Preservation of the ovary: a reevaluation

Transcription

1 FERTIUTY AND STERILITY Copyright e 1984 The American Fertility Society Printed in U.s A. Preservation of the ovary: a reevaluation Celso-Ram6n Garcia, M.D. *t Winnifred Berg Cutler, Ph.D.t Department of Obstetrics and Gynecology, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania The incidence of routine ovariectomy approximates 20% to 30% of all women at hysterectomy. The propriety of this practice is evaluated from three perspectives: (1) the review of the longevity of ovarian hormonal function throughout life, (2) the review of the low risk of subsequent disease in the retained ovary, and (3) the review of epidemiologic considerations. Because oophorectomy and the loss of its steroid contribution has such a profound influence on many body functions, with the most devastating relation to osteoporosis, and because there are no meaningful data in the literature to support the value of routine oophorectomy, removal of ovaries should only be performed when the ovaries are diseased. Fertil SteriI42:510, 1984 The 1980s have been viewed as a time when greater efforts must be directed toward improving the health and welfare of the maturing female. A reappraisal of our attitudes concerning routine oophorectomy and its implication in the welfare ofthe female is mandatory. The gynecologist frequently is required to decide between ovarian preservation versus ablation, particularly when hysterectomy is performed for benign disease. This is a significant problem, because the current incidence of hysterectomy in the United States approaches 60% by the time women reach 65 years of age. In the younger woman, the consensus is almost always favored, namely, ovarian preservation. On the other hand, in the women past 40, the reverse is usually true-routine ovariectomy. The gynecologist performing a hysterectomy is concerned with the potential of ma- Received June 1, 1984; accepted June 26, *William Shippen Jr. Professor and Director, Division of Human Reproduction. treprint requests: Dr. Celso-Ram6n Garcia, Department of Obstetrics and Gynecology, 106 Dulles Building, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, Pennsylvania :j:research Associate. 510 Garcia and Cutler Preservation of the ovary lignant transformation in the preserved ovary or ovaries, which could be a deadly prospect. Nonetheless, removing the ovaries in an ovulating woman deprives her of significant hormonal support, which often is difficult to replace adequately. The question of the propriety of routine ovariectomy during hysterectomy is best evaluated from four perspectives: (1) the review of the longevity of ovarian function, (2) the risk of subsequent disease in the retained ovaries, (3) a consideration of current data on ovariectomy, and (4) the epidemiologic considerations. LONGEVITY OF OVARIAN FUNCTION While it has been commonly stated that ovaries become essentially nonfunctional sometime after the mid-40s, the accumulated weight of evidence supports the appropriateness of reexamining this long-held view. As the ovary ages, it continues to contribute to the steroidal milieu of the menopausal woman, albeit in a declining fashion. As early as 1965, Novak et all had shown that postmenopausal ovaries frequently maintained a steroid capability for several decades after menses had ceased.

2 Morphologic evidence suggests that the aging ovary is quite different from the younger ovary, particularly after the cessation of ovulation. Nonetheless, the human postmenopausal ovary is not the completely inert, nonfunctional fibrous mass that many formerly thought it to be.2 There is a gradual diminution in ovarian mass that occurs throughout the 30s and progresses more rapidly after the age of The differences between the old and the young ovary, especially after age 55, are quite striking; the decreasing population density of follicular structures and a correlative increase of the stroma are evident.4 Nonetheless, these older ovaries, replete with stroma material, are now understood to actively produce androstenedione (.:14 A)-the hormone that, in the menopausal woman, is converted to estrone (E1) in the fat depots ofthe body. This pathway can be significant in preventing osteoporosis. McNatty et a1. 5 have shown that postmenopausal stroma function differently than premenopausal stroma. Their in vitro analysis of the production of progesterone, androgen, and estrogen showed that, in the younger ovaries, all of the ovarian compartments were active, and stromal tissue had lower levels of cellular activity, mitotic activity, and cell hypertrophy than thecal tissue. In the postmenopausal ovaries, the situation was reversed: the level of cellular activity in the stroma was quite high, and considerable hypertrophy was observed. Other evaluations of steroid production and responsiveness to gonadotropins in isolated postmenopausal stroma tissue show that cortical stroma produces measurable amounts of a4a, estradiol (E2), and progesterone, in vitro, while hyperplastic stromal tissue yields even greater a4a and E2. 6 Hormone secretion of ovaries at hysterectomy was studied by Mikhail,7 who offered that the menopausal ovarian vein was rich in dehydroepiandrosterone and E1. Longcope et al. 8 also reported on a spectrum of ovarian function in postmenopausal women via venous-arterial differences in studies during hysterectomy procedures. Combining the evidence from morphologic, histochemical, in vitro steroidogenic, and ovarian vein catheter studies leads us to confirm a lifelong ovarian developmental pattern. There is a greater appreciation of relative mass toward stromal tissue with increasing age; and, with this increase of stromal tissue, there results an increase in the capacity to synthesize a 4 A. The ovaries of women in the menopausal years, often late into the menopause, continue to secrete androgens which may support the well-being and general health of the older woman. Peripheral conversions of these androgens to estrogen are well documented. Certainly the availability of these steroids for such conversion will be terminated upon oophorectomy. Consequently, perspectives on the propriety of routine ovariectomy, in the absence of ovarian disease, are being reexamined as the evidence supporting postmenopause ovarian function accumulates. Moreover, the term "quiescent ovary," used to describe all older ovaries, is no longer justifiable. POSTHYSTERECTOMY OVARIAN ACTIVITY The incid~nce of retention of ovarian cyclicity after hysterectomy remains somewhat unclear. The majority of posthysterectomy patients under age 48 continue to show an ovarian cycle, according to any of several criteria: bioassay of weekly urine samples,9 cyclic records of premenstrual tension phenomenon,10 plasma hormone evaluation, and studies of vaginal smears.ll However, the phenomenon appears to be less than universal. Ranney and Abu-Ghazaleh12 evaluated the future function and control of ovarian tissue that is retained in vivo during hysterectomy and concluded that approximately 50% of their large sample continued to show clinical signs of ovarian hormone production (Le., vaginal tissue maintenance), but the other 50% did not. This was the only study of those just described that sampled very large groups of women; and these results, therefore, suggest that some women stop showing ovarian cyclicity shortly after hysterectomy. The nature of the influence of an intact uterus on ovarian function is currently unresolved; but with the recent discovery of uterine secretions of large quantities of prostaglandins, there is reason to study the issuep Potentially, the reduction in prostaglandin after hysterectomy could be a factor in the loss of ovarian cyclicity. Alternatively, the loss of the putative reflex pathway from cervix to pituitary (as is found in lower mammals)14 could also be responsible. POSTOOPHORECTOMY ENDOCRINE ACTIVITY Studies of ovariectomized women before, immediately postoperatively, and at various time intervals after surgery have been generally consistent. Both gonadotropins predictably show a rapid rise, which, by 3 weeks, can easily have Garcia and Cutler Preservation of the ovary 511

3 reached 10 times preoperative levels.15, 16 Likewise, within 3 hours, estrogen drops to 60% of the presurgical level,17 reaches a nadir by 5 days after surgery, 18 and levels off thereafter at the new lower values. Hormone replacement therapy does somewhat reduce these gonadotropin/steroid levels. Folliclestimulating hormone more closely approaches its preoperative levels.15, 19 In one study, luteinizing hormone changes required a combination estrogen and progestin hormone therapy. 15 E2 levels in plasma increase to preoperative levels when estrogen replacement therapies are sufficiently concentrated. 19 However, no estrogen dose is able to equilibrate both the gonadotropins and the steroids at the preoperative equivalency in women 45 to 53 years old. In order to reduce gonadotropins to preoperative levels, one must produce a hyperestrogenic state.19 The ovarian hormones, then, probably include other substances, which are not replaced by estrogen or progestins. Oophorectomized women frequently experience hot flushes, and studies have shown that those women who do flush postoperatively have significantly lower d 4 A levels than those women who do not17-another reflection ofthe value ofpreservation of the ovaries. Also noteworthy is the significant decline in epidermal thickness that follows oophorectomy at any age.20 This epidermal thickness can be restored, or the decline prevented, by a weak estrogen (estriol succinate, 2 mg/day); whereas a stronger estrogen (estradiol valerate, 2 mg/day) sometimes produces the opposite effect.21 The most critical issue, however, is loss of bone mass leading to osteoporosis, which oophorectomy is known to initiate. It is relevant to know that lowered El and d 4 A levels are established risk factors for osteoporosis. In contrast, E2 and testosterone concentrations have not been identified as significant in assessing the osteoporosis risk factors.22 RISK OF SUBSEQUENT OVARIAN DISEASE BENIGN OVARIAN TUMORS Varying types of ovarian tumors may be encountered-each having its distinct anatomic and clinical properties A knowledge of gross anatomic disease aided by the histologic capabilities of the pathologist, particularly via frozen section, may be most helpful in deciding whether oopho- rectomy or simple resection of the pathologic portion-e.g., endometriosis, benign cystic teratomas, etc-is sufficient. MALIGNANT OVARIAN TUMORS The incidence of ovarian cancer varies markedly with age. In a study of the epithelial cancer rates of the ovary in over 2000 cases at the M. D. Anderson Hospital,27 it was found that the peak years for this cancer are the 40s to the late 60s, paralleling the time during which estrogen levels are declining most precipitously. In that study, the wealthy had a lower survival rate, and postoperative radiation was noted to be better able to improve the survival rate than postoperative chemotherapy. As therapeutic techniques change, reevaluation will, no doubt, alter this perspective. The size of the largest remaining cancer mass in the body was more predictive of survival than the number of focal malignant sites. Interestingly enough, despite the present consensus to the contrary, the spillage of cystic contents of the mass at surgery did not lower the survival rate. Five-year survival rates were also noted to vary considerably as a function of age. Survival rates decrease with age. The fact that ovarian cancer was so resistant to treatment led to the routine removal of perfectly healthy ovaries under the assumption that such action would prevent potential ovarian cancers. However, the presently available data do not support the logic of this course. EPIDEMIOLOGIC CONSIDERATIONS The risk of ovarian cancer in women in whom hysterectomy was contemplated for benign uterine disease has now been studied in two different ways. One can look at the ovarian cancer patients and compare them with patients who have not undergone prior ovarian ablation. One can ask what the hysterectomy rate was for each population. If it were dangerous to retain the ovaries after a hysterectomy, one would expect to find a higher frequency of formerly hysterectomized women among ovarian cancer patients than among those without ovarian cancer. The opposite is true. Studies have consistently shown that ovarian cancer patients have a much lower incidence of hysterectomy than is found in the general population. For example, Annegers et a1. 28 reported a 5% prior hysterectomy rate in ovarian cancer patients, compared with a 23% hysterec- 512 Garcia and Cutler Preservation of the ovary

4 tomy rate in age-matched women who had not undergone prior ovariectomy. Two other studies published in the 1950s showed a similarly low 4%29 and 4.5%30 rate of prior hysterectomy among the ovarian cancer patients. Unfortunately, even though these data are quite clear in showing that hysterectomy in ovarian cancer patients is disproportionately lower, misleading logic has been applied for the reverse conclusion,31 i.e., that ovaries should be removed at hysterectomy. This incorrect conclusion has been widely cited and, thereby, a false premise perpetuated. Another line of investigation also supports the safety of retaining the ovaries at hysterectomy. Prospective rates of ovarian cancer in ovaries retained after hysterectomy also support the absence of a risk.32 A cohort study following 900 hysterectomized women for 20 years showed an overall rate of subsequent ovarian cancer at 0.2% in the sample.32 The women who had both ovaries preserved showed a much lower rate (0.01%) of subsequent cancer than those who had only one ovary preserved (0.3%). There is, therefore, a consistent and clear picture when we scrutinize the data rather than analyzing the published conclusions. The goal of surgical prevention of ovarian cancer should not conclude in a decision for oophorectomy at hysterectomy. In fact, in 1982, a report of intraabdominal carcinomatosis (indistinguishable from ovarian carcinomatosis) after prophylactic oophorectomy in ovarian cancerprone families showed the futility of such a course.33 Oophorectomies were performed "prophylactically" on 28 members of 16 families that were at high risk of ovarian carcinoma. Three of these women subsequently developed disseminated intraabdominal malignancy.33 The authors concluded that the development of intraabdominal carcinomatosis in oophorectomized women from ovarian cancer-prone families suggests that genetic susceptibility is not limited to ovarian carcinoma but extends to cancers arising in tissues embryologically related to the ovary. It should be pointed out that the incidence of ovarian cancer is extremely low. There appears, therefore, dubious advantage to be gained by the routine removal of healthy ovaries at hysterectomy. In spite of what appears to be a rather clear case against routine ovariectomy during hysterectomy, current surgical practice has been different. Using data from the National Center for Health Statistics, Dicker et al. 34 evaluated women ranging in age from 25 to 44 during the inter- val of 1970 to They reported that ovariectomy during hysterectomy for benign causes was occurring about 25% of the time and did not change throughout the years the data were collected. Older women, the group from 40 to 44, had an approximate 50% rate of ovariectomy at hysterectomy. In light of the currently available knowledge demonstrating hormone secretion by ovaries in the 40s, 50s, and 60s (particularly a4a), the value of such hormones in reducing the risk of osteoporosis, and the lack of advantage in preventing ovarian cancer by oophorectomy, the routine practice of oophorectomy is challenged. While those who have inadequate sources of androgen or peripheral conversion capacity may benefit from hormonal replacement, there remain a significant (15%) number who do not require hormonal support. Not only will oophorectomy most often be ineffective in preventing ovarian cancer; but, more important, the loss of these ovarian secretions may play a role in producing the degenerative sequence of osteopenia and osteoporosis. This pathophysiologic sequence of osteoporosis can be more often favorably modified by estrogen hormonal replacement therapy. The osteoporotic process has recently been reviewed.35 Nonetheless, some osteoporotic patients are resistant to these normally effective measures, as is sometimes the case in the relief of some of the other postmenopausal symptoms. The evidence continues to support the theory that ovaries should be retained unless they are diseased. CONCLUSIONS In the face of the exceedingly low incidence of ovarian cancer and its questionable prevention by prophylactic oophorectomy, routine oophorectomy would deprive enormous numbers of women of the essential benefits afforded by these steroidsecreting organs. One exception might be the case of familial ovarian carcinoma syndrome.33, Clearly, in such an instance, the patient must be properly informed of all options and considerations, including the possibility of subsequent disseminated peritoneal carcinomatosis in some even after oophorectomy. Because oophorectomy has such profound influences at every age, particularly its devastating relation to osteoporosis, and because there are no meaningful data in the literature to support the value of routine oophorectomy, we suggest that oophorectomy only be performed when the ovaries are diseased. Garcia and Cutler Preservation of the ovary 513

5 REFERENCES 1. Novak ER, Goldberg B, Jones GS: Enzyme histochemistry of the menopausal ovary associated with normal and abnormal endometrium. Am J Obstet Gynecol 93:669, Guraya S: Histochemical observations on the corpus luteum atreticum of the human postmenopausal ovary with reference to steroid hormone synthesis. Arch Ital Anat.Embriol 56:189, Tervila L: The weight of the ovaries after stress ending in -death. Ann Chir Gynaecol Felin 47:232, NicosiaSV: Morphological changes in the human ovary through life. In Comprehensive Endocrinology: The Ovary, Edited by L Martini, GB Serra. New York, Raven Press, 1983, p McNatty KP, Makris A, DeGrazia C, Osathanondh R, Ryan KJ: The production of progesterone, androgens, and estrogens by granulosa cells, thecal tissue and stromal tissue by human ovaries in vitro. J Clin Endocrinol Metab 49:687, Dennefors B, Janson P, Knutson F,Hamberger L: Steroid production and responsiveness to gonadotropin in isolated stromal tissue of human postmenopausal ovaries. Am J Obstet Gynecol 136:997, Mikhail G: Hormone secretion by the human ovaries. Gynecol Invest 1:5, 1970 _ 8. Longcope C, Hunter R, Franz C: Steroid secretion-by the postmenopausal ovary. AmJ Obstet Gynecol 138:564, Beavis ELG, Brown JB, Smith MA: Ovarian function after hysterectomy with conservation of the ovaries in premenopausal women. J Obstet Gynaecol Br Commonw 76: 969, Backstrom CT, Boyle H: Persistence of premenstrual tension symptoms in hysterectomized women. Br J Obstet Gynaecol 88:530, DeNeef JC, Hollenbeck ZJR: The fate of ovaries preserved at the time of hysterectomy. Am J Obstet Gynecol 96:538, Ranney B, Abu-Ghazaleh S: The future function and control of ovarian tissue which is retained in vivo during hysterectomy. Am J Obstet Gynecol 128:626, Charbonnel B, Kremer M, Gerozissis K, Dray F: Human cervical mucus contains large amounts of prostaglandins. Fertil Steril 38:109, Cutler WB, Garcia C-R: The psychoneuroendocrinology of the ovulatory cycle of woman. Psychoneuroendocrinology 5:89, Wallach EE, Root AW, Garcia C-R: Serum gonadotropin responses to estrogen and progestogen in recently castrated human females. J Clin Endocrinol Metab 31:376, Yen SSC, Tsai OC: The effect of ovariectomy on gonadotropinrelease. J Clin Invest 50:1149, Barlow DH, Macnaughton MC, Mowat J, Coutts JRT: Hormone profiles in the menopause. In Functional Morphology of the Human Ovary, Edited by JRT Coutts. Baltimore, University Park Press, 1981, p Hunter DJ, Julier D, Franklin M, Green E: Plasma levels of estrogen, luteinizing hormone, and follicle-stimulating hormone following castration and estradiol implant. Obstet Gynecol 49:180, Garcia and Cutler Preservation of the ovary 19. Utian W, Katz M, Davy D, Carr P: Effect ofpremenopausal castration and incremental dosages of conjugated equine estrogens on plasma follicle-stimulating hormone, luteinizing hormone and estradiol. Am J Obstet Gynecol 132:297, Punnonen R, Raurama L: The effect of long-term oral oestriol succinate therapy on the skin of castrated women. Ann Chir Gynaecol 66:214, _Punnonen R: Effect of castration and peroral estrogen therapy on the skin. Acta Obstet Gynecol Scand 21:1, Crilly R, Horsman A, Marshall DH, Nordin BEC: Prevalence, pathogenesis and treatment of postmenopausal osteoporosis. Aust NZ J Med 9:24, Reed MJ, Hutton JD, Beard RW, Jacobs HS, James VH: _Plasma hormone levels and. oestrogen production in a postmenopausal woman with endometrial carcinoma and an ovarian thecoma. Clin Endocrinol (Ox!) 11:141, Rome HM, Fortune DW, Quinn MA, Brown JB: Functioning ovarian tumors in postmenopausal women. Obstet Gynecol 57:705, Sternberg WH: The morphology, androgenic function, hyperplasia, and tumors of the human ovarian hilus cells. Am J Pathol 25:493, Gordon A, Rosenstein N, Parmley T, Bhagavan B: Benign cystic teratomas in postmenopausal women. Am J Obstet Gynecol 138:1120, Smith JP, Day TG: Review of ovarian cancer at the University of Texas Systems Cancer Center MD Anderson Hospital and Tumor Institute. Am J Obstet Gynecol 135:984, Annegers JF, Strom H, Decker DG, Dockerty MD, O'Fallon WM: Ovarian cancer: reappraisal of residual ovaries. Am J Obstet Gynecol 97:124, Smith GV: Ovarian tumors. Am J Surg 95:336, Counseller VS, Hunt W, Haigler FH: Carcinoma of the ovary following hysterectomy. Am J Obstet Gynecol 69:538, Grogan RH: Reappraisal of residual ovaries. Am J Obstet Gynecol 97:124, Randall CL: Ovarian conservation. In Progress in Gynecology, Edited by JV Meigs, SH Sturgis. New York, Grune & Stratton, 1963, p Tobachman JK, Tucker MA, Kase R, Greene MH, Costa J, Fraumen JF: Intraabdominal carcinomatosis after prophylactic oophorectomy in ovarian cancer prone families. Lancet 2:795, Dicker R, Greenspan J, Strauss L, Cowart M, Scally M, Peterson H, DeStefano F, Rubin G, Ory H: Complications of abdominal and vaginal hysterectomy among women of reproductive age in the United States. Am J Obstet Gynecol 144:841, Cutler WB, Garcia C-R: Osteoporosis. In The Medical Management of Menopause and Premenopause: Their Endocrinologic Basis. Philadelphia, J. B. Lippincott Co., 1984, p Barber HRK: Epidemiology of cancer of the ovary. In Ovarian Carcinoma, Second edition. New York, Masson Publishing, 1982, p Lynch H, Albano W, Lynch J, Lynch P, Campbell A: Surveillanceand management of patients at high genetic risk for ovarian carcinoma. Obstet Gynecol 59:589, Piver MS, Barlow JJ, Sawyer DM: FaJllilial ovarian cancer: increasing in frequency? Obstet Gynecol 60:397, 1982