Endometrial adenocarcinoma and the polycystic ovary syndrome GARY P. WOOD, M.D. RICHARD C. BORONOW, M.D.

Jackson, Mississippi

While endometrial adenocarcinoma is the second most common female genital malignancy, only four per cent of the cases occur in women less than 40 years of age. The relative rarity of this disease in _young women requires that we be especially attuned to those who are at high risk. This paper presents two case reports of women with polycystic ovarian disease who developed endometrial adenocarcinoma at 24 years of age. The pathophysiology qf polycystic ovarian disease and its relationship to the development of endometrial adenocarcinoma are discussed.

very heavy "periods" for about 4 months prior to admission. Her menarche had occurred at 15 years of age and menses had always been very irregular. She had also had an increased growth of dark, heavy facial hair for about 6 years. The patient's height was 65 inches, weight 293 pounds, blood pressure 152/90 mm. Hg. She was extremely obese, with moderate facial hirsutism (Fig. 1). Breast development was good and the findings on pelvic examination were unremarkable, although the examination was somewhat difficult. Significant laboratory data included: Hemoglobin (Hgb.), 8.0 Gm. per 100 mi.; hematocrit (Hct.), 24 per cent; white blood cell count (WBC), 10,600 per cubic millimeter; platelets, 360,000 per cubic millimeter; serum iron, 55 }J-g; serum iron-binding capacity, 449 J.tg per 100 mi.; Hgb. electrophoresis, AA; blood urea nitrogen (BUN), 5 mg. per 100 mi.; bilirubin (total), 0.7 mg. per 100 mi.; glucose (fasting), 90 mg. per 100 mi. Thyroid studies were within normal limits, as were 24 hour urinary 17-ketosteroids and 17-0H steroids. The intravenous pyelogram and skull x-rays were unremarkable and the Papanjcolaou smear was negative. She did not return again for 9 months. During the interval she had had more profuse vaginal bleeding and, at the time of her second admission. the Hgb. was 3.8 Gm. per I 00 mi. and Hct. was 15 per cent. After adequate transfusion, a dilatation and curettage was performed and a large amount of tissue obtained which showed both endometrial adenomatous hyperplasia and adenocarcinoma. On obtaining the tissue diagnosis, a total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed. The ovaries were enlarged, with numerous subcapsular follicular cysts but no recent or old corpora lutea. The ovaries showed "capsular" thickening as well as thecal hyperplasia.

ENDOMETRIAL adenocarcinoma, the second most common female genital malignancy, is primarily a disease of older women, with 75 per cent of all cases occurring after the age of 50 and only 4 per cent occurring before the age of 40. 1 While the clinical associations of hypertension, diabetes mellitus, obesity, and nulliparity are well established for older patients, a somewhat different profile is apparent for the very young women who develop endometrial adenocarcinoma. There have been recent reports of patients with Turner's syndrome who developed endometrial adenocarcinoma after long-term treatment with oral diethylstilbestroF- 5 and the occurrence of endometrial adenocarcinoma in patients with the polycystic ovary syndrome (PCO) has also been reported. a-s Our report of two patients with PCO who both developed endometrial adenocarcinoma at 24 years of age will illustrate the profile of the patient who is at risk for this malignancy at an early age.

Case reports Case 1. W. S., a 24-year-old, married, black, nulligravid woman, was initially referred because of

From the Divisions of Endocrinology and Oncology, Department of Obstetrics and Gynecology, University Mississippi Medical Center. Received for publication july 1, 1974.

of

Revised December 18, 1974. Accepted january 16, 1975. Reprint requests: Dr. Gary P. Wood, Department of Obstetrics and Gynecology, University of Arkansas Medical Center, Little Rock, Arkansas 72201.

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Endometrial adenocarcinoma and polycystic ovaries

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Case 2. S. S., a 24-year-old, unmarried, white, nulligravid woman, had had her menarche at 15 years of age. Her menses had always been very irregular and were usually quite heavy. Ten months prior to admission she had been started on oral contraceptives to "regulate" her menses. Even with oral contraceptives she continued having excessive vaginal bleeding both during and between menses, and just prior to admission a dilatation and curettage was done which showed endometrial adenomatous hyperplasia and adenocarcinoma. She had had moderate facial acne and heavy, dark hair on her chest and breasts for several years. Her height was 59 inches, weight 170 pounds, and blood pressure 130/-0 mm. Hg. She was moderately obese, with good breast development. She had facial acne and numerous dark hairs on her chest and breasts. Pelvic examination was unremarkable. Significant laboratory data included: Hgb., 10.3 Gm. per 100 mi.; Hct. , 29 per cent; WBC, 4,000 per cubic millimeter; platelets, 286,000 per cubic millimeter; bilirubin (total), 0.6 mg. per 100 mi.; BUN, 10 mg. per 100 ml. Plasma testosterone was 109 ng. per 100 mi. (normal female, 30 to 95). The 17-ketosteroid output (urine) was unremarkable and the Pap smear was reported as negative. Initial therapy consisted of intrauterine radium, which was followed in one week by total abdominal hysterectomy and bilateral salpingo-oophorectomy. Both ovaries were slightly enlarged with bilateral cortical thickening, numerous follicular cysts, and thecal hyperplasia. No corpora lutea were present but there were several old corpora albicans.

Fig. 1. Patient W. S. (case 1) showing the obesity and hirsutism characteristic of these patients.

Comment It has only been in the last few years, with the development of sensitive and specific radioimmunoassays for protein and steroid hormones, that the true nature of polycystic ovarian disease has become apparent. Recent work by Yen and associates 9 has shown that women with PC:O have chronically depressed serum levels of follicle-stimulating hormone (FSH) as well as chronically elevated levels of luteinizing hormone (LH) which are devoid of any cyclic peaks usually associated with ovulation. The low levels of FSH are consistent with the failure of follicular maturation seen in the PCO ovary and the elevated LH levels explain much of the remainder of the ovarian pathology. Kirschner and jacobs, 10 by means of 3 sampling from ovarian and adrenal vein catheters, have shown that the ovary is the major site of androgen production (primarily androstenedione and testosterone) in patients with PCO. Several studies have shown that, in the female, acute treatment with human chorionic gonadotropin (HCG) or LH will result in increased

androgen production. 11 - 13 In view of this growing bulk of data, there can be little question that chronic hyperstimulation of the ovary with LH can result in o\'arian hyperthecosis and increased androstenedione and testosterone production. It has also been shown that, in the rhesus monkey, chronic androgen stimulation will result in ovarian capsular fibrosis similar to that seen in the PCO syndrome. 14 It seems, therefore, that the ovarian changes seen in the PCO syndrome are a result of abnormal stimulation rather than being a primary ovarian disorder. While the cause of the abnormal gonadotropin release is not known, it is known that female rats, if treated with androgens during the first 5 days of life, will later develop a syndrome which is quite similar to the human PCO syndrome, with increased androgen production, polycystic ovaries, and anovulation. 15 It is speculated that this early androgen exposure results in a "masculinization" of the hypothalamus and, while this etiology is unlikely for most human subjects with PCO, the concept of a male-type hypothalamic drive is quite plausible.

142 Wood and Boronow

The persistent, if asynchronous and incomplete follicular activity in the PCO syndrome does result in persistent estrogen production which may be augmented to a considerable degree by extraovarian conversion of androstenedione to estrone as has been shown by MacDonald and associates. 16 In view of present data, we must assume that this prolonged estrogen stimulation of the endometrium, without the modifying effect of intermittent progesterone, can

Januar~ 13, 1976 Am . .J. Obstet. Gmeml.

produce hyperplastic and even neoplastic changes in the endometrial glands. The natural history of this disorder with the progression from hyperplastic to neoplastic changes in the endometrium has been very well documented by Chambian and Taylor. 17 Since the endometrial adenocarcinomas which develop in these young women tend to be well differentiated, the prognosis for survival after adequate therapy is very good. 18

REFERENCES

l. Gusberg, S. B., and Frick, H. C.: Gynecologic Cancer, ed. 4, Baltimore, 1970. The Williams & Wilkins Company.

chap. 8, p. 362. 2. Wilkinson, E. J., et al.: Obstet. Gynecol. 42: 193, 1973. 3. Canlorbe, P., Chartier, M., and Vink, L.: Ann. Pediatr. (Paris) 14: 323, 1967. 4. Cutler, B.S., et al.: N. Engl. J Med. 287: 628, 1972. 5. Dowsett, J. W.: AM. J. 0BSTET. GYNECOL. 86: 622, 1963. 6. Jackson, R. L., and Dockerty, M. B.: AM. J. 0BSTET. GYNECOL. 73: 161, 1957. 7. Somers, S.C., Hertig, A. T., and Bengloff, H.: Cancer 2: 957, 1949. 8. Dockerty . .M. B., et al.: AM. J. OBSTET. GvNECOL. 61: 966, 1951. 9. Yen, S. S.C., Vela, P., and Rankin,J.:J Clin. Endocrinol. 30: 435, 1970. 10. Kirschner, M. A., and Jacobs, J. B.: J. Clin. Endocrinol. Metab. 33: 199, 1971.

11. Pauerstein, C. j., and Solomon, D.: Obstet. Gynecol. 28: 692, 1966. 12. Lauritzen, C., Shackelton, C. H. L., and Mitchell. F. L.: Acta Endocrinol. (Kbn.) 61: 83, 1969. 13. Lanthier. A., and Sandor, T.: Metabolism 9: 861, 1960. 14. Scott, R. B., and Wharton, L. H.: AM. ]. 0BsTET. GYNECOL 78: 1020, 1959. 15. Swanson, H. E., and VanDer Werfften Bosch,J.J: Acta Endocrinol. 47: 37, 1964. 16. MacDonald, P. C., Grodin, P. C., and Sitteri. P. K.: Excerpta Med. Int. Congr. Ser. 184: 770, 1968. 17. Charnbian, D. L., and Taylor, H. B.: Obstet. Gynecol. 36: 659, 1970. 18. Boronow, R. C.: Carcinoma of the Corpus: Treatment at M. D. Anderson Hospital, in Cancer of the Uterus and Ovary, Chicago, 1969, Year Book Medical Publishers, Inc.

Endometrial adenocarcinoma and the polycystic ovary syndrome.

While endometrial adenocarcinoma is the second most common female genital malignancy, only four per cent of the cases occur in women less than 40 year...
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