Pharmacokinetics and pharmacodynamics of 7alpha-methyl-19-nortestosterone after intramuscular administration in healthy men.

7alpha-Methyl-19-nortestosterone (MENT) is a potent synthetic androgen that is resistant to 5alpha-reductases and therefore less prone to over-stimulate the prostate. It is a good candidate for implant administration in long-term androgen replacement therapy for hypogonadal men or as part of a male contraceptive system. To investigate the pharmacokinetics of MENT after i.m. administration, single i.m. injections of 2, 4 or 8 mg of micronized MENT were given in aqueous suspension to 18 healthy men in two clinics. Blood was sampled frequently for 8 h and 1, 2, 3, 4 and 9 days after the injections. Serum MENT concentrations were determined by radioimmunoassay. Peak MENT concentrations were dose-dependent and were reached about 1-2 h after the injections. Doubling the dose of MENT resulted in an increase of 60% in peak serum MENT concentrations. The mean +/- SE clearance rate was 1790 +/- 140 l/day. The antigonadotrophic activity of MENT was investigated by giving six consecutive daily i.m. injections of 1, 2 or 4 mg of MENT to 24 healthy men in two clinics. Blood was sampled before each injection and up to 24 days after the last injection. Serum testosterone and gonadotrophin concentrations (determined by radioimmunoassay and fluoroimmunoassay respectively) decreased in a dose-dependent and statistically significant manner. The highest dose caused a 74% fall in testosterone, a 70% fall in luteinizing hormone, and a 57% fall in follicle stimulating hormone concentrations. MENT injections did not cause any side-effects. The results show that MENT is a potent antigonadotrophic agent in men.

Mechanisms of action of intrauterine devices.

The major effect of all intrauterine devices (IUD) is to induce a local inflammatory reaction in the endometrium whose cellular and humoral components are released into the uterine cavity. This inflammatory reaction has a variable effect on the reproductive strategy of the species studied. For example, this foreign body reaction can be localized within the uterus of rodents; and in farm animals it can have striking extrauterine effects. Thus, the action of IUDs in humans cannot be discerned from animals. In humans, copper ions released from Cu-IUDs enhance the inflammatory response and reach concentrations in the luminal fluids of the genital tract that are toxic for spermatozoa and embryos. In women using the IUD, the entire genital tract seems affected, at least in part, because of luminal transmission of the fluids that accumulates in the uterine lumen. This affects the function or viability of gametes, decreasing the rate of fertilization and lowering the chances of survival of any embryo that may be formed, even before it reaches the uterus. Studies on the recovery of eggs from women using IUDs and from women not using contraception show that embryos are formed in the tubes of IUD users at a much lower rate compared with nonusers. This is believed to be the major action of IUDs. Therefore, the common belief that the major mechanism of action of IUDs in women is through destruction of embryos in the uterus (i.e., abortion) is not supported by the available evidence. In Cu-IUD users, it is likely that few spermatozoa reach the distal segment of the fallopian tube, those that encounter an egg may be in poor condition. Thus, the few eggs that are fertilized have little chance for development and their possibility for survival in the altered tubal milieu become worse as they approach the uterine cavity.

PIP: All IUDs induce a local inflammatory reaction that disturbs the functioning of the endometrium and myometrium and changes the microenvironment of the uterine cavity. Moreover, these effects alter signaling between uterus and ovary. The entire genital tract seems affected, at least in part because of luminal transmission of fluids accumulating in the uterine lumen. Copper or progesterone-releasing IUDs may attenuate or accentuate the inflammatory response, disturb the physiology of the gametes in the female genital tract, or destroy the viability of the embryos or endometrial receptivity to implantation. Studies on the recovery of eggs reveal that embryos are formed in the tubes of IUD users at a significantly lower rate compared to non-users. This, rather than the destruction of embryos in the uterus, appears to be the IUD's major mechanism of action.

Receptors for androgen-binding proteins: internalization and intracellular signalling.

In plasma, most steroid hormones are bound and transported by the specific binding protein, testosterone-estradiol-binding globulin (TeBG). For years, it was believed that the only function of this protein was to regulate the concentration of free steroids in plasma. However, a number of reports have provided evidence for the presence of specific TeBG receptors on plasma membranes. Furthermore, the interaction of TeBG with its receptor was shown to be inhibited when steroids are bound to TeBG, suggesting that TeBG is an allosteric protein. The purpose of this manuscript is to review the evidence that androgen-binding proteins bind to membrane receptors, and, in some cells, this binding stimulates cAMP accumulation, and transfer TeBG/ABP into tissue as a consequence of receptor mediated endocytosis. Recent studies from our laboratories have demonstrated binding and uptake of TeBG by MCF-7 breast cancer cells. The interaction of unligated rabbit TeBG with membranes from MCF-7 cells resulted in a time and concentration-dependent increase in adenylate cyclase activity. The TeBG alone also had a reproducible effect on intact cells by increasing cAMP accumulation by 30-35%. The addition of DHT to cells, after TeBG has been allowed to bind, resulted in increases in cAMP of greater than 4-fold. This effect was not blocked by antiandrogens. These data support the hypothesis that extracellular SHBG is a regulator of cellular function through a membrane receptor that is coupled to adenylate cyclase.

Induction of male sexual behavior in the rat by 7 alpha-methyl-19-nortestosterone, an androgen that does not undergo 5 alpha-reduction.

The synthetic steroid 7 alpha-methyl-19-nortestosterone (MENT) binds with high affinity to the androgen receptor and exerts biological effects at some peripheral target tissues with a potency greater than that of naturally occurring androgens. In vivo, MENT does not undergo enzymatic 5 alpha-reduction and as a consequence, its biologic action on prostate and other organs of the male reproductive tract is not amplified as is that of testosterone (T). Thus, in castrated rats, a dose of MENT that will maintain normal muscle mass and gonadotropin levels will not maintain normal prostate and seminal vesicle weights. To investigate the ability of MENT to restore male sexual behavior in castrated rats, varying doses of MENT acetate were administered for 4 wk by use of s.c. mini-osmotic pumps. Animals treated with T acetate (200 micrograms/day) and nontreated intact animals served as positive controls, while a group of animals receiving vehicle alone were the negative controls. Steroid acetates are rapidly converted to T and MENT in blood. Appropriate steroid delivery was assessed by measurement of serum androgen concentrations. Male behavioral parameters were recorded twice per week. At the end of treatment, the weights of sex accessory organs were also recorded. The administration of MENT acetate at daily doses of 100 micrograms and 10 micrograms induced full copulatory behavior in a manner similar to that observed with doses of 200 micrograms T acetate.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding of sex-hormone-binding globulin (SHBG) to testicular membranes and solubilized receptors.

UNLABELLED: Sex-hormone-binding globulin (SHBG) binds to a specific protein on the surface of prostate, epididymis, and a human breast cancer cell line (MCF-7), and is internalized by these cells. The present study demonstrated specific binding of SHBG to receptor on membranes prepared from rat testes. The binding was saturable, specific, and time and temperature dependent. Scatchard analysis of these binding studies suggested that SHBG binds to a single class of sites on testicular membranes with a Kd at 37 degrees C of 5 x 10(-8) M and a binding capacity of 30 +/- 0.6 pmol/mg protein. These binding characteristics are similar to the SHBG receptor on human prostate and MCF-7 cells. Solubilization of the receptor resulted in a 5-fold increase in its binding capacity (158 +/- 0.3 pmol/mg protein) and a 10-fold decrease in binding affinity (Kd at 37 degrees C = 6.5 x 10(-7) M). The apparent molecular weight of the testicular SHBG receptor, as estimated by gel filtration, was M(r) = 174,000. CONCLUSION: a specific binding site for SHBG was identified on testicular membranes. This binding site has been tentatively identified as a SHBG receptor based on its physical properties in testicular membrane preparations and following solubilization.