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ABSTRACT

The inhibitory effect of various corticosteroids and synthetic analogues on the stress-induced release of corticotrophin was measured in adult male rats by means of the adrenal ascorbic acid depletion test. All the compounds examined were active, dexamethasone and prednisolone being the most effective inhibitors.

A single subcutaneous injection of a microcrystalline aqueous suspension of prednisolone (1.5 mg per rat), given about 2 hours before left-sided adrenalectomy, blocked completely the adrenal ascorbic acid depletion. Quantitative assays of a purified corticotrophin preparation were carried out with hypophysectomized and prednisolone-treated intact rats. The latter were less sensitive to corticotrophin, but the slopes of the calibration curves and the standard deviations appeared to be the same in both instances.

It is concluded that it is feasible to replace the surgical hypophysectomy by prednisolone pretreatment in the ascorbic acid depletion test for corticotrophin.

It has been reported by several investigators that a state of unresponsiveness may develop in man during long-term administration of adrenocorticotrophic hormone (ACTH). This refractory state manifests itself by a gradual or more sudden disappearance of the clinical, metabolic and hormonal effects, initially produced by the hormone. No convincing explanation of this phenomenon has so far been given. One might assume that an exhaustion of the adrenal cortex, failure of the target organs to respond to the corticosteroids, or the formation of specific inhibitory substances against ACTH (antihormone) could play a part. As ACTH is a protein hormone, it would indeed be difficult to understand why the ACTH preparations (usually of porcine origin) should not give rise to the formation of inhibitory substances in man, when administered parenterally for long periods. Holbrook et al. (1951) submitted 35 patients, suffering from rheumatoid arthritis, to long-term administration of ACTH. In 40 per

The preparation of the alcoholic solution of KOH for the Callow modification of the Zimmermann reaction (Callow et al., 1938) involves some difficulties. The grinding of the KOH pellets in a mortar is a rather hard job, and the substance is exposed to the air during the procedure. Furthermore the solution is stable only for a few days, when kept at 4° C. In the freezing box, however, it can be stored for 2—3 weeks, or more.

The stabilization of the KOH solution by ascorbic acid, introduced by Carter & Wilson (1947), was advantageous, as the solution was stable for at least 3 months, when kept cold. The procedure is, however, rather complicated and time-consuming. It is necessary to cool the reagents in crushed ice and to keep the solutions under nitrogen during the preparation as well as afterwards.

We had been using the Callow method of preparing the KOH

1. Hamburger C.: Correlation between blood groups and mental diseases. Significance of blood group determinations in inoculation malaria (in Danish). Hosp.tid. 72 (1929) 1188.

2. Hamburger C.: Untersuchungen über die Agglutininabilität und Absorptionsfähigkeit gewaschener Blutkörperchen. Acta path. microbiol. scand. 7 (1930) 191.

3. Hamburger C.: Untersuchungen über die Agglutinabilität und Absorptionsfähigkeit aufbewahrter Blutkörperchen. Acta path. microbiol. scand. 7 (1930) 199.

4. Hamburger C.: Über den Isoagglutiningehalt des Retroplazentarblutes. Z. Rassenphysiol. 3 (1930) 67 (also in Danish: Hosp.tid. 73 (1930) 757).

5. Hamburger C.: A case of luetic brain stem paralysis (in Danish). Hosp.tid. 73 (1930) Proc. neurol. Soc. 25.

6. Hamburger C. & Pedersen-Bjergaard K.: On the recovery of hypophyseal hormone from urine of pregnant women (in Danish). Ugeskr. Læg. 92 (1930) 647.

7. Hamburger C.: Hypophyseal hormone in urine of castrated male subjects (in Danish). Ugeskr. Læg. 93 (1931) 27.

8. Hamburger C.: Sur la différence entre le Prolan A, provenant de femmes enceintes et de castrats. C. R. Soc. Biol. (Paris) 112 (1933)

It is with some hesitation that I have accepted the invitation to present an Opening Lecture on 'Gonadotrophins', because it is several years since I have been actively engaged in research work on these hormones. On the other hand, I have had the opportunity of taking part in these investigations almost from their very beginning, and my first ten years of research were devoted to the gonadotrophic hormones.

The relation between various methods of administration of testosterone preparations and the excretion of 17-ketosteroids in man has been the subject of four previous publications by the author and his associates (Hamburger & Kaae, 1949, Hamburger, 1949, Hamburger, Birket-Smith & Kaae, 1952, Hamburger, 1956). Last year the author had the pleasure of reading an historical and geographical review on the use of suppositories in human medicine by the Danish pharmacist Else Ifversen (Ifversen, 1957). In view of the advantages of the rectal administration of therapeutic agents, an attempt was made to explore the possibility of applying androgens per rectum. Suppositories containing androgens had apparently not been on the market, and in the literature no references to the subject were found. The results of some preliminary experiments were very encouraging, and on the author's request 'Leo Pharmaceutical Products', Copenhagen, kindly prepared suppositories and tablets containing testosterone and some of its esters.

The possibility of substituting surgical hypophysectomy in the assay of corticotrophin according to Sayers et al. (1948) by a »chemical hypophysectomy« by the administration of adrenolytic drugs, has been the subject of several publications in the course of the last three years. Castaigne (1952) studied the adrenal ascorbic acid in rats treated with adrenolytic compounds and subsequently exposed to stress. As the release of corticotrophin was prevented, the author suggested the use of »hypophysectomie médicamenteuse« in the Sayers test. Aron, Chambon & Voisin (1953) confirmed these observations and found that an intramuscular injection of chlorpromazine (1–5 mg./100 gm. body weight) given to intact rats 4 hours before the operation inhibited the stress-induced corticotrophin release to such an extent that the animals could be used in the Sayers test. Holzbauer & Vogt (1954), however, found that the ascorbic acid depletion was not prevented in rats pre-treated with chlorpromazine (1–1.5 mg. subcutaneously/100

The pharmaceutical firms still endeavour to obtain new and better testosterone compounds, i. e. preparations combining a high biological activity with a long period of action. New esters of testosterone and organic acids have been tried in oily solution or as crystals in aqueous suspension. Some of these have been found to possess a very slow rate of absorption but the absorption may be delayed to such an extent that the quantity of testosterone liberated per unit of time is so small that no biological effect can be expected.

The effectiveness of new testosterone compounds is usually evaluated in one of the following ways: 1) administration to castrated male test animals (changes in weight of prostate or seminal vesicles in rats, or size of the comb of capons); 2) clinical effects in male subjects suffering from hypogenitalism (growth of pubic hair, quantity of semen, frequency of erections, sexual libido and