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

Abstract

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.

Comparison of 7α-methyl-19-nortestosterone effectiveness alone or combined with progestins on androgen receptor mediated-transactivation

“…It is also important to mention that although MENT does not undergo further metabolism to 5a-reduced metabolites, reduction of the 4-ene-double bond of LNG and NET does not change Transcriptional androgenicity of MENT significantly their androgenic transcriptional activities (Sundaram et al 1995, Garcia-Becerra et al 2004) so as to have unwanted effects upon the prostate. Our results may also support promising approaches for male fertility regulation in terms of raising the dose of progestins to improve sperm suppression and minimize MENT nonreproductive androgenic effects (Anderson & Baird 2002, von Eckardstein et al 2003, Walton et al 2007.…”

“…Recently, Walton et al (2007) showed that combination of MENT with a progestin resulted in rapid inhibition of spermatogenesis similar to the combined testosterone formulation and pointed out the importance of the synthetic progestin dose over the androgen dose in improving spermatogenesis suppression. However, subjects treated with four MENTimplants exhibited higher and longer spermatogenesis suppression (von Eckardstein et al 2003) than subjects treated with two MENT implants plus two ENG implants (Walton et al 2007). Four MENT implants induced azoospermia or severe oligozoospermia (sperm count !1!10 6 /ml) in 82% and 100% of subjects during the first and second 6-month periods of treatment respectively.…”

“…Indeed, in contrast to testosterone, MENT is less potent on male accessory sex glands compared with its ability to suppress gonadotropins; MENT otherwise can be aromatized to 7a-methyl-E 2 (LaMorte et al 1994). These observations indicate that MENT, as a component for androgen replacement therapy or male contraceptive, has health-promoting effects, particularly by avoiding hyperstimulative effects on the prostate, including prostatespecific antigen (Kumar et al 1992, Morali et al 1993, Cummings et al 1998, Anderson et al 2003, von Eckardstein et al 2003, Walton et al 2007, and those derived from MENT aromatization (LaMorte et al 1994, Anderson et al 1999.…”

“…In this regard, MENT when administered to healthy men leads to gonadotropin suppression and inhibition of spermatogenesis making it potentially useful as a male contraceptive (von Eckardstein et al 2003). In the case of testosterone, combination with gonadotropin-inhibiting agents such as progestins results in a more effective formulation for spermatogenic suppression than testosterone alone (Bebb et al 1996).…”

Update on Male Hormonal Contraception: Is the Vasectomy in Jeopardy?

“…A dose response trial of 7a-methyl-19-nortestosterone (MENT) was initiated in 35 healthy volunteers to assess effects of serum gonadotropins and sperm production. 52 This synthetic androgen is more potent than testosterone, is resistant to 5 a-reduction and has diffusion characteristics that make it wellsuited for a depot implant. Initial data showed relatively good efficacy, but typical testosteronerelated side effects.…”