Preservation of the Ovary: A Reevaluation
Copyright ©1984 Fertility and Sterility (Vol.42. No.4 October, 1984)
Celso-Ramon Garcia, M.D.
Winnifred B. Cutler, Ph.D.
See also Dr. Cutler's invited 1996 article for Menopause Management, Oophorectomy at Hysterectomy After 40? A Practice that Does Not Withstand Scrutiny
A Message From Dr. Cutler:
When I was working at the University of Pennsylvania with my mentor, Professor of Gynecology, Chief of Reproductive Endocrinology Dr. Celso-Ramon Garcia, in the late 1970s and early 1980s, I asked him why healthy ovaries were routinely being removed at hysterectomy in woman over 40 years of age. He told me that ovarian cancer risks caused medical schools to teach ovariectomy as a good medical practice.
I asked how often do women get ovarian cancer? And is there any relationship between a non cancer condition in the uterus, and the likelihood of subsequently developing ovarian cancer? Dr. Garcia had been taught that there was evidence to suggest that women were better off having healthy ovaries removed while a surgeon had easy access to them during a hysterectomy.
We decided to investigate and our search of published papers led us to conclude that the “evidence” had been based on a grammatical error. The literature had been misquoted.
Our research further suggested that the studies recommending ovariectomy were erroneous. We concluded that the ovary does contribute to the hormonal well-being of women past their reproductive years and should be left intact especially during hysterectomy if possible. Dr. Garcia insisted I write the first draft of our discovery and we worked together to produce the following paper, published in 1984. By 1986 he was excited to tell me that half of the medical schools in the US had changed their suggestions and were now recommending a reconsideration of the common practice of ovariectomy.
- - Winnifred Cutler, Ph.D. Athena Institute 2004
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.
The 1980’s 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 of the 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 malignant 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 form 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 al1.. Had shown that postmenopausal ovaries frequently maintained a steroid capability for several decades after menses had ceased.
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 be2.
There is a gradual diminution in ovarian mass that occurs throughout the 30s and progresses more rapidly after the age of 453. 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 evident4. Nonetheless, these older ovaries, replete with stroma material, are now understood to actively produce androstenedeione – the hormone that, in the menopausal woman, is converted to estrone, in the fat depots of the body. This pathway can be significant in preventing osteoporosis.
McNatty et al5 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 estradiol, and progesterone, in vitro, while hyperplastic stromal tissue yields even greater androstenedeione and estradiol6. Hormone secretion of ovaries at hysterectomy was studied by Mikhail7, who offered that menopausal ovarian vein was rich in deyhdroepiandrosterone 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 stormily tissue with increasing age; and with this increase of stromal tissue, there results an increase in the capacity to synthesize androstenedione. 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 reexamines ad the evidence supporting postmenopause ovarian function accumulates. Moreover, the term “quiescent ovary” used to describe all older ovaries, is no longer justifiable.
POST- HYSTERECTOMY OVARIAN ACTIVITY
The incidence 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 samples9, cyclic records of premenstrual tension phenomenon10, plasma hormone evaluation, and studies of vaginal smears11. However, the phenomenon appears to be less than universal. Ranny 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 (i.e. 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 influence of an intact uterus on ovarian function is currently unresolved; but with recent discovery of uterine secretions of large quantities of prostaglandins, there is reason to study the issue13.
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)14could also be responsible.
POST OOPHORECTOMY ENDOCRINE ACTIVITY
Studies of ovariectomized women before, immediately postoperatively, and at various time intervals after surgery have been generally consistent. Both gonadotropin predictably show a rapid rise, which, by 3 weeks, can easily have reached 10 times preoperative levels 15, 16. Likewise within 3 hours, estrogen drops to 60% of the presurgical level17, 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. Follicle-stimulating hormone more closely approaches its preoperative levels15,19. In one study, luteinizing hormone changes required a combination estrogen and progestin hormone therapy15. E2 levels in plasma increase to preoperative levels when estrogen replacement therapies are sufficiently concentrated19. 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 state19. 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 (A) levels than those women who do not17 – another reflection of the value of preservation of the ovaries.
Also noteworthy is the significant decline in epidermal thickness that follows oophorectomy at any age20. 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 effect21. The most critical issue, however, is loss of bone mass leading to osteoporosis, which oophorectomy is known too initiate. It is relevant to know that lowered E1 and (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 properties23-26. 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 oophorectomy 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 that 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.
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. Once 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 that among those without ovarian cancer. The opposite is true. Studies have consistently show that ovarian cancer patients have a much lower incidence of hysterectomy than is found in the general population. For example, Annegers et al28. Reported a 5 % prior hysterectomy rate in ovarian cancer patients, compared with a 23% hysterectomy rate in age-matched women who had not undergone prior ovariectomy. Two other studies published in the 1950s showed a similarly low 4% and 4.5%30 rate of prior hysterectomy among the ovarian cancer patients. Unfortunately, even though these data are quiet clear in showing that hysterectomy in ovarian cancer patients is disproportionately lower, misleading logic has been applied for the reverse conclusion31, i.e., that ovaries should be removed at hysterectomy. This incorrect conclusion has been widely cited and, thereby, a false premise perpetuate.
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 risk32. A cohort study following 900 hysterectomized women for 20 years showed an overall rate of subsequent ovarian cancer at 0.2% in the sample32. 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 oophoroctomy in ovarian cancer-prone families showed the futility of such a course33.
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 malignancy33 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 cnancers 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 al34. evaluated women ranging in age from 25 to 44 during the interval of 1970 to 1977.
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 currently available knowledge demonstrating hormone secretion by ovaries in the 40s, 50s, and 60s, (particularly A) 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 reviewed35.
Nonetheless, some osteoporotic patients are resistant to these normally effective measures, as is sometimes the case in the relief of some of the other postemenopausal symptoms. The evidence continues to support the theory that ovaries should be retained unless they are diseased.
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 steroid-secreting organs. One exception might be the case of familial ovarian carcinoma syndrome33,36-38.
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 I the literature to support the value of routine oophorectomy, we suggest that oophorectomy only be performed when the ovaries are diseased.
LETTER TO THE EDITOR & AUTHORS' REPLY:
To the Editor:
We would like to thank Doctors Garcia and Cutler for their very provocative paper. It certainly has caused those with interests in reproductive endocrinology and gynecology oncology to reevaluate the management of the ovary in conjunction with a hysterectomy in women over 40 years of age.
It is a given well-established, and well-documented fact that the ovary may produce hormones well into the sixties, acting after menopause primarily as an androgen-producing organ, and causing, through peripheral conversion, the production of estrone. We know, though, because osteoporosis and other stigmata develop in postmenopausal women because of the relatively insufficient quantities of estrogen, that this hormonal production is virtually ineffective. Therefore, one must conclude that there is no strong reason to leave the ovary intact at the time of hysterectomy with the aim being production of effective hormonal substances in the menopausal years.
The question, with regard to castrating the woman in her fifth decade, is not whether her ovaries will function effectively in the postmenopausal years, but whether they will function in the years between castration and menopause. There is definite controversy as to whether the ovary continues to function normally after hysterectomy because of a compromised blood supply. Nevertheless, the critical question, is whether leaving the ovary in at the time of hysterectomy has sequelae with regard to future benign and malignant ovarian disease.
Ovarian cancer is the major cancer health hazard for the female pelvic reproductive organs. There will be more deaths this year form ovarian cancer than total deaths from cervical and endometrial cancer combined. Recent epidemiologic studies suggest that the a patient at highest risk for developing ovarian cancer is a middle or upper class white woman who is nulliparous or of low parity.
In evaluating Garcia and Cutler’s proposed evidence to support leaving the ovaries behind in women undergoing hysterectomy, one can only wonder how many women cited in their supporting references and operated on in the 1930s and 1950s actually fell into the high risk group for ever developing ovarian cancer. One must be skeptical about white nulligravidas or women of low parity constituting the overwhelming majority of these patients. Unfortunately, this sort of epidemiologic data is not available in the studies quoted by the authors. Pure familial ovarian cancer syndromes are rare. One must be very skeptical about the three cases cited by the authors as being typical of common epithelial cancer of the ovary. One of the latter patients died with brain metastases, and a second one died 2 months after diagnosis with metastases to the liver and subcutaneous tissue; clearly these are highly virulent cancers. Additional questions have been raised about whether sections of the ovaries from these three patients were adequate to rule out microscopic disease at the time of prophylactic oophorectomy.
The concept of leaving a visibly normal ovary behind in a woman aged 40 to 50, as suggested by the authors, when the contrallateral ovary is involved with a ‘benign process” such as endometriosis or a benign teratoma is simply not good clinical judgment. The concept of performing frozen section analysis on the normal ovary when a benign tumor is present in the ovary may potentially compromise ovarian function further in women aged 40 to 50. Routine use of frozen section analysis of all ovaries to be left intact at the time of hysterectomy would be extremely expensive and would involve an inherent risk of missing microscopic disease.
In conclusion, there seems to be no need to leave a perimenopausal or postmenopausal ovary in situ even though it continues to function for perhaps 10 or even 20 years. The hormonal function is ineffective in preventing postmenopausal symptoms. Ovarian neoplasm remains a major health hazard for these women. Satisfactory estrogen and progesterone replacement in women over 40 is a reality. Each adversarial side awaits more and better information.
Alan H. DeCherney, M.D.
Peter E. Schwartz, M.D.
Department of Obstetrics and Gynecology
Yale University of School of Medicine
New Haven, CT 06510-8063
August 20, 1985
References for this Letter to the Editor:
1. Garcia, C-R, Cutler WB: Preservation of the ovary: a reevaluation. Fertil Steril 42:510, 1984
2. Janson PO, Jansson I: The acute effect of hysterectomy on ovarian blood flow. Am J Obstet Gynecol 127:349, 1977
3. Stone SC, Dickey RP, Mickal A: The acute effect of hysterectomy on ovarian function. Am J Obstet Gynecol 117: 193, 1973
Reply of the Authors Garcia and Cutler (To DeCherney, Schwarcz letter)
Until improvements in therapy are more evolved, our colleagues should be cognizant of the hazards and risks of ovariectomy and the all too frequent potential inability to correct for the missing ovarian hormones by replacement regimens.
A. Their statement :"...because osteoporosis...develop(s) in postmenopausal women...this (ovarian post-menopausal) hormonal production is virtually ineffective. Therefore, one must conclude that there is no strong reason to leave the ovary intact..."
1. Removing the source of a significant production of estrone (whether through estradiol conversion into estrone in the younger woman or androstenedione conversion into estrone in the mature ovary), (1) ignores the fact that 40% of women do not experience the development of osteoporosis and (2) increases the risk of metabolic bone disease for those 60% who are subject to osteoporosis. McNatty demonstrated that stromal tissue from a menopausal ovary contains more androstenedione, and its conversion product, estrone, are much more relevant as risk factors than estradiol or other identified steroids correlating with the prediction of osteoporosis, even the aging ovary appears to contain a built-in mechanism to inhibit osteoporosis.
2. The use of osteoporosis as a single gauge in defining the value of aging ovaries is inappropriate. Ovarian hormones provide meaningful physiologic effects other than simply contributing to a positive bone mineral metabolism. For example, a large loss of sexual motivation (arousal, fantasy life, and desire) in oophorectomized, 46 year old women in prospective, double-blind crossover placebo -controlled trials has been shown, and the sexual motivation was found to be replaceable through androgen. Thus, although we currently do not know the precise appropriateness of androgen replacement for optimal body function, the androgen contribution of aging ovaries is acknowledged.
3. It is naive to believe that oophorectomy followed by hormonal replacement therapy does bring the patient back to the endocrine status she enjoyed prior to ovariectomy. The amount of estrogen replacement therapy currently being prescribed does not bring the gonadotropin level back to normal. Moreover, the role of ovarian androgen secretion in sexual motivation further demonstrates our currently primitive understanding of the manifold functions of the maturing ovary.
4. The degree of osteoporosis is a complex function of steroid levels (principally estrone), adequate ingestion of absorbable calcium, sufficient vitamin D, and appropriate levels of parathyroid hormone and calcitonin
5. Their statement that the critical question is the risk of ovarian cancer in retained ovaries at the time of hysterectomy.
1. There are no data that support that removing the ovaries is preventative of subsequent ovarian-type cancer.
2.Ovarian cancer deaths occur relatively infrequently (11,600 per year) in relation to deaths secondary to cardiovascular disease (485,000 per year) and during recovery from hip fracture.
We agree that significant ovarian disease needs to be addressed. However, gynecologic surgeons are much too prone to remove both ovaries even when there is minimal endometriosis in the pelvis where the other ovary may have minimal benign disease that can be resected or even when the ovary is normal. Resection of the endometriosis and preservation of the normal ovary is a more preferable option in protecting the general health of women even at age 40 to 50.
Physiologic age is not always compatible with chronologic age. It is obvious that it is good clinical judgement to make the correct decision about the appropriateness of retaining a normal ovary in a woman of age 40 to 50 when encountering benign disease in the pelvis. Frozen section should be used when necessary, but not routinely. However, a very superior knowledge of gross anatomic gynecologic pathology is essential. Physicians uncomfortable with their knowledge of these tissue abnormalities should not expose their patients to the increased risk of routine ovariectomy simply to ease feelings of responsibility. All the risks must be weighed appropriately.
Despite the decline in reproductive system circulating steroids being about equivalent for men and women, testes, perhaps because they are more accessible, are more reluctantly removed than are ovaries. Removal of ovaries occurs less frequently at vaginal hysterectomy than abdominal hysterectomy even with similar benign pelvic disease.
We remind those who would consider whether or not to remove an organ that is healthy that the burden of proof question ought to rest with the remover and that we should remember the dictum, "Above all, do not harm."
References to REPLY FROM AUTHORS LETTER
1. McNatty KP, Hunter WM, McNeilly AS, Sawers RS: Changes in the concentration of pituitary and steroid hormones in the follicular fluid of human Graafian follicles throughout the menstrual cycle. J.Endocrinol. 64:555, 1975
2. Sherwin BB, Gelfand MM, Brender W: Androgen enhances sexual motivation in females: a prospective crossover study of sex steroid administration in surgical menopause. Psychosom Med 47:339, 1985.
3. Vital statistics of the United States: Death statistic references
4. Cutler WB, Garcia CR: Sexuality and hormones. In The Medical Management of Menopause and Premenopause: Their Endocrinologic Basis. Philadelphia, J.B. Lippincott, 1984, p.92
REFERENCES TO THE PAPER,
PRESERVATION OF THE OVARY: A REEVALUATION
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29. Smith GV: Ovarian tumors. Am J Surg 95:336, 1958
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33. 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, 1982
34. 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, 1982
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36. Barber HRK: Epidemiology of cancer of the ovary. In Ovarian Carcinoma, Second edition. New York, Masson Publishing, 1982, p 25
37. Lynch H, Albano W, Lynch J, Lynch P, Campbell A: Surveillance and management of patients at high genetic risk for ovarian carcinoma. Obstet Gynecol 59:589, 1982
38. Piver MS, Barlow JJ, Sawyer DM: Familial ovarian cancer: increasing in frequency? Obstet Gynecol 60:397, 1982