Gonadotropin dynamics in XX males.

Hypothalamic-pituitary gonadotropin function was evaluated in two postpubertal XX males. Serum levels of LH and FSH were moderately elevated, and the serum testosterone level was low. A subnormal response by testicular Leydig cells to hCG was observed. The LH and FSH responses to LRH were normal. A significant LH increase was observed after castration. Weekly administration of testosterone enanthate (250 mg) for 10 consecutive weeks caused a reduction (greater than 75%) in gonadotropins and abolishment of the LRH pituitary response. No differences were observed in terms of gonadotropin dynamics compared with other forms of hypergonadotropic hypogonadism. These results indicate that XX males exhibit hypergonadotropic hypogonadism secondary to testicular failure with a preserved androgen responsiveness of the hypothalamic-pituitary unit.

Mechanism of action of levonorgestrel: in vitro metabolism and specific interactions with steroid receptors in target organs.

Levonorgestrel (LNG) is a synthetic steroid that displays potent progestational and androgenic effects but it lacks estrogen-like activity. To examine the mode of action of this progestin, we studied its metabolism in vitro in target organs and the specific interactions of LNG and its metabolites with putative steroid receptors. The results demonstrated that [3H]LNG was efficiently converted to A-ring reduced derivatives when incubated with rat hypothalamus and pituitary. Under optimal incubation conditions, [3H]5 alpha-dihydro LNG (5 alpha-LNG) and [3H]3 alpha,5 alpha-tetrahydro LNG (3 alpha,5 alpha-LNG) were identified as the major metabolic conversion products, while [3H]3 beta,5 alpha-LNG formation occurred to a lesser extent. A-ring reduction of LNG was NADPH-dependent. Assessment of the relative binding affinities of LNG and its derivatives to progesterone (PR), androgen (AR) and estrogen (ER) receptors by displacement analysis revealed that unchanged LNG binds with high affinity to PR and AR but not to ER. 5 alpha-LNG exhibited a diminished though significant interaction with PR and an enhanced binding affinity for AR as compared with LNG, indicating that 5 alpha-reduction of LNG increases its affinity for AR. The most striking finding was that further reduction of the 5 alpha-LNG molecule at C-3 abolished its binding activity to PR, AR, and even to ER. The overall data provides a plausible explanation for the lack of estrogen agonistic action of LNG and for its potent progestational and androgenic effects.

Regional and temporal progression of reactive astrocytosis in the brain of the myelin mutant taiep rat.

Reactive astrocytosis in taiep rats was shown by glial fibrillary acidic protein (GFAP) immunoreactivity measured by means of enzyme-linked immunosorbent assay and indirect immunofluorescence. Increased GFAP immunoreactivity was first observed in the brainstem of 15-day-old taiep rats and was widespread throughout all brain regions at 6 months of age. Characteristically, astrocytes were hypertrophic and displayed strong GFAP fluorescence. The pattern of these reactive cells may correlate with the process of dysmyelination in the taiep rat.

Stereospecificity of the intracellular binding of norethisterone and its A-ring reduced metabolites.

The interaction of norethisterone (NET) and four A-ring reduced metabolites of NET with cytosol receptors for progesterone (PR), androgen (AR), and estrogen (ER) was investigated. Cytosol preparations from: uteri of adult estrogen-primed castrated rats, ventral prostates of adult castrated rats and uteri of immature rats were used as the source of PR, AR, and ER respectively. 3H-Labeled ORG-2058, R-1881, and 17 beta-estradiol were used as the radioligands. The results of competitive studies disclosed that: the most efficient competitor for PR binding sites was NET (Ki = 1.1 X 10(-7) M) followed by 5 alpha-dihydro NET (5 alpha-NET), whereas the 3 alpha,5 alpha; 3 beta,5 alpha and 3 alpha,5 beta-tetrahydro NET derivatives were ineffective the most efficient competitor for AR binding sites was 5 alpha-NET (Ki = 1 X 10(-8), immediately followed by NET, while the three tetrahydro NET derivatives were not competitors and remarkable competition for ER binding sites was only exhibited by the 3 beta,5 alpha-tetrahydro NET derivative (Ki = 4.6 X 10(-8) M) and to a lesser extent by its 3 alpha,5 alpha-epimeric alcohol, while NET and 5 alpha-NET were completely ineffective. These findings demonstrate the stereospecificity of the intracellular binding of NET and its reduced metabolites with cytosol steroid putative receptors, and provide biochemical support to the understanding of the variety of hormone-like effects observed after the in vivo administration of NET.