Nick Siddle, M.R.C.O.G.t:!: Philip Sarrel, M.D. Malcolm Whitehead, M.R.C.O.G. til

FERTILITY AND STERILITY Copyright c 1987 The American Fertility Society Vol. 47, No.1, January 1987 Printed in U.8A. The effect of hysterectomy on the age at ovarian failure: identification of a subgroup of women with premature loss of ovarian function and literature review* Nick Siddle, M.R.C.O.G.t:!: Philip Sarrel, M.D. Malcolm Whitehead, M.R.C.O.G. til King's College School of Medicine and Dentistry, and Chelsea Hospital for Women, London, United Kingdom The age at ovarian failure was determined in 9 women who had previously undergone abdominal hysterectomy with bilateral ovarian conservation and in 226 women who had undergone a spontaneous menopause. The mean age of ovarian failure in the hysterectomized group was 45.4 ± 4. years (standard deviation), and this was significantly lower than the mean age of 49.5 ± 4.4 years in the nonhysterectomized control group (P <.1). There was a significant correlation between the age at hysterectomy and the age of ovarian failure in the women who were 44 years or less at the time of ovarian failure (r =.62, P <.1), implying a causal relationship. The indication for hysterectomy did not influence the time of ovarian failure. Two explanations are proposed as to how conventional surgery for hysterectomy may adversely affect ovarian function. Fertil Steril47:, 1986 In addition to suffering from the usual problems of ovarian failure, such as vasomotor instability and lower genital tract symptoms, women who undergo premature loss of ovarian function are at an increased risk of osteoporosis 1 and myocardial infarction. 2 Thus, ovarian conservation at the time of hysterectomy in women who are < 45 years of age is an accepted surgical practice. It is Received February 17, 1986; revised and accepted September 15, 1986. *Supported by a grant to M.I.W. from the Imperial Cancer Research Fund Laboratories, Lincoln's Inn Fields, London, United Kingdom. t Academic Department of Obstetrics and Gynaecology, King's College School of Medicine and Dentistry. thonorary Lecturer, Chelsea Hospital for Women. Visiting Senior Lecturer. Present address: Yale University School of Medicine, New Haven, Connecticut. /lreprint requests: Malcolm Whitehead, M.R.C.O.G., Senior Lecturer/Consultant, Academic Department of Obstetrics and Gynaecology, King's College School of Medicine and Dentistry, Denmark Hill, London SE5 8RX, United Kingdom. widely held that surgery for hysterectomy has no adverse effects upon the function of the conserved ovaries. This belief is based upon numerous studies performed during the past century that have reported that, after hysterectomy, the time of ovarian failure is not advanced. 3-14 However, careful examination of the medical literature reveals that although the majority of women continue to have normal ovarian function after hysterectomy, a substantial minority (and in some studies a majority) of hysterectomized women do indeed experience premature ovarian failure. 3-14 In the absence of neoplasia, most gynecologists discharge their patients from postoperative care 6 weeks after surgery. Patients who subsequently develop troublesome estrogen-deficiency symptoms may be referred back to the gynecologist but, in our experience, are often treated by the family physician or are referred to a menopause clinic. Thus, the gynecologist may be unaware of the true incidence of estrogen-deficiency symp- 94 Siddle et ai. Hysterectomy and ovarian failure Fertility and Sterility

. toms that follows hysterectomy. From experience in two large specialized menopause clinics, it was our impression that hysterectomy with ovarian conservation was associated with premature loss of ovarian function in some women. Therefore, we have reviewed our patients' case records. MATERIALS AND METHODS This retrospective study was performed in the Menopause Clinics at King's College Hospital and the Chelsea Hospital for Women. The case notes of 96 women who had attended either clinic with a variety of symptoms were appraised: 7 had undergone a spontaneous or "natural" menopause, and 26 had undergone hysterectomy. The patient was considered suitable for admission to this study only if she had never used exogenous estrogens and only if she had presented with at least 6 months' amenorrhea and with persistent symptoms such as vasomotor instability and/or vaginal dryness, which are unequivocally due to a lack of estrogen. Vasomotor instability was defined as hot flashes and/or night sweats sufficient to disturb the daily routine and/or sleep pattern. Vaginal dryness was defined as a complaint of a reduction in vaginal lubrication: in patients who were sexually active, this reduction had to be sufficient to require the use of a lubricant jelly or to render intercourse difficult. Clinical evidence of vaginal atrophy-thinning of the vaginal skin and alteration in color-also had to be present. In addition to these criteria, patients under the age of 47 years at presentation had to have plasma gonadotropin levels within the postmenopausal range for our laboratory. We chose this age because a previous epidemiologic study of the climacteric reported a mean age at menopause of 51.4 years with a standard deviation (SD) of 3.8. 15 Thus, patients under 47 years of age were more than 1 SD below the mean, and we required biochemical evidence of ovarian failure in this younger age group. In women undergoing a spontaneous menopause, the age at menopause was equated with the time of ovarian failure. In the hysterectomized subjects, the onset of persistent estrogendeficiency symptoms was equated with the time of ovarian failure. Hysterectomized women were admitted only if the abdominal route had been used and if the onset of symptoms had occurred after surgery; if both ovaries had been conserved Vol. 47, No, 1, January 1987 and if surgery had been performed for a nonmalignant condition. No patient had received pelvic radiotherapy. In patients undergoing surgery at either King's College or Chelsea Hospital, these criteria were validated by reference to the medical records; in patients who had undergone surgery at another hospital, these factors were validated either through correspondence with the family physician or with the surgeon. All patient ages and the interval between surgery and the onset of symptoms were recorded in completed years. Data from 229 women who had undergone a spontaneous menopause (henceforth termed the nonhysterectomized group), and from 9 women had undergone abdominal hysterectomy (the hysterectomized group) fulfilled our inclusion criteria. The most frequent reasons for excluding patients were previous use of exogenous estrogens, a lack of patient certainty regarding the age at onset of persistent symptoms, or a lack of documentation confirming that two apparently normal ovaries had been conserved at hysterectomy. In 71 of the 9 hysterectomized women, there was a single indication for hysterectomy and only one disease had been diagnosed histologically. In 19 women, there were multiple indications for hysterectomy, and/or more than one disease had been diagnosed by the pathologist-for example, co-existing fibroids and pelvic inflammatory disease. These 19 subjects were classified as having "multiple" indications. With one exception, all hysterectomized and nonhysterectomized subjects were white Europeans: the exception was an Asian who had undergone hysterectomy. Appropriate nonparametric analyses were performed because the data on age at menopause and age at ovarian failure were not normally distributed. AGE AT OVARIAN FAILURE RESULTS Figure 1 is a scattergram of the age at ovarian failure in the two groups. The age range in the nonhysterectomized women was 3 to 58 years (mean,49.5 ± 4.4 [SD] years). The age range for the hysterectomized group was 33 to 55 years (mean, 45.4 ± 4. years), and this was significantly lower than that of the nonhysterectomized group (Mann-Whitney test, P <.1). Siddle et a1. Hysterectomy and ovarian failure 95

AGE AT OVARIAN FAILURE NORMAL MENOPAUSE = Mean 49 S years n=229 p < 1 Mann - Whitney POST HYSTERECTOMY Mean = 45 4 years n 9 = 6..........".... 3L- Figure 1 Scattergrams of the age at ovarian failure in 229 women who had undergone a spontaneous menopause and in 9 women after hysterectomy with bilateral ovarian conservation. RELATIONSHIPS BETWEEN AGE AT HYSTERECTOMY AND AGE AT OVARIAN FAILURE The interval between hysterectomy and age at ovarian failure is shown in Figure 2. In 31 patients (34%), ovarian failure.occurred within 2 years of surgery, whereas in some patients, as long as 15 years elapsed. Twenty of the 31 pa- tients experiencing ovarian failure within 2 years of surgery and 25 of 46 patients experiencing loss of ovarian function within 4 years of hysterectomy were < 45.4 years old when their symptoms developed. In total, 4 (44.4%) of the 9 hysterectomized patients had developed ovarian failure by age 45.4 years. These 4 patients were more than 1 SD below the mean age at ovarian failure for our nonhysterectomized group. The relationship between age at hysterectomy and age at ovarian failure was determined for the entire hysterectomy group: this was statistically significant (r =.6, P <.1). This relationship was investigated further by dividing the hysterectomized patients into two groups: those experiencing ovarian failure at age 44 years or less (33 patients) and those experiencing ovarian failure at age 45 years or more (57 patients). There was a statistically significant correlation (r =.62, P <.1) for the former (group 1, Figure 3), but no correlation was observed (r =.32, P >.5) for the latter (group 2, Fig. 3)_ RELATIONSHIPS BETWEEN INDICATION FOR HYSTERECTOMY AND AGE AT OVARIAN FAILURE We determined whether the disease process that resulted in symptoms necessitating hysterhysterectomy TO OVARIAN FAI LURE 58 Group 2 r a O 32 Age ;;, 45 at CMlrian failure.!! 53 I- Z UJ ti l/} 15 4 UJ a: a: :::l -.J u. o 45 "' 1 4 ::::> z z 45 :: o 8 34 Group 1 r= 62 p< OO1!i 8 8 8 8& 8 o 9 5 UJ 5 o 8 35 Age <45 at ovarian failure 32'----2L5--------32----------4----45 1 5 1 15 INTERVAL (years) Figure 2 The interval between hysterectomy and the onset of estrogendeficiency symptoms in 9 women. 96 Siddle et ai. Hysterectomy and ovarian failure AGE AT HYSTERECTOMY (Log scale) Figure 3 Relationships between age at ovarian failure and age at hysterectomy in 33 women developing estrogen-deficiency symptoms at age 44 years or less (group 1), and in 57 women developing symptoms at age 45 years or more (group 2). Fertility and Sterility

... I:!!... I&J so II..., -..... ".............. a u... x.. Q:: 4.. l- oq I&J 3... p=ns Figure 4 Age at the time of ovarian failure for the various indications for surgery. ectomy might also be the cause of the earlier than expected ovarian failure. The age at the time of ovarian failure for the various indications for surgery is shown in Figure 4. These were compared with the use of nonparametric analysis of variance (Kruskal-Wallis test): there were no differences between the surgical groups. DISCUSSION Identification of the precise time of ovarian failure can be difficult if hysterectomy has been performed. Ovarian failure is a gradual process associated with fluctuations in steroidogenesis and, therefore, gonadotropin levels. We considered relying on the presence of elevated gonadotropin levels to make the diagnosis in both hysterectomized and nonhysterectomized women, but we believe this to be unreliable in retrospective analysis: ovarian failure may have occurred many months, if not years, prior to the time of gonadotropin estimation. In our younger women, we demanded the presence of elevated gonadotropin levels to confirm the diagnosis and to exclude other causes of secondary amenorrhea. Because it is generally accepted that the presence of persistent estrogen-deficiency symptoms indicates loss of significant ovarian function, we equated this with the time of ovarian failure in the hysterectomized subjects. Given the limitations of retrospective investigation, we believe that our criteria for diagnosing ovarian failure in this group are valid and that measuring age in completed years was sufficiently sensitive for the purposes of this study. In our opinion, the present data provide persuasive evidence that hysterectomy may advance the time of ovarian failure. The mean age at ovarian failure was significantly lower in the hysterectomized, as compared with the nonhysterectomized, group (Fig. 1, P <.1). However, it is also clear that not all women were equally affected by hysterectomy. Indeed, some women appear not to have been affected, and 44 patients did not experience symptoms of ovarian failure until at least 5 years had elapsed after surgery (Fig. 2). A subgroup of women appeared to suffer early loss of ovarian function, which was causally related to hysterectomy. Symptoms of ovarian failure arose in 31 patients within 2 years of hysterectomy and in 46 patients within 4 years of surgery. Importantly, 2 of the 31 patients, and 25 of the 46 patients, were < 45 years old when these symptoms arose. It is stressed that in total 4 (44.4%) ofthe 9 hysterectomized women had developed ovarian failure by age 45.4 years. In the nonhysterectomized group, only 29 (13%) of 229 women had experienced ovarian failure by this age (Fig. 1). Although our hysterectomized and nonhysterectomized groups were matched for race, reason for clinic referral, and lack of exposure to exogenous estrogens, it is possible that bias has occurred in patient selection. We did not control for cigarette use, but the lowering of age at menopause in tobacco users is small. I6 Even if heavy cigarette consumption occurred only in the hysterectomized women, we doubt very much whether this could explain the differences that we observed. It might be argued that women who undergo hysterectomy have certain physiologic characteristics that make them more likely to report ovarian failure earlier than women with an intact uterus: additionally, hysterectomized women, having previously been exposed to medical procedures, might be less frightened of a hospital environment and therefore request hospital referral more readily than nonhysterectomized women. Although we know of no data to support these arguments, they are clearly important sources of potential bias which we cannot completely eliminate. Furthermore, it might be argued that younger, symptomatic, hysterecto- Vol. 47, No.1, January 1987 Siddle et ai. Hysterectomy and ovarian failure 97

mized women might be preferentially referred because of physician bias. Again, we are not aware of any published data that demonstrate that the nonhysterectomized, symptomatic woman receives a less sympathetic response from her medical attendant than her hysterectomized counterpart. Physician bias of this nature could, perhaps, be best investigated by comparing age at referral to a clinic between hysterectomized and nonhysterectomized subjects with minimal symptoms insufficient to disturb well-being. We were not able to do this because all our subjects had symptoms sufficiently severe to reduce their quality of life prior to referral. Estimates of the time at ovarian failure differed between our groups. Six months' amenorrhea and the presence of persistent symptoms was the end point in the nonhysterectomized group, whereas the time of onset of persistent symptoms was the end point in the hysterectomized subjects. We considered using the onset of symptoms as the end point for comparisons, but believe this to be unreliable as a determinant of ovarian failure. In some women, the onset of vasomotor symptoms can predate the menopause by some years17: in our clinical experience, women in their early 4s with flashes and sweats experience them only premenstrually, not persistently. We believe our definitions to be the best compromise for timing of ovarian failure in a retrospective analysis. Despite these limitations, our finding that a subgroup of women developed ovarian failure at an early age following hysterectomy is supported by the medical literature. The major studies of ovarian function following hysterectomy published during the last 5 years from which numerical data can be extracted are shown in Table 1.3-14 We have extracted the numbers of women with unilateral or bilateral ovarian conservation who were < 45 years at the time of operation, and the numbers subsequently developing ovarian failure according to the authors' criteria. These have varied from the presence of hot flashes alone to the use of vaginal smears, and most recently, biochemical methodology. In the majority of cases we have selected the figures relating to women with flashes. Because details of the time of assessment of individual women are only available in two papers, 11, 12 more detailed analyses are not possible. However, all the authors reported a subgroup of women with premature ovarian failure, the percentage ranging from 16.7%13 to 57.5%4 (mean, 23.5% ± 5.3%). Most authors ignored this subgroup: for example, Whitelaw,1 using measurements of urinary pregnanediol and a bioassay to determine gonadotropin activity, concluded that "continued ovarian activity is manifest in the majority of these subjects years after operation." However, "the majority" in this study means 18 of 24 women, because in the other 6 Table 1. Studies of Ovarian Function After Hysterectomy with B ilaterallu nilateral Ovarian Conservation Years of % Early' Criteria Authors No. of patients follow-up ovarian fbllure for failure Comment Sessums and Murphy, 37 1-14 32.4 Flashes All < 36 years at time of 9323 operation Kretzschmar and Gard- 64 1--3 57.5 Flashes Retrospective questioniner, 19354 naire: unclear if unilateral or bilateral ovarian conservation Dippel, 1939 5 42 1.7-8 17 Flashes Mainly women who had cesarean hysterectomy Richards, 1951 6 24 2-6 27 Flashes All < 45 years old at time of operation Bancroft-Livingstone, 353 2-12 32 Flashes All < 45 years old at time 19547 of operation Grogan and Duncan, 363 Up to 6 14.6 Flashes Only one ovary conserved 19558 in some patients Randall et ai., 1957 9 47 5-1 23 Smears Whitelaw, 19581 24 2-8 25 Flashes and gonadotropins Leverton, 1958 11 144 7 2 Flashes and gonadotropins DeNeef and Hollenback, 115 Up to 2 35.6 Flashes 196612 Beavis et ai., 196913 48 1-14 16.7 Urinary estrogens Ranney and Abu- 59 1-2 23 Flashes Data abstracted from au- Ghazaleh, 197714 thors' scattergrams Gath, 198418 119 4 28 Flashes 98 Siddle et ai. Hysterectomy and ovarian failure Fertility and Sterility

subjects the author stated "menopause was probably reached." Beavis et al.13 used symptomatic assessments and serial urinary estrogen and pregnanediol measurements as indicators of ovarian activity. They concluded that "ovarian function continued normally up to the time of the menopause." Our understanding of their data is that 16.7% of women experienced premature loss of ovarian function. Ranney and Abu-Ghazaleh14 relied solely on the presence of symptoms to assess ovarian function. Their study group was 1263 women. The authors concluded that "normal ovaries which are retained in vivo during hysterectomy will usually produce female hormones in each individual patient for the inherited duration of years." However, careful examination of the authors' scattergrams for the 59 women who were < 4 years old at the time of surgery indicates that 23% of this group experienced loss of ovarian function prematurely. The most recent prospective study of which we are aware is ongoing at Oxford and is an investigation of the psychiatric sequelae of hysterectomy. Professor Gath has kindly reviewed his data for us and reports the following among women under the age of 44 years at the time of hysterectomy in whom the ovaries were conserved18: within 6 months of surgery, 17.6% of the women were experiencing hot flashes and 24.3% had sweating. Eighteen months after operation, hot flashes were reported by 19.5% and sweating by 18.5% of patients. Four years after operation, 24.6% of women experienced hot flashes and 28.1 % had sweating; 25% of the women also reported vaginal dryness. Comparisons between the above studies are, we believe, inappropriate because of differences in study design, inclusion criteria, and length of follow-up. Nonetheless, it is clear that in each reported series some women have experienced premature ovarian failure following hysterectomy. Why should a subgroup of women develop ovarian failure at an early age after hysterectomy? If a disease had caused symptoms necessitating hysterectomy, and thereafter the ovarian failure, it would be expected that this disease would be associated with an increased incidence of earlier ovarian failure. However, this was not observed in this study: indeed, the age of ovarian failure was not related to the indication for surgery (Fig. 4). However, when the age at hysterectomy was Vol. 47, No.1, January 1987 compared with the age at ovarian failure, a significant correlation was observed for those women developing loss of ovarian function aged 44 years or below. This implies a causal relationship independent of the indication for surgery and not present if ovarian fail ure developed after age 45 (Fig. 3). How may hysterectomy affect ovarian function? It is possible that surgery compromises the vascular supply to the ovary. Alternatively, the uterus ay make an important endocrine contribution to normal ovarian function. The latter is unlikely to account for sudden ovarian failure, but the possibility that both mechanisms may operate to cause earlier than expected ovarian failure, even many years after surgery, cannot be excluded. In support of the first explanation, Stone et al.19 reported an acute drop in serum estradiol levels when hysterectomy was performed during the follicular phase of the cycle, from 6 pg/ml preoperatively to 2 pg/ml by the third postoperative day. No such reductions were observed in the control group of women undergoing laparoscopy. With the use of 133 Xenon clearance to measure ovarian blood flow immediately preoperatively and postoperatively, Janson and Jansson2 reported that surgery reduced blood flow by between 52% and 89%. Cattanach21 has recently reported a reduction in estrogen production in four of seven women after tubal ligation. He developed a hypothesis to explain how ligation of the medial uterine supply to the ovary might change intraarterial dynamics, increase intraarterial pressure, and damage the ovarian microcirculation, even if the lateral ovarian blood supply is not affected by surgery. The elegant studies of Sessums and Murphy22 have clearly demonstrated that the presence of uterine tissue is important for normal ovarian follicular development in rabbits. Animals that had undergone hysterectomy 12 months previously had only half the number of follicles, as compared with rabbits with intact uteri. However, rabbits that had undergone hysterectomy, but in which endometrium had been implanted into the anterior abdominal wall, had 4% more follicles than the hysterectomized group. Irrespective of the cause of the early ovarian failure, it is clear that hysterectomy increases the frequency of consultations for estrogen-deficiency symptoms. Roos23 compared the number of visits to a doctor by 2332 hysterectomized women and Siddle et ai. Hysterectomy and ovarian failure 99

2533 women after cholecystectomy. The number of visits in the hysterectomized group was 2.5 times greater than that following cholecystectomy, and Roos concluded "menopause symptoms increase after hysterectomy. Ageing alone contributed little to this increase since similar increases occurred in neither the cholecystectomy nor the population samples." We believe that we have demonstrated that hysterectomy may advance the time of ovarian failure in some women. However, with any menopause clinic sample of patients investigated retrospectively, it is impossible to eliminate every source of bias, and therefore we caution against extrapolating our incidence data to the general population. Because the consequences of early ovarian failure in terms of mortality and morbidity are considerable,1, 2 we believe that further prospective research is urgently needed to determine the incidence of early ovarian failure in the general population and also to elucidate the mechanisms involved. In the meantime, two practical approaches to patient management are suggested. The first is not to dismiss women as neurotic if they return soon after hysterectomy complaining of estrogen-deficiency symptoms. Under these circumstances, ovarian function should be properly assessed by gonadotropin measurements. The second is more speculative and is to avoid placing clamps close to the ovary during hysterectomy to minimize the risk of damaging the ovarian vascular arcade. Acknowledgments. The assistance of Mrs. Helen Kenna, Miss Frances Stewart, and Miss Julie Bennett in the preparation of the manuscript is much appreciated. REFERENCES 1. Johansson BW, Kaij L, Kullander S, Lenner H-C, Svanberg L, Astedt B: On some late effects of bilateral oophorectomy in the age range 15-3 years. Acta Obstet Gynecol Scand 54:449, 1975 2. Centerwall BS: Premenopausal hysterectomy and cardiovascular disease. Am J Obstet Gynecol 139:58, 1981 3. Sessums JV, Murphy DP: Hysterectomy and the artificial menopause. Surg Gynecol Obstet 55:286, 1932 4. Kretzschmar N, Gardiner S: A consideration of the surgical menopause after hysterectomy and the occurrence of cancer in the stump following subtotal hysterectomy. Am J Obstet Gynecol 29:168, 1935 5. Dippel AL: The role of hysterectomy in the production of menopausal symptoms. Am J Obstet Gynecol 37:111, 1939 6. Richards NA: The surgical menopause following hysterectomy: a study of 332 cases. Proc R Soc Med 44:496, 1951 7. Bancroft-Livingston G: Ovarian survival following hysterectomy. J Obstet Gynaecol Br Emp 61:628, 1954 8. Grogan RH, Duncan CJ: Ovarian salvage in routine abdominal hysterectomy. Am J Obstet Gynecol 7:1277, 1955 9. Randall CL, Birtch PK, Harkins JL: Ovarian function after the menopause. Am J Obstet Gynecol 74:719, 1957 1. Whitelaw RG: Ovarian activity following hysterectomy. J Obstet Gynecol Br Emp 65:917, 1958 11. Leverton JCS: Some aspects of ovarian conservation at hysterectomy for benign conditions. J Obstet Gynaecol Br Emp 65:839, 1958 12. DeNeef JC, Hollenback ZJR: The fate of ovaries preserved at the time of hysterectomy. Am J Obstet Gynecol 96: 188, 1966 13. Beavis ELG, Brown JB, Smith MA: Ovarian function af ter hysterectomy with conservation of the ovaries in premenopausal women. J Obstet Gynaecol Br Commonw 76: 969, 1969 14. Ranney B, Abu-Ghazaleh S: The future function and fortune of ovarian tissue which is retained in vivo during hysterectomy. Am J Obstet Gynecol 128:626, 1977 15. Benedek Jaszmann W: The epidemiology of the climacteric syndrome. In Management of the Menopause and Postmenopausal Years, Edited by S Campbell. Lancaster, MTP Press, 1976, p 11 16. Kaufmann DW, Slone D, Rosenberg L, Miettinen OS, Shapiro S: Cigarette smoking and age at natural menopause. Am J Public Health 7:429, 198 17. Bungay GT, Vessey MP, McPherson CK: Study of symptoms of middle life with special reference to the menopause. Br Med J 282:181, 198 18. Gath C: Personal communication 19. Stone SC, Dickey RP, Mickal A: The acute effect of hysterectomy on ovarian function. Am J Obstet Gynecol 121:193, 1975 2. Janson PO, Jansson I: The acute effect of hysterectomy on ovarian blood flow. Am J Obstet Gynecol 127:349, 1977 21. Cattanach J: Oestrogen deficiency after tubal ligation. Lancet 1:847, 1985 22. Sessums JV, Murphy DP: The influence of endometrium upon the rabbit ovary after hysterectomy. Surg Gynecol Obstet 56:6, 1933 23. Roos NR: Hysterectomies in one Canadian province: a new look at riskslbenefits. Am J Public Health 74:39, 1984 1 Siddle et al. Hysterectomy and ovarian failure Fertility and Sterility