page,
K. Lin,
B. D. Anawalt,
A. M. Matsumoto,
C. N. Snyder,
B. T. Marck,
W. J. Bremner, and
J. K. Amory
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Abstract
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 Inter-testicular Testosterone was 2508 nmol/liter (1753, 3502 nmol/liter).
Inter-testicular Testosterone 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.
Intratesticular testosterone (IT-T) is essential for spermatogenesis. In men with infertility secondary to hypogonadotrophic hypogonadism, injections of human chorionic gonadotropin (hCG), which mimics the activity of LH, stimulates the testicular biosynthesis of testosterone. Treatment with hCG (often in combination with injections of FSH) leads to spermatogenesis and fertility in approximately two thirds of men (
1).
In rodents, 75% reductions in IT-T are still compatible with normal spermatogenesis; however, sperm production falls off sharply below this threshold (2,3,4). However, the minimum concentration of IT-T necessary for spermatogenesis in man is unknown. This may be relevant in male hormonal contraceptive development because spermatogenesis is not consistently suppressed in some men, despite marked suppression of gonadotropins. In these men,
persistently elevated IT-T concentrations may allow for ongoing spermatogenesis despite gonadotropin suppression (5,6,7,8). A better understanding of the relationship between low concentrations of IT-T and spermatogenesis would be useful to optimize the treatment of male infertility and would inform efforts to develop a male hormonal contraceptive.
Understanding the intratesticular steroid environment in man is challenging. Until recently methods for measuring intratesticular hormone concentrations in men required testicular biopsy (
9,
10,
11); therefore, prior studies were performed mainly in infertile men requiring testicular biopsy and general anesthesia for the evaluation and treatment of their condition. More recently the technique of fine-needle tissue aspiration has been used to obtain intratesticular fluid in normal men (
5,
12,
13,
14). This technique can be safely performed in the outpatient setting using local anesthesia without serious adverse effects. We previously used this technique to examine the dose-response relationship between hCG as a proxy for LH and IT-T in normal men. However, although the doses of hCG in our previous work were lower than those used to treat patients with hypogonadotropic hypogonadism, IT-T concentrations were similar to those in untreated normal men (
15). In addition, our previous work relied on exogenous testosterone to suppress the hypothalamic-pituitary-gonadal axis, and there was concern that the exogenous testosterone could potentially increase IT-T concentrations. Therefore, in this study, we experimentally induced low levels of IT-T in normal men using the GnRH antagonist, acyline, and subsequently stimulated testicular testosterone biosynthesis with very low doses of hCG, lower than we used previously. In addition, we included a group of men treated with exogenous testosterone to determine whether treatment with testosterone would affect intratesticular steroid concentrations. In this way, we sought to ascertain the dose-response relationship between very low doses of LH-like stimulation and IT-T in man.
