Clinical Experience With Danazol

William P. Blackmore, Ph.D., M.D.
Director of Division of Clinical Research, 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

Introduction
It has been recognized that the treatment of endometriosis improves during periods of anovulation, whether by natural or drug-induced means. Therefore, based on the endocrinological profile of danazol, a large multiclinic study was conducted to determine the efficacy and tolerance of danazol in endometriosis. Of 370 patients to whom danazol was administered, 237 had surgically-proven endometriosis before entering the study. Of these patients, 96 had repeat surgical intervention to evaluate the presence, absence or regression of endometrial tissue. All patients were in the reproductive age group.

Method
Each patient was seen at monthly intervals for clinical evaluation. This consisted of the assessment of changes in dysmenorrhea, pelvic pain, dyspareunia and induration of the cul-de-sac, as well as physical examination and a series of laboratory tests. Duration of treatment averaged five to seven months, although a few patients received therapy up to nine months. Complete laboratory tests and cytological examination of vaginal smears and endometrial biopsies were obtained monthly. Based on the mild androgenic and antigonadotropic properties of danazol (Danocrine, Winthrop), the following parameters were specifically checked for occurrence or absence: flushes, sweats, vaginal bleeding, change in libido, voice change, hair growth, breast change, acne, weight change and blood pressure. Danazol was administered orally two times daily for a total daily dose ranging from 200 to 800 mg, those taking the latter dose comprising 75% of the patients.

Results
Analysis of the results indicated no significant difference between clinically and surgically diagnosed patients with regard either to presenting symptomatology or relief given by danazol. Therefore, results for all patients are combined. Dysmenorrhea, the most frequent presenting symptom, was relieved in 95% of the patients at the 800 mg dose, with similar response, although with less patients, noted at the lower doses. Relief from pelvic pain occurred in 88% of the patients with the 800 mg dose, with similar response at the lower doses. Additionally, 83% of the patients experienced relief for dyspareunia at the 800 mg dose and 81% experienced changes in induration of the cul-de-sac at 800 mg. The overall response to the combined doses of danazol in 370 patients showed a marked response in the parameters evaluated.

The response in symptomatology occurred between one and three months after treatment was initiated. The earliest change reported by patients was relief from dysmenorrhea, followed by relief of pelvic pain, dyspareunia and changes in induration of the cul-de-sac.

Further evidence of efficacy was provided by objective evaluation of the presence or absence of ectopic endometrial tissue following treatment. In 96 patients who had repeat laparoscopic examination, 96% of those on the 800 mg dose had partial to complete resolution at the end of treatment and 73% had complete resolution of endometrial implants. Significant response was also seen at the 600 mg dosage.

A parameter indicative of the antigonadotropic effect of danazol and indirect evidence of anovulation, was the response on menstrual (vaginal) bleeding. Of 204 patients who entered the study with a normal menstrual cycle, 97% became anovulatory at the end of the first month or during the second month following treatment at the 800 mg dose. Amenorrhea also occurred at the lower doses.

The effect of danazol on vaginal cytology resulted in a shift to a lower estrogenic state from premeditation control. At the 800 mg dose, where the majority of patients had moderate to high estrogenic activity before treatment, there was a significant shift to lower estrogenic activity in 85% of the patients. Recording the daily basal body temperature changes demonstrated that 131 of 135 (97%) became anovulatory. This was confirmed by daily luteinizing hormone (LH) and follicle-stimulating hormone (FSH) serum measurements, with an absence of the anticipated hormonal surge. A prompt return of menstrual function and ovulation following termination of medication was noted in those patients where follow-up was available. Data available on the first 76 patients in whom menses were suppressed while on the drug revealed that all returned to regular menses within 60 days. In 60 of the patients who had become anovulatory on danazol, and for whom postmedication basal body temperature charts were available, 53 became ovulatory within 60 days following termination of medication.

Discussion
A comprehensive review of the laboratory parameters obtained before medication, at monthly intervals during and one month postmedication, revealed no significant or prolonged abnormality attributed to danazol.

The most frequently observed adverse effects with the 800 mg daily dose, which were attributed to the mild androgenic and anabolic action of danazol, were: acne, 14%; edema 6%; increased hair growth, 4%; weight gain, 2%; voice change, 1%. There appeared to be a dose/response relationship in regard to side effects.

A special study was conducted to evaluate the effects of danazol on ovarian, thyroid, pituitary and adrenal function in seven normal females and three patients with clinically-diagnosed endometriosis who received 800 mg daily for three months. The results were generally as anticipated and within normal limits. T-4 was suppressed, presumably due to steroid effect on proteinbinding globulin. Free thyroxin did not change. Response of the 17-hydroxycorticoids to metapyrone revealed normal function of the pituitary gland's ability to secrete adrenal corticotropic hormone (ACTH) and of the adrenal to respond. Glucose tolerance tests conducted on patients with surgically proven endometriosis who received 800 m4 daily for six months revealed no change.

In conclusion, results obtained from a multiclinic study on 370 patients with endometriosis treated for an average of five to seven months at doses of 200, 400, 600 and 800 mg daily, those taking the latter dose* comprising 75 percent of the patients, revealed that (I) danazol caused a significant resolution of endometrial implants; in the majority of cases, resolution was complete with no residual evidence of the disease; (2) danazol did not cause any significant or prolonged changes, as evidenced by a comprehensive battery of laboratory tests; (3) danazol caused suppression of the pituitary-ovarian axis as manifested by menstrual changes, vaginal cytology, uniphasic basal body temperature and ovulation-it is significant that within 60 days the changes that occurred had reverted to normal patterns; and (4) danazol had no significant effect on ovarian, thyroid, pituitary or adrenal function.

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