Testosterone Inhibition of Estradiol-Induced Stimulation of Adrenal 11 - and 18-Hydroxylation

Abstract

The regulatory roles of estrogen in corticosteroidogenesis have been studied in numerous research efforts and found to be both stimulatory (1, 2) and inhibitory (3)(4)(5)). Androgens are known to effect adrenal (6, 7) and liver hydroxylation of steroids (8, 9). Sex differences in adrenal size ( lo), steroid half-life (1 1, 12), and plasma steroid content (1 1) are well known. The reasons for these differences involve varied abilities to produce, maintain, and metabolize corticosteroids, but the basic mechanisms underlying the differences elude definitive exposition. The present paper presents studies on one aspect of steroidogenesis, namely 1 lpand 18-hydroxylation of DOC by adrenal homogenates after in vivo administration of testosterone and 17J3-estradiol and suggests an antagonism between the actions of these two hormones oin hydroxylation by adrenal mitochondria.Materials and Methods. Alternating left and right control adrenals were removed from Sprague-Dawley or Holtzman rats and pooled. Immediately thereafter each animal received an iv injection of 1 pg 17p-estradiol in 2 pl of propylene glycol and 0.25 ml normal saline. Thirty minutes later contralateral glands were removed, pooled, and homogenized in 0.25 M sucrose to a 0.5% adrenal suspension. Control or estradiol-treated adrenal homogenates were added to incubation flasks to give a final concentration of 1 mg adrenal per ml of incubation medium which was composed of 8 mM phosphate buffer (pH 7.3-7.4), 3.85 mM KCl, 0.9 mlM MgC12, 3.85 mM NaCl, and 20 mM SUCcinate. All preparatory steps were performed at 0-4'. Incubation flasks were preincubated 5 min with shaking a t 3 7 O immediately after addition of homogenate. Deoxycorticosterone (DOC) (2 p M , 0.005 ,&/flask) was then added and incubation proceeded for 8 min, after which metabolic activity was terminated by addition of 3 vol of cyclohexane. Samples were shaken and the cyclohexane extract removed, dried, and counted in a Packard Tricarb liquid scintillation spectrometer. The aqueous phase was then again similarly treated with 3 vol of chloroform. Duplicate extractions were performed previously in which the incubation products were separated by paper chrornotography in a benzene: formamide system. Comparison of the two methods showed the cyclohexane extract to contain DOC and the chloroform fraction to contain corticosterone (B) and 18-OH DOC. Recoveries were 93.2 t 1.9% for the DOC and 92.1 t 2.5% for the B and 18-OH DOC Percentage conversion to B and 18-OH DOC was used to calculate nanomoles of DOC converted per mg protein per minute. Protein determination was by the method of Lowry et al. (14).Orchiectomies were performed via midline scrota1 incision. Depot testosterone1 was administered immediately after surgery, which was 7 to 17 days prior to removal of the adrenals.Results. Adrenal homogenates from intact female rats treated with 1 pg 17p-estradiol iv 30 min prior to sacrifice hydroxylated more DOC than control adrenals from the same animals, the average values for 10 experiments being respecti...

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