Pharmacology of Danazol

Gordon O. Potts, Ph.D.
Vice President, Research Administration. Sterling-Winthrop Research Institute, Rensselaer, New York

Endometriosis, Aspects and Proceedings of a Symposium
Saint John's Hospital and Health Center, Santa Monica, California
Editor: J.J. Marik

The objective of this presentation is 1) to provide the rationale for the development of danazol; 2) to present the hormonal profile of this novel steroid.

It is well established that estrogens, progestogens and androgens are effective inhibitors of the pituitary-gonadal axis. This principle was utilized at least in part in the development of the oral contraceptives which consist of various combinations of estrogens and progestogens. These hormones, as well as androgens, are used in the treatment of a variety of clinical syndromes, (e.g. , endometriosis, dysmenorrhea, dysfunctional uterine bleeding, fibrocystic mastitis, etc.).

The hormonal approach to the management of endometriosis is based on the induction of a state of pseudopregnancy, wherein the patient becomes anovulatory and amenorrheic. In addition, these steroids have a direct action on ectopic endometrial tissue. The estrogens and progestogens produce a decidual transformation of the functioning endometriotic tissue, which leads to decidual necrosis and absorption. The androgens produce an involution of the endometriotic tissue via a direct effect.

A review of the endocrine and metabolic effects, as well as the adverse reactions encountered when estrogens, progestogens and androgens are administered in the treatment of endometriosis, is not within the scope of this paper. However, it seems appropriate to conclude that the overt sex-hormonal effects of these steroids restrict their clinical usefulness; the thromboembolic potential of the estrogens is of particular concern.

Thus, it was conceived that a drug which possesses marked pituitarygonadotropin inhibitory activity and which has little, if any, estrogenic, progestational or androgenic activity would have broad clinical applicability.

Danocrine® (danazol) was synthesized at the Sterling-Winthrop Research Institute as a member of a large series of heterocyclic steroids distinguished by the addition of the isoxazole moiety to the A ring of a steroid, in this case ethisterone. Extensive laboratory studies have established that danazol is an orally active, pituitary-gonadotropin inhibitory agent devoid of estrogenic and progestational activity. This steroid has weak impeded androgenic activity. The uniqueness of danazol lies in the marked separation of pituitarygonadotropin inhibitory activity from overt sex-hormone activity.

More specifically, the inhibitory effect of danazol on the synthesis and/or release of pituitary-gonadotropic hormones was evaluated utilizing a variety of rodent and rhesus monkey bioassay systems. The gonads and sex accessory organs decrease in weight and function as the circulating levels of follicular stimulating hormone (FSH) and luteinizing hormone (LH) are decreased in response to the administration of danazol. Similarly, the circulating levels of estradiol and progesterone in the female and testosterone in the male are decreased. The levels of FSH, LH, estradiol, progesterone and testosterone are characterized as being in the low-normal range, reflecting the inhibitory effect of danazol on normal cyclicity.

Separate studies wherein danazol was administered concurrently with tritiated estradiol or testosterone provide evidence that danazol competes with these two feedback hormones for receptors in the pituitary. Danazol also blocks the pituitary response to the administration of luteinizing-hormone releasing factor (LH-RF), supporting the conclusion that danazol is exerting its inhibitory effect at the level of the pituitary. No effect was observed on adrenal corticotropic hormone (ACTH), thyrotropic stimulating hormone (TSH), etc., consistent with the selectivity of danazol on pituitarygonadotropic hormones.

Danazol is neither estrogenic nor progestational. Danazol has weak androgenic activity. This steroid does not possess either glucocorticoid or mineralocorticoid activity.

In summary, we have established that danazol is an orally active, pituitary-gonadotropin inhibitory agent devoid of estrogenic and progestational activity. This steroid has weak androgenic activity. Danazol is unique in possessing such a profound separation of pituitary-gonadotropin inhibitory activity from overt sex-hormone activity.

Back to Table of Contents