Ovarian function after radical hysterectomy for Stage IB carcinoma of cervix LINDA R. ELLSWORTH, M.D., PH.D. H. HUGH
ALLE~.
M.D., F.R.C.S.(C.)
JEFFREY A. NISKER, M.D., F.R.C.S.(C.) London, Ontario, Canada Ovarian function was assessed in 20 patients after radical hysterectomy and lymph node dissection for Stage IS cervical carcinoma. All patients were under 45 years of age, and four were or had been on estrogen therapy for postmenopausal symptoms. The other 16 patients were free of symptoms and demonstrated premenopausal gonadotropin profiles. Fourteen of these 16 had luteal phase serum progesterone levels. Only one patient required reoperation for a pathologic condition of the adnexa. A surgical approach to Stage IS cervical carcinoma conserves ovarian function in 80"1.. of patients. (AM. J. 0BSTET. GYNECOL 145:185, 1983.)
THE TREATMENT OF Stage IB carcinoma of the cervix may be radiotherapy or radical hysterectomy with pelvic lymph node dissection. With radiotherapy, a premature radiation menopause is produced, since the radiotherapy dosage used is far above the level shown to produce castration. 1 Our group 2 and others3- 8 have urged a surgical approach in young patients in order to preserve the effects of ovarian hormones on end-organs. There has been disagreement in the literature about the function and fate of conserved ovaries even after hysterectomy for benign disease. The trauma of radical surgery could theoretically compromise the ovarian blood supply and, hence, subsequent ovarian function. In this study, clinical and biochemical indices of postoperative ovarian function in 20 patients were evaluated.
Material and methods Twenty patients who were under 45 years of age at the time of follow-up were assessed. AU had had a radical hysterectomy and pelvic lymph node dissection performed by one surgeon (H. H. A.) between 1963 and From the Department of Obstetrics and Gynaecology, University of Western Ontario, and Ontario Cancer Treatment and Research Foundation, Landon Clinic. Presented at the Thirty-eighth Annual Meeting of the Society of Obstetricians and Gynaecologists of Canada, Toronto, Ontario, Canada, june 15-19, 1982. Reprint requests: Dr.]. A. Niskn', Victoria Hospital, Colborne 3, London, Ontario, Canada N6A 4G5. 0002-9378/83/020185+04$00.40/0
© 1983 The C. V. Mosby Co.
Table I. Hormonal profile after radical operation with ovarian conservation for Stage IB cervical carcinoma No. of patients Postmenopausal symptoms or estrogen therapy Premenopausal luteinizing hormone and folliclestimulating hormone Luteal phase progesterone (>6 nmoles/L) Total
4 16 14 20
*Criteria for postmenopausal gonadotropins: luteinizing hormone and follicle-stimulating hormone both >20 miU/ ml, follicle-stimulating honnone > luteinizing hormone.
1981, and all had had at least one ovary conserved. The mean postoperative interval was 4.8 years. Three patients were between 3 and 6 months postoperatively, ten patients were from 6 months to 5 years, and seven patients were more than 5 years. All patients were 41 years of age or younger at the time of operation. The mean age of the patients was 35.4 years, with five patients 34 years old or less, nine patients 35 to 40 years old, and six patients 40 or more years old. Assessment of ovarian function included a hormonal profile and interview. Venous blood samples were taken on the day of the interview for measurement of luteinizing hormone, follicle-stimulating hormone, and progesterone, and 14 days later the progesterone level was measured again. Luteinizing hormone and folliclestimulating hormone were both measured by standard 185
186 Ellsworth, Allen, and Nisker
January 15, 198g Am. J. Obstet. Gynecol.
Table ll. Serum luteinizing hormone, follicle-stimulating hormone, and progesterone after radical hysterectomy and lymph node dissection with ovarian conservation Postoperative interval
Patient No.
Luteinizing hormone (IU/ml)
Follicle-stimulating hormone (IU lml)
30
3 yr
11
2
36
2 yr
47
3
36
l yr
I0.5
7.4
5
39
I yr
23.8
8.6
6
40
2 yr
13.8
10.4
7
28
3 mo
48
14
8
36
2 yr
12.8
9.8
9
41
4 mo
11.8
12.6
10
29
4 yr
2.6
2.4
13
43
15 yr
14
40
3 yr
(l) 10.5 (2) 73.8 159
15
33
4 yr
17.1
8.2
16
37
8 yr
I4.3
17.1
18
31
5 yr
12.4
12.1
19
36
2 yr
58.8
18.2
20
30
3 yr
17.5
ll.8
9.6 I3
(1)
5.9 (2) 22.2 85.5
Progesterone* (nmoles/L) 9.5 (2) 11.1 <1.6
( l)
t
(1) 70.0 (2) 3.3 (1) 60.4 (2) 3.1 (l) 35.0 (2) 2.9 (1) 85.8 (2) 2.0 (1) 25.4 (2) 2.2 (I) 3.7 (2) 1.9 (l) 95.4 (2) 1.6 (1) 44.5 (2) 3.4 (1) 2.6 (2) 15.9 (l) 3.0 (2) 22.3 ( 1) <1.6 (2) 36.2 (1) 27.0
(2) 2.1 (1) 6 (2) 19.1 ( 1) 1.9 (2) 22.9
*Luteal phase, 6 to 64 nmoi/L. tDid not have second determination.
radioimmunoassay in duplicate with use of a double antibody method with 1251-labeled hormone. 9 Progesterone was measured in duplicate by standard radioimmunoassay with use of3H-Iabeled hormone. 9 Patient interviews specifically inquired about symptoms of ovarian hormonal function or estrogen-deprivation before and after operation. Statistical evaluation was performed with the x2 test. 1() Results
In this series of 20 patients, five had one ovary conserved and 15 had both ovaries conserved. Four patients had been or were currently on estrogen replacement (Table I). With the use of the criteria for postmenopausal gonadotropins luteinizing hormone and follicle-stimulating hormone levels greater than 20 IU/ml, with luteinizing hormone greater than folliclestimulating hormone, 16 patients could be considered to have premenopausal luteinizing hormone and follicle-stimulating hormone levels. In addition, 14 of these 16 demonstrated progesterone values in the luteal
range (>6 nmol/L). Nine of the latter 14 noted subjective symptoms of cyclic ovarian function, such as mittelschmerz. The hormone levels for patients who demonstrated continued ovarian function are shown in Table II. A more detailed examination of patients who demonstrated ovarian failure is provided in Table III. Significantly more patients with ovarian failure had only one ovary conserved (three of four), in comparison to those with normal ovarian function (two of 16) (p < 0.05). Moreover, those patients who showed ovarian failure were all more than 5 years postoperative (l 0, 18, 5, and 8 years), with a significantly longer (p < 0.005) postoperative interval than that of the group with normal ovarian function. Other factors which may be relevant in the group with postmenopausal symptoms include a history of a previous ovarian cystectomy (Patient No. 11) and a unilateral oophorectomy at the time of radical hysterectomy (Patient No. 17), with the incidental finding of a mucinous cystadenocarcinoma, for which the patient received Alkeran. Patients No. 4
Ovarian function after radical hysterectomy
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187
Table III. Ovarian failure after radical operation with ovarian conservation for carcinoma of the cervix Postoperative interval (yr)
Patient No.
No. of ovaries conserved
Comments
10
4 ll
42 44
12
36
18 6
17
37
8
and No. 12 were placed on replacement therapy during the first postoperative years, and Patients No. 11 and No. 17 each began estrogen replacement 5 years postoperatively at ages 31 and 35, respectively. Only one patient required reoperation (at age 39, 10 years after radical hysterectomy) for removal of a peritoneal inclusion cyst and adherent ovary and fallopian tube. The other adnexa were preserved, and the patient's present hormonal status suggests ovarian function. Comment
In this study, 80% of the women retained ovarian function after a radical operation for Stage IB carcinoma of the cervix, as demonstrated by premenopausal patterns of gonadotropins, and including luteal phase progesterone levels in 70%. Only one patient required a further surgical procedure for adnexal complications related to her original operation. Although the objective of preserving ovarian function is frequently cited in reports on operations for cervical carcinoma, 2 - 8 there is little information in the literature in regard to ovarian function after the extensive operations required for treatment of cervical carcinoma. Previous reports have documented continued ovarian function after simple hysterectomy for benign disease. Beling and associates 11 measured urinary pregnanediol before and after hysterectomy and concluded that cyclic ovarian function continues after hysterectomy. In another study, measurement of plasma progesterone and luteinizing hormone indicated normal ovarian cyclicity postoperatively. 12 Similarly, Corson and associates 13 reported that midluteal progesterone levels were unchanged after operations for benign disease. The earliest work in the area of radical operation with ovarian conservation reported the assessment of 27 patients by history, physical examination, and laboratory investigation (vaginal smears, follicle-stimulating hormone bioassay, and urinary estrogens). 3 Only one of 27 patients had hot flashes and elevated levels of follicle-stimulating hormone: the rest were said to have continued ovarian function. In a report on radical op-
2
Previous ovarian cystectomy Previous tubal ligation. Off estrogen replacement. Ele· vated gonadotropins Unilateral oophorectomy. Mucinous adenocarcinoma Treated with Alkeran
erations for invasive cervical carcinoma in pregnancy, Thompson and associates'1 assessed ovarian function in eight patients. Three patients (ages 47, 50, and 52 years) were postmenopausal, and five (3 i years old or less) showed cyclic production of estrogen and progesterone. The current study, utilizing more recent radioimmunoassay techniques, supports these earlier observations. There has been some controversy in regard to ovarian disease and eventual oophorectomy when ovaries are conserved at the time of radical hysterectomy. A "residual ovary syndrome," consisting of a pelvic mass, pelvic pain, and possible dyspareunia subsequent to hysterectomy, has been described. 14 In a large series of hysterectomies with ovarian conservation performed by one surgeon. 14 of 1.557 patients, or O.H9%. required reoperation for a pathologic condition of the adnexa. 1 ~ (Fifteen patients underwent radical hysterectomy, and the remainder had simple hysterectomy for benign disease.) However, in a series on radical operation for cervical carcinoma with ovarian conservation, 5 10 of 183 patients had subsequent operations for a pathologic condition of the adnexa (nine for cystic degeneration and one for ovarian carcinoma). This is a much higher rate of reoperation than that tound in the present study or in the other study in this area. 15 We suggest that this complication appears to be uncommon and should not present a serious obstacle to preservation of normal-appearing ovaries at hvsterectomy (whether for benign disease or carcinoma of the cervix). This study of ovarian function in 20 patients after radical operations for Stage IB cervical carcinoma found that: (1) four patients were or had been receiving estrogen therapy. suggesting ovarian failure; (2) 16 patients were free of postmenopausal symptoms and showed premenopausal levels of gonadotropins, suggesting continuing ovarian function; (3) 14 of these 16 had luteal phase progesterone levels, suggesting cyclic ovarian function; (4) only one patient required reoperation for a pathologic condition of the adnexa, suggesting that this is a rare complication.
188 Ellsworth, Allen, and Nisker
January 15. 1983
Am,
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8. DiSaia, P. J.: Surgical aspects of cervical carcinoma. Cancer 48:548, 1981. 9. Abraham, G. E.: Radioimmunoassay of steroids in biological fluids, Clin. Biochem. 7:193, 1974. 10. Snedecor, G. W., and Cochran, W. G.: Statistical Methods, Ames, Iowa, 1967, The Iowa State University Press. pp. 215-219. 11. Beling, C. G., Marcus, S. L., and Markham, S. M.: Functional activity of the corpus luteum following hysterectomy, J. C1in. Endocrinol. Metab. 30:30, 1970. 12. Doyle, L. L., Barclay, D. L., Duncan, G. W., and Kirton, K. T.: Human luteal function following hysterectomy as assessed by plasma progestin, AM.]. OBsTET. GYNECOL. 110:92, 1971. 13. Corson, S. L., Levinson, C.J., Batzer, F. R., and Otis, C.: Hormonal levels following sterilization and hysterectomy, ]. Reprod. Med. 26:363, 1981. 14. Grogan, R. H.: Reappraisal of residual ovaries, AM. J. 0BSTET. GYNECOL. 97:124, 1967. 15. Ranney, B., and Abu-Ghazaleh, S.: The future function and fortune of ovarian tissue which is retained in vivo during hysterectomy, AM. J. 0BSTET. GYNECOL. 128:626, 1977.