1 Department of Obstetrics and Gynecology, Central Hospital of Päijät-Häme, Keskussairaalankatu 7, 15850 Lahti, 2 Department of Obstetrics and Gynecology, University of Helsinki and Health Services Research Unit, Stakes, Lintulahdenkuja 4, PL 220, 00531 Helsinki, 3 Department of Obstetrics and Gynecology, University of Helsinki, Haartmaninkatu 2, 00290 Helsinki, 4 Health Services Research Unit, Stakes, Lintulahdenkuja 4, PL 220, 00531 Helsinki, 5 Department of Obstetrics and Gynecology, University of Turku, Kiinanmyllynkatu 48, 20520 Turku, 6 Department of Obstetrics and Gynecology, University of Oulu, Oulun yliopistollinen keskussairaala, PL22, 90221 Oulu, 7 Department of Obstetrics and Gynecology, University of Tampere, Tampereen yliopistollinen keskussairaala, PL 2000, 33521 Tampere and 8 Department of Obstetrics and Gynecology, University of Kuopio, Kuopion yliopistollinen sairaala, PL 1777, 70211 Kuopio, Finland
9 To whom correspondence should be addressed. e-mail: halmesma{at}mappi.helsinki.fi
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Abstract |
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Key words: FSH/hot flushes/hysterectomy/levonorgestrel-releasing intrauterine system/menopausal symptoms
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Introduction |
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The levonorgestrel-releasing intrauterine system (LNG-IUS) has recently been advocated as an effective alternative to hysterectomy in the treatment of menorrhagia (Lähteenmäki et al., 1998; Hurskainen et al., 2001
). Studies with LNG-IUS on ovarian function show only a minimal effect (Nilsson et al., 1984
; Söderström-Anttila et al., 1997
). However, none of the studies has compared hysterectomy and LNG-IUS in terms of the effect on FSH levels or menopausal symptoms.
We performed a randomized controlled trial to compare ovarian function and menopausal symptoms among women with menorrhagia who had been randomized to treatment with hysterectomy or LNG-IUS.
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Materials and methods |
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LNG-IUS (Mirena, Leiras Co., Turku, Finland) was inserted during the randomization visit. Hysterectomy was performed abdominally, vaginally or laparoscopically at the discretion of the physician. The follow-up visits took place 6 and 12 months after hysterectomy or application of the LNG-IUS.
The study was approved by the Ethics Committees of all university hospitals and STAKES (National Research and Development Center for Welfare and Health).
Questionnaire
All women completed a questionnaire including information on body mass index (BMI), smoking, method of contraception and menopausal symptoms at the randomization visit and 6 and 12 months after the treatment. The Kupperman test of menopausal distress was used to measure menopausal symptoms (Kupperman et al., 1959). It is a 10-item questionnaire of hot flushes, sweating, insomnia, nervousness, melancholia, vertigo, weakness, pain, headache and palpitation. The scores range from 0 to 3 (none, mild, moderate and severe). The Kupperman index was calculated as reported (Kupperman et al., 1959
).
Laboratory investigations
Serum FSH and estradiol levels were measured at baseline and 6 and 12 months later. Baselines of all the blood samples were measured at the early follicular phase (period days 17). FSH levels were measured by an immunofluorometric method (Wallac, Turku, Finland). Serum estradiol concentrations were measured from a subgroup of 100 women at Helsinki University Central Hospital by using a 125I-RIA kit (DPC Corporation, Los Angeles, CA).
Statistical analysis
All analyses were performed according to the intention-to-treat principle unless otherwise indicated. Students t-test for independent samples and Wilcoxon test were used to test differences in main outcomes between the groups pre- and post-treatment. Changes in outcome measures within the groups were tested by paired sample t-test and signed rank test. A multiple regression model was used to test association between FSH levels and explaining factors and between Kupperman test variables and explaining factors. The variable of the Kupperman test was added in dichotomized form, and potential explaining factors either in continuous (BMI and age) or dichotomized form (treatment modality, smoking and sterilization). Probability values 0.05 were considered significant.
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Results |
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In the hysterectomy group, serum FSH increased from 8.4 ± 0.6 IU/ml (mean ± SEM) to 9.2 ± 1.0 IU/ml at 6 months and to 13.8 ± 1.9 IU/ml at 12 months post-operatively. The corresponding figures in the LNG-IUS group were 8.7 ± 0.8, 8.4 ± 1.1 and 9.2 ± 1.0 IU/ml, respectively (Figure 1). Within the groups, the increase of serum FSH was significant after 12 months (P = 0.001). Serum FSH was significantly higher in the hysterectomy group at the 12 month follow-up visit (P = 0.005). Surgical technique did not influence FSH levels (data not shown). Regression analysis showed significant association between FSH levels and age (P = 0.001) and treatment modality (P = 0.020). We also analysed the results by age by looking seperately at women <43 years old versus those 43 years old. Among younger women, FSH decreased (1.9 ± 0.5 IU/ml) in the LNG-IUS group and increased (1.5 ± 1.5 IU/ml) in the hysterectomy group. Among older women, the corresponding changes were an increase of 1.3 ± 1.4 IU/ml and an increase of 8.0 ± 2.3 IU/ml. In both groups, the difference between younger and older women was significant (P = 0.04 and P = 0.01, respectively). There were no significant differences between the groups in serum estradiol levels (mean 30 ± 0.02 pg/ml in the LNG-IUS group and 28 ± 0.02 pg/ml in the hysterectomy group) at 12 months follow-up.
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After 12 months follow-up, the total Kupperman index did not change either within or between the groups. However, in both groups, there was a significant improvement in insomnia (P = 0.001 in the hysterectomy and P = 0.03 in the LNG-IUS group), palpitations (P = 0.01 in the hysterectomy and P = 0.02 in the LNG-IUS group), melancholia (P = 0.03 in the hysterectomy and P = 0.02 in the LNG-IUS group), weakness (P = 0.0001 in both groups), vertigo (P = 0.03 in the hysterectomy and P = 0.0002 in the LNG-IUS group), pain in muscles (P = 0.0001 in both groups), and deterioration in nervousness (P = 0.0001 in the hysterectomy and P = 0.04 in the LNG-IUS group) and headache (P = 0.0001 in both groups) (Table II). No difference was shown between the groups, except that pain (P = 0.03) and headache (P = 0.01) were more common in the LNG-IUS group at 12 months follow-up (Table II). Hot flushes increased significantly among hysterectomized women (P = 0.02) but not among LNG-IUS users (P = 0.95) during 12 months follow-up, but there was no significant difference between the groups (P = 0.16) (Table II). Logistic regression analysis for variables showed association between hot flushes and treatment modality [odds ratio (OR) 3.5, confidence interval (CI) 1.279.50] and age (OR 1.24, CI 1.041.42), and between pain and treatment modality (OR 1.7, CI 1.062.88).
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Discussion |
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Early small studies have found no significant changes in ovarian function after hysterectomy (DeNeef and Hollenbeck, 1966; Beavis et al., 1969
; Ranney and AbuGhazaleh, 1977
). However, due to limitations of the study designs, no firm conclusions can be drawn from these studies.
Subsequent studies have shown that both menopausal hormone profile and climacteric symptoms develop earlier after hysterectomy compared with controls without hysterectomy (Riedel et al., 1986; Menon et al., 1987
; Siddle et al., 1987
; Kaiser et al., 1989
; Oldenhave et al., 1993
; Hartmann et al., 1995
; Derksen et al., 1998
; Cooper and Thorp, 1999
; Stadberg et al., 2000
). The younger the age at hysterectomy, the more severe were the symptoms (Siddle et al., 1987
; Kaiser et al., 1989
; Oldenhave et al., 1993
). However, it has been difficult to rule out selection bias since none of the studies have been randomized. Even if control groups were included, confounding factors have been difficult to rule out (Siddle et al., 1987
; Kaiser et al., 1989
). Our results are in accordance with these studies suggesting that hysterectomy impairs ovarian function. In the current randomized study, the effect of key confounding factors such as age, parity, BMI, smoking and history of sterilization could be eliminated.
The mechanism by which simple hysterectomy impairs ovarian function remains unclear. According to one theory, diminished arterial blood flow leads to increased intercellular congestion and oedema, which may result in stromal cell hyperplasia, thickening of the tunica albuginea, a significant decrease in follicular reserve of the ovaries, and endocrinological disturbances (Souza et al., 1986). Ovaries produce less inhibins which is seen as a rise in the FSH level (Muttukrishna et al., 2002
). The vascular theory is also supported by reports suggesting ovarian dysfunction after uterine artery embolization (Payne et al., 2002
; Tulandi et al., 2002
).
Another theory suggests an interaction between the endometrium and the ovaries. Accordingly, the balance between ovaries and endometrium is changed, which may affect the ovarypituitary gland axis. This may explain the report of the rise of serum FSH level after both hysterectomy and endometrial ablation (Derksen et al., 1998).
In the current study, the effect of hysterectomy on menopausal symptoms and hormonal changes was compared with that in women using LNG-IUS. In LNG-IUS users, low serum concentrations of LNG have only a weak effect on ovarian function; after the first year of use, 85% of all menstrual cycles are ovulatory according to serum progesterone concentrations (Nilsson et al., 1984). Ovaries of LNG-IUS users respond similarly to gonadotrophin stimulation compared with non-users. Oocyte maturation remains unaffected (Söderström-Anttila et al., 1997
) and systemic side effects are rare (Barbosa et al., 1990
; Ronnerdag and Odlind, 1999
). In this study, the FSH levels in the serum increased 4% among LNG-IUS users. An equal rise in FSH is seen among women of similar age with normal reproductive health (Burger et al., 1999
; Erdem et al., 2002
).
Cooper and Thorp (1999) reported that smoking increases serum FSH levels twice as much as hysterectomy. Our study does not support this. Regression analysis revealed no correlation between smoking and serum FSH levels. Probably smoking must be heavy to affect FSH. As only 12% smoked >10 cigarettes per day in our study, it has no effect on FSH levels. Blood samples for the measurement of FSH 6 and 12 months after the treatment were not adjusted according to the menstrual cycle in either group since many of the patients had amennorhea or irregular light bleeding. This may have introduced a systematic bias to the detection of the increased FSH levels, although this is unlikely since this was the case in both groups. The Kupperman test of menopausal distress was developed to measure symptoms in menopausal women. Among the premenopausal women included in the study, the Kupperman index may have been too insensitive to show minor differences between the groups. Some of the symptoms measured, such as vertigo, headache or muscle pain, probably have origins other than menopause. The study is limited by the relatively small number of patients, short duration of follow-up and the single hormone assays. Rising serum FSH levels in the hysterectomy group occurred mainly during the last 6 months of follow-up, showing that it is important to expand the observation period.
In summary, the present study suggests that hysterectomy may impair ovarian function, as seen by rising FSH levels and increasing incidence of menopausal symptoms. Since hysterectomy is a common treatment modality for a benign disease, it is important to remember that the long-term effects of hysterectomy may include impaired ovarian function.
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Submitted on May 29, 2003; accepted on September 26, 2003.