Hysterectomy versus GnRH agonist for dysfunctional uterine bleeding in premenopausal women

Dysfunctional uterine bleeding (DUB) in premenopausal women is a common problem leading to medical or surgical intervention. The aim of this study was to compare GnRH agonist and hysterectomy in treatment of DUB in premenopausal women. In a randomized clinical trial, 250 patients of age, 40 to 55 years with complaint of abnormal uterine bleeding resistant to routine medications were enrolled into the study. Ninety seven patients after ruling out organic, was randomized to receive either hysterectomy or 4 doses of diphereline. Two groups followed up 6 and 24 months after intervention. From 97 patients, 85 accomplished the study. Bleeding stopped in 91.8% of patients after 2nd dose of diphereline, which is beyond 6 and 24 months, 73.33 and 40.9% had amenorrhea, respectively. There were no significant differences between two groups in pelvic pain, mastalgia, sleep disorders, sexual function, stress incontinence and urgency after 2 years follow up. Low back pain, urinary frequency and depression were significantly higher in patients that underwent hysterectomy (P = 0.03, P = 0.03 and P < 0.001, respectively). There was more satisfaction of treatment (67.5% versus 44.4%, P = 0.004) and better quality of life after 2 years (34.1% versus 16.7%, P = 0.08) in diphereline group. GnRH agonist is an appropriate alternative to hysterectomy for treatment of DUB in premenopausal women.


INTRODUCTION
About 600000 women in the USA undergo hysterectomy in a year, and this procedure has become one of the most common major surgeries in this country (Farquhar and Steiner, 2002;Carlson et al., 1994).Hysterectomy is frequently performed in premenopausal women for abnormal uterine bleeding (AUB) (Showstack et al., 2006;Munro, 2001).
The first therapeutic approach for AUB is medical therapy, such as progestines, combined estrogen and progesterone, prostaglandin synthetase inhibitors and antifibrinolytics.
Since medical therapy can not always resolve the problem and on the other hand may be associated with complications, so, hysterectomy is recommended as an absolute solution (Showstack et al., 2006).Hysterectomy for treatment of AUB is a very effective method, and postoperative mortality and morbidity is relatively low (Myers and Steege, 1999).Although, long term complications after this surgery have not been completely assessed, some disorders, such as chronic pelvic pain, lower urinary tract dysfunction, pelvic relaxation, sexual dysfunction, psychologic problems and even ovarian failure have been reported (Brown et al., 2000;Rolnick et al., 2001;Cooper et al., 1997;Broder et al., 2000).
However, recent studies have noted improvement in quality of life and sexual function after hysterectomy (Showstack et al., 2006;Rolnick et al., 2001;Kuppermann et al., 2004;Learman et al., 2004;Bongers et al., 2004).Medical treatments often affect endometrium and cause vascular contraction.Break through bleeding is a side effect of some drugs which leads to discontinuation of treatment by patient.GnRH agonists have been used for treatment of AUB.Down regulation of GnRH receptors results in hypogonadism condition which stops bleeding.We designed a clinical trial to compare the effects of medical therapy versus hysterectomy in premenopausal women suffering from abnormal uterine bleeding.

MATERIALS AND METHODS
In a randomized clinical trial 250 patients with AUB that were referred to Alzahra Teaching Hospital from 2009 to 2010 were recruited into this study.Inclusion criteria were premenopausal women of age 40 to 55 years with at least 6 months AUB which was defined as menstrual bleeding longer than 7 days or heavy bleeding leaded to anemia (Hct < 32%), ruling out endometrial carcinoma or atypical hyperplasia by dilation and curettage (D&C), not responding to routine medications like medroxy progesterone acetate, or combined oral contraceptives, tranexamic acid and nonsteroidal anti-inflammatory drugs (NSAIDS) and ruling out organic disorders of uterus and ovaries by ultrasonography.Patients who were anemic for other reasons, desired to preserve fertility, suspected current pregnancy and had endocrinopathy, coagulopathy or contraindication for receiving GnRH agonist excluded from the study.For 250 eligible patients, blood tests including βhCG, Hb, Hct, Plt count, PT, PTT, TSH, prolactin, fasting blood sugar (FBS) and creatinin, ultrasonography and D&C were performed.Ninety seven patients who required inclusion criteria enrolled into the study and after taking written informed consent, randomized to two groups, hysterectomy versus GnRH agonist.Forty eight patients underwent total abdominal hysterectomy ± salpyngo-oophorectomy (TAH ± BSO) and 49 patients received diphereline 3.75 mg intramuscular (IM) every 28 days until 4 doses.A questionnaire filled out before intervention, 6 and 24 months after intervention.For assessment of quality of life, standard WHOQOL questionnaire was used.For prevention of vasomotor symptoms and osteoporosis in patients in diphereline group and those that received TAH ± BSO ordered to take fluoxetine capsule 20 mg daily, alendronate tablet 70 mg weekly and calcium-D tablet 500 mg BID.Data were analyzed by SPSS.15 software using statistical tests such as t-test, chi-square and ANOVA.P value < 0.05 was considered significant.

RESULTS
From 97 patients enrolled into the study, 85 accomplished the study (Figure 1).According to the results of this study, there were no significant differences between two groups in age, education, monthly income, parity, contraception method, endometrial thickness, amount and duration of menstrual bleeding, mean hematocrit (Hct) and mean body mass index (BMI) at entry to the study (Table 1).
Bleeding stopped in 91.83% and mostly decreased in 8.16% of patients after second dose of diphereline.After 6 months follow up, 73.33% of patients in drug group had amenorrhea, 11.11% declined bleeding and in 15.55% the pattern of bleeding had not changed.Two years after drug therapy, from 44 patients who accomplished the study, 18 (40.9%)had amenorrhea, 15 (34.09%) decreased bleeding, 4 (9.09%)abnormal bleeding and 7 (15.9%)underwent hysterectomy.Some amenorrheic patients (18.5%) regained bleeding 8 ± 2 weeks after last dose of diphereline.Endometrial thickness significantly decreased after using GnRH agonist (6.57± 2.11 mm after 6 month, P = 0.002 and 6 ± 3.42 mm after 24 m, P = 0.001).Although, pelvic and limbs pain were not significantly different between two groups, low back pain was higher in hysterectomized patients (P = 0.03).
Comparison of symptoms between two groups during 2 years follow up has been summarized in Table 2.
Sexual desire and satisfaction did not differ between groups after 6 and 24 months (P > 0.05).The cost for hysterectomy was at least 4 times the medical therapy (P < 0.001).
There was more satisfaction of treatment after 2 years in GnRH agonist group (67.5% versus 44.4%; P = 0.004).
The patients that received medical therapy had better quality of life after 2 years (34.1% versus 16.7%; P = 0.08).

DISCUSSION
The prevalence of AUB in general population is about 11 to 13% and rises to 24% in about 36 to 40 years.Different medical therapies including levonorgestrel releasing intrauterine device (IUD), tranexamic acid, progestins, combined oral contraceptive pill (OCP), NSAIDS, danazol and GnRH agonist have been effective for treatment of DUB (Marret et al., 2010).Surgical treatment has been recommended in failed medical therapy which conservative method like endometrial ablation or hysterectomy can be used.Although, Bongers et al. (2004) reported tranexamic acid as the most effective medical therapy for DUB, Marret et al. (2010) showed higher ranking for levonorgestrel IUD and advised tranexamic acid to be used when hormonal therapy is contraindicated or immediate pregnancy is desired (Bongers et al., 2004;Marret et al., 2010).However, hysterectomy is not advocated as first-line therapy for DUB (Marret et al., 2010).One hundred and fifty premenopausal women with DUB unresponsive to usual medical treatment randomized to receive either a hysterectomy or GnRH agonist.We used diphereline as a GnRH agonist in this study.This drug is prepared with lyophilization mechanism to keep in room temperature.It lacks allergens like dexteran and does not make disturbing spotting similar to progestins or combined oral contraceptives.Besides, it has no side effects on serum lipoproteins, such as high dose progestins.The stimulatory effect is observed 24 h after the first injection, mean plasmatic concentrations of estradiol, LH and FSH increase significantly.At subsequent injections, they will be consistently suppressed, showing hypogonadal levels.
Regarding the premenopausal age of patients and the ability of developing medical menopause by diphereline, we chose this drug as an alternative therapy for hysterectomy.Most of the previous studies which compared medical treatments such as medroxy progesterone acetate, anti-fibrinolytic tranexamic acid, non-steroidal anti-inflamatory drugs, levonorgestrel releasing IUD and the combined oral contraceptive with hysterectomy concluded that hysterectomy in spite of high complication rate is a preferable approach for resolving clinical symptoms and is associated with a high satisfaction rate and good quality of life (Showstack et al., 2006;Rolinck et al., 2001;Kuppermann et al., 2004;Learman et al., 2004;Bongers et al., 2004).Learman et al. (2004) in a clinical trial compared clinical outcome after hysterectomy or expanded medical treatment and after 6 months follow up of 63 premenopausal women with AUB found out greater symptom improvement in the hysterectomy group than medical group for pelvic pain (P < 0.01), urinary urgency (P = 0.03), incomplete bladder emptying (P = 0.03), breast pain (P = 0.02) and cessation of vaginal bleeding (87% versus 11%, P < 0.001) (Learman et al., 2004).In the present study, the rate of pelvic limbs and breast pain, urgency, stress incontinence and sleep disorders did not significantly differ between two groups, but greater improvement in low back pain (P = 0.03), urinary frequency (P = 0.03) and depression (P < 0.001) was observed in diphereline group.Kuppermann et al. (2004) reported similar results to Learman et al. (2004)  = 0.04) and overall health (12 versus 2, P = 0.006) (Kuppermann et al., 2004).Varner et al. (2004) and Marjoribanks et al. (2006) reported that surgical treatment in first one year has better control of clinical symptoms than oral hormonal drugs and has less side effects and costs, whereas we could not show significant difference between studied groups in quality of life and sexual satisfaction.Carlson et al. (1994) showed that 6.6% of women who perform hysterectomy does not obtain favorite results and may experience pain and depression.In the present study 47.7% versus 35.5% of patients, 6 months after hysterectomy or medical therapy and 31.7%versus 15.9% after two years experienced depression (P < 0.001).The rate of satisfaction of hysterectomy for non malignant reasons in first year after surgery has been reported to be 21.4 to 63.9% (Kuppermann et al., 2010).Improvement of sexual function following elective hysterectomy for DUB has been indicated in the most of the women which was higher in vaginal than abdominal hysterectomy (Maas et al., 2003;Peterson et al., 2010).
Post hysterectomy depression and sexual dysfunction has been significantly related to psychosocial condition and sexual function before surgery.Also, preserving or removing ovaries during hysterectomy could affect sexual functioning (Maas et al., 2003).Showstack et al. (2006) and Rolinck (2001) in a randomized clinical trial compared medical therapy with hysterectomy and in one year follow up reported high costs for surgery, and 43% of patients who received medical therapy finally underwent hysterectomy which was only 15.9% in the current study.In contrast to our study, they stated surgical therapy improves quality of life more than medical therapy.
According to our results, there was no significant difference between hysterectomy and diphereline groups in the majority of clinical symptoms in short and long terms follow up, and even urinary symptoms have been greatly improved in medical therapy group.The patients' satisfaction of treatment and quality of life were greater in diphereline group after 2 years.

Conclusion
It seems that GnRH agonist is a comparable alternative for hysterectomy in management of refractory dysfunctional uterine bleeding in premenopausal women.

Figure 1 .
Figure 1.The CONSORT flow chart of participants.

Table 1 .
Basic characteristics of studied groups at entry to the study.

Table 2 .
Comparison of symptoms between two studied groups.