Robert Gaunt

Pharmacologic alteration of steroid hormone functions

A large number of compounds can modify the function, synthesis, or metabolism of steroid hormones. These are not necessarily otherwise related chemically or pharmacologically. The drugs used as examples in this review were selected to show the wide variety of potential sites and modes of action. While many compounds have been shown to interfere with one or another step in the biosynthesis of corticosteroids, the number of known substances having any profound effect on gonadal steroidogenesis is surprisingly few. On the other hand, many more compounds are known either to mimic or modify the end‐organ response to gonadal than to adrenal steroids. The field of endocrine pharmacology is being rapidly widened as systematic searches are now being made for drugs which affect endocrine function either as a primary or incidental action.

Sulfonamide compounds with high diuretic activity

Abstract Several related compounds are more active than chlorothiazide in enhancing water, sodium, and, generally, potassium excretion in rats. Of these, hydrochlorothiazide had from seven to twenty-one times the potency of chlorothiazide, depending upon the parameter measured and conditions of test. After administration of the drug, an increased rate of sodium excretion preceded marked change in water excretion. Hydrochlorothiazide modified renal response to vasopressin, reserpine, syrosingopine, aldosterone, DCA, and prednisolone and to adrenalectomy. It did not modify the hypertensive response to hydrocortisone but did inhibit blood pressure rise in adrenal regeneration hypertension when given chronically, but not acutely.

ACTH-suppressing action of aldosterone.

Summary Crystalline aldosterone suppressed the release of pituitary ACTH in animals exposed to the stress of cold as judged by adrenal ascorbic acid determinations. Its activity in this respect approximated one-third that of cortisone and eight times that of desoxycorticosterone

Effect of New Adrenal Steroids on Electrolyte and Water Excretion

Summary The effects of prednisone, prednisolone, hydrocortisone and desoxycorticosterone on excretion of water, sodium, and potassium, were compared in water-loaded adrenalectomized rats. All steroids stimulated water diuresis and potassium excretion. Hydrocortisone, prednisone and prednisolone were equi-potent; desoxycorticosterone was weaker. Hydrocortisone, prednisone and prednisolone stimulated sodium excretion at all doses having any effect and were again approximately equipotent. Desoxycorticosterone had the opposite effect and caused sodium retention. The relative inability of the Δ1-steroids to cause sodium retention under conditions of clinical use is, therefore, not associated with any comparable inability to cause natriuresis under appropriate circumstances.

A new diuretic drug dependent on the adrenal for its action.

Summary 2- [2,6-Diphenyl-4 (1-pyrrolidinyl) cyclohexyl] - pyridine (Su- 15049) caused marked natriuresis and water diuresis in rats without consistent effects on potassium excretion. Its natriuretic actions were abolished by adrenalectomy. In adrenalectomized animals Su-15049 did not modify the response to aldosterone except when the latter was given in the massive doses (0.5 mg/rat) expected to have some glucocorticoid-like effects. Cortisol or corticosterone, however, made adrenalectomized animals responsive to Su-15049, and the presence of cortisol permitted the drug to antagonize the Na-retaining effects of aldosterone. No corticoid substitution therapy was found, however, that enabled adrenalectomized animals to respond to Su-15049 in regard to potassium excretion precisely as did normal ones. Su-15049 has some activity in conventional anti-inflammatory tests.

Steroids which prevent cortisone from causing atrophy of the adrenal.

Several workers 1, 4, 5, e, 10 have shown that testosterone and other steroids have a limited effect in preventing the adrenal atrophy resulting from hypophysectomy. WINTER, ~-~OLLINGS and STEBBINS 8, 9, GAUNT, HOWELL, ANTONCHAK and LEATHEM ~, 3 and ZIZrSE 11 found that methylandrostenediol or testosterone propionate prevented partially or completely the adrenal atrophy which follows cortisone t~eatment. The work from our laboratory included observations on numerous other substances. Several C-19 and C-20 steroids were found to antagonize the adrenalinhibiting effect of cortisone, whereas all the C-21 steroids tried were either weak or ineffective. I t was observed a, 9 that adrenal weight maintenance was associated with the maintenance of essentially normal sudan-staining adrenal lipids. Except for the zona glomerulosa, the adrenals of animals treated with cortisone alone were almost devoid of stainable lipid. Under the conditions used the steroids antagonizing the effects of cortisone had little, if any, effect on the adrenal when given alone. I t is known, however, that several of them will cause adrenal a trophy if given in sufficient dosage and for sufficient time v. The work reported here is an extension of the above-mentioned studies and was conducted for the following purposes: 1. To explore the actions of selected additional compounds with the hope of being able to define the characteristic chemical structure of the steroids requisite for the observed antagonism to cortisone; 2. to determine which of the active steroids were most effective in preventing cortisone inhibition of the adrenal; 3. to ascertain whether the action of cortisone could b e antagonized over a long period of time; and 4. to compare the action of estrogenic compounds to those of non-estrogenic steroids with respect to their influence on the adrenal.

Effect of an Adrenal 17α-Hydroxylase Inhibitor on Gonad Function

Summary 7-Chloro-3,4-dihydro-2-(3-pyridyl)-1 (2H)-napthalenone (Su-10603), a compound known to inhibit particularly 17α-hydroxylation in the adrenal of the dog, was studied for its effects on gonad and adrenal function in rats. Administration to immature animals for 30 days (100-400 mg/kg/day) inhibited growth of seminal vesicles, ventral prostates, levatores ani and uteri without other obvious effects. It was similarly active in adrenalectomized rats. These results are consistent with previous demonstrations that the drug interferes with testosterone synthesis in vitro. The Su-10603 also inhibited the response of immature males but not females to chorionic gonadotropin as judged by weights of sex accessories. It interfered with the normal processes of pregnancy by means as yet undetermined. Unlike the situation in the dog, it was without effect on adrenal morphology or the corticosterone secretion rate in rats.

Effect of Aminoglutethimide in Adrenal Regeneration Hypertension

Summary Aminoglutethimide, when given by stomach tube daily to rats for 7 weeks beginning immediately after adrenal enucleation, reduced markedly the development of adrenal regeneration hypertension. This effect was not due to a reduction of intake of salt drinking solutions. Relative to controls, the drug did not influence renal, cardiac, or thyroid weights. It is postulated that the drug inhibited the secretion of an as yet unidentified steroid that causes adrenal regeneration hypertension.