IN 1935 Stein and Leventhal described the syndrome of amenorrhea associated

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1 '"'.. Stein-Leventhal Syndrome: Resection Versus Clomiphene Therapy MELVN R. COHEN, M.D... N 1935 Stein and Leventhal described the syndrome of amenorrhea associated with bilateral polycystic ovaries. This syndrome of menstrual irregularity, a history of sterility, masculine-type hirsutism, and less consistently, retarded breast development and obesity, has been well documented through the years. n 1964, Stein summarized his series of 108 patients extending over a period of 34 years. He reported cyclic menses occurring in 95% of the patients after bilateral ovarian wedge resection. Among the 83 women complaining of infertility, 71 (85%) became pregnant, with a total of 181 pregnancies. n this series there were 5 sets of twins, which is about 3 times the normal rate of multiple births. Stein further stated that after wedge resection, restoration of fertility is permanent. First Greenblatt, then Kistner,4 stated that clomiphene citrate was a most effective drug in the treatment of the Stein-Leventhal syndrome. Kistner advised that clomiphene replace the surgical approach as the treatment of choice, and summarized the results of 1704 individual case reports, 391 of which were considered to describe polycystic ovary disease. 5 Of the 391 patients treated with clomiphene, 305 (78%) responded with evidence of ovulation. No figures are given as to the percentage of pregnancies in this group. Roy and associates, in reporting their results in induction of ovulation with clomiphene in 179 women, report 35 patients classified as having Stein-Leventhal syndrome. The 35 patients were treated during 134 cycles; 32 of them ovulated and menstruated, during 117 cycles, but only 6 conceptions occurred. From the Department of Obstetrics and Gynecology, Michael Reese Hospital and Medical Center, the Chicago Medical School, and The Fertility nstitute, Chicago,. Presented at the 22nd Annual Meeting of the American Fertility Society, Chicago,., Apr. 29-May 1,

2 766 COHEN FERTLTY & STERLTY MATERALS AND METHODS We have treated 91 anovulatory patients with clomiphene citrate and have especially evaluated the effects of this drug in 24 patients, classified as 'having typical Stein-Leventhal syndrome. The enlarged cystic ovaries characteristic of this syndrome were diagnosed by pneumoperitoneum, culdoscopy, or at laparotomy. These 24 patients ranged in age from 19 to 30, and were treated with clomiphene citrate, in amounts from mg. per course of treatment. There were 60 courses of treatment given in this group of patients. RESULTS During the 60 treatment cycles, 40 cycles were classified as having typical diphasic temperature curves; 20 cycles were monophasic. Of the 24 patients, 20 responded at some time with a diphasic temperature curve; 4 patients did not respond during any course of therapy. There were 8 pregnancies in 7 patients; 5 were term single birth deliveries, and 1 patient delivered triplets at term. Two patients are currently pregnant. One patient is listed for two separate periods of treatment. She originally received a course of 500 mg. clomiphene during 1 month, promptly conceived, and delivered a term normal child. Two years later she returned, again amenorrheic, and responded after 2 courses of clomiphene; she again delivered a term normal child. Three patients who had had prior bilateral ovarian wedge resections at other institutions responded to clomiphene as far as basal body temperatures were concerned, but conception did not follow. Six patients were considered clomiphene failures, and since have had ovarian resections. Five of these patients have become pregnant. Four of them have delivered term normal children, and 1 had a miscarriage at 6 months' gestation. One patient experienced a mild papular rash, 1 complained of diplopia, and 1 complained of Hushes. n 8 patients, ovarian cysts occurred. n 7 patients these cysts were small and disappeared spontaneously. One patient developed huge ovarian cysts after her fifth course of clomiphene and underwent laparotomy. CASE REPORT Patient No was first seen Apr. 29, 1963, at the age of 19. She had been married for 2 years; birth control had never been used and she had never been pregnant. Menarche occurred at age 13. Menstrual periods had always been

3 i VOL. 17, No.6, 1966 STEN-LEVENTHAL SYNDROME 767 irregular (30-90 days), with a 7-day moderate flow. An attempt had been made to regulate her periods with oral progestins. Basal body temperatures had been monophasic. Physical examination disclosed an oily-type skin, acne of the face and back, but no hirsutism. Pelvic examination showed the uterus to be small, normal in size, and erect, with adnexa negative to palpation. Laboratory findings were: PB, 5.4; 17-ketosteroids, 9.4 mg. Culdoscopy performed on Oct. 15, 1963, disclosed typical bilateral polycystic ovaries. The surface of each ovary showed a thickened capsule; there were a few blood vessels coursing over both ovaries. There was a single, markedly superficial follicle present on the left ovary. Endometrial biopsy showed proliferative endometrium. A pneumoperitoneum confirmed the diagnosis of Stein-Leventhal syndrome. Stilbestrol, from 0.1 to 0.5 mg. daily, improved her acne and the 17-ketosteroid level dropped to 6.3 mg. Five courses of clomiphene citrate 100 mg. daily varying from 5 to 7 days, were given. This therapy was followed by diphasic temperature curves, and menstrual-like bleedings. During the third course of therapy, transient diplopia occurred. During the fourth course of treatment, a small, left ovarian cyst was palpated. On Nov. 1, 1964, clomiphene 100 mg./day was given for 7 days. During this cycle, in addition to the clomiphene, stilbestrol, 0.1 mg. daily, was given in the hope of improving cervical mucus. She was again seen on Nov. 16, 1964, at which time she complained of severe hot flushes. Pelvic examination disclosed a large left ovarian cyst. One week later on Nov. 23, 1964, both ovaries were grossly enlarged and she was hospitalized. On Nov. 24, 1964, laparotomy (Fig. 1) disclosed a left ovarian cyst measuring 15 cm. in diameter, and a right ovarian cyst measuring 10 cm. in diameter. Grossly, the ovarian capsule was thin-walled and multiple large cysts filled with a yellowish, clear fluid crowded the cortex of each ovary. A bilateral ovarian resection was performed. Section disclosed a corpus luteum cyst of one ovary (Fig. 2) and large follicular and theca lutein cysts of both ovaries (Fig. 3). The patient made an uneventful recovery, began to menstruate regularly with diphasic curves, and conceived during March This pregnancy terminated at 6 months. PATHOLOGY n 1951, Leventhal and Cohen described in detail the gross and microscopic pathology present in the typical bilateral polycystic ovary. Grossly at operation the ovaries appear to be elongated to a size approaching the size of the uterine fundus. The enlargement is in the form of an interpolar elongation, the ovary appearing tense and oval, or egg-shaped. The tunica albuginia is thick, tough and pearly white. Sections [Fig. 4] made by cutting reveal a fibrous-appearing capsule, and stroma framing innumerable follicle cysts, which contain a clear fluid. Microscopically, the tunic is very thick and fibrous. n some sections, this marked thickening seems to push the primordial follicles toward the hilus. The follicles are in various stages of development,

4 768 COHEN FERTLTY & STERLTY Fig. 1. (Patient No ) Clomiphene-induced ovarian cysts at laparotomy. Fig. 2. Section of corpus luteum cyst after clomiphene citrate therapy (X 1.'10) Fig. 3. Theca lutein cyst after clomiphene citrate therapy. (X 150)

5 VOL. 17, No.6, STEN-LEVENTHAL SYNDROME but the findings of a cumulus with contained ovum is unusual. The granulosa may be thick and many-layered, but most often there is a single layer of granulosa cells, or none at all. One of the most significant and consistent findings is a marked hyperplasia of the theca interna cells. Not infrequently, luteinization r Fig. 4. Section of typical ovary in Stein-Leventhal syndrome. (X 6) was noted in this hyperplastic layer. Evidence of very rapid growth of the theca cells was demonstrated by the presence of numerous mitotic figures. n many sections, the hyperplastic theca layer was richly vascularized. The absence of corpora lutea was striking and in only one case of the present series was a corpus luteum found. The marked and persistent hyperplasia of the theca interna with numerous mitoses is a finding not seen in the normal ovary. n summary, the characteristic pathologic findings are: ( 1) follicle cysts, (2) hyperplasia of the theca interna, associated not infrequently with luteinization, and (3) fibrosis. Table 1 compares the microscopic characteristics of ovaries resected after clomiphene citrate therapy in 4 of the 5 patients who underwent lapatable 1. Microscopic Characteristics of Bilateral Polycystic Ovaries Resected After Clomiphene Citrate Therapy Pt. No Laparotomy Clomiphene date date 11/24/64 3/1/66 8/21/62 9/8/62 11/1/64 1/17/66 5/25/62 4/30/62 Cortew Multiple cysts Thin Thick Thick Thick Large Small Small Small Theca Vascularity luteinization Corpus luteum Cyst Organizing

6 770 COHEN FERTLTY & STERLTY rotomy. The fifth patient was operated on at another institution and the report stated that the ovaries were typical of bilateral polycystic ovaries. n patient No. 6198, clomiphene therapy was begun on Nov. 1, 1964, in dosage of 100 mg. daily for 7 days and laparotomy was performed on Nov. 24, A tissue section demonstrates what can happen to a typical polycystic ovary under the influence of a large dose of clomiphene citrate. The capsule is thinned out, cysts become quite large, and there is intense vascularity with intense theca luteinization (Fig. 3). n this patient, a corpus luteum cyst (Fig. 2) was present. n patient No. 8118, clomiphene therapy had been begun on Jan. 17, 1966; 100 mg. daily was given for 7 days. A monophasic curve was noted afterwards and withdrawal bleeding occurred about 3 weeks later. However, the month before, she had responded with a diphasic temperature curve to a dose of 500 mg. clomiphene. The pathology section was typical of a polycystic ovary except for the presence of an organizing corpus luteum. Sections for patients No and No were typical of polycystic ovaries untreated with clomiphene citrate. DSCUSSON There has been a good deal of speculation as to whether a Stein-Leventhal syndrome really exists. Goldzieher and Axelrod have stated that the symptom complex is not specific. From data tabulated for 1079 cases of polycystic ovarian disease from 187 references, hirsutism occurred in 69%, infertility in 74%, and amenorrhea in 59%. Obesity, virilization, cyclic menses, functional bleeding, and dysmenorrhea occurred less frequently; in 15% of the cases a biphasic basal temperature was reported and in 22% a corpus luteum was found at operation. Goldzieher and Axelrod concluded that the Stein-Leventhal syndrome calls attention to a small and perhaps not especially unique fraction of polycystic ovarian disease. They further state that the success of wedge resection in correcting the infertility and menstrual disorders associated with polycystic ovaries has been in a large measure responsible for the wide and continued interest in this disease. n their reports of results of wedge resections in patients with polycystic ovarian disease from the same group of cases, they found that regular cycles occurred in 80%, pregnancy in 63%, and decreased hirsutism in 16% of patients. Whether or not such a syndrome exists, the results of ovarian resection in selected cases is extremely successful. Goldzieher and Axelrod quote Southam, "the more estrogenic activity and the less androgenic activity

7 VOL. 17, No.6, 1966 STEN-LEVENTHAL SYNDROME 771 l there is, the better the results of wedge resection are likely to be." t has been our impression also that our results either with clomiphene or wedge resection depend in great measure upon whether endogenous estrogen is present. When endogenous estrogen, as evidenced by a mucorrhea with moderate spinnbarkeit and positive ferning, is present, the results of therapy improve. n a previous publication,! we have shown that clomiphene at first is antiestrogenic and that later, estrogen is released as evidenced by mucorrhea, with ovulation occurring. We have noted that some patients will respond to clomiphene without producing ovulatory mucus. Should this occur, it would be necessary to prescribe exogenous estrogens along with clomiphene, or resort to homologous intrauterine insemination. As a matter of fact, in the patient who conceived the set of triplets, the latter procedure was carried out because of the presence of a dry cervix at the time of the induced ovulations. Although the percentage of biphasic temperature curves is quite high with the use of clomiphene, the number of pregnancies is comparatively low. Perhaps this could be improved with the employment of homologous intrauterine insemination. However, this modality of therapy is difficult inasmuch as it is difficult to predict the exact time of ovulation, which can occur from 2 to 15 days after initiation of clomiphene therapy. t is our belief that prior to ovarian resection, trial courses of clomiphene therapy should be given. The number of courses of therapy depends largely on whether any side effects occur. The occurrence of temporary cystic swelling of the ovaries is not a contraindication to the continuation of therapy. These cysts usually disappear in time. n the case report presented, we chose to resect these ovaries immediately rather than wait for involution, because we were interested in evaluating the pathology produced by this drug. The dose given to this patient was large (700 mg.). We have learned that patients with typical polycystic ovaries are especially sensitive to clomiphene and perhaps a trial dose of no more than 50 mg.jday for 5 days should be tried. Prior therapy with clomiphene citrate in no way altered our results with bilateral ovarian resection. n this small series of 6 patients who underwent bilateral wedge resection, 5 promptly conceived, and we are hopeful that the sixth patient will yet conceive. CONCLUSONS 1. n a group of 24 patients with the Stein-Leventhal syndrome treated with clomiphene citrate during 60 cycles, 40 cycles showed typical diphasic temperature curves. Only 4 cases were completely refractory to therapy.

8 772 COHEN FERTLTY & STERLTY 2. There were 8 pregnancies in 7 patients treated with clomiphene; 5 were term single births, 2 patients are currently pregnant, and 1 patient delivered triplets at term. 3. Six patients were considered clomiphene failures and have had ovarian resections; 5 of them have conceived. 4. Side effects to clomiphene were minimal except in 1 patient who developed large bilateral cysts. Her case report is included. 5. The pathology of the Stein-Leventhal syndrome is reviewed. 6. n the Stein-Leventhal syndrome we urge an adequate trial of therapy with clomiphene citrate before resorting to bilateral ovarian resection. 111 N. Wabash Ave. Chicago, ll REFERENCES 1. COHEN, M. R, and PEREZ-PELAEZ, M. The effect of norethindrone acetate-ethinyl estradiol, clomiphene citrate, and dydrogesterone on spinnbarkeit. Fertil Steril 16: 141, GOLDZEHER, J. W., and AXELROD, L. R Clinical and biochemical features of polycystic ovarian disease. Fertil Steril14:631, GREENBLATT, R B., BARFELD, W. E., JUNGCK, E. c., and RAY, A. W. nduction of ovulation with MRL/41. lama 178:101, KSTNER, R W. Further observations on the effects of clomiphene citrate in anovulatory females. Arner 1 Obstet Gynec 92:380, KSTNER, R W. nduction of ovulation with clomiphene citrate. Obstet Gynec Survey 20:873, LEVENTHAL, M. L., and COHEN, M. R Bilateral polycystic ovaries, the Stein syndrome. Arner J Obstet Gynec 61:1034, Roy, S., GREENBLATT, R B., MAHESH, V. B., and JUNGCK, E. C. Clomiphene citrate: Further observations on its use in induction of ovulation in the human and on its mode of action. Fertil Steril14:540, STEN, 1. F., and LEVENTHAL, M. L. Amenorrhea associated with bilateral polycystic ovaries. Arner 1 Obstet Gynec 29: 181, STEN, 1. F., SR. Duration of fertility following ovarian wedge resection-stein Leventhal syndrome. Western 1 Surg 78:237, 1964.