Principles of Hormonal Therapy of Endometriosis

Stanley Friedman, M.D.
Associate Clinical Professor of Obstetrics and Gynecology, U.C.L.A. School of Medicine, Los Angeles; The Tyler Clinic

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

The two major assumptions underlying the hormonal treatment of endometriosis are that 1) pregnancy or pseudopregnancy ameliorates endometriosis and, 2) anovulatory patients rarely have endometriosis. Both of these assumptions may be challenged.

Although pregnant or pseudopregnant patients are anovulatory, their hormonal milieu is different from that of the spontaneously anovulatory patient. Estradiol secretion in anovulatory patients does not attain the peak levels seen in ovulating women and there is no significant progesterone production. In contrast, pregnant or pseudopregnant patients produce or receive large amounts of estrogenic and progestogenic substances. Thus, there does not seem to be a mechanism common to both anovulatory women and the pregnant and pseudopregnant women that would account for the absence or the relief of this disease. Indeed, I have been unable to find any good reference for the statement that endometriosis is rare in anovulatory patients.

On the other hand, with the increased use of the laparoscope to diagnose endometriosis, there are several recent reports which indicate that anovulation and endometriosis coexist much more frequently than had been assumed in the past. The fact that endometriosis has often been reported in abdominal wounds following cesarean section, and in episiotomy scars, indicates that the pregnant or pseudopregnant state may not always be all that prohibitive to the development of this disease.

Nevertheless, if we assume that the development of endometriosis does depend on ovarian steroid secretion in a normal cyclical fashion, the ideal treatment would be the suppression of these cyclical secretions without superimposing exogenous steroids which may have a variable effect, in addition to their well-known drawbacks. A second satisfactory treatment would be the use of an agent which has a direct local effect on the endometriotic lesions without necessarily affecting hypothalamic-pituitary-gonadal function.

Let us now consider the indications and contraindications for the medical management or hormonal treatment of endometriosis. A prerequisite for therapy is the laparoscopic confirmation of the diagnosis. There is little virtue in treating patients with undocumented endometriosis "empirically" for 6 to 12 months when they complain of infertility and are anxious to get pregnant.

Table I gives the indications for hormonal therapy. Long-term therapy is most applicable where laparoscopy has indicated minimal endometriosis, there are no large endometriotic lesions of the ovaries, and the pelvic structures are not matted together and fixed.

Some or all of the lesions may have been electrocoagulated at laparoscopy, in which case hormonal therapy might be looked upon as insurance. Such therapy is particularly applicable to the highly symptomatic patient who does not have lots of pathology and is disinterested in pregnancy, or who is approaching the menopause. The use of long-term therapy for recurrent endometriosis following surgery is an admission of defeat of the initial treatment and is a therapeutic long-shot. The only other treatment in such a situation would be so-called radical surgery or castration. Vaginal endometriosis may be a cause of dyspareunia and is usually an extension of endometriosis of the cul-de-sac. In this case, surgical excision could present considerable difficulty, and long-term hormonal therapy is worth a try.

Short-term therapy has been advocated as a means of softening endometriotic lesions and making the surgical dissection somewhat easier. There is a difference of opinion as to the effectiveness of pre-operative use of hormones. I do like to use hormonal therapy postoperatively because of the possibility that some endometriotic lesions may have been missed. Since these patients are usually infertile and are quite anxious about trying to get pregnant as soon as possible after the surgery, I usually do not treat them for more than three months.

Table 3 gives the various hormonal agents that are available for use. Estrogen-progestogen combinations are the most popular hormonal method of treating endometriosis and, at this juncture, I would like to pay tribute to Dr. Robert Kistner as the man who introduced progestational treatment. About 20 years ago, doing a caesarean section in a patient with endometriosis, he observed that the lesions could be virtually wiped away. Histologic studies showed that some of these lesions had undergone hyalinization and fibrosis. This observation, together with the observation that pregnancy often cured pre-existing endometriosis, ushered in the pseudopregnancy treatment. It was felt that such treatment was effective because the induced amenorrhea prevented progression of the disease and secondly, that the large doses of progestational agents caused a decidual transformation and subsequent necrosis or necrobiosis of the lesions. Although the local effects were probably induced by the progestational agents alone, estrogen was added because the progesterones are not good ovulation inhibitors and because estrogen reduced the incidence of break-through bleeding.

Today, most practitioners use one of the oral contraceptives on a continuous daily basis with the smallest amount that will maintain the patient amenorrheic. Should breakthrough bleeding occur, the dose is increased. Contraindications to the use of this therapy are the same as those of oral contraceptive therapy, namely, breast or endometrial cancer, thromboembolic disease, vascular headaches and so forth. Side effects of nausea, edema and weight gain may also be marked, should it be necessary to use high doses of oral contraceptives because of breakthrough bleeding.

The advantages of progestational agents alone are that the usual contraindications of oral contraceptive therapy do not apply and side effects may be avoided or minimized. Provera®- (Upjohn) and Norlutin~ (Parke-Davis) are most commonly used. Norlutin® may have a more profound local effect than Provera,® but it is also androgenic, so that its advantages are balanced by its disadvantages. The disadvantage of progestational therapy is that breakthrough bleeding is fairly common, even at high doses, and therapy often may have to be supplemented with estrogens. Nevertheless, my own preference is for a progestational agent alone, and if estrogen is needed, it is added. As for Depo-Provera® (Upjohn), although 100 to 150 mg is an excellent ovulationsuppressant and produces fairly well-sustained amenorrhea for two or three months, I do not feel it has a place in the treatment of any disease in any woman who is planning or hoping for a pregnancy at a future date. The fact that a substantial number of women are rendered permanently anovulatory with this agent, and that there are suitable alternatives available, dictates that it should be avoided in a patient planning a family. If future pregnancy has unequivocally been ruled out, then this would be an excellent choice when there are minimal lesions and abundant symptoms.

Androgens are one of the older methods of treatment of endometriosis. The doses used are well below the amounts that would suppress ovulation and it is believed they work by causing the endometriotic lesions to atrophy through a direct local effect. One of the hypothetical ideal agents described earlier would have only a local effect on the endometriotic lesion without any effect on hypothalamic-pituitary-gonadal function, and the androgens would seem to fit the bill. Unfortunately, the line between the therapeutic efficacy of androgens and their virilizing effects is a thin one and I believe they have a very limited use in endometriosis, having seen many unhappy women given androgen therapy for a variety of diseases who then report more complaints from the androgen than from the disease being treated.

Estrogens, like androgens alone, were among the first drugs used for the treatment of endometriosis. In reviewing recent literature on the treatment of endometriosis, estrogen therapy has fallen into disuse. There would seem to be little justification for the use of estrogen alone since this disease is estrogen-dependent and estrogens alone are not good ovulation-inhibitors. Furthermore, the effect of estrogen in causing "exhaustion atrophy" of endometriotic lesions has not been well documented.

The most exciting thing to happen in the management of endometriosis since progestogen treatment was instituted 20 years ago has been the introduction of danazol (Danocrine®, Winthrop). Preliminary studies with danazol indicate that it may represent the hypothetical ideal agent, that is, a drug capable of suppressing cyclic ovarian activity by way of the hypothalamicpituitary axis, without superimposing potent exogenous steroids.

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