Danazol
Danazol was the first drug approved in America for treatment of endometriosis by pseudomenopause, and it came as no surprise to find out that it does not eradicate endometriosis since it was never scientifically proved that the menopause eradicates endometriosis.

It is now realized that Danazol does not eradicate endometriosis of any stage or location, and the hopes dashed by Danazol seem to be a combined result of historically misplaced expectations, errors of visual identification, and failure to confirm clinical observations by biopsy. Reports on the use of Danazol for endometriosis have shown an actual decrease in fertility in treated women with minimal or mild disease compared to operative laparoscopy or observation only, while the improved pregnancy rate following surgical therapy for disease associated with pelvic adhesions has long been recognized.

Since there is a surprisingly high background pregnancy rate of up to 57% in untreated disease in infertile patients, the true effect of medical or surgical therapy on fertility is difficult to determine, since it may be small. It seems most likely that much of the "improved" fertility after treatment is due to the natural history of endometriosis, not to the treatment itself.

Urologists have questioned the use of Danazol for endometriosis involving the urinary tract, noting it to be ineffective for relief of obstructive ureteral endometriosis. Since Danazol does not eradicate endometriosis, it is also not surprising that it is ineffective in long term relief of pain.

GnRH agonists
GnRH agonists such as Synarel, Lupron and Zoladex are the heirs to Danazol. They seek to mimic the hypoestrogenic menopausal state by inducing a profound suppression of pituitary gonadotropins. However, since this approach shares Danazol's historical basis of origin, one would naturally predict that GnRH agonists would replicate Danazol's shortcomings, although with different side-effects.

An early report on the efficacy of one GnRH agonist, Buserelin, assessed response of the endometrium rather than endometriosis, assessed the visual appearance of endometriosis at the conclusion of therapy when errors of visual identification are common, and spoke of disappearance and resorption of lesions without biopsy proof. The definite impression was left that GnRH agonist therapy resulted in physical eradication of disease.

The large multicenter randomized, Danazol-controlled, study of Nafarelin-treated patients which helped gain its FDA approval, although impressive on the surface, repeats some of the errors found in earlier studies of medical therapy. The study was based on the undefined and unreferenced statement that "endometriosis resolves after ovariectomy and menopause." Of 236 patients begun on therapy with either of two doses of Nafarelin or one dose of Danazol, almost 10% were immediately censored from the study for various reasons. Visualization at laparoscopy before and at the end (when ovarian suppression can give the false impression that disease has been eradicated) of Synarel therapy was used to assess response of the disease.

The undefined concept of "resolution" was the endpoint of therapy. "Resolution" may mean many things to many people, including such disparate results as physical destruction or eradication ("cure"), partial eradication, visual improvement which indicates physical eradication, or visual improvement alone with no implication as to the physical eradication of disease. Biopsy control was not used to ensure that all patients had endometriosis or that all lesions visualized were indeed endometriosis.

It is not known whether all of the eighteen investigators in the study had the same degree of expertise in diagnosing endometriosis in all of its subtle manifestations. Other peritoneal changes such as chronic inflammation or microcalcification can sometimes mimic endometriosis, and without biopsy, there is no way to be certain what is or is not endometriosis. Patients treated with Synarel were compared to Danazol, but not to placebo. The decision not to compare Synarel to placebo was made on ethical grounds. Although the ethical concerns were not detailed, presumably it was because an earlier study had shown pain relief during therapy.

Concern has been voiced that medical (or surgical) studies of infertility which do not include a placebo group may over-represent the fertility results, since the background pregnancy rate with untreated endometriosis is up to 57%. Detailed analysis of this study indicates it is actually not a study of infertility patients, however. Nonetheless, the crude pregnancy rate among the unstated number of patients treated with Synarel who later attempted pregnancy was between 30-52% by 12 months after treatment ended. Since the group attempting pregnancy presumably included patients with normal but untested fertility, this is not an impressive pregnancy rate following therapy. Long-term follow-up was not done; patients were followed only until they became pregnant, or until 12 months after treatment ended. Follow-up was apparently done primarily for patients attempting pregnancy. By 6 months after the end of treatment, 15% of the original 236 patients entered in the study had been censored or apparently lost to follow-up.

The choice of symptoms and methodology of study of symptom response during treatment was somewhat illogical. Ironically, dysmenorrhea was clustered with dyspareunia and pelvic pain not related to menstruation, and a total symptom score was developed to assess symptom response during treatment. Since Nafarelin in high dose is a potent inhibitor of ovarian function, most women can be expected to become amenorrheic while on therapy. Since dysmenorrhea is usually thought of as pain or cramps due to the menstrual flow, cessation of menses for any reason will obviously result in improvement of dysmenorrhea. Since this improvement is assured by amenorrhea, this may skew the results of symptom response in an artificially favorable direction by lumping a symptom which will always respond to amenorrhea (dysmenorrhea) with symptoms which may not respond to amenorrhea (dyspareunia, pain not associated with the menstrual flow). It would have been more helpful to assess the individual response of each symptom. Since it is known that other causes of pelvic pain are also estrogen-responsive (such as fibroids or adenomyosis), improvement of symptoms during therapy cannot be ascribed with absolute certainty to improvement of symptoms caused by endometriosis. Improvement of symptoms is therefore based on the assumption that symptoms were all due to endometriosis.

While endometriosis is a potent cause of pain, and while it may be true that much of the pain relief experienced during treatment may truly have been caused by endometriosis, we simply do not know for certain that the observed improvement represented a favorable response of symptoms due to endometriosis. This is a reprise of Kistner's postulate of an "assumed fact." This is why it is much safer to study biopsy-proven evidence of persistence or recurrence of endometriosis after medical or surgical treatment, since this is the only measurement which is absolutely indicative of the true response of the disease to treatment. Anything else is just a matter of opinion, not fact. This study was recently sent to all gynecologists by Syntex after FDA approval of Synarel as a promotion of the drug.