Regression of uterine leiomyomas after treatment with gestrinone, an antiestrogen, antiprogesterone

Regression of uterine leiomyomas after treatment with gestrinone, an antiestrogen, antiprogesterone

Elsimar M. Coutinho, M.D., Genevieve Azadian Boulanger, M.D., and Maria Tereza Gon~ralves, M.D.

Salvador, Bahia, Brazil

Ninety-seven women, aged 18 to 53 years, with uterine leiomyomas diagnosed by bimanual palpation and ultrasonography, were treated for 4 to 13 months with gestrinone, a potent steroidal, antiestrogen, antiprogesterone. Thirteen women were <30 years old and six 50 years old or older. Forty-six women were 30 to 40 years old and 32 others were 40 to 50 years old. Sixty-one women were nulliparous. Patients were divided in a random fashion into three groups according to treatment schedule. In group A, 34 patients received capsules containing 5 mg of gestrinone twice weekly. In group B, 36 patients received 2.5 mg capsules three times weekly. In group C, 27 patients were instructed to insert 2.5 mg tablets in the vagina three times weekly. Uterine volume was measured by ultrasonography before and at the end of treatment. At the end of 4 months, uterine volume fell from 303 to 251 cm3 in group A, from 361 to 266 cm3 in group B, but increased from 371 to 387 cm3 in group C. For those patients treated for 10 ( ± 1) months, mean uterine volume fell from 368 to 282 cm3 in group A and from 384 to 327 cm3 in group B, but increased from 262 to 290 cm3 in group C. Mean uterine volume of patients who were treated for 13 ( ± 1) months also fell from 325 to 259 cm3 in group A, from 416 to 268 cm3 in group B, and from 406 to 399 cm3 in group C. Changes in uterine volume measured at the time of discontinuation for the various groups revealed volume decrease in 71 and increase or no change in 26. Differences between groups A, B, and C were statistically significant when comparisons were made at 4 and 13 months. Uterine bleeding ceased by the second month of treatment in half the patients initially complaining of menometrorrhagias. After 4 months of treatment, 95% of the women were amenorrheic. Hemoglobin increased in 85 of 90 patients for whom values were available before treatment began. Both dyspareunia and chronic pain were significantly reduced by the gestrinone treatment. Androgenic side effects such as seborrhea, acne, and hirsutism, whenever they occurred, were benign and reverted soon after discontinuing the medication. (AM J OBSTET

GYNECOL 1986;155:761-7.)

Key words: Uterine leiomyomas, gestrinone treatment, endometrial atrophy, uterine shrinkage, fertility restoration

Although the etiology of leiomyomas is unknown, both clinical and biochemical evidence tend to implicate estrogens as the single most important factor in the pathogenesis of these tumors. I. 2 Progesterone, on the other hand, has been reported to counteract the stimulating effects of estrogen on myoma development and growth, but attempts to use progestins in the treatment of leiomyomas have proved disappointing. Goodman' reported six cases of clinically diagnosed uterine leiomyomas which regressed following therapy with progesterone, but his study was based on pelvic examination and was poorly documented. Segaloff et al.4

were unable to find radiographic or microscopic evidence of involution of myomas in women treated by

progesterone before hysterectomy, and Goldzieher et al. 5 reported in 1966 that continuous administration of 2 mg of estrogen-free norethindrone daily for periods of 1 to 3 months had no effect on uterine myomas in 14 women. The same authors reported, however, that medrogestone (6,17-dimethyl-6-progesterone) given in the very high dose of 25 mg daily for 21 days evoked intense degenerative changes in both small and large myomas exceeding those seen at the end of pregnancy; the changes induced by medrogestone progressed to fibrosis and hyalinization. 5 Thus it is not surprising that, despite the large number of progestins and 19-norsteroids made available to clinicians during the last 20 years, no other serious attempts to treat myomas with new potent progestins were made.

From the Maternidade Climerio de Oliveira, Federal University of Bahia School of Medicine.

Supported by the Rockefeller Foundation. Received for publication September 16, 1985; revised April I, 1986;

accepted june 3, 1986. Reprint requests: Prof. Elsimar M. Coutinho, Maternidade Climerio

de Oliveira, Federal University of Bahia, Salvador, Bahia, Brazil.

In 1981 we proposed long-term use of an antiestrogen, antiprogesterone, R-2323, to conservatively treat leiomyomas in young women desirous of fertility. 6 One such patient, infertile because of a large serous leiomyoma, conceived after prolonged (2 years) treatment with gestrinone (R-2323). Treatment with gestrinone

761

762 Coutinho, Boulanger, and Goncalves October 1986 Am J Obstet Gynecol

Table I. Uterine volume according to group before and at the end of 4 months of gestrinone treatment

Uterine volume before· treatment Uterine volume after treatment Group Measurement (em') (em')

A N 34 33 Mean 303 251 SD 178 165 Median 258 213 Range 99-775 58-677

B N 36 36 Mean 361 266 SD 293 229 Median 285.5 169.5 Range 71-1346 49-1061

c N 27 26 Mean 371 387 SD 271 329 Median 289 297 Range 89-1154 67-1367

Analyses of covariance of A and Bas compared to C were statistically significant with p = 0.047.

Table II. Uterine volume according to group at 10 months(± 1 month)

Uterine volume before treatment Uterine volume after treatment Group Measurement (em') (em3

)


B N 15 15 Mean 384 327 SD 328 292 Median 244 174 Range 90-1255 92-1061


Analysis of covariance revealed no statistically significant difference between groups A, B, and C.

not only allowed reestablishment of patency of tubes previously blocked by the tumor in that patient but also suppressed menorrhagia, allaying the need for an almost inevitable hysterectomy. The successful treatment in this patient encouraged us to try the same therapy on other patients having leiomyomas of various types and sizes in order to evaluate the potential of this drug as a conservative treatment of these benign but potentially hazardous tumors. The present study reports a clinical trial involving 97 leiomyoma patients who were treated with gestrinone for 4 to 13 months.

Patients and methods

Ninety-seven women, aged 18 to 53 years, with uterine leiomyomas diagnosed by bimanual palpation and ultrasonography, were enrolled in this trial. Thirteen women were <30 years old and six were 350 years. Forty-six women were 30 to 40 years old, and the other 32 were 40 to 50 years old. Only patients dis-

playing symptoms such as bleeding irregularities, dyspareunia, or pelvic discomfort were admitted. The women had menorrhagia (90 women), metrorrhagia (80 women), and/or intermenstrual bleeding or spotting (22 women). Fifty-one subjects had complaints of pain or abdominal discomfort. Thirty-six women had already had one or more term pregnancies, whereas 61 were nulliparous. Involuntary infertility of 32 years' duration was reported by 62 women. Twenty-six of these reported one or multiple spontaneous abortions or stillbirths.

Patients were admitted in a random fashion into one of three groups. In group A, 34 patients received capsules containing 5 mg of gestrinone (Roussel-Uclaf, Paris, France) twice weekly by oral route. In group B, 36 patients received 2.5 mg capsules three times weekly also by oral route. In group C, 27 patients were instructed to insert tablets containing 2.5 mg of gestrinone in the vagina three times weekly. Age distribution

Volume 155 Number 4

Regression of leiomyomas treated with gestrinone 763

Table III. Uterine volume according to group before and at the end of 13 months (±I month) of gestrinone treatment

Uterine volume before treatment Uterine volume after treatment Group Measurement (em') (em')


B N 13 13 Mean 416 268 SD 316 190 Median 345 205 Range 135-1346 80-774


Analysis of covariance after logarithmic transformation of the data. Values for A and B significantly different from C with p = 0.04.

in the three groups was comparable. In group A, mean age was 37.76 years (range, 18 to 53). In group B, the mean age was 37.17 years (range, 24 to 52) and in group C, the mean age was 37.32 years (range, 25 to 53).

The main criterion of efficacy was reduction in uterine volume as measured by ultrasonography. Two or more ultrasonographic evaluations (ADR SL 4000) were made before starting treatment in order to obtain the mean of three uterine diameters: anteroposterior, longitudinal, and transverse. The product of the three values was then multiplied by the constant 0.45 to provide the estimated uterine volume. Logarithmic transformation was made on the data to equalize variance of the three treatment groups and to achieve a normal distribution inside each treatment group. Analyses of covariance were carried out with the initial volume as covariant and with factor of treatment. Pairwise comparisons were carried out on least square means according to Tukey's procedure. Homogeneity of regression was checked at every step and satisfied. The X2 test was used to evaluate percentages of response categories between the groups. The mean normal uterine volume in our clinic population has been established over the last 2 years as being between 64 and 82 em'. Hematocrit, red blood cell count, and hemoglobin were measured before and at the end of treatment.

Results

All patients completed at least 4 months of treatment. Uterine volume was estimated at the end of this period for all except two patients who were unavailable. Following 4 months of treatment, mean uterine volume fell from 303 to 251 em' in group A and from 361 to 266 em' in group B. In group C, the mean uterine volume increased from 371 to 387 em'. The differences

between groups A, B, and C were statistically significant (p = 0.04 7). The range of values and means with standard deviation for each one of the three groups is shown in Table I.

Seventy-two patients remained on treatment beyond 4 months. Thirty-two women discontinued treatment at 9 to 11 months and were reevaluated before being discharged. Seven of these were in group A, 15 in group B, and nine in group C. Mean uterine volume of the seven patients of group A decreased from 368 to 282 cm3

• In group B mean uterine volume fell from 384 to 327 em', whereas in group C mean uterine volume increased from 262 to 290 em'. Table II shows range, means, and standard deviation of uterine volume for these three groups of patients.

The remaining 40 patients were treated for 12 to 14 months and reevaluated only at the end of treatment. Two patients became pregnant before reevaluation of their nonpregnant uterine volume could be made. Mean uterine volume of 17 patients of group A decreased from 325 to 259 em'. Mean uterine volume of 13 patients in group B decreased from 416 to 268 em'. In nine patients of group C the mean uterine volume was almost unchanged: 406 em' at the beginning and 399 em' at the end of treatment. Differences between groups A, B, and Care significant with p = 0.04. Values for the groups treated for one year or longer are shown in Table Ill.

For all groups, changes in uterine volume measured at the time for discontinuation revealed that volume was increased or unchanged in 26 women and decreased in 71 women. In group A uterine volume decreased in 26 patients, whereas it increased or was unchanged in eight. In group B uterine volume decreased in 30 patients and increased or was unchanged in only

764 Coutinho, Boulanger, and Gonc;alves

Fig. 1. A, Longitudinal real-time ultrasound scan of a myomatous uterus in a 31-year-old symptomatic patient. Uterine volume is 143 cm3

. B, Ultrasound scan of same patient, asymptomatic after 7 months of gestrinone treatment (5.0 mg twice weekly orally). Uterine volume is 97 cm3

• C, Ultrasound scan of same patient after 14 months of treatment. Uterine volume is 89 ems. Note progressive reduction in uterine volume and disappearance of myomatous mass.

six. In group C uterine volume increased or was un

changed in 12, having decreased in 15. Inspection of ultrasonographic pictures of individual

cases revealed shrinkage of both myomatous nodules

and normal myometrial tissue (Fig. 1). In most cases

October 1986 Am J Obstet Gynecol

Fig. 2. A, Longitudinal real-time ultrasound scan of a myomatous uterus of a 35-year-old symptomatic patient. Uterine volume is 309 cm3

• B, Ultrasound scan of same patient after 8 months of gestrinone therapy (5 mg twice weekly). Patient is symptom-free. Uterine volume is 147 ems. Note the marked reduction in uterine volume and the involution of myomatous masses.

where myomatous nodules protrude from the uterine profile, shrinkage of the tumor itself could be clearly

demonstrated (Fig. 2). Manual palpation revealed not

only reduction in uterine volume but marked softening

of tumoral masses in most patients of groups A and B.

Even in patients whose uterine volume underwent little

change, softening of hard uterine masses occurred. Uterine bleeding ceased by the second month of

treatment in approximately half of these patients com

plaining of menometrorrhagias on inclusion. Of a total

of 80 patients having such a complaint, 42 (52%) be

came amenorrheic before completing 2 months of

treatment. By the end of 4 months of treatment 76 women (96%) were amenorrheic; by the end of 12

months, of the 54 patients remaining under treat

ment, 50 (92%) were amenorrheic. The disappearance of uterine bleeding according to treatment group is shown in Table IV.

Spotting was markedly diminished during treatment.

Volume 155 Number 4


Table IV. Disappearance of menstrual bleeding including menorrhagia and metrorrhagia when present at the beginning of treatment

Length of treatment (mo)

Group 1 or 2 3 or 4 5 or 6 7, 8, or 9 11 or 12

A 12/27 25/26 26/26 21/21 18118 B 16/30 28/30 26/30 24/25 17/21 c 14/23 23/23 23/23 18119 15/15

Table shows the number of patients no longer bleeding compared to the number of patients who originally reported either menorrhagia or metrorrhagia (for example, only 12 of 27 patients of group A had ceased bleeding at the end of 2 months, while I 8 of 18 were amenorrheic at the end of 12 months).

Table V. Disappearance of spotting according to treatment group

Group

A B c


1 or 2

4/6 7111 5/5

I 3 or 4

3/6 7111 3/4

5 or 6

5/6 9111 3/4

7, 8, or 9

4/6 8/11 3/4

10,1l,or12

5/5 8110 3/3

Numbers indicate patients who ceased spotting compared to patients having the complaint before treatment began.

At the end of 1 to 2 months of treatment, 16 of 22 patients presenting this complaint on admission had stopped spotting. At the end of 12 months of treatment, 16 of 18 patients who complained of spotting at the beginning and who remained in the study had stopped spotting. Table V shows the disappearance of spotting according to treatment group and duration of the treatment.

Hemoglobin increases occurred in 85 of 90 patients for whom values were available before treatment began and following discontinuation. In four patients hemoglobin levels decreased further during treatment, and in only one were values unchanged. Red blood cell count increased in 54 patients, remained the same in 21, and decreased in 15. Hematocrit value increased in 65, remained the same in 18, and decreased in 7. Mean red blood cell count increased from 3,856,000 mm' to 4,013,000 mm3 at the time of discontinuation. Hemoglobin likewise increased from a mean of 12.38 gm at the beginning of the trial to 13.16 gm at the end. Hematocrit increased from a mean of 36.9% to 38.4%.

Dyspareunia also diminished during treatment. At the end of 2 months of treatment, 12 patients of 41 who complained of dyspareunia on admission reported complete disappearance of pain or discomfort during coitus. At 6 months the number of patients reporting disappearance of dyspareunia had increased to 27. At 12 months, 19 of 24 of those who complained of dyspareunia at the beginning and who remained in the study reported no discomfort or pain during intercourse. Table VI shows the evolution of dyspareunia in the various treatment groups during treatment. Chronic pain unrelated to coitus had also been reduced

by the treatment in every one of the groups, as shown in Table VII. Although only 18 of 41 patients who complained of chronic pain at the beginning reported cessation of pain at the end of 2 months of therapy, all 25 remaining in the study at the end of 1 year were pain free. Changes in body weight were moderate. A mean increase of 2 kg occurred in patients treated orally and 1 kg in patients treated vaginally. Only 13 patients, all in groups A and B, gained ~3 kg during the treatment period. No relevant changes in blood pressure were noted. Mean systolic pressure at the beginning of the trial for all treatment groups was 120 mm Hg at the beginning and 122 mm Hg at the end. Only one patient developed hypertension. This patient's systolic pressure increased from I 27 mm Hg at the beginning of treatment to 155 mm Hg after 1 year.

After discontinuation of treatment 11 women became pregnant: four in group A, six in group B, and one in group C. Eight pregnancies continued to term. The other three ended prematurely, with two of these being stillbirths. All eight pregnancies occurred in women who were <40 years of age and who had been treated for at least 4 months.

Undesirable side effects included seborrhea and acne, which affected approximately 40% of all patients, and muscular and joint pain, which was reported by 14% of all patients. Joint pain was reported as having a rheumatic nature and responded favorably to treatment with antiinflammatory compounds and analgesics such as aspirin, indomethacin, or piroxicam.Less common complaints were curling of hair (three patients), chloasma (five), moderate hirsutism (5), nervousness (4), increased libido (4), decreased libido (3), hair loss

766 Coutinho, Boulanger, and Gonc;alves October 1986 Am J Obstet Gynecol

Table VI. Disappearance of dyspareunia during gestrinone treatment

Group

A B c

I or 2

3/13 4115 5/13

n

2112 7115

10/12*

3 or 4

I %

17 47 83


5 or 6

5112 10115 12113

7, 8, or 9

5/10 9/11 9/11

10, Jl, or I2

517 9/9 5/8

Numbers indicate patients who no longer had the complaint compared to patients originally complaining of dyspareunia. *p = 0.005 (x' test).

Table VII. Disappearance of chronic pelvic pain during gestrinone treatment

Group

A B c


I or 2

2/15 8115 8/11*

I 3 or 4

14/15 12115 lOll!

5 or 6

14114 15115 IIIli

7, 8, or 9

11/11 11115 10/10

10, II, or I2

717 IIIII 717t

Figures indicate patients reporting cessation of pain compared to patients originally complaining of pelvic pain unrelated to coitus.

*p = 0.007 (x' test). tNot significant.

(6), and hoarseness (6). Some of these side effects occurred in the same patients. Fifty-three patients reported no undesirable side effects.

Only a few patients discontinued because of side effects such as acne and seborrhea or because the treatment failed to alleviate symptoms. Most patients discontinued therapy because they considered themselves cured of their major complaint, that is, excessive irregular uterine bleeding and/or abdominal discomfort. For this reason many women discontinued therapy even when ultrasonography revealed moderate or no improvement. Persistence of symptoms such as bleeding or dyspareunia accounted for only five of 25 patients discontinuing therapy at 4 months. Androgenic side effects, such as seborrhea, hirsutism, or hoarseness, were considered compelling reasons for discontinuation by only two patients. Another two patients, despite significant improvement, opted for surgical treatment on their private gynecologist's or family doctor's advice.

Comment Gestrinone is a trienic 19-norsteroid with potent an

tiestrogenic and anti progesterone properties. The drug was developed originally as a long-acting contraceptive, either as a pill for once-a-week administration or as an implant for subdermal application, effective for 1 year.7.8 Because of its marked inhibitory effects on estrogen and progesterone receptor-rich tissues such as the endometrium and mammary gland, gestrinone has been used successfully in the treatment of endometriosis and benign breast disease."· 10

The present study shows that prolonged gestrinone treatment may also cause the growth of uterine myomas to revert. More important, gestrinone treatment provides effective control of excessive bleeding associated with those tumors. The compound also inhibits gonadotropin secretion, disallowing ovulation and consequently preventing the occurrence of menstruation. Inhibition of gonadotropin secretion is just one of the mechanisms by which gestrinone treatment reduces bleeding. The quickness of the suppression of uterine bleeding points to a direct inhibiting effect on the endometrium. Prolonged treatment appears to induce endometrial atrophy, suppressing intermenstrual bleeding and spotting, which probably originates in hyperplastic endometrium, and stands out as one of the most distressing features of the disease. The long-lasting amenorrhea developing during gestrinone treatment is in fact the most rewarding effect for both patient and physician because it removes the urgency for surgical intervention and allows restoration of depleted iron reserves in anemic patients.

The vaginal route of administration, which was proposed as an alternative for those patients who developed gastric intolerance to steroids and as a practical means to bypass the liver and increase bioavailability of the drug, turned out to be less effective than expected. Although blood levels of gestrinone resulting from vaginal administration were sufficient to inhibit ovulation and prevent menstruation, they appeared to be inadequate to saturate myometrial receptors and inhibit tumor growth. The relative inefficiency of the vaginal route in reducing uterine volume, which may be ex-

Volume 155 Number 4

plained either by inadequate blood levels resulting from insufficient vaginal absorption or by the inappropriateness of dosage, have in fact turned the group of patients treated by the vaginal route into a control group.

Although the number of successful pregnancies was small, it should be noted that of those 62 women who reported involuntary infertility before gestrinone therapy, probably less than half that number still had the potential or the desire to conceive. Many were more than 40 years old, and others had bilateral tubal occlusion or troubles with ovulation in addition to their leiomyomas. Some had infertile or subfertile husbands, and a few were divorced. Moreover, at the time of the writing this report >40% of patients had less than 1 year of follow-up following discontinuation. A more accurate evaluation of the efficacy of gestrinone therapy will require careful selection of cases, since factors such as the patient's age and the tumor's size and recency appear to influence therapeutic response.

Although other possible mechanisms of inducing shrinkage of myomas may be achieved by creation of an artificial menopause through pituitary desensitization by luteinizing hormone-releasing hormone analogs, the results of the present trial show that gestrinone treatment achieves, in addition to a reduction in tumor size, prompt suppression of excessive bleeding and relief of pain, without the inconvenience of menopausal symptoms that may develop when luteinizing hormone-releasing hormone analogs are used. 1

L 1" The

treatment may also be useful in conditioning patients for surgery because it allows restoration of depleted iron reserves before and reduces risk of bleeding during the operation itself.


REFERENCES

I. John AH, Martin R. Growth of leiomyomata with estrogen-progesterone therapy. J Reprod Med 1971 ;6:49.

2. Pollow K, Geilfuss J, Boquoi E, Pollow B. Estrogen and progesterone binding proteins in normal human myometrium and leiomyoma tissue. J Clin Chern Clin Biochem 1978; 16:503.

3. Goodman AL. Progesterone therapy in uterine fibroma. J Clin Endocrinol Metab 1946;6:402.

4. Segaloff A, Weed JC, Sternberg WH, Parson D. The progesterone therapy of human uterine leiomyomas. J Clin Endocrinol Metab 1949;9: 1273.

5. Goldzieher JW, Maqueo M, Ricaud L, Aquilar JH, Canales E. Induction of degenerative changes in uterine myomas by high-dose progestin therapy. AM J 0BSTET GYNECOL 1966;96: 1078.

6. Coutinho EM. Conservative treatment of uterine leiomyoma with the anti-estrogen, anti-progesterone, R-2323. IntJ Gynecol Obstet 1981;19:357.

7. Mora G, Faundes A, Pastore U. Clinical evaluation of an oral progestin contraceptive, R-2323, 5 mg, administered at weekly intervals. Contraception 1974;10:145.

8. Coutinho EM, Da Silva AR, Carreira CM, Chaves MC, Adeodato Filho J. Contraceptive effectiveness of silastic implants containing the progestin R-2323. Contraception 1975; II :625.

9. Coutinho EM. Treatment of endometriosis with gestrinone (R-2323), a synthetic antiestrogen, antiprogesterone. AM J 0BSTET GYNECOL 1982; 144:895.

10. Coutinho EM, Azadian-Boulanger G. Treatment of fibrocystic disease of the breast with gestrinone, a new trienic synthetic steroid with anti-estrogen, anti-progesterone properties. Int J Gynecol Obstet 1984;22:263.

II. Fillicon M, Hall DA, LoughlinJS, Rivier J, Vale W, Crowley WF. A conservative approach to the management of uterine leiomyoma: pituitary desensitization by a luteinizing hormone releasing hormone analogue. AMJ OBSTET GYNECOL 1983;147:726.

12. Healy DL, Fraser HM, Lawson SL. Shrinkage of a uterine fibroid after subcutaneous infusion of an LHRH agonist. Br Med J 1984;289: 1267.

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Regression of uterine leiomyomas after treatment with gestrinone, an antiestrogen, antiprogesterone