Retention of normal ovarian function after M. G.
hysterectomy
Metcalf, V. Braiden and J. H. Livesey
Department of Endocrinology, received
Christchurch School of Medicine, Christchurch, New Zealand
16 March 1992
ABSTRACT
What are the long-term effects of hysterectomy on the ovaries of normal women? Ninety-three women aged 29\p=n-\44 years (median, 38 years) who had undergone hysterectomy for benign reasons 0\m=.\3\p=n-\9\m=.\1 years prior to investigation, contributed urine samples twice weekly for a period of 53\p=n-\149 days (median 102 days) for pregnanediol analysis. The interval between successive pregnanediol peaks and their increment over baseline were measured. The median peak interval was 27\m=.\3 days, and 93\m=.\3% of all intervals were of 21- to 35-days duration. Of the
337 peaks observed, 96\m=.\7%met the criteria previously used to define an ovulatory cycle. These are similar to the figures reported for menstruant women of comparable age. ANOVA showed no significant effect of age or time since hysterectomy on either the interval between peaks or peak increment (P > 0\m=.\10in all cases). The evidence suggests that the ovaries of women who have no uterus behave like those of intact
INTRODUCTION
sudden break in a regular pat¬ menstrual cycles is often the first sign of the ovarian dysfunction which will eventually lead to the menopause. This is the start of the meno¬ pausal transition, a period during which menses occur at irregular intervals and anovulatory cycles are common (Treloar, 1981 ; Metcalf, Donald & Livesey, 198le). In many menstruant women the beginning and end of the menopausal transition may be readily identified from the menstrual record. In hysterectom¬ ized women by comparison, menstruation does not occur and another marker of ovarian dysfunction must be found. In the present paper we use the peak excretion of urinary pregnanediol which in ovulatory cycles precedes menstrual onset by about 7 days (Metcalf & Livesey, 1988a). Before the start of the menopausal transition, ovulation is the norm (Metcalf, 1988) and pregnanediol peaks appear at regular intervals. After the start of the menopausal transition this regularity is lost. Anovulation is com¬ mon and cycles vary markedly in length. The distance between successive pregnanediol peaks provides a measure of this variability. In this report we test the hypothesis that a hysterec¬ tomy is associated with premature ovarian failure by searching for age-related changes, (a) in the length of the pregnanediol cycle and (b) in the amplitude of the pregnanediol peaks in women who have no uterus. The possibility that ovarian failure is a function of time since hysterectomy is also examined.
women.
Journal
In normal
tern of
Much is known about menstrual cyclicity (Treloar, & Brown, 1967; Vollman, 1977) and luteal function (Vollman, 1977; Landgren, Unden & Diczfalusy, 1980; Lenton, Sulaiman, Sobowale & Cooke, 1982; Metcalf, 1983) in normal women, but little about the ovarian cycles of women who have no uterus. In many mammals a uterus is essential for the orderly regression of the corpus luteum (Anderson, 1973); in women it seems that the uterus does not
Boynton, Behn
control luteal
regression. There may be a long-term effect however, and opinions differ as to whether the removal of the uterus is (Roos, 1984; Siddle, Sarrel & Whitehead, 1987; Kaiser, Kusche & Würz, 1989), or is not (Whitelaw, 1958; De Neef & Hollenbeck, 1966; Anderson, 1973; Ranney & Abu-Ghazaleh, 1977; Ellsworth, Allen & Nisker, 1983) associated with premature ovarian failure. The evidence is often nebulous, being based either on the retrospective examination of patient records (Ranney & AbuGhazaleh, 1977; Roos, 1984; Siddle et al 1987), or on hormonal or histological data obtained during the course of a single day (De Neef & Hollenbeck, 1966; Kaiser et al 1989) or cycle (Whitelaw, 1958; Ellsworth et al 1983). Such information is difficult to interpret ; identification of the complex changes which occur as the ovaries start to fail (Metcalf, Donald & Livesey, 1981a; Metcalf, 1988) requires a different
approach.
of Endocrinology (1992) 135,
women a
ovulatory
597\p=n-\602
SUBJECTS AND METHODS
Subjects Ninety-three hysterectomized women aged 29-44 years (median, 38 years; quartiles, 34 and 41 years) took part in the study. Consent was obtained from each of the participants following a full explanation of the aims of the study and of the procedures which would be used. The women had two ovaries. Hys¬ terectomy had taken place 0-3-9-1 years prior to the start of the study (median, 2-6 years; quartiles, 1-0 and 4- 8 years) for benign reasons, of which the most common were menorrhagia (complained of by 81% of the women), pain (31%), fibroids (22%) and prolapse (14%). With few exceptions, the women were of Euro¬ pean origin and none had overt signs of endocrine or1 other abnormalities apart from headache, allergies such as asthma and hay fever, and joint pain; 89% claimed that their health was good or excellent. None took hormone preparations either during the study or in the 3 months preceding it, and women with > one hot flush per day were excluded. Body weights ranged from 85 to 165% of ideal (Metropolitan Life Insur¬ ance Co., 1959: median, 112%; quartiles, 102 and 127%). Subjects were selected from a larger group of 318 similar women in such a way as to optimize the spread of ages and of times since hysterectomy. Four of these 3 f 8 women ( 1 3%) complained of daily hot ·
flushes.
Samples Each woman contributed an early morning sample of urine twice weekly for 53-149 days (median, 102 days ; quartiles, 94 and 119 days). This protocol was accept¬ able to the Ethical Committee of the Canterbury Area Health Board.
Methods
Pregnanediol in urine was measured by gas chro¬ matography (Metcalf, 1973) or by an enzyme-linked
immunosorbent assay (Lewis, Clifford & Elder, 1990). Creatinine was measured by an autoanalyser tech¬ nique (Fraser & Sontrop, 1979). Interassay coeffici¬ ents of variation for the pregnanediol assays were 6-2% and 5-7% respectively, and for the creatinine assay it was 5-0%. The ratio of pregnanediol (pmol) to creatinine (mmol) in urine parallels progesterone secretion (Metcalf, Evans & Mackenzie, 1984) and can be used to monitor the waxing and waning of the corpus luteum. In this paper a pregnanediol peak is defined as any rise in the pregnanediol to creatinine ratio for which (i) the sum of two successive values exceeds 0- 5
the maximum value is not less than threefold than the basal value. When the sum of two successive values exceeds 0-7 the ovarian cycle in which the peak occurs is termed an ovulatory cycle (Metcalf, 1983). The method used to locate the centre of a pregnanediol peak is shown in Fig. la and the approximation used to estimate its amplitude in Fig. lb. Ovarian failure is associated with a persistent eleva¬ tion in the urinary excretion of the pituitary hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), to levels above 0-8 IU creatinine/ mmol (Metcalf & Livesey, 1979), together with a persistent depression in urinary oestrogen excre¬ tion below 5 nmol/mmol creatinine (Rae, Mole & Paterson, 1988). To monitor ovarian dysfunction the excretion of oestrone-3-glucuronide was measured by an enzyme-linked immunosorbent assay (Elder, Manley & Lewis, 1990) and LH by the LKB Delphia immunofluorometric assay (Pharmacia Diagnostics, 1989). Interassay coefficients of variation for the oestrone assay were 6-8% and for the LH assay 3-28-6%. and
(ii)
higher
Statistical
analysis
The data were examined by repeated measures analy¬ sis of variance (ANOVA) and covariance for two covariates (time and age), and one or other of two dependent variables (interval between successive preg¬ nanediol peaks or size of the pregnanediol increment) using BMPD programme 2V (Dixon, 1985). RESULTS
pregnanediol peaks Ninety of the 93 women in the study had two or more pregnanediol peaks during the time they were observed. The intervals between these peaks ranged in length from 15-8 to 83-1 days, with 93-3% between 21 and 35 days (Fig. 2). Interval duration was exam¬ ined by ANOVA. There was no significant effect of either age (F(l,89) 0-47; =0-49) or time since hysterectomy (F(l,89) 2-75; P 0-10), and no significant interaction between the two covariates (F(2,178)=l-53; P 0-22). The distribution of peak intervals is shown in Fig. 2. Only three of the 90 women had peak intervals longer than 40 days. Interval between successive
=
=
=
=
Peak increments
Ninety-one women had at least one pregnanediol peak during the study. The amplitude of these peaks over baseline was analysed similarly. Again, there was
2-0-
3-5% with the sum of the two highest ratios < 0-7. In all, 96-7% of these peaks met the criteria used previ¬ ously (Metcalf, 1983) to define an ovulatory cycle.
1-5.
S "3
I o
0-5.
- 0-7, and
DISCUSSION
The evidence presented in this paper does not support the hypothesis that a hysterectomy predisposes women to premature ovarian failure. First, there was little evidence of the hot flushes which are common in menopausal and ovariectomized women. Secondly,
18
20
22 24 26 28 30 32 34 36 38 40 Interval duration (days)
42
A83
62
figure 2. Time elapsing between successive pregnanediol peaks in 93 women aged 29-44 years who had had a hysterectomy 0-3-9-1 years before ; distribution of 238 interpeak intervals (median duration, 27-3 days; quartiles, 25-1 and 29-3 days). Three of the women had either no pregnanediol peaks or a single peak.
for the 99% of women who did not complain of fre¬ quent hot flushes, there was no significant effect of either age or time since hysterectomy on the pregnane¬ diol parameters associated with the length of the ovar¬
(a) -o > C cd
Dß
a
cu
e
2?
_
o
§
i°i26 A:3 fi tto-o-ci
OJ O-o—O-Ó J
ian
iV»
^ o a.
1-, (b)
•J
ö
ja 0
20
60 40 Observation
80
100
120
day
3. Urinary hormone patterns in a woman aged 42 (a) in the 3 months leading up to hysterectomy and (b) from 1-3-1-6 years after hysterectomy. Flags indicate the start of menstrual bleeding, italic numbers the length of the menstrual cycle in days and asterisks the estimated position of the pregnanediol peaks. Bars refer figure
years
toLH.
cycle and with the ability of the corpus luteum
secrete
to
progesterone. This lack of effect is in accord
with the evidence of Whitelaw (1958) and of Ellsworth et al (1983) who compared indices of pro¬ gesterone secretion at approximately 2-weekly inter¬ vals in hysterectomized women aged 28-47 years. They found signs of ovulation in 75 and 70% of them respectively and evidence of oestrogen activity in 90 and 80%. The further observation by De Neef & Hollenbeck (1966) of smear characteristics typical of the luteal phase in women whose uterus had been removed 15 and 21 years before, also supports the notion that a uterus is not essential for normal ovar¬ ian function. Contrary views have been expressed. Roos (1984) examined the case reports of 2332 women who had no uterus and noted that the fre¬ quency of oestrogen-deficiency symptoms was at least twice that reported by menstruant women after cholecystectomy. Siddle et al (1987) in a similar type of study compared the case notes of hysterectomized and menstruant women attending two menopause clinics. In the hysterectomized group persistent hot flushes or vaginal dryness were taken to be proof of ovar¬ ian failure; in the menstruant group persistent
amenorrhoea was an added requirement. The authors claim that hysterectomy advanced the time of meno¬ pause by approximately 4 years, but do not discuss the effect of the more rigorous criteria used to identify ovarian failure in menstruant women. The evidence is for this reason difficult to interpret. In a third study (Kaiser et al 1989), the findings were based on a single measurement of FSH and LH made at an unknown time in the ovarian cycle. Such evidence is inadequate to describe the ovarian hormone cycle of normal women, let alone the complex changes which occur with the approach of the menopause. The claim by the Kaiser group that a 'hysterectomy accelerates the onset of the menopausal hormone profile' must therefore be taken on trust. In summary, evidence in support of the hypothesis is tenuous. There are remarkable similarities between the indi¬ ces of ovarian function observed in this series of hysterectomized women and those reported for men¬ struant women, (i) Vollman (1977) found that the median duration of the menstrual cycle in 1771 nor¬ mal women aged 29-44 years was 27-4 days, a figure which differs little from the median of 27-3 days for the interval between successive pregnanediol peaks in the present study, (ii) Both Vollman (1977) and Treloar et al (1967) noted that the variation in men¬ strual cycle length was low after the age of 25 years until about 6 years prior to the menopause. This regul¬ arity was preserved when there was no uterus. In the present series, 93-3% of the peak intervals were between 21 and 35 days in duration, comparable to the 93-6% incidence of 21- to 35-day menstrual cycles reported for normal women (Metcalf, 1983). Abnormally prolonged intervals, as.shown in Fig. 3, were associated with hormone patterns which are often seen in the menopausal transition (Metcalf et al 1981 ). (iii) The frequency of ovulatory cycles also appeared to be undiminished by hysterectomy. In an earlier study (Metcalf, 1983) we noted that 96-3% of the menstrual cycles observed in 129 normal women (aged 29-44 years) met the pregnanediol criteria used to identify ovulation; in the present study, 96-7% of the pregnanediol peaks met the same criteria, (iv) Even the amplitude of the pregnanediol peaks was similar in women with and without a uterus. The med¬ ian amplitude in 48 normal women (aged 25-39 years) was 1-20 pmol/mmol creatinine (Metcalf & Livesey, 19886), a value which is close to the mean peak incre¬ ment of 1-16 observed in the present study. No agerelated changes were detected in either series. These similarities support the view that ovaries which are undamaged during hysterectomy 'will usually produce female hormones for the inherited duration of years' (Ranney & Abu-Ghazaleh, 1977). On present evidence it seems reasonable to assume that the ova¬ ries of women who have no uterus behave like those of normal women. ...
ACKNOWLEDGEMENTS
This study was supported by the Medical and Health Research Councils of New Zealand and by the Can¬ terbury Area Health Board. Our thanks are due to the gynaecologists at Christchurch Women's Hospital for permission to approach women on the waiting list for hysterectomy, to the staff of the Biochemistry Departments of the Christchurch and Princess Mar¬ garet Hospitals for the hormone measurements, and to Mrs J. Verdonk and Mr C. Fortune who prepared the manuscript.
REFERENCES
Anderson,
L. L. (1973). Effects of hysterectomy and other factors luteal function. In Handbook of Physiology, section 7, vol II: Female Reproductive System, part 2, pp. 69-86. Ed. R. O. Greep. Washington D.C. : American Physiological Society. De Neef, J. C. & Hollenbeck, . J. R. (1966). The fate of ovaries preserved at the time of hysterectomy. American Journal of Obstetrics and Gynecology 96, 1088-1097. Dixon, W. J. (1985). BMPD Statistical Software. Berkeley: Uni¬ versity of California Press. Elder, P. ., Manley, L. & Lewis, J. G. (1990). Use of a mono¬ clonal antibody to estrone-3-glucuronide in an enzyme-linked immunosorbent assay (ELISA). Journal of Steroid Biochemistry 36, 439-443. Ellsworth, L. R., Allen, H. H. & Nisker, J. A. (1983). Ovarian function after radical hysterectomy for stage 1 carcinoma of the cervix. American Journal of Obstetrics and Gynecology 145, 185-188. Fraser, C. G. & Sontrop, M. E. (1979). Assessment of the Beckman creatinine analyzer. Clinical Biochemistry 2, 46-49. Kaiser, R., Kusche, M. & Würz, H. (1989). Hormone levels in women after hysterectomy. Archives of Gynecology and Obstetrics 244, 169-173. Landgren, B. M., Unden, A. L. & Diczfalusy, E. (1980). Hor¬ monal profile of the cycle in 68 normally menstruating women. Acta Endocrinologica 94, 89-98. Lenton, . ., Sulaiman, R., Sobowale, O. & Cooke, I. D. (1982). The human menstrual cycle : plasma concentrations of pro¬ lactin, LH, FSH, oestradiol and progesterone in conceiving and non-conceiving women. Journal of Reproduction and Fertility 65, 131-139. Lewis, J. G., Clifford, J. K. & Elder, P. A. (1990). Monoclonal antibodies to pregnanediol-3-glucuronide: application to a direct enzyme-linked immunosorbent assay of urine. Steroids 55, 314-318. Metcalf, M. G. (1973). Rapid gas Chromatographie assay for progesterone metabolites in urine. Clinical Biochemistry 6, 307-320. Metcalf, M. G. (1983). Incidence of ovulation from the menarche to the menopause : observations of 622 New Zealand women. New Zealand Medical Journal 96, 645-648. Metcalf, M. G. (1988). The approach of the menopause: a New Zealand study. New Zealand Medical Journal 101, 103-106. Metcalf, M. G., Donald, R. A. & Livesey, J. . (1981a). Pituitaryovarian function in normal women during the menopausal tran¬ sition. Clinical Endocrinology 14, 245-255. on
M. G., Donald, R. A. & Livesey, J. H. (19816). Classifi¬ cation of menstrual cycles in pre- and perimenopausal women. Journal of Endocrinology 91, 1-10. Metcalf, M. G., Evans, J. J. & Mackenzie, J. A. (1984). Indices of ovulation : comparison of plasma and salivary levels of progesterone with urinary pregnanediol. Journal of Endocrinology 100, 75-80. Metcalf, M. G. & Livesey, J. H. (1979). Use of small samples of urine to monitor gonadotrophins in menopausal women. Clinica Chimica Ada 94, 287-293. Metcalf, M. G. & Livesey, J. . (1988a). Technique for locating the start of the ovarian cycle in women who have no uterus. European Journal of Obstetrics, Gynaecology and Reproductive Biology 27, 237-243. Metcalf, M. G. & Livesey, J. H. (19886). Pregnanediol excretion in fertile women : age-related changes. Journal of Endocrinology 119, 153-157. Metropolitan Life Insurance Co. (1959). Statistical Bulletin 40, 3. Pharmacia Diagnostics (1989). DELFIA hLH Spec Kit 1244-031. Rae, M. H., Mole, P. . & Paterson, C. R. (1988). Evaluation of urinary oestrogen assays after the menopause and their poten¬ tial for screening. Clinica Chimica Ada 176, 71-82.
Metcalf,
. & Abu-Ghazaleh, S. (1977). The future function and fortune of ovarian tissue which is retained in vivo during hys¬ terectomy. American Journal of Obstetrics and Gynecology 128, 626-634. Roos, N. R. (1984). Hysterectomies in one Canadian province: a new look at risks/benefits. American Journal of Public Health 74, 39-46. Siddle, N, Sarrel, P. & Whitehead, M. (1987). The effect of hys¬ terectomy on the age at ovarian failure : identification of a sub-group of women with premature loss of ovarian function and literature review. Fertility and Sterility 47, 94-100. Treloar, A. E. (1981). Menstrual cyclicity and the premenopause. Maturitas 3, 249-264. Treloar, A. E., Boynton, R. E., Behn, B. G. & Brown, B. W. (1967). Variation of the human menstrual cycle through reproductive life. International Journal of Fertility 12, 77-126. Vollman, R. F. (1977). The length of the menstrual cycle. In The Menstrual Cycle, pp. 19-72. Philadelphia: WB Saunders. Whitelaw, R. G. (1958). Ovarian activity following hysterectomy. Journal of Obstetrics and Gynaecology of the British Commonwealth 65, 917-932.
Ranney,
hysterectomy
Metcalf, V. Braiden and J. H. Livesey
Department of Endocrinology, received
Christchurch School of Medicine, Christchurch, New Zealand
16 March 1992
ABSTRACT
What are the long-term effects of hysterectomy on the ovaries of normal women? Ninety-three women aged 29\p=n-\44 years (median, 38 years) who had undergone hysterectomy for benign reasons 0\m=.\3\p=n-\9\m=.\1 years prior to investigation, contributed urine samples twice weekly for a period of 53\p=n-\149 days (median 102 days) for pregnanediol analysis. The interval between successive pregnanediol peaks and their increment over baseline were measured. The median peak interval was 27\m=.\3 days, and 93\m=.\3% of all intervals were of 21- to 35-days duration. Of the
337 peaks observed, 96\m=.\7%met the criteria previously used to define an ovulatory cycle. These are similar to the figures reported for menstruant women of comparable age. ANOVA showed no significant effect of age or time since hysterectomy on either the interval between peaks or peak increment (P > 0\m=.\10in all cases). The evidence suggests that the ovaries of women who have no uterus behave like those of intact
INTRODUCTION
sudden break in a regular pat¬ menstrual cycles is often the first sign of the ovarian dysfunction which will eventually lead to the menopause. This is the start of the meno¬ pausal transition, a period during which menses occur at irregular intervals and anovulatory cycles are common (Treloar, 1981 ; Metcalf, Donald & Livesey, 198le). In many menstruant women the beginning and end of the menopausal transition may be readily identified from the menstrual record. In hysterectom¬ ized women by comparison, menstruation does not occur and another marker of ovarian dysfunction must be found. In the present paper we use the peak excretion of urinary pregnanediol which in ovulatory cycles precedes menstrual onset by about 7 days (Metcalf & Livesey, 1988a). Before the start of the menopausal transition, ovulation is the norm (Metcalf, 1988) and pregnanediol peaks appear at regular intervals. After the start of the menopausal transition this regularity is lost. Anovulation is com¬ mon and cycles vary markedly in length. The distance between successive pregnanediol peaks provides a measure of this variability. In this report we test the hypothesis that a hysterec¬ tomy is associated with premature ovarian failure by searching for age-related changes, (a) in the length of the pregnanediol cycle and (b) in the amplitude of the pregnanediol peaks in women who have no uterus. The possibility that ovarian failure is a function of time since hysterectomy is also examined.
women.
Journal
In normal
tern of
Much is known about menstrual cyclicity (Treloar, & Brown, 1967; Vollman, 1977) and luteal function (Vollman, 1977; Landgren, Unden & Diczfalusy, 1980; Lenton, Sulaiman, Sobowale & Cooke, 1982; Metcalf, 1983) in normal women, but little about the ovarian cycles of women who have no uterus. In many mammals a uterus is essential for the orderly regression of the corpus luteum (Anderson, 1973); in women it seems that the uterus does not
Boynton, Behn
control luteal
regression. There may be a long-term effect however, and opinions differ as to whether the removal of the uterus is (Roos, 1984; Siddle, Sarrel & Whitehead, 1987; Kaiser, Kusche & Würz, 1989), or is not (Whitelaw, 1958; De Neef & Hollenbeck, 1966; Anderson, 1973; Ranney & Abu-Ghazaleh, 1977; Ellsworth, Allen & Nisker, 1983) associated with premature ovarian failure. The evidence is often nebulous, being based either on the retrospective examination of patient records (Ranney & AbuGhazaleh, 1977; Roos, 1984; Siddle et al 1987), or on hormonal or histological data obtained during the course of a single day (De Neef & Hollenbeck, 1966; Kaiser et al 1989) or cycle (Whitelaw, 1958; Ellsworth et al 1983). Such information is difficult to interpret ; identification of the complex changes which occur as the ovaries start to fail (Metcalf, Donald & Livesey, 1981a; Metcalf, 1988) requires a different
approach.
of Endocrinology (1992) 135,
women a
ovulatory
597\p=n-\602
SUBJECTS AND METHODS
Subjects Ninety-three hysterectomized women aged 29-44 years (median, 38 years; quartiles, 34 and 41 years) took part in the study. Consent was obtained from each of the participants following a full explanation of the aims of the study and of the procedures which would be used. The women had two ovaries. Hys¬ terectomy had taken place 0-3-9-1 years prior to the start of the study (median, 2-6 years; quartiles, 1-0 and 4- 8 years) for benign reasons, of which the most common were menorrhagia (complained of by 81% of the women), pain (31%), fibroids (22%) and prolapse (14%). With few exceptions, the women were of Euro¬ pean origin and none had overt signs of endocrine or1 other abnormalities apart from headache, allergies such as asthma and hay fever, and joint pain; 89% claimed that their health was good or excellent. None took hormone preparations either during the study or in the 3 months preceding it, and women with > one hot flush per day were excluded. Body weights ranged from 85 to 165% of ideal (Metropolitan Life Insur¬ ance Co., 1959: median, 112%; quartiles, 102 and 127%). Subjects were selected from a larger group of 318 similar women in such a way as to optimize the spread of ages and of times since hysterectomy. Four of these 3 f 8 women ( 1 3%) complained of daily hot ·
flushes.
Samples Each woman contributed an early morning sample of urine twice weekly for 53-149 days (median, 102 days ; quartiles, 94 and 119 days). This protocol was accept¬ able to the Ethical Committee of the Canterbury Area Health Board.
Methods
Pregnanediol in urine was measured by gas chro¬ matography (Metcalf, 1973) or by an enzyme-linked
immunosorbent assay (Lewis, Clifford & Elder, 1990). Creatinine was measured by an autoanalyser tech¬ nique (Fraser & Sontrop, 1979). Interassay coeffici¬ ents of variation for the pregnanediol assays were 6-2% and 5-7% respectively, and for the creatinine assay it was 5-0%. The ratio of pregnanediol (pmol) to creatinine (mmol) in urine parallels progesterone secretion (Metcalf, Evans & Mackenzie, 1984) and can be used to monitor the waxing and waning of the corpus luteum. In this paper a pregnanediol peak is defined as any rise in the pregnanediol to creatinine ratio for which (i) the sum of two successive values exceeds 0- 5
the maximum value is not less than threefold than the basal value. When the sum of two successive values exceeds 0-7 the ovarian cycle in which the peak occurs is termed an ovulatory cycle (Metcalf, 1983). The method used to locate the centre of a pregnanediol peak is shown in Fig. la and the approximation used to estimate its amplitude in Fig. lb. Ovarian failure is associated with a persistent eleva¬ tion in the urinary excretion of the pituitary hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), to levels above 0-8 IU creatinine/ mmol (Metcalf & Livesey, 1979), together with a persistent depression in urinary oestrogen excre¬ tion below 5 nmol/mmol creatinine (Rae, Mole & Paterson, 1988). To monitor ovarian dysfunction the excretion of oestrone-3-glucuronide was measured by an enzyme-linked immunosorbent assay (Elder, Manley & Lewis, 1990) and LH by the LKB Delphia immunofluorometric assay (Pharmacia Diagnostics, 1989). Interassay coefficients of variation for the oestrone assay were 6-8% and for the LH assay 3-28-6%. and
(ii)
higher
Statistical
analysis
The data were examined by repeated measures analy¬ sis of variance (ANOVA) and covariance for two covariates (time and age), and one or other of two dependent variables (interval between successive preg¬ nanediol peaks or size of the pregnanediol increment) using BMPD programme 2V (Dixon, 1985). RESULTS
pregnanediol peaks Ninety of the 93 women in the study had two or more pregnanediol peaks during the time they were observed. The intervals between these peaks ranged in length from 15-8 to 83-1 days, with 93-3% between 21 and 35 days (Fig. 2). Interval duration was exam¬ ined by ANOVA. There was no significant effect of either age (F(l,89) 0-47; =0-49) or time since hysterectomy (F(l,89) 2-75; P 0-10), and no significant interaction between the two covariates (F(2,178)=l-53; P 0-22). The distribution of peak intervals is shown in Fig. 2. Only three of the 90 women had peak intervals longer than 40 days. Interval between successive
=
=
=
=
Peak increments
Ninety-one women had at least one pregnanediol peak during the study. The amplitude of these peaks over baseline was analysed similarly. Again, there was
2-0-
3-5% with the sum of the two highest ratios < 0-7. In all, 96-7% of these peaks met the criteria used previ¬ ously (Metcalf, 1983) to define an ovulatory cycle.
1-5.
S "3
I o
0-5.
- 0-7, and
DISCUSSION
The evidence presented in this paper does not support the hypothesis that a hysterectomy predisposes women to premature ovarian failure. First, there was little evidence of the hot flushes which are common in menopausal and ovariectomized women. Secondly,
18
20
22 24 26 28 30 32 34 36 38 40 Interval duration (days)
42
A83
62
figure 2. Time elapsing between successive pregnanediol peaks in 93 women aged 29-44 years who had had a hysterectomy 0-3-9-1 years before ; distribution of 238 interpeak intervals (median duration, 27-3 days; quartiles, 25-1 and 29-3 days). Three of the women had either no pregnanediol peaks or a single peak.
for the 99% of women who did not complain of fre¬ quent hot flushes, there was no significant effect of either age or time since hysterectomy on the pregnane¬ diol parameters associated with the length of the ovar¬
(a) -o > C cd
Dß
a
cu
e
2?
_
o
§
i°i26 A:3 fi tto-o-ci
OJ O-o—O-Ó J
ian
iV»
^ o a.
1-, (b)
•J
ö
ja 0
20
60 40 Observation
80
100
120
day
3. Urinary hormone patterns in a woman aged 42 (a) in the 3 months leading up to hysterectomy and (b) from 1-3-1-6 years after hysterectomy. Flags indicate the start of menstrual bleeding, italic numbers the length of the menstrual cycle in days and asterisks the estimated position of the pregnanediol peaks. Bars refer figure
years
toLH.
cycle and with the ability of the corpus luteum
secrete
to
progesterone. This lack of effect is in accord
with the evidence of Whitelaw (1958) and of Ellsworth et al (1983) who compared indices of pro¬ gesterone secretion at approximately 2-weekly inter¬ vals in hysterectomized women aged 28-47 years. They found signs of ovulation in 75 and 70% of them respectively and evidence of oestrogen activity in 90 and 80%. The further observation by De Neef & Hollenbeck (1966) of smear characteristics typical of the luteal phase in women whose uterus had been removed 15 and 21 years before, also supports the notion that a uterus is not essential for normal ovar¬ ian function. Contrary views have been expressed. Roos (1984) examined the case reports of 2332 women who had no uterus and noted that the fre¬ quency of oestrogen-deficiency symptoms was at least twice that reported by menstruant women after cholecystectomy. Siddle et al (1987) in a similar type of study compared the case notes of hysterectomized and menstruant women attending two menopause clinics. In the hysterectomized group persistent hot flushes or vaginal dryness were taken to be proof of ovar¬ ian failure; in the menstruant group persistent
amenorrhoea was an added requirement. The authors claim that hysterectomy advanced the time of meno¬ pause by approximately 4 years, but do not discuss the effect of the more rigorous criteria used to identify ovarian failure in menstruant women. The evidence is for this reason difficult to interpret. In a third study (Kaiser et al 1989), the findings were based on a single measurement of FSH and LH made at an unknown time in the ovarian cycle. Such evidence is inadequate to describe the ovarian hormone cycle of normal women, let alone the complex changes which occur with the approach of the menopause. The claim by the Kaiser group that a 'hysterectomy accelerates the onset of the menopausal hormone profile' must therefore be taken on trust. In summary, evidence in support of the hypothesis is tenuous. There are remarkable similarities between the indi¬ ces of ovarian function observed in this series of hysterectomized women and those reported for men¬ struant women, (i) Vollman (1977) found that the median duration of the menstrual cycle in 1771 nor¬ mal women aged 29-44 years was 27-4 days, a figure which differs little from the median of 27-3 days for the interval between successive pregnanediol peaks in the present study, (ii) Both Vollman (1977) and Treloar et al (1967) noted that the variation in men¬ strual cycle length was low after the age of 25 years until about 6 years prior to the menopause. This regul¬ arity was preserved when there was no uterus. In the present series, 93-3% of the peak intervals were between 21 and 35 days in duration, comparable to the 93-6% incidence of 21- to 35-day menstrual cycles reported for normal women (Metcalf, 1983). Abnormally prolonged intervals, as.shown in Fig. 3, were associated with hormone patterns which are often seen in the menopausal transition (Metcalf et al 1981 ). (iii) The frequency of ovulatory cycles also appeared to be undiminished by hysterectomy. In an earlier study (Metcalf, 1983) we noted that 96-3% of the menstrual cycles observed in 129 normal women (aged 29-44 years) met the pregnanediol criteria used to identify ovulation; in the present study, 96-7% of the pregnanediol peaks met the same criteria, (iv) Even the amplitude of the pregnanediol peaks was similar in women with and without a uterus. The med¬ ian amplitude in 48 normal women (aged 25-39 years) was 1-20 pmol/mmol creatinine (Metcalf & Livesey, 19886), a value which is close to the mean peak incre¬ ment of 1-16 observed in the present study. No agerelated changes were detected in either series. These similarities support the view that ovaries which are undamaged during hysterectomy 'will usually produce female hormones for the inherited duration of years' (Ranney & Abu-Ghazaleh, 1977). On present evidence it seems reasonable to assume that the ova¬ ries of women who have no uterus behave like those of normal women. ...
ACKNOWLEDGEMENTS
This study was supported by the Medical and Health Research Councils of New Zealand and by the Can¬ terbury Area Health Board. Our thanks are due to the gynaecologists at Christchurch Women's Hospital for permission to approach women on the waiting list for hysterectomy, to the staff of the Biochemistry Departments of the Christchurch and Princess Mar¬ garet Hospitals for the hormone measurements, and to Mrs J. Verdonk and Mr C. Fortune who prepared the manuscript.
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