Maturitas 29 (1998) 133 – 138 The effect of hysterectomy and endometrial ablation on follicle stimulating hormone (FSH) levels up to 1 year after surgery J.G.M. Derksen a, H.A.M. Brolmann b,*, M.A.H.M. Wiegerinck b, H.L. Vader c, ¨ A.P.M. Heintz a b a Department of Obstetrics and Gynecology, Uni6ersity Hospital, Utrecht, The Netherlands Department of Obstetrics and Gynecology, Sint Joseph Hospital, P.O. Box 7777, 5500 MB Veldho6en, The Netherlands c Department of Clinical Chemistry, Sint Joseph Hospital, Veldho6en, The Netherlands Received 16 October 1997; received in revised form 28 January 1998; accepted 30 January 1998 Abstract Objecti6es: In this study the hypothesis was tested, that in premenopausal patients FSH-levels would rise after ‘simple hysterectomy’. As endometrial ablation is not supposed to compromise ovarian bloodflow, there would be no such change in ablated patients. Methods: Between January 1995 and April 1996, consecutive premenopausal patients with dysfunctional uterine bleeding who were scheduled for hysterectomy or endometrial ablation were asked to participate in the study. Bloodsamples were drawn before surgery, six weeks, six months and one year after surgery. FSH and oestradiol (E2) were assayed. In all patients data about length and weight were collected to calculate Body Mass Index (BMI). Every visit patients filled in a questionnaire, containing questions about typical climacteric complaints, combined in a five-point scale. Results: Except for a significant difference in preoperative FSH-level between both groups, there were no significant differences regarding age, Body Mass Index (BMI), oestradiol (E2) or the percentage of women with vasomotor complaints. Compared to the preoperative starting level, six weeks, six months and one year after surgery a significant rise in serum FSH in the hysterectomy group, as well as in the ablation group was found. However there was no significant difference in FSH increase between both groups. One third of the patients in both groups had typical climacteric complaints as flushing and nocturnal sweating. Conclusions: Assaying serum FSH-levels before and after uterine surgery and comparing hysterectomized patients and patients after endometrial ablation, we found a significant rise in FSH-level up to one year after surgery in both groups postoperatively, indicating impaired ovarian function. There was no difference in FSH-levels between both groups.Therefore major uterine surgery (hysterectomy, ablation) may prelude an earlier onset of menopause. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Hysterectomy; Endometrial ablation; Ovarian function; Menopause * Corresponding author. Tel.: +31 40 2588385; fax: +31 40 2588387. 0378-5122/98/$19.00 © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0378-5122(98)00018-8 134 J.G.M. Derksen et al. / Maturitas 29 (1998) 133–138 1. Introduction Hysterectomy is one of the most frequently performed major operations in Western countries. Common indications to perform a hysterectomy are uterine leiomyomas (30%), dysfunctional uterine bleeding (20%), endometriosis and adenomyosis (20%), genital prolaps (15%) and malignant conditions of the uterus [1]. The majority of the patients is premenopausal at the time of hysterectomy. In case of dysfunctional uterine bleeding alternative surgical treatments are available like hysteroscopic electroresection of the endometrium or other forms of ablative therapy. Endometrial ablation is considered to be a cost-effective therapy with satisfaction rates of 70 – 90%, while preserving the uterus [2]. Evidence that a simple hysterectomy may harm ovarian function is increasing but still circumstantial [3 – 8] and results are sometimes controversial [9,10]. Increased boneloss after premenopausal hysterectomy is reported [11] as well as cardiovascular disease [12], both conditions associated with ovarian failure. By blocking the circulation of the uterine vessels, hysterectomy can reduce ovarian bloodflow [13], which may result in loss of follicular reserve [7] and premature menopause [5]. Follicle stimulating hormone (FSH), being a gonadotropic hormone, is a marker of ovarian failure [14]. However most studies are cross-sectional [6,15] and longitudinal studies in hysterectomized patients are lacking. In this study the hypothesis was tested, that in premenopausal patients FSH would rise after ‘simple’ hysterectomy. As endometrial ablation is not supposed to harm ovarian bloodflow, there would be no such change in ablated patients. 2. Materials and methods Between January 1995 and April 1996 consecutive premenopausal patients with menstrual disorders (menorrhagia, dysmenorrhoea due to endometriosis, adenomyosis and leiomyomatosus) and genital prolaps who were scheduled for hysterectomy or endometrial ablation were asked to participate in our study. Ethical committee approval for research and written informed consent in all patients was obtained. The premenopause was defined by a regular menstrual cycle. Excluded were patients older than 49 years of age, patients with a preoperative FSH \ 15 IU/l and patients who had one or both ovaries removed in the past or in the present hysterectomy, e.g. women with malignant conditions of the uterus. All patients were operated on by the same surgical team, using similar operative techniques in the different procedures. In the hysterectomy group (n = 65) simple abdominal hysterectomy (n= 20), vaginal hysterectomy (n= 26), laparoscopically assisted vaginal hysterectomy (LAVH) (n= 13) and laparoscopically assisted supravaginal hysterectomy (LASH) (n= 6) were performed. In the group women treated with endometrial ablation (n= 23) electroresection of the endometrium (n = 5) and endometrial ablation with the hot fluid balloon (ThermaChoice, Gynaecare, CA) (n = 18) were performed. None of the entered patients received any type of steroid treatment in the postoperative period. Bloodsamples were drawn irrespective of the menstrual cycle before surgery, 6 weeks, 6 months, and 1 year after surgery. Follicle stimulating hormone (FSH) and oestradiol (E2) were assayed. FSH was measured in serum by an immunometric sandwich technique (Amerlite). The mean FSH-value and reference interval (9 2 standard deviations) in our laboratory for premenopausal women is 3.3 IU/l (0.7–7.9). The maximum value for the midcycle FSH-value is 12.3 IU/l. Oestradiol was measured with a direct radio-immunoassay technique (clinical assays). Simultaneously patients completed a questionnaire, containing questions addressing vasomotor complaints and vaginal dryness scored in a fivepoint scale according to Oldenhave [8]. These complaints were labeled ‘typical’ climacteric complaints. In all patients data were collected about length and weight to calculate the Body Mass Index (BMI). There were 109 patients, who entered the study. Due to drop out, which is explained in detail later, data of 88 patients were available for further analysis. J.G.M. Derksen et al. / Maturitas 29 (1998) 133–138 135 Table 1 Characterisitics in premenopausal patients in the hysterectomy group (n = 65) and the endometrial ablation group (n =23) Hysterectomy (n= 65) Age in years (S.D.) Body Mass Index (S.D.) Preop FSH IU/l (S.D.) Preop oestradiol (S.D.) Preop vasomotor symptoms Endometrial ablation (n =23) P 40.8 (4.2) 24.2 (4.4) 3.8 (2.4) 0.25 (0.24) 5/65 (8%) 40.6 (5.5) 24.1 (4.4) 4.8 (2.2) 0.30 (0.26) 2/23 (9%) NS** NS 0.03 * NS NS * After log transformation to normal probability plots. ** Not significant. 2.1. Statistics The data were analyzed statistically by the (Yates corrected) Chi-square test and t-test for independent or paired samples. Skewed data were transformed logarithmically to normal distributions (normal probability plot). A P value B 0.05 was considered to indicate statistically significant difference. 3. Results Between January 1995 and April 1996, 109 patients underwent hysterectomy or endometrial ablation and entered the study. In three patients, unexpected adnexal surgery, on ovarian or fallopian tube, was performed. In three patients, hysterectomy was performed because of persistent vaginal bloodloss after an ablative procedure within one year after the initial surgical procedure and 14 patients were lost to follow-up due to non responding. In 89 patients, the data in four points of time were complete. After exclusion of one patient with a preoperative FSH of 24 IU/l, the data of 88 patients were available for further analysis. There was a slight but statistically significant difference in preoperative FSH-levels between both groups. Age, Body Mass Index (BMI), oestradiol (E2) or the percentage of women with typical climacteric complaints was not statistically different between the groups (Table 1). Compared to the preoperative level, 6 weeks, 6 months and 1 year after surgery, a significant rise in serum FSH was found in the hysterectomy group, as well as in the ablation group (Fig. 1). Patients with a preoperative FSH-level \ 15 IU/l were excluded. Six weeks after surgery 10% (9/88) of the other women had a serum level FSH \ 15 IU/l, after 6 months 8% (7/88) and 1 year postoperatively 10% (9/88) (Table 2). These changes were not statistically different and did not differ according to the type of surgery. Less than half of the women with FSH-values more than 15 IU/l complained of flushing and sweating. Within the first half-year postoperatively, a significant rise in E2 was detected in the hysterectomy group. In the smaller ablation group, the same trend was seen but was not significant (Fig. 2). No differences in hormonal levels in the postoperative period between patients after hysterectomy and endometrial ablation could be detected. Power analysis shows that only a difference in FSH-level of 4 IU/l or more can be detected with a power (1-beta) of 80%, alpha being 95% in a sample of 90 patients. Although only patients with a preoperative FSH-level B 15.1 IU/l were included, 7.7% (5/65) in the hysterectomy group complained of moderate to severe flushing and sweating before operation. In the hysterectomy group these numbers were 6 weeks, 6 months and 1 year after surgery 7.7% (5/65), 17% (11/65) and 17% (11/65), in the ablation group 13% (3/23), 17.4% (4/23) and 8.7% (2/23), respectively. 4. Discussion In the current study in premenopausal patients, we found a statistically significant rise in serum- 136 J.G.M. Derksen et al. / Maturitas 29 (1998) 133–138 Fig. 1. Median FSH levels, 5, 25, 75, and 95 percentiles before and after hysterectomy with ovarian preservation and endometrial ablation. FSH levels of hysterectomized patients (n = 65) AB, AC, AD: PB0.01, CD: P B 0.05. Ablated patients (n = 23): AB, AC, AD: P B 0.05. t-Test after log-transformation to normal probability plot. FSH and E2 6 weeks, 6 months and 1 year after uterine surgery, comprising hysterectomy as well as endometrial ablation compared to preoperative values. From 6 weeks on serum-FSH- and E2-levels did not change significantly up to one year after surgery. An ‘acute effect’ on the ovaries left in situ within one week after simple hysterectomy, was already established in a longitudinal study [3]. After vaginal or abdominal hysterectomy a significant decrease in the peripheral levels of circulating steroids (E2 and progesterone) was seen, as well in the proliferative phase as in the luteal phase in comparison to the same measurements after a mere diagnostic laparoscopy. In most patients the decrease was more apparent in the second postoperative day and lasted for more than three days. However, serum FSH-levels, obtained daily, failed to show any significant short term change compared to preoperative values. In an other longitudinal study the sex-hormonal profile was assayed in premenopausal patients [16]. Patients who had both ovaries preserved at hysterectomy, were compared to patients, in whom a unilateral oophorectomy was performed at hysterectomy. Before the operation ovarian function was evaluated by measuring FSH, LH and E2. This was repeated at regular intervals until 6 months postoperatively. The ‘acute effect’ (decrease of E2 within the first week postoperatively) of hysterectomy on ovarian function was confirmed, but also a steady rise of the gonadotropins in the first half year after unilateral oophorectomy was shown. In patients with both ovaries preserved at hysterectomy, no such changes in gonadotropic hormones were seen. In cross-sectional studies hypergonadotropism was found in hysterectomized premenopausal women [6]. These findings were related to a higher incidence of climacteric symptoms after hysterectomy [8] and an earlier menopause [5]. In an elegant peroperative experiment, using a 133Xenon clearance technique in five women before and immediately after abdominal hysterectomy, Janson et al. could demonstrate an acute reduction of ovarian bloodflow, immediately after ligation of the uterine vessels [13]. He assumed this reduction in bloodflow was responsible for the ‘steroid drop’ after hysterectomy. In the current study a possible confounding effect of the high midcyclic FSH-values is ruled out by setting the cut-off level at 15 IU/l (Table 2). This value exceeds the maximum value in our laboratory for the midcycle peak level of FSH J.G.M. Derksen et al. / Maturitas 29 (1998) 133–138 137 Table 2 Patients with postoperative FSH levels up to 15 IU/l or more, according to type of surgery, as well as the portion of patients with vasomotor symptoms Time after surgery FSH \15 IU/l after hysterectomy (n= 65) FSH \15 IU/l after endometrial ablation (n =23) 6 Weeks (%) with VMSa (%) 6 Months (%) with VMS (%) 1 year (%) with VMS (%) 6/65 (10%) 1/6 (16%) 5/65 (8%) 0 7/65 (11%) 2/7 (28%) 3/23 (13%) 1/3 (33%) 2/23 (8.7%) 0 2/23 (8.7%) 1/2 (50%) a VMS, vasomotor symptoms. (12.3 IU/l). As all samples were randomly drawn in the menstrual cycle, it is unlikely that a larger proportion of women is midcyclic on three separate occasions after the operation — thus explaining the higher mean FSH levels — than before. An unexpected the finding was the equal rise of FSH level after the operation in both hysterectomized and ablated patients. A paracrine effect of the endometrium on the ovarium function, as seen in rabbits is often suggested, but never scientifically substantiated in humans. On the other hand, one can speculate, that also after endometrial ablation in some way the uterine and thereby the ovarian bloodflow is reduced, resulting in an ‘acute effect’, described by Stone [3]. To proof a relationship of uterine surgery and a rise of the FSH levels, participation of a control group without uterine surgery should be appropriate. How to explain the possible longer term effects of hysterectomy on the ovaries, which are clearly demonstrated in the pathological anatomical study of Souza et al. [7]. He biopsied the ovaries of premenopausal women during abdominal hysterectomy and one year later at laparoscopy. Besides thickening of the tunica albuginea and stromal hyperplasia, the ovarian histology one year after hysterectomy showed an impressive reduction of follicular reserve (standardized count at magnification of × 25 decreased from 7.8 to 1.0). As follicular depletion and a compromised Fig. 2. Median oestradiol (E2) levels 5, 25, 75, and 95 percentiles before and after uterine surgery. E2 levels of hysterectomized patients (n = 65): AB, AC: PB 0.05. AD: P= 0.08. Changes in E2-levels of ablated patients (n = 23) were not significant. t-Test after log-transformation to normal probability plot. 138 J.G.M. Derksen et al. / Maturitas 29 (1998) 133–138 ovarian response can stimulate the hypophysis to produce FSH (which explains the rise of FSH-levels), FSH itself may stimulate a greater proportion of the primordial follicles entering the growing pool, as is demonstrated in rats [17], resulting in higher E2-levels. This autocatalytic process accelerates follicular depletion and results ultimately in ovarian exhaustion and declining E2-levels. It is therefore plausible that a postoperative rise in FSH-levels is associated with earlier menopause. In the current study, 11% (7/65) and 9% (2/23) of the patients 1 year after hysterectomy and endometrial ablation, respectively, had FSH-levels \ 15 IU/l, showing declining follicular reserve. Only one third of them had typical climacteric complaints as flushing and sweating. The missing correlation between hormone values and the presence or severity of vasomotor complaints is well established [8]. Bearing in mind the increased risk of ostopenia and cardiovascular disease after hysterectomy and the absence of the climacteric signal of irregular menses, a prospective study of the possible benefits of hormonal screening after premenopausal hysterectomy and, in case of amenorrhoea, after premenopausal endometrial ablation is recommended. 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