ELSIMAR METZKER COUTINHO, M.D.
Salvador, Bahia, Brazil
Fertility Association’s system had extensive adhesions, which included the bowel.
From the Department of Maternal and Child Health
Federal University of Bahia, School of Medicine,
Maternidade Climerio de Oliveira.
Supported by the Rockefeller Foundation.
Received for publication January 14, 1982.
Revised April 23, 1982.
Accepted August 2, 1982.
Reprint request: Dr. Elsimar Metzker Coutinho, Department of Maternal and Child Heal-
th, Federal University of Bahia, School of Medicine, Maternidade
Climerio de Oliveira, Salvador, Bahia, Brazil.
Purpose: evaluation of the effect of elcometrine on ovarian endometriomata.
Method: subdermal implants containing 50 mg elcometrine were inserted in 51 women with ovarian endometriomata, the volumes of which were recorded by vaginal sonography before and after each three-month interval of treatment. A new implant was inserted every 6 months according to the need for continuing treatment. Results: at admission, 74% of patients presented with dysmenorrhea, 57% chronic pelvic pain and 31% dyspareunia. Pain was rated as severe or incapacitating by 82% of the subjects. A total of 924 months of observation was recorded during the four years of study. Relief of pain was observed during the first month of treatment and severe or incapacitating pain was no longer reported by ansubject by the end of the first trimester Volume of endome-triomata was reduced in 86% of the patients.
In 45%, ovarian volume was restored to nor-mal. In 41% the volume reduction was incomplete and in 14% there was no volume reduc-tion.
Seventy-seven percent presented amenorrhea during treatment. The most common ad-verse events were decreased libido (21%) and feeling of heaviness in lower limbs (14%). One year after discontinuation of treatment, 33% of the patients were symptomless, while 28% presented recurrence of the endometrioma-
ta before 3 months post-discontinuation. Thirty-nine percent of the patients preferred to continue using the method in order to main-tain amenorrhea.
Conclusion: elcometrine is effective in reducing ovarian endometriomata, without some of the side effects of other treatments.
Keywords: in infertility. Pelvic pan, chronic. Endometriosis. Ovarian endometriomata.
Twenty patents with endometriosis diagnosed by laparoscopy were treated with the anti-estrogen, antiprogesterone gastrinone (R-2323) for 8 to 8 months. The drug was administered in B dose of 5 mg twice weekly. According to the American Fertility Society’s classification of endometriosis, five patients were classified as having mild (Stage 1), eight as having moderate (Stage II), and seven as having severe endometriosis (Stage III). All pa-tients became amenorrheic at the end of the second month of treatment, and symptomless at the end of the third month. Of nine women who had the potential and the desire to conceive, three conceived within 3 months after termination of treatment. Two more became pregnant within 1 year, and another, 14 months after termination of treatment. Five preg-nancies progressed to term. One patient. aborted. Two of the three woman who did not conceive had subfertile husbands. Major side effects recorded were seborrhea and acne, which subsided after discontinuation of therapy. Treatment of endometriosis with gestri-none otters the advantage of effective clearing of lesions with relatively low dosage and frees the patient from the daily administration of drugs required by similar conservative
hormonal therapies. (AM. J. OBSTET GYNECOL 144:895, 1982).
GESTRINONE (13-ethyl-17-alpha-ethinyl-17-hydroxygona-4,9,11-trien-3 one) is a synthetic trienic 19-norsteroid with antigonadotropic properties, which has been used experimentally as a long-acting contraceptive. On the basis of the affinity of gestrinone for progresterone receptors, Raynaud and associates2 characterized this compound as an antiprogesterone. Gestrinone binds to androgen and aldosterone receptors but without exerting any marked antiandrogenic or antialdosterone effect. The compound is slightly androgenic, an effect which may be accentuated by a marked antiestrogenic action. The antiestrogenic effect of gestrinone, however, is not well understood, since it counteracts the uterotropic effects of estrogen without bind-ing to estrogen receptors. The compound has been used as a weekly and midcycle oral contraceptive for women. As an oral contraceptive, the drug proved to be
active at doses as low as 5 mg weekly4. As an intradermal implant, it provided contraceptive protection
for as long as 1 year. The main side effects recorded in clinical trials were amenorrhea, breast hypotrophy, and acne, all associated with the antiestrogenic and antiprogesterone properties of the drug. The endometrium of women on gestrinone becomes markedly atrophic, an effect which can last several months after discontinua-tion of therapy. This inhibition of endometrial tissue suggested its use in the treatment of endometriosis.
From December, 1978, to July, 1981, 66 women with endometriosis were treated with gestrinone in our clinic. We report here the outcome of the treatment for the first group of 20 women who completed 2 years of follow-up.
Patients and methods
Twenty patients with endometriosis diagnosed by laparoscopy were treated with gestrinone for a period of 6 to 8 months. The drug, supplied by Roussel-Uclaf (Paris), was administered orally in a dose of mg twice weekly According to the point system upon which the classification of endometriosis by the American Fertility Association is based five patients were considered to have mild endometriosis (Stage 1), eight had moderate (Stage II), and the other. seven had severe (Stage III). None of the subjects scored more than 30 points, although two of those classified as having Stage III ac-cording to the American.
Except for two women who had had hysterectomies previously, all subjects had reg-ular menstruation. Fifteen women had the potential to conceive. These patients had at least one patent tube and ovulated normally. Of these, only nine desired to conceive Four had completed their families previously, and two women were not married. Five women could not conceive because of sequelae of previous operations, such as bilateral tubal occlusion rind tuboovarian adhesions, or because of hysterectomy. Among those who desired to conceive, infertility lasted from a minimum of 3 to as long as 12 years.
Twelve subjects had the full course of treatment of 8 months; seven subjects discontinued treatment 6 months, since they were considered to be clinically cured; and one subject discontinued treatment at 4 months, because she had opted for an operation on the advice of her private physician. All those on the shorter 6-month course had endo-metriosis in the mild or moderate category.
Bleeding episodes that occurred during the first 2 months of treatment were rare. Whenever they did occur, the patients reported them to be less painful than those that oc-curred during the pretreatment phase. One patient reported spotting during the first 6 weeks of treatment, but no pain. By the end of the second month of treatment, all patients were amenorrheic
Except for one patient who had severe endometriosis, all subjects were free of dyspareunia by the second month of treatment, and were completely symptomless by the third month of treatment.
Of the nine women who not only desired but also had the potential to conceive, three became pregnant within 3 months after termination of treatment; two more became preg-nant within 1 year, and another,
14 months after termination of treatment. One woman be-came pregnant a second time after being delivered of a normal infant, and at the time of this writing is in the thirtieth week of the second pregnancy.
One of those who conceived within 3 months of termination of therapy had an early abortion, followed by two more pregnan-cies, both of which ended in abortion. No ectopic pregnancies were recorded in this group of patients.
Two of the three women who desired to conceive but had not become pregnant by the end of the second posttreatment year had husbands with poor sperm counts who failed to respond to treatment. Moreover, one of them (Subject No. 18) was 42 years old at termination of therapy. Only one of the other three patients failed to conceive despite frequent attempts to do so (Subject No. 1).
Of the six women who conceived, only one had severe endometriosis; two had mild and the other three had moderate endometriosis. In three patients, endometriosis recurred within 6 months after the first 8-month course of gestrinone, and they had to be treated for an additional course of months. Table I summarizes the results of treat-ment.
Acne and seborrhea of varying severity, but usually mild, developed in all subjects. Hoarseness developed in three subjects. A moderate reduction in breast size and flaccidity occurred in two subjects. Transient leg pain and edema was reported by 12 patients. One patient reported tingling in the fingers. Transient nausea, that occurred usually on the days on which the drug was taken, was reported by four subjects.
All side effects subsided immediately after discontinuation of therapy. No significant change in blood pressure was recorded, but most patients (14) gained weight (1.0 to 4.4 kg) in 8 months. Two patients lost weight (less than 2 kg). In four, no change in body weight occurred.
No alteration in blood cell counts, serum cholesterol, glucose, transaminases, blood urea nitrogen, and alkaline phosphatase was recorded during the treatment period.
It has been estimated that endometriosis may affect at least 25% of all women in the third and four decades. The disease, which may be incapacitating in many cases, is a major cause of infertility. Both radical and conservative operations have been used to treat the most severe cases, but medical treatment is usually preferred in moderate and mild cases of endometriosis Various hormonal preparations have been used during the last 20 years, all of them having as an aim the abolishment of menstruation and inhibition of endometrial growth. Progestins, estrogen, and progestin combinations and contraceptives that contain estrogens and 19-norsteroids all have been used7,8. During the last 10 years, danazol, an isoxazol derivative of 17- alpha-ethinyl testosterone, has been widely promoted as possibly the most effective agent. Several authors reported symptomatic improvement in 55% to 87.5% of patients treated with danazol9-11. Pregnancy rates subsequent to danazol therapy are approximately 40%, but at least one
author claimed a pregnancy rate of 72.2%12
Recurrence of endometriosis after discontinuation of danazol therapy has beenreported to be in the range of 39% within less than 1 year.11 The recommended doses of danazol vary from 200 to 800 mg daily for as long as 1 year. These high dosages seem to be necessary to effect endometrial atrophy. In fact, some patients may require as much as 1,000 mg daily to relieve symptoms6.
In the present clinical trial, gestrinone compares favorably with danazol in both symptomatic relief and pregnancy rates. Although only six of nine women who not only wished to conceive but also had the potential to do so did conceive within 2 years after termination of the treatment (66%). in fact, only one subject had unexplained infertility after a full course of gestrinone, since the other two subjects had infertile husbands. Symptomatic relief was achieved in most patients within the first month of treatment, and within 3 months, all subjects except one were free of pain.
The 5 mg dose of gestrinone twice weekly that is required to induce endometrial atrophy represents a significant reduction over danazol therapy. which requires a min-imum of 200 mg daily or 1,600 mg weekly, a dose that is 160 times higher. The very low effective dose of gestrinone frees the patient. from a daily administration regimen and renders the long-terns treatment much more acceptable. Acceptability is also reflected in the very low incidence and intensity of side effects, which are usually mild and easily tolerated. The low toxicity of gestrinone was well documented in clinical trials aimed at the development of a male contraceptive pill when the drug was administered at doses of 50 mg weekly13.
- Goutinho, E.M.: Clinical experience with implant contraception, Contraception 18:411, 1978.
- Raynaud, J. P., Bonne, C., Bouton, M. M., Moquilewsky, M., Philibert, D., and Azadian-Boulanger, G.:
Screening for anti-hormones by receptor studies, in Proceedings of the Fifth International Gongress on
Hormonal Steroids, Mexico City, 1974. Amsterdam, 1974, Excerpta Medica.
- Sakiz, E., Azadian-Boulanger, G., Larague, F., and Raynaud, J. P.: A new ap-proach to estrogen-free
contracption based on progesterone receptor blockade by midcycle administration of ethyl-norgestrie-
none (R 2323), Contraception 10:467., 1974.
- Mora, G., Faundes, A., and Patore, V.: Clinical evaluation of an oral progestin contraceptive, R-2323 5
mg administered at weekly intervals, Contraception 10:145, 1974.
- Coutinho, E. M., da Silva, A. R.. Carreira, C. M.. Chaves, M. C., and Adeodato Filho, J.: Contraceptive
effectiveness of Silastic® implants containing the pro-gestin R-2323, Contraception 11625, 1975.
- American Fertility Society Classification of Endometriosis, Fertil. Steril. 32:635, 1979,
- Chalmers, J. A: Danazol in the treatment of endometriosis, Drugs 19:331, 1980.
- Kistner, R.W.: The treatment by inducing pseudopregnancy with ovarian hor-mones, a reported of 58
cases, Fertil. Steril. 10:539, 1959.
- Audebert, A. J. M., Bernard, I., and Emperaire, J.C.: Treatment of endometriosis with Danazol, Gyne-
cologie 1:29, 1977.
- Lauersen, N. H., Wilson, K. H., and Birnbaum, S.: Danazol, an antigonadotropic agent, in the treat-
ment of pelvic endometriosis, AM J. OBSTET. GYNECOL. 123:742, 1975.
- Dmowski, W. P. Endocrine properties and clinical application od Danazol, Fertil. Steril. 31.237, 1979,
- Dmowski, W.P., and Cohen, M. R.: Antigonadotropin (danazol) in the treatment of endometriosis.
AM. J. OBSTET, GYNECOL 130:41,1978.
- Coutinho, E M.. and Melo, J. F.: Successful inhibition of spermatogenesis in man without loss of libi-
do: A potential approach to male contraception, Contraception 8:207, 1973.
- Coutinho, E. M.: Conservative treatment of uterine leiomyoma with the anti-estrogen anti-progeste-
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