Panel Discussion I

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

DR. J. J. MARIK, MODERATOR: Dr. Greenblatt, would you like to open the panel discussion?

DR. GREENBLATT: Thank You. I would like to raise a question about treating a patient following castration or removal of the ovaries because of endometriosis. Should the patient be treated with estrogen? And if so, when?

Most physicians are afraid to treat a patient with estrogen after a hysterectomy, since there may be some residual lesions left which could not be removed. I would wish to make a plea that these residual endometrial foci be allowed to recede, without instituting estrogen therapy for at least three to six months.

After that period of time, however, it is perfectly safe to treat that patient with as much estrogen as necessary. I have done so for over 25 years and have not regretted it. There may be an occasional exception to this rule, but we have seen patients of this type who are refused any hormone replacement for fear of reawakening a dormant endometrial focus. And that is a mistake.

Of course, a patient can be treated immediately by employing estrogenprogestogen combination therapy. But it should be understood that, in almost every case, estrogens are safe to be given six months after surgery.

DR. KISTNER: I would agree with what Dr. Greenblatt has said, but with one word of caution.

If one operates on a patient who has extensive cul-de-sac endometriosis and finds the posterior vagina thickened and fibrotic, it is usually due to endometriosis. In such cases, there is usually endometriosis also in the rectovaginal septum, and the rectum is adherent against the cervix and posterior vagina.

I would agree with Dr. Greenblatt's proposal not to give this patient estrogens for a certain period of time, which is very wise. But once estrogen therapy is begun, it is important to be very careful to administer a very low dose where there is rectovaginal and posterior-cuff endometriosis. We usually begin with 0.3 mg of sodium-estrone sulfate and later increase to 0.625 mg. The estrogen is given for 21 days of each month, starting on the fourth or fifth postoperative day.

I do agree with Dr. Greenblatt that if there is extensive endometriosis, it would be wise to let that endometriotic tissue wither away, although I doubt that it will do so. I think that dormant areas of endometriosis may be reactivated years later by excessive doses of estrogen or estrogen-progestogen in sequence. The endometrium of a 95-year-old woman can be reactivated by adequate estrogen.

I am not in favor of treating recurrent endometriosis after hysterectomy with estrogen-progestogen combinations. Pseudopregnancy was originally used in patients who desired subsequent pregnancy. It provides palliation and temporary improvement, not cure. Many patients with recurrent endometriosis after hysterectomy will develop vasomotor symptoms when the estrogen is discontinued. But these vasomotor symptoms will frequently disappear following the administration of Depo-ProveraO (Upjohn). This progestogen also produces necrosis and degeneration of areas of endometriosis. I believe that danazol (Danocrine`", Winthrop) would be equally effective in producing amelioration of symptoms, but I am not certain about its effect on vasomotor symptoms.

MODERATOR MARIK: Dr. Clyman, would you care to comment?

DR. CLYMAN: I don't use estrogens for endometriosis. Androgens had, of course, been primarily used for endometriosis from the 1930's until 1960, prior to the introduction of estrogen-progestogen agents for pseudopregnancy. Combination therapy was actually first introduced in 1955 in Puerto Rico, but we did not make very much use of these agents until they became generally available in the early 1960's.

Androgen is still used at Johns Hopkins, however-either methyltestosterone, 5 mg, or halotestin, 5 mg daily. Provided that the dosage is not excessively high, androgenic activity can be avoided.

These agents should not be used, of course, in patients who already have acneiform eruptions on the face, hirsutism or receding hairline. Regardless of the dosage such patients may be given, they are likely to believe that these drugs are exacerbating these problems, whether danazol, estrogenprogestogen combinations or estrogen alone is employed. These patients often complain that whatever steroid is given them causes side effects.

The androgens do help, although the dose used should not go above 200250 mg a month, and the patient should be carefully monitored. Androgenicity, however, usually does not occur at this dosage level. I haven't had any severe reactions to these agents during some 15 years of use before changing to the new agents, including danazol.

Danazol itself is a testosterone derivative, although with minimal or no androgenic activity.

When it is used, androgen therapy in the dosage mentioned should be continued for a period of at least one, or as long as two years, but should be discontinued at the slightest clinical evidence of androgenicity. We should remember that androgens were the only agents available until the estrogenprogestogens, and now danazol, were introduced. We have still used these drugs when patients could not tolerate the combination oral contraceptive therapy or because of chronic cystic mastitis, hypertension or other vascular phenomena, which made the usage of these drugs contraindicated. This, of course, was before danazol was available. Danazol is an exceptional drug, which I think has great promise.

MODERATOR MARIK: Dr. Cohen, would you discuss the use of other agents for treatment of endometriosis?

DR. COHEN: The one agent we should be certain to review is danazol. In this regard, I would like to give credit to two members of the panel, Dr. Kistner and Dr. Greenblatt, for developing the use of pseudopregnancy as a mainstay in the treatment of endometriosis. Dr. Greenblatt should also be recognized for originating the term "pseudomenopause" in connection with danazol.

I would also like to acknowledge the senior author of several key papers that have been published on danazol, Dr. Paul Dmowski.

MODERATOR MARIK: Dr. Friedman raised a question about pre-operative and postoperative treatment of endometriosis. Dr. Clyman, do you feel that there is any merit in treating endometriosis prior to surgery, or following surgery with any type of hormonal treatment?

DR. CLYMAN: I like to use pretreatment for four to six months before operating, in the case of abdominal surgery.

MODERATOR MARIK: What treatment do you use?

DR_ CLAYMAN: I have used Ovral'R, Danocrine", Enovid~, and other drugs for such treatment. They all cause considerable change to occur in some of the endometriomas. In the case of endometriosis with large chocolate or endometrial cysts, progestational or anti gonad otropi c pretreatment reduces the size of the lesion, making the dissection somewhat easier.

In patients who have fibroids, it should be remembered that their size may increase, although if one is going to do myomectomy through surgery, I don't think it makes very much difference.

In the event of a cornual resection, however, where the patient has endometriosis with bilateral cornual occlusion with adenomyosis, then I would not use any pseudopregnancy agents, so as to avoid any excessive loss of blood. However, the vascularity and bleeding in such surgery does not seem to be increased with the use of danazol.

DR. KISTNER: I would like to look again at the early days of clinical investigation utilizing pseudopregnancy in the late 1950's. The reason I administered the various estrogen-progestins prior to surgery was not to exaggerate areas of endometriosis so that they could be identified and excised, nor to soften fibrotic cleavage planes, but to study the effect of these new synthetic progestins on areas of endometriosis so that we could document the morphologic changes, specifically necrobiosis, fibrosis and absorption.
At the present time, I do not use pre-operative pseudopregnancy routinely, but I am guided by the endoscopic examination. If there is a delay between laparoscopy and surgery, I use pseudopregnancy pre-operatively only in those patients in whom there is extensive endometriosis producing anatomic deformity.

At the present time, I use pre-operative pseudopregnancy in perhaps one case out of ten, which is a considerable change from 10 to 15 years ago. In those days, we were looking for progestin effect. I did make the statement in 1960 that if there is extensive fibrosis due to endometriosis, the dissection is made easier if pre-operative pseudopregnancy is utilized.

Furthermore, I no longer use pseudopregnancy postoperatively except in patients in whom all areas of active endometriosis cannot be removed. In general, I would like these patients to become pregnant as soon as possible. They are instructed accordingly.

One must be careful, however, in patients who have had extensive ovarian resection, or in those who are placed on pseudopregnancy following surgical treatment, since a few will demonstrate a certain degree of inadequate luteal phase. This merits attention and treatment, because one may have cured the patient of endometriosis and tubal deformity, only to have luteal phase insufficiency result in persistent infertility.

MODERATOR MARIK: Thank you. I would like to extend that question a little bit. If you do a laparoscopy and find that the patient has a mild degree of endometriosis, which you try to excise or cauterize, you cannot be sure that you have treated all lesions completely. Would you consider treating these patients with any type of hormonal treatment post-laparoscopy?

DR. COHEN: I think part of the answer to that question depends on the patient's age. If she is in her thirties, l think it would be unfortunate to prevent her from having a baby for a period of six to nine months. In such cases, I would treat for the so-called poor luteal phase. My pragmatic approach would be to perhaps give this patient human chorionic gonadotropin (HCG) or even Pergonal," because I think it is important for her to become pregnant. However, if the patient is in her twenties, I would treat her.

DR. KISTNER: I am sure that all of us would fulgurate small areas of endometriosis. However, I don't like to fulgurate endometriosis on the bowel serosa. I prefer to excise the areas and cover them with omental or peritoneal grafts.

In those patients who do not have tubo-ovarian anatomical distortion, that is, endometriosis involving the ovaries only, I have had excellent results by the use of pseudopregnancy alone. If you were then to ask why women who have endometriosis on the round or uterosacral ligaments are infertile, I would be unable to answer you. Hormonal therapy does occasionally result in pregnancy in these patients, but I don't know why.

DR. COVEN: On the question of cauterizing implants, I don't think cautery does any good at all, although I will perhaps take a biopsy mainly for documentation.

If an ovary is adherent, I do want to release it. If I can get it up easily with a metal probe so that it is freely movable, and evacuate some chocolate material, to my mind that is sufficient. I would say, for example, that it is unnecessary to cauterize an isolated endometrioma of the left uterosacral ligament, since it is impossible to remove every microscopic evidence of endometriosis.

This is the type of patient, if she is young, that I would suppress. If she is older, I think it would be wrong to prevent her from having a child for a period of a year, and thus take a year of reproductive life away from her.

MODERATOR MARIK: Dr. Clyman, do you burn the lesions when doing culdoscopy or laparoscapy''

DR. CLYMAN: On culdoscopy and laparoscopy, I have been burning lesions for 15 years. As I mentioned before, when they recede from a large lesion clown to a small orange-red lesion, I take a biopsy and then destroy them.

But again, as we have discussed, we don't know the degree of presence of lesions deeper in the ovarian substance. More often than not, when we take out an endometrioma of the ovary, we find other small endometriomas within the substance of the ovary in the higher portion, or even deeper. So it is questionable as to how much good we are doing, although I still continue to burn lesions when they are available to me. Then the patient is placed on progestational steroid therapy.

DR. GREENBLATT: I would like to say that testosterone, properly used, is not as arrhenomimetic as it has been implied. We use two pellets (150 mg) of testosterone, or at the most, three pellets, every six months. Not many patients are going to have any degree of masculinization at that dosage, and it is surprising how many patients conceive and how many improve from the point of view of pain and other symptoms.

Even if only 50% of the patients experience alleviation of pain, it is worthwhile to consider its use. It should be noted that by using it orally or by injection, considerably too much testosterone is given, so two or three pellets of testosterone subcutaneously or behind the gluteus muscle should be used at six-month intervals. Danazol, of course, is preferred.

DR. KISTNER: Why is the pellet so important'? Why can't one establish the same dosage with oral medication'?

DR. CLYMAN: Another problem with the pellets is that they are not available in the United States, although they can be obtained in Canada.

DR. GREENBLATT: Schering Corporation (Bloomtield, New Jersey) and Bartor Pharmacals (Rye, New York), through Bartor International (Box 1242, Palm Desert, Calif.), will supply pellets and implanters in the United States.

MODERATOR MARIK: The following question has been asked of Dr. Greenblatt and Dr. Kistner: What do you use in your posthysterectomy endometriosis patients during the first three to six months to relieve the vasomotor symptoms'?

DR. KISTNER: We use sodium estrone sulfate, 0.625 mg, starting on the fourth or fifth postoperative day, given daily for 21 days of each month.

DR. GREENBLATT: I prefer to wait a little longer, and use testosterone in the interim.

MODERATOR MARIK: Another question has been submitted for Dr. Kistner: Following an actual pregnancy, the endometrium certainly recovers. Why then do ectopic endometriosis cells not similarly recover? What is the physiology whereby only ectopic endometrial cells respond by being permanently suppressed, whereas endometrium is not? Also, why does DepoProvera"' have long-lasting sterilizing effects while oral Proves"" does not, as Dr. Friedman has indicated?

DR. KISTNER: The ectopic endometria respond in exactly the same fashion as does the endometrium in its normal state. But I think probably you are confusing the marked antiestrogenic effect of medroxyprogesterone acetate with the prolonged effect. I cringed when you used the term "sterility." There is "temporary infertility" due to anovulation, not "sterility."

Furthermore, I would have to disagree with Dr. Friedman, who said that depo-medroxyprogesterone acetate should be given only to those people who have a rather short reproductive life expectancy.

I have used medroxyprogesterone acetate in patients with endometrial hyperplasia and carcinoma in situ and endometriosis. And I will continue to use it, if this is the only agent available to secure a hormonal regimen. In other words, if I can use Ovral® or Enovid® to secure pseudopregnancy, I would probably do so. But in some patients, because of contraindications or of side effects from estrogen, gonadotropin inhibitors such as medroxyprogesterone acetate (MPA) or danazol are preferable.

I disagree strongly with those who say that MPA produces "sterility." I have yet to find a patient, so treated, in whom I could not induce ovulation. As long as the ovary retains its follicular apparatus, it should respond to Clomid'G' or PergonaV"' followed by HCG. I don't prefer MPA in the management of endometriosis, but occasionally it is very advantageous. The advantage of danazol is the fact that it does not have the prolonged antigonadotropic activity of MPA.

DR. FRIEDMAN: I think I was very careful not to use the word "sterile." I said patients were rendered anovulatory. And, as you said, you can get any patient with ova to ovulate with Pergonal," but nevertheless, it is certainly not advantageous to have to start treating a patient with Pergonal because she has been made anovulatory from Depo-Provera.'!'

DR. KISTNER: I would agree, unless she has become pregnant because you have eliminated her endometriosis, in which case the therapeutic regimen was excellent.

DR. FRIEDMAN: But we do have available other methods of treatment. A number of patients rendered anovulatory from Depo-Provera`' will apparently ovulate with Pergonal,`"' at a cost of perhaps thousands of dollars per month for therapy, and yet remain unable to conceive. So I think this agent should be limited to the few situations in which you really have no other choice.

MODERATOR MARIK: Another question has been directed to Dr. Kistner: There are patients who are completely unresponsive to combined therapy, such as one patient with proven vaginal endometriosis who was suppressed for six to nine months with no change at all in the lesions. Could you comment on this situation?

DR. KISTNER: In our original studies, about 85% of patients responded to estrogen-progestogen combinations and 15% did not. Surprisingly, the patients I have seen with vaginal endometriosis have been most responsive. One of our first patients in 1959 was one that we biopsied every four weeks and showed the sequence of decidua followed by necrobiosis and eventual replacement by fibro-connective tissue.

I cannot answer the question why, if this is truly endometrium, it does not respond, except perhaps that it is similar to the basal layer of the endometrium in its natural habitat, which does not respond either. And, as you know, the basal layer will respond to progesterone in only about 20-25% of cases.

Perhaps if this patient did not respond it might have been due to a malabsorption syndrome or to inadequate dosage, although this is conjecture. Perhaps Dr. Greenblatt can give us an answer to this question.

DR. GREENBLATT: Dr. Shanklin, can you give us some idea of how many patients with endometriosis do not have cyclic changes each month in their endometrial implants? I would estimate that perhaps only 75% of endometriosis patients have an attempt at cyclic change, and that over 25% do not show these changes and remain in the proliferative phase.

DR. SHANKLIN: We have studied this question from the standpoint of analyzing cases where there are luteal effects on the endometrial mucosa and we have found that less than 50% showed responsiveness. In addition, we have found no instance, in a series of perhaps 50 cases, in which the response was in phase with the corpus luteum and the mucosa.

DR. GREENBLATT: Yes, I think that might explain why many patients do not respond to estrogen-progestogen type of therapy; namely, that the endometrium is not responsive.

MODERATOR MARIK: The following question has been submitted. In the patient over 30-35 who does not want children, we can do a hysterectomy, leaving one ovary, or half of an ovary, and the patient obtains tremendous relief of pain, which was her primary complaint. This relief is accomplished without any progesterone, or pseudopregnancy, as the hysterectomy alone can provide fantastic relief. What causes this relief of pain?

DR. GREENBLATT: But I would ask why take the chance of a recurrence in the remaining part of the ovary, do a complete extirpation, and give the patient estrogen replacement? In fact, substitutional estrogens will frequently work much better than does the partial ovary.

DR. KISTNER: I would like to answer that question. I think that if the hysterectomy produced pain relief, the source of the pain had been in the uterus or the adjacent tissues. Therefore, no pain due to endometriosis has been eliminated. Rather, the patient's pain might have been due to pelvic congestion syndrome or adenomyosis, but not to endometriosis.

I believe that one of the major errors in operative gynecology is to permit an ovary to remain in situ when you are operating for extensive endometriosis. I don't mean to say that when you perform a hysterectomy for carcinoma in situ of the cervix or a leiomyoma, and there is one focus of one endometriosis on the ovary in a 32-year-old patient, that you need do a BSO. But, if you do a hysterectomy for extensive endometriosis and permit the ovary to remain in situ, what is going to reactivate her endometriosis? Obviously, the endogenous estrogen and progesterone.

The only way that endometriosis can be produced in the animal is by cyclic stimulation, utilizing estrogen followed by progesterone. There is no other way of producing endometriosis. And some of the most mismanaged patients that I have seen have been those who have had one, two or three inadequate surgical procedures with an ovary left in. Then I see them with extensive active endometriosis as a result of persistent activity of that ovary.

DR. GOOD: I would like to address a question to both Dr. Clyman and Dr. Kistner. The question has been asked that if one were going to treat a patient with a pseudopregnancy regimen prior to surgery, which drug should be used? Dr. Clyman mentioned Ovral," but it is an estrogen-dominant oral contraceptive. This can be demonstrated by doing maturation indices on patients, and studying the character of the menstrual patterns in patients on Ovral,'p as evidence that it is an estrogen-dominant effect.

That is to say, if a patient has cramping and prolonged menses with Ovral, and one
then places that patient on an agent containing instead 50 mcg of mestranol and I mg of norethindrone, the patient immediately improves. That is to say, a combination such as Norinyl® 1/50 or Ortho-Novum® 1/50 gives much lighter menses, much less stimulation of the endometrium.

As we observe these patients, they are improved because they have less cramping and shorter periods. So I could not in conscience use an agent such as Ovral,® which contains 50 mcg of a more potent estrogen-but remember, it is the 3-methyl ether derivative that is less potent. I could not agree that one should place these patients on Ovral® as a pretreatment regimen.

DR. CLYMAN: I have had extensive experience with Ovral® in over 100 cases of endometriosis, and in fact I ran a study on this drug and published the results some ten years ago. I do not find that it is predominantly estrogendependent. The progestational steroid is a very potent, synthetic one, not a naturally-occurring steroid, and its potency is such that one-tablet-a-day continuous therapy is usually sufficient. If there is breakthrough bleeding, this can be increased to two tablets daily, and it is rare that we ever have to increase the dosage beyond two tablets a day to obtain complete amenorrhea and total relief of symptoms.

On laparoscopy or culdoscopy; we can see the same recession of the lesion. I examine lesions of the biopsy both histologically and by electron microscopy, and have observed the same results as we obtain from progressive doses of Enovid,® Norlestrin® acetate with ethinyl estradiol, or any similar combination.

Where you have large chocolate cysts, you do not have a very great reduction in size, but such agents make the dissection easier at the time of surgery. Where you have fibroids in addition to endometriosis, it would best be treated with danazol, as estrogen-progestogen increases the size of fibroids while danazol does not.

DR. KISTNER: I would agree completely with Dr. Clyman. Since Ovral ® first became available, I have used it extensively.

Personally, I don't think there is that much difference between the various agents as far as the effect on endometriosis is concerned. But they do differ in the incidence and severity of side effects.

Ovral® pseudopregnancy can be obtained with a maximum of two tablets daily, in my experience.

DR. GREENBLANTT: As you know, in the "delay-of-menses test", a standard dose of an estrogen is given, to determine the amount of progestogen required to postpone the onset of menses by two weeks, administering both estrogen and progestogen. In this test, norgestrel is the strongest progestogen we have ever used. So, on the basis of this evidence, it is not a weak progestogen at all; in fact, from the milligram-for-milligram point of view, it is the strongest progestogen available.

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