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The Effect of Gonadotropin Withdrawal and Stimulation with Human Chorionic Gonadotrop

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by , 03-09-2012 at 05:15 PM (766 Views)
Dose-Dependent Increase in Intratesticular Testosterone by Very Low-Dose Human Chorionic Gonadotropin in Normal Men with Experimental Gonadotropin Deficiency

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Endocrine Research

Dose-Dependent Increase in Intratesticular Testosterone by Very Low-Dose Human Chorionic Gonadotropin in Normal Men with Experimental Gonadotropin Deficiency

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

- Author Affiliations

Departments of Medicine (M.Y.R., S.T.P., B.D.A., A.M.M., C.N.S., W.J.B., J.K.A.) and Obstetrics and Gynecology (K.L.) and Center for Research in Reproduction and Contraception (M.Y.R., S.T.P., B.D.A., A.M.M., C.N.S., W.J.B., J.K.A.), University of Washington, Seattle, Washington 98195; and Geriatric Research, Education, and Clinical Center (A.M.M., B.T.M.), Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108

Address all correspondence and requests for reprints to: Mara Y. Roth, M.D., University of Washington, 1959 NE Pacific Street, Box 357138, Seattle, Washington 98195. E-mail: [email protected].

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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.

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.
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Subjects and Methods

Healthy men, aged 1850 yr, were recruited for this study using rosters from prior research studies and newspaper and online advertisements. Informed consent was obtained from all subjects before the screening evaluation. Subjects had to have a normal history and physical examination (body mass index 1932 kg/m2), including a normal andrological history, normal testicular volume as measured by a Prader orchidometer, a normal prostate examination, normal serum gonadotropins and testosterone levels, and normal seminal fluid analysis based on the 1999 World Health Organization criteria with sperm concentration greater than 20 million/ml, greater than 50% motility, and greater than 15% normal morphology (16). Exclusion criteria included poor general health; abnormal blood test results; active skin conditions that would prevent the use of testosterone gel; active alcohol or drug abuse; history of testicular or scrotal surgery; infertility; chronic pain syndrome; use of steroids, testosterone, or medications that might affect androgen metabolism including ketoconazole, glucocorticoids; known bleeding disorder; or use of medications that may affect bleeding time (such as ongoing aspirin or warfarin use). All subjects had to agree to use a reliable form of contraception during the study.

The study design is illustrated in Fig. 1⇓. Briefly, after enrollment, subjects were randomized to one of five treatment groups and also randomized to the side of the unilateral testicular fine-needle aspirations (right vs. left on d 1 vs. d 10) by two random number sequences. Previous studies have shown a very high correlation between testes in a given man (12, 13). All subjects had a baseline testicular fine-needle aspiration on d 1. Local anesthesia was provided using 1% buffered lidocaine injected into the spermatic cord. A blood sample was obtained for quantification of serum hormones immediately after lidocaine administration and within 210 min of the aspiration. For the testicular aspiration, a 19-gauge needle was used as previously described (12, 13, 15). After the procedure, all subjects received a sc injection of the GnRH antagonist acyline (NeoMPS, San Diego, CA) 300 μg/kg into the abdominal skin. Subjects then received the first dose of medication based on treatment group randomization: group 1 received placebo hCG (normal saline) sc every other day for five doses, group 2 received 15 IU hCG (Pregnyl; Organon, Roseland, NJ) sc every other day for five doses, group 3 received 60 IU hCG sc every other day for five doses, group 4 received 125 IU hCG sc every other day for five doses, and group 5 received the 1% testosterone gel, Androgel (Solvay, Marietta, GA) 7.5 g daily for 10 d. hCG administration was performed by study personnel at scheduled visits.
Fig. 1.
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Fig. 1.

Study design.

On d 10, all subjects returned to the clinic for vital signs assessment, documentation of adverse events, and concomitant medications and a physical examination. All subjects then had a testicular fine-needle aspiration of the testis not aspirated on d 1, with contemporaneous serum hormone assessment after lidocaine administration. Subjects returned on d 17 and 40 for a physical examination, blood draw, and seminal fluid analysis to ensure that their physical examinations, hormone, and other laboratory measurements and seminal fluid parameters had returned to normal. Subjects whose blood or semen parameters had not returned to normal returned monthly until all values had normalized. The Institutional Review Board of the University of Washington approved this study protocol before study initiation. In addition, this trial was registered in advance (, National Clinical Trials no. 00839319).