Gonadotrophin and testosterone suppression by 7α-methyl-19-nortestosterone acetate administered by subdermal implant to healthy men

Noé, Gabriela; Suvisaari, Janne; Martin, Cécile; Moo-Young, Alfred J.; Sundaram, K.; saleh, shahenda; Quintero, Enrique; Croxatto, Horacio B.; Lähteenmäki, Pekka

doi:10.1093/humrep/14.9.2200

Cited by 41 publications

(20 citation statements)

References 12 publications

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“…In vivo MENT Ac release rate was estimated from recovered implants, following the extraction procedure described by Noe et al (17). Monthly postremoval visits continued until sperm concentrations returned to 20 million/ml or higher.…”

Section: Methodsmentioning

confidence: 99%

“…7␣-Methyl-19-nortestosterone (MENT) is a synthetic androgen that is more potent than T for gonadotropin suppression and is resistant to 5␣-reduction, with potential advantages when used as a contraceptive (15)(16)(17). MENT acetate (Ac) has diffusion characteristics that are well suited for delivery via subdermal implants.…”

mentioning

confidence: 99%

“…MENT Ac is rapidly hydrolyzed in vivo to MENT, the biologically active molecule (18). Before undertaking this trial, the MENT implant system was studied in a 4-wk trial in normal men (17) and in a 6-wk trial in hypogonadal men (19). No adverse toxicological effects were observed in either trial, permitting initiation of the dose-finding trial described here.…”

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confidence: 99%

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A Clinical Trial of 7α-Methyl-19-Nortestosterone Implants for Possible Use as a Long-Acting Contraceptive for Men

Eckardstein

Noé

Brache

et al. 2003

The Journal of Clinical Endocrinology &Amp; Metabolism

107

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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.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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A Clinical Trial of 7α-Methyl-19-Nortestosterone Implants for Possible Use as a Long-Acting Contraceptive for Men

Eckardstein

Noé

Brache

et al. 2003

The Journal of Clinical Endocrinology &Amp; Metabolism

107

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“…#E-8875) (Sigma, St. Louis, MO) to ethylene and vinyl acetate (EVA) tubing (Elvax 770, 9% VA; 2.15 mm ID Â 2.4 mm OD, DuPont, Wilmington, DE). Earlier studies have estimated that implants using EVA had a steroid (e.g., MENT, 7a-methyl-19-nortestosterone) release rate of 90 mg/cm/day in vivo (in humans) when placed under the skin (Noe et al, 1999;von Eckardstein et al, 2003) versus $30 mg/cm/day for Silastic implants (Kincl et al, 1968;Robaire et al, 1979). Both ends of the EVA tubing were sealed by heat using a soldering iron (Cat.…”

Section: Preparation Of Steroid Implantsmentioning

confidence: 99%

Disruption of Sertoli‐germ cell adhesion function in the seminiferous epithelium of the rat testis can be limited to adherens junctions without affecting the blood–testis barrier integrity: An in vivo study using an androgen suppression model

Xia

Wong

Lee

et al. 2005

Journal Cellular Physiology

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During spermatogenesis, both adherens junctions (AJ) (such as ectoplasmic specialization (ES), a testis-specific AJ type at the Sertoli cell-spermatid interface (apical ES) or Sertoli-Sertoli cell interface (basal ES) in the apical compartment and BTB, respectively) and tight junctions (TJ) undergo extensive restructuring to permit germ cells to move across the blood-testis barrier (BTB) as well as the seminiferous epithelium from the basal compartment to the luminal edge to permit fully developed spermatids (spermatozoa) to be sloughed at spermiation. However, the integrity of the BTB cannot be compromised throughout spermatogenesis so that postmeiotic germ cell-specific antigens can be sequestered from the systemic circulation at all times. We thus hypothesize that AJ disruption in the seminiferous epithelium unlike other epithelia, can occur without compromising the BTB-barrier, even though these junctions, namely TJ and basal ES, co-exist side-by-side in the BTB. Using an intratesticular androgen suppression-induced germ cell loss model, we have shown that the disruption of AJs indeed was limited to the Sertoli-germ cell interface without perturbing the BTB. The testis apparently is using a unique physiological mechanism to induce the production of both TJ- and AJ-integral membrane proteins and their associated adaptors to maintain BTB integrity yet permitting a transient loss of cell adhesion function by dissociating N-cadherin from beta-catenin at the apical and basal ES. The enhanced production of TJ proteins, such as occludin and ZO-1, at the BTB site can supersede the transient loss of cadherin-catenin function at the basal ES. This thus allows germ cell depletion from the epithelium without compromising BTB integrity. It is plausible that the testis is using this novel mechanism to facilitate the movement of preleptotene and leptotene spermatocytes across the BTB at late stage VIII through early stage IX of the epithelial cycle in the rat while maintaining the BTB immunological barrier function.

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“…Earlier studies have shown that implants using EVA had a steroid release rate (e.g. of 7 -methyl-19-nortestosterone) of 90 µg/cm/day in vivo when placed under the skin in humans (Noe et al 1999, von Eckardstein et al 2003. Animal surgery was performed in adult rats (400 g bw) under anesthesia using ketamine HCl at 60 mg/kg bw (i.m.).…”

Section: Preparation Of Steroid Implants and Their Placement Subdermamentioning

confidence: 99%

α2-Macroglobulin expression in the liver in response to inflammation is mediated by the testis

Lui

Cheng²,

Mruk³

et al. 2005

Journal of Endocrinology

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Earlier studies have shown that germ cells or germ cell-conditioned media are capable of regulating 2 -macroglobulin ( 2 -MG, a non-specific protease inhibitor) expression by Sertoli cells and hepatocytes cultured in vitro. These results illustrate a possible physiological link between testes and liver regarding 2 -MG production. Using a series of surgical procedures including castration, hemicastration, and hepatectomy coupled with Northern blot and immunoblot analyses, we report herein that the surge in 2 -MG expression in the liver in response to inflammation is indeed regulated, at least in part, by the testis via testosterone. It was found that hepatectomy induced at least a tenfold increase in the steady-state mRNA and protein production of 2 -MG in the liver. However, castration induced a mild but not statistically significant induction of 2 -MG in the liver in contrast to sham operation or hemicastration alone, when hemicastration alone could induce liver 2 -MG production by almost fourfold. Perhaps most important of all, hepatectomy accompanied by castration significantly reduced the liver 2 -MG response to the surgery-induced inflammation compared with hepatectomy alone, illustrating that the removal of the testicles can induce a loss of signal communications between the testis and the liver, rendering a significant loss of the 2 -MG response to experimentally induced inflammation in the liver. Interestingly, this lack of response of the liver to surgery-induced inflammation regarding 2 -MG production following castration could be restored, at least in part, by using testosterone implants placed subdermally 6 days prior to orchiectomy. Collectively, these results illustrate that a physiological link does indeed exist between the testis and the liver, and that testes per se can influence the liver 2 -MG expression in response to inflammation in vivo possibly via testosterone or testosterone-induced biological factor(s).

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Gonadotrophin and testosterone suppression by 7α-methyl-19-nortestosterone acetate administered by subdermal implant to healthy men

Cited by 41 publications

References 12 publications

A Clinical Trial of 7α-Methyl-19-Nortestosterone Implants for Possible Use as a Long-Acting Contraceptive for Men

A Clinical Trial of 7α-Methyl-19-Nortestosterone Implants for Possible Use as a Long-Acting Contraceptive for Men

Disruption of Sertoli‐germ cell adhesion function in the seminiferous epithelium of the rat testis can be limited to adherens junctions without affecting the blood–testis barrier integrity: An in vivo study using an androgen suppression model

α2-Macroglobulin expression in the liver in response to inflammation is mediated by the testis

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