Neurosteroids are steroids produced within the nervous system. Based on behavioural responses evoked in animals by synthetic steroid injections, several studies suggested neurosteroid involvement in important neurophysiological processes. These observations should be correlated only to neuroactive effects of the injected steroids. Neurosteroids mostly control the CNS activity through allosteric modulation of neurotransmitter receptors within concentration ranges used by neurotransmitters themselves. Therefore, neurosteroid production within pathways controlling a neurophysiological process is necessary to consider neurosteroid involvement in that process. Because of the increasing speculation about pain modulation by neurosteroids based on pharmacological observations, we decided to clarify the situation by investigating neurosteroidogenesis occurrence in sensory pathways, particularly in nociceptive structures. We studied the presence and activity of cytochrome P450side chain cleavage (P450scc) in rat pain pathways. P450scc-immunoreactive cells were localized in dorsal root ganglia (DRG), spinal cord (SC) dorsal horn, nociceptive supraspinal nuclei (SSN) and somatosensory cortex. Incubation of DRG, SSN or SC tissue homogenates with [3H]cholesterol yielded the formation of radioactive metabolites including [3H]pregnenolone of which the synthesis was reduced in presence of aminogluthetimide, a P450scc inhibitor. These first neuroanatomical and neurochemical results demonstrate the occurrence of neurosteroidogenesis in nociceptive pathways and strongly suggest that neurosteroids may control pain mechanisms.

Cellular distribution and bioactivity of the key steroidogenic enzyme, cytochrome P450side chain cleavage, in sensory neural pathways.

During the last decade aminoglutethimide has been recognised as a valuable alternative in endocrine therapy for advanced breast cancer. Although some side effects do occur, most often these are initial effects which subside within a few weeks, and cessation of therapy is not usually indicated. Aminoglutethimide was originally introduced as an inhibitor of steroidogenesis in the adrenal cortex. It was soon recognised, however, that inhibition of the non-glandular aromatase, blocking the conversion of androgenic prohormones to oestrogens, was more important, resulting in decreased blood levels of oestrogens. In this review the role of aromatase inhibition as the only important aspect of the mechanism of action of aminoglutethimide is challenged. Evidence has accumulated during the last few years that aminoglutethimide is a most potent inducer of microsomal enzymes. In addition to the pharmacological implications this has (suggesting important interactions), it also points to the possibility that levels of oestrogens are decreased due to accelerated metabolism of these hormones. Based on new experimental data, and also clinical work with alternative aromatase inhibitors, it appears that the antitumour activity of aminoglutethimide may be due to both aromatase inhibition and accelerated metabolism of oestrogens. This seriously challenges the importance of aromatase inhibition alone as a strategy in endocrine therapy of breast cancer, and furthermore suggests that accelerated metabolism of key hormones is an alternative strategy to be explored.

Mechanisms of action of aminoglutethimide as endocrine therapy of breast cancer.

TEROID HORMONES and their synthetic analogues are extensively used as antiinflammatory agents, immunosuppressants, and contraceptives, and often used in combination with other drugs. The interaction between steroids and other drugs is complex and may involve alterations in steroid hormone secretion, excretion, metabolic degradation, and steroidogenesis. Knowledge of drug-steroid interactions, therefore, becomes a matter of practical concern to the physician caring for patients who receive steroids along with a variety of other medications. This review will focus on the interactions between steroids and some commonly used and interesting drugs. Drugs influence steroid metabolism by altering the peripheral degradation of the steroid, inhibiting steroidogenesis, or affecting the hypothalamus or pituitary with resultant alterations in steroid production. This article will review the first two mechanisms.

Effects of some clinically encountered drugs on steroid synthesis and degradation

SUMMARY
The effect of aminoglutethimide (AG) 4 × 250 mg (670 mg/m2 daily by mouth) on the excretion of free cortisol (radio-immunoassay) and of its metabolites THE, THF-alloTHF, cortolone and β-cortolone (gas chromatography on capillary column) was studied monthly during 3 – 5 months in four adolescents (one girl, three boys) aged 15.9 – 18 years with Cushing's syndrome due to bilateral adrenal hyperplasia, but without evidence of a pituitary tumour.

Under AG, all compounds decreased to a minimum after 1 – 2 months. The decrease of THE- THF-allo THF was most marked, followed by cortolone-β-cortolone and free cortisol. The sum of the conjugated metabolites was normalized, but free cortisol remained high. A rebound was noted after 3 – 5 months of continued treatment. This was associated with clinical relapse (weight gain, increasing blood pressure). With AG, a non-steroidal peak appeared on the chromatograms.

It is concluded that: (1) AG is only temporarily effective in diminishing the excretion of cortisol and its metabolities; (2) paradoxical increments of 17-ketosteroids as reported from colorimetric analysis are non-specific and are probably due to the non-steroidal peak; and (3) AG appears to modify steroid catabolizing liver enzymes (inhibition of 5β-reductases and/or 3a-dehydrogenase, possibly stimulation of 20a- and 20β-dehydrogenases). This could increase the biological half-life of cortisol and contribute to the clinical rebound, which is due to increased ACTH-secretion.

Because of its excellent short-term effects, AG appears to be useful to prepare patients for bilateral adrenalectomy.

Effect of aminoglutethimide on urinary cortisol and cortisol metabolites in adolescents with cushing's syndrome

SINCE Wilkins et al. (1950) demonstrated that cortisone decreased markedly the output of urinary 17-oxosteroids and biologically active androgens in congenital adrenal hyperplasia (CAH), treatment of affected patients has until the present consisted of cortisone acetate or one of the newer synthetic analogues, and, in addition, fludrocortisone and extra dietary salt for the salt-losing cases. Adequate treatment usually results in normal growth and development. Patients with salt-loss frequently have episodes of adrenal insufficiency associated with febrile illnesses, and here an increase in both glucocorticoid and mineralocorticoid dosage is required. Good maintenance in salt-losers, however, can be obtained with a dosage level higher than is normally required for non-salt losers. Freedom from adrenal crises in these salt-losers is achieved at the expense of normal linear growth. In a series of CAH cases observed over 22 years, 13 of 15 salt-losers were ultimately of short stature (New et al. 1965). This may be due to the fact that in these salt-losers the high doses of corticosteroids impede linear growth in the first year of life when growth velocity is normally greatest. Subsequent attempts to allow catch-up growth by reduction in glucocorticoid dosage is frequently accompanied by a more rapid advance in ossification than in linear growth. Advanced ossification in relation to chronological age is also seen in non-salt-losers who come late under observation. Opinion varies as to the best drug or combination of drugs which, while restraining bone maturation in these two groups of patients, will allow full linear growth. Several authors (Raiti and Newns 1964, Bergstrand 1966) have reported good results with cortisone acetate in cases treated early, but acknowledge the difficulties in obtaining full adult stature in those coming late for treatment. Laron and Pertzelan (1968~) prefer to use hydrocortisone rather than the newer synthetic analogues. Dexamethasone may be of particular value when ossification is advanced since it seems to retard bone maturation more than linear growth (Hubble 1965). Since the advanced ossification is due to synthesis of adrenal androgens, the ideal therapeutic rtgime might be expected to include an antiandrogen to combat their effects, thus allowing the administration of quantities of glucocorticosteroids insufficient to cause growth retardation but adequate for general metabolic requirements. The antiandrogen, Cyproterone ( I , 2a-methylene-6-chloro-A 4 , s-pregna___ Royal Hospital for Sick Children. Oakbank, Glasgow, C.4.

Matys Z

Papers

Clinical experiences with aminoglutethimide (Elipten), a new inhibitor of steroid biosynthesis in the adrenal gland

Inhibitions of steroid biosynthesis in the adrenal gland by aminogluthetimide (Elipten CIBA) and its practical significance