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  • 1. Single or repeated gonadotropin-releasing hormone agonist treatment avoids hysterectomy in premenopausal women with large symptomatic fibroids with no effects on sexual function Anna Myriam Perrone1 , Federica Pozzati1 , Barbara Di Marcoberardino1 , Martina Rossi1 , Martina Procaccini1 , Alice Pellegrini1 , Donatella Santini2 and Pierandrea De Iaco1 1 Unit of Oncologic Gynaecology and 2 Unit of Pathology, S. Orsola-Malpighi Hospital, Bologna, Italy Abstract Aim: The aim of our study was to explore the effects on symptoms and female sexual function of the medical management with gonadotropin-releasing hormone agonist (GnRHa) in women of more than 45 years old compared to surgical management. Methods: Women with symptomatic uterine fibroids were enrolled to participate to the present open-label study. We offered two different treatment options: medical with GnRHa for 6 months (group A) or hysterec- tomy (group B). The patients were reviewed in follow-up for 24 months. The impact of medical or surgical therapy on sexual life was evaluated. Results: No significant differences were found in population characteristics between the two groups. GnRHa treatment was efficient in reducing symptoms in 88% of patients but 22% of patients needed adjunctive cycles of medical therapy. After 24 months, 16% of the patients did not complete the study. The failure percentage of the medical treatment was 12%. No severe side-effects were recorded, and eight patients had reached meno- pause. No significant differences were observed in the Female Sexual Function Index score in each domain between the medical and surgical groups, with total scores of 18.94 Ϯ 10.16 and 22.00 Ϯ 8.86, respectively (mean Ϯ standard deviation), and the prevalence of dysfunction was 12% and 22%, respectively, similar to the general population of the same age. Conclusion: We found that medical therapy with GnRHa is a satisfactory alternative to surgery for fibroids in women of more than 45 years old. Key words: fibroids, GnRHa, medical treatment, peri-menopausal women, surgery. Introduction Uterine fibroids are benign monoclonal tumors of the smooth muscle cells of the myometrium most common in premenopausal women.1 These tumors are estrogen dependent, developed during the reproductive period, and are suppressed with menopause.2 Traditional treat- ments for symptomatic fibroids involve various types of surgical techniques (myomectomy and hysterec- tomy). Generally, myomectomy is the preferred Received: November 19 2012. Accepted: March 25 2013. Reprint request to: Dr Anna Myriam Perrone, Unit of Oncologic Gynaecology, S. Orsola-Malpighi Hospital, via Massarenti 13, 40138 Bologna, Italy. Email: Conflict of interest: The authors declare no conflict of interest. bs_bs_banner doi:10.1111/jog.12135 J. Obstet. Gynaecol. Res. Vol. 40, No. 1: 117–124, January 2014 © 2013 The Authors 117 Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology
  • 2. approach in young women who want to preserve their fertility whereas hysterectomy is generally proposed in perimenopausal women.3,4 Recently, medical management, androgens, anti- progestogens, raloxifene and gonadotropin-releasing hormone agonist (GnRHa) and antagonist is an attrac- tive strategy for many gynecologists in the manage- ment of uterine fibroids.5–10 These drugs have some advantages when compared with surgery as they are easily administrated and lack postoperative complica- tions (pelvic organ adhesion, postoperative bleeding and pain), but published work reports a high recur- rence rate 6–12 months after discontinuation of treatment.11–14 Due to the high relapse rate, medical therapy does not appear to represent a definitive choice in young patients with symptomatic uterine fibroids, but in women who are near menopausal status (age Ն45 years, defined as perimenopausal) medical treatment may be definitive and the patients may avoid hysterectomy.15 Among the drugs currently used for uterine fibro- matosis, GnRHa appear to be the most effective in the shortest time, but the use is limited in time by side- effects related to hypoestrogenism as vasomotor insta- bility, vaginal dryness and bone loss, which preclude the long-term use of these compounds.16 Only one study has evaluated the possibility that after 45 years some perimenopausal women may transit to natural menopause in an unexpectedly short period, and waiting for menopause, medical therapy may avoid hysterectomy.15 The use of a GnRHa in premenopausal women may be one of the best choices for three prin- cipal reasons: (i) it is the most effective drug in control- ling uterine bleeding and in reducing the volume of fibroids; (ii) there is the possibility of administration of GnRHa for short period of time; and (iii) the possibility to repeat administration after a period free from treatment. Bleeding and other symptoms related to fibroids can compromise women’s sexuality.17,18 Few studies have explored the effects of uterine fibroids on female sexual function. Some authors found an increased prevalence and incidence of dyspareunia and non-cyclic pelvic pain19 but others do not confirm this data.20 Some studies report the impact of pelvic surgery and hypoestrogenism on sexual function,21–24 but no data has evaluated the effects of GnRHa treatment for fibroid on sexual function in perimenopausal women. The aim of our study was to explore the effective- ness, limitations and female sexual function effects of the conservative medical management with GnRHa in perimenopausal women aged 45 years or older with symptomatic fibroids compared to the surgical approach (hysterectomy). Methods Between 2005 and 2009, among women with aged 45 years or older with symptomatic uterine fibroids that had been referred to our center to be scheduled for hysterectomy, we invited 100 consecutive patients to participate in the present open-label study: some patients received medical treatment with depot GnRHa (group A) and the others received surgical manage- ment (group B). The study was approved by the local ethics committee and all patients signed an informed consent. Inclusion criteria were: the presence of one or more intramural/subserosal, intramural, intramural/ submucosal, submucosal fibroids larger than 4 cm, and symptoms such as abnormal uterine bleeding, anemia (Յ12 g/dL), pelvic pain, compression syndrome and bulge-like sensation, urinary or intestinal symptoms. The number of fibroids was not an exclusion criteria. The group A patients agreed to i.m. GnRHa every 90 days (leuprolide acetate 11.25 mg; Takeda Pharmaceu- ticals, Osaka, Japan) for at least 6 months. The group B patients were submitted to hysterectomy by laparo- scopic or laparotomic route according to the surgeon’s experience and the uterine volume. All patients agreed to be evaluated for a period of 2 years. Exclusion criteria were: small submucosal fibroid with uterine longitudinal diameter of 20 cm or more, malignancies, chronic disease such as diabetes and renal failure, interstitial cystitis, irritable bowel syn- drome, endometriosis and antidepressant medications known to affect sexual function. At baseline, the patients were submitted to physical examination and pelvic transvaginal ultrasound. Symptom assessment such menorrhagia, pain, com- pression syndrome and a bulge-like sensation were measured using a 4-point scale: 0, none; 1, mild; 2, moderate; and 3, severe symptoms. The volume of the largest fibroid was calculated by measuring the three main diameters (D1, D2, D3) and applying the formula of the ellipsoid (length ¥ height ¥ width ¥ 0.52). Group A patients were reviewed at 6, 12 and 24 months after GnRHa administration, and any medical or surgical treatment or the need for repeated use of GnRHa treatment were recorded. Failure of the medical treatment included: (i) the need for hysterec- tomy or myomectomy; and (ii) discontinuation of A. M. Perrone et al. 118 © 2013 The Authors Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology
  • 3. GnRHa treatment (treatment for <6 months) due to poor patient compliance or complications. To evaluate the impact of the medical and surgical therapy on sexual life, patients were interviewed about their sexual activity 24 months after treatment. We administrated validated questionnaires to both groups (A and B) to evaluate sexual function and sexual dis- tress related to sexual activity: the Female Sexual Func- tion Index (FSFI)25,26 and the Female Sexual Distress Scale (FSDS).27,28 All patients were interviewed about their sexuality before the treatment. Sexually inactive patients were asked to state the reason for their inac- tivity and were not included in the final analysis.27,28 Statistical analysis All continuous data are expressed in terms of mean and standard deviation of the mean and range. Unpaired Student’s t-test was performed to investigate continuous variable differences between the groups. Pearson’s c2 -test, calculated by the Monte Carlo method, was performed to investigate the relationships between grouping variables. For all tests, P < 0.05 was considered significant. Statistical analysis was carried out by means of the Statistical Package for the Social Sciences software ver. 9.0. Results Characteristics of the two groups at baseline The characteristics of the population (groups A and B) are shown in Tables 1 and 2. No significant differences were found between the two groups in the severity of symptoms, except for mild bulge-like sensation which was more common in group B (P < 0.05). First follow-up after 6 months of medical treatment Forty-six out of 50 patients (92%) completed medical treatment with GnRHa injection for at least 6 months without additional hormonal supplement. Vaginal spotting was noted in 26 of the patients (57%) after the first injection and 35 (76%) were in amenorrhea after the second dose. Hemoglobin (Hb) levels and symp- toms such menorrhagia, pain and bulge-like sensations decreased significantly and a 53% reduction in fibroids volume from baseline was noted in this group after 6 months of therapy (Table 3). Four patients did not complete the treatment: two (4%) were lost to follow-up, while two (4%) interrupted GnRHa treatment after the first dose because of climacteric symptoms, refused add-back therapy and required hysterectomy. Apart from these patients, the menopausal symptoms induced by GnRHa treatment, as hot flashes, sweating and headaches (in 40%, 10% and 22% of women, respectively) were well tolerated. Second follow-up after 12 months of medical treatment Ten out of 46 (22%) patients required a second cycle of GnRHa because of recurrence of mild and moderate menorrhagia. Adjunctive medical treatments such as tranexamic acid and progestins were administrated in eight out of 46 (17%) patients. Fourteen out of 46 (30%) were in amenorrhea (10 patients received the second cycle of GnRHa treatment). Hb levels and the intensity of symptoms such menorrhagia, pain and bulge-like sensations were similar to those reported at first follow-up (Table 3). One patient was submitted to hys- terectomy because the severe menorrhagia was not Table 1 Population characteristics Baseline Group A Group B P Mean Ϯ SD n (%) Mean Ϯ SD n (%) Age (years) 48.7 Ϯ 3.2 — 49.5 Ϯ 2.0 — ns Body mass index (kg/m2 ) 27.7 Ϯ 5.3 — 28.2 Ϯ 2.0 — ns Parity 0 — 17/50 (34) — 15/50 (30) ns 1 — 19/50 (38) — 21/50 (42) ns 2 — 14/50 (28) — 12/50 (24) ns Ն3 — — — 2/50 (4) ns Baseline hemoglobin level (g/dL) 9.5 Ϯ 1.5 — 9.8 Ϯ 2.0 — ns P Յ 0.05 Student’s t-test. Group A, leuprolide treatment; group B, surgical treatment (hys- terectomy). ns, not significant; SD, standard deviation. GnRHa uterine fibroid treatment and sexual function © 2013 The Authors 119 Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology
  • 4. Table 2 Severity of symptoms and fibroids characteristic in the two groups. Data are presented as number or percentage (%) Symptoms Group A Group B P n (%) n (%) Pain 20/50 (40) 25/50 (50) ns Mild 17/20 (85) 18/25 (72) ns Moderate 3/20 (15) 6/25 (24) ns Severe 0 1/25 (4) ns Menorrhagia 45/50 (90) 49/50 (98) ns Mild 13/45 (29) 15/49 (31) ns Moderate 14/45 (31) 15/49 (31) ns Severe 18/45 (40) 19/49 (38) ns Bulge-like sensation 14/50 (28) 17/50 (34) ns Mild 3/14 (21) 6/17 (35) <0.05 Moderate 5/14 (36) 6/17 (35) ns Severe 6/14 (43) 5/17 (30) ns Volume of larger fibroid 427.46 Ϯ 293.05 460.33263.03 ns No. of fibroids for each patient 1 18/50 (36) 15/50 (30) ns 2 10/50 (20) 15/50 (30) ns Ն3 22/50 (44) 20/50 (40) ns Location of fibroids for each patient Subserosal 0 0 ns Intramural/subserosal 15/50 (30) 14/50 (28) ns Intramural 17/50 (34) 18/50 (36) ns Intramural/submucosal 13/50 (26) 12/50 (24) ns Submucosal 5/50 (10) 6/50 (12) ns P Յ 0.05 t-test. Group A, leuprolide treatment; group B, surgical treatment (hysterectomy). ns, not significant Table 3 Characteristics of patients submitted to leuprolide treatment during follow-up Clinical parameters Baseline First follow-up Second follow-up Third follow-up 0 months 6 months 12 months 24 months Mean Ϯ SD Mean Ϯ SD Mean Ϯ SD Mean Ϯ SD Hemoglobin level (g/dL) 9.16 Ϯ 2.18 12.87 Ϯ 0.55* 11.22 Ϯ 0.22* 11.16 Ϯ 0.27* Volume of larger myoma cm3 427.46 Ϯ 293.05 201.35 Ϯ 172.88* 224.00 Ϯ 154.03* 218.05 Ϯ 135.02* Symptoms n (%) n (%) n (%) n (%) Pain 20/50 (40) 10/46 (22)* 09/45 (20)* 6/42 (14)* Mild 17/20 (85) 8/10 (80) 9/9 (100) 4/6 (67) Moderate 3/20 (15) 2/10 (20) — 1/6 (17) Severe — — — 1/6 (17) Menorrhagia 45/50 (90) 10/46 (22)* 18/45 (40)* 20/42 (48)* Mild 13/45 (29) 10/10 (100) 12/18 (67) 14/20 (70) Moderate 14/45 (31) 0 (0) 6/18 (33) 4/20 (20) Severe 18/45 (29) — — 2/20 (10) Bulge-like sensation 14/50 (28) 10/46 (22)* 13/45 (29)* 10/42 (24)* Mild 3/14 (21) 9/10 (90) 8/13 (61) 8/10 (80) Moderate 5/14 (36) 1/10 (10) 5/13 (39) — Severe 6/14 (43) — — 2/10 (20) Patients dropped out 0/50 (0) 4/50 (8)†, ‡ 1/50 (2)§ 3/50 (6)¶ Patients in amenorrhea 0/50 (0) 35/46 (76) 14/46 (30) 8/42 (19) Data are presented as mean Ϯ standard deviation (SD) or n (%). The definitions of symptoms (pain, menorrhagia, bulge sensation) are available in the text. *Compared with baseline, all P < 0.005. †Lost to follow-up. ‡Climacteric symptoms. §Uterine sarcoma. ¶Did not respond to therapy: hysterectomy. A. M. Perrone et al. 120 © 2013 The Authors Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology
  • 5. controlled by the leuprolide and the volume of the fibroid was unchanged. The final diagnosis was uterine sarcoma. Third follow-up after 24 months of medical treatment No adjunctive cycles of GnRHa were recorded. Three out of 10 patients, who in the second follow-up were submitted to a second cycle of GnRHa, underwent hys- terectomy because of persistent symptoms such as menorrhagia, pain and bulge-like sensation. Eight patients were in menopause; the diagnosis was made after 12 months of amenorrhea without medical hor- monal therapy. Hb levels and the intensity of symp- toms such menorrhagia, pain and bulge-like sensations were similar to first and second follow-up in 42 patients. After 24 months, the percentage of failure of the medical treatment was 12% (two patients did not complete medical treatment and were submitted to surgery and four patients were submitted to hysterec- tomy after at least one cycle of treatment with GnRHa). Sexual function after 24 months of medical and surgical treatment All 42 patients in group A (we excluded the six patients submitted to hysterectomy) and all 50 patients in group B completed the FSFI and FSDS questionnaires. All patients in both groups were sexually active. By FSFI, 30 of the 42 (71%) women in group A and 34 of the 50 (68%) women in group B scored 26.5 or less. Among the two groups, no significant difference was observed in the FSFI score in each domain (desire, arousal, lubri- cation, orgasm, satisfaction, pain, and total score) (Table 4). When considered alone, the average FSDS score was 7.16 Ϯ 8.76 and 11.27 Ϯ 11.39 for group A and group B, respectively (P = 0.2). Among women who achieved an FSFI final score of 26.5 or less, five of the 30 (16%) women in group A and 11 of the 34 (32%) women group B scored more than 15 in the FSDS ques- tionnaire. The overall prevalence of sexual dysfunction (FSFI Յ26.5 and FSDS >15) was five of 42 (12%) and 11 of 50 (22%) women in groups A and B, respectively (P = 0.5). Discussion Our study shows that, in women over 45 years old with large symptomatic uterine fibroids, GnRHa, adminis- trated once or via repeated cycles over 6 months, is effective in significantly reducing the volume of fibroids, leading to a significant improvement in symp- toms. The administration of GnRHa does not affect the quality of the sex life of these women in comparison to those who have undergone hysterectomy. Ours is one of the few studies to have evaluated the long-term efficacy of GnRHa therapy on large fibroids in women over 45 years with the intent of avoiding or reducing the number of hysterectomies for this condi- tion in women approaching menopause.15 We offered this therapeutic strategy to patients without assessing their hormonal milieu. In fact, follicle-stimulating hormone and other hormones such as anti-Müllerian hormone are considered to be less effective in assessing the menopausal status of women after 45 years.29,30 The decision for therapy is therefore based on clinical parameters, such as menorrhagia, budge-like sensation and absence of menopausal symptoms. Data in the published work show that hysterectomy is one of the most commonly practiced procedures in gynecological centers, but in spite of the wide experi- ence of gynecological surgeons, it is not without com- plications.31,32 Possible injury to other pelvic organs, severe perioperative anemia, chronic pelvic pain syn- drome and post-surgical adhesions have all been described. Hysterectomy requires a variable convales- cence period which depends on the type of surgical access and complexity added to the fact that it is an operation often seen by women as a mutilating expe- rience which also affects their femininity.33,34 Treatment with GnRHa is recognized as most effec- tive in reducing fibroid volume and symptoms after only three months of therapy, however, the effects are transient and, as is described in the published work, fibroids return to their original size approximately 6 months after discontinuation the drug, although the positive effects on symptoms tend to last longer.35–37 In our study, we observed that the positive effects of GnRHa administration on volume and clinical Table 4 Female Sexual Function Index scores after 24 months of the medical and surgical treatment Domains Group A Group B P Յ 0.05 Desire 2.82 Ϯ 1.26 3.16 Ϯ 1.31 ns Arousal 2.87 Ϯ 1.77 3.49 Ϯ 1.56 ns Lubrication 3.40 Ϯ 2.15 3.82 Ϯ 1.69 ns Orgasm 3.14 Ϯ 1.98 3.70 Ϯ 1.62 ns Satisfaction 3.33 Ϯ 1.90 3.99 Ϯ 1.79 ns Pain 3.36 Ϯ 2.33 3.83 Ϯ 2.08 ns Total 18.94 Ϯ 10.16 22.00 Ϯ 8.86 ns Data are presented as mean Ϯstandard deviation. P Յ 0.05 t-test. Group A, gonadotropin-releasing hormone analog treatment. Group B, surgical treatment (hysterectomy). GnRHa uterine fibroid treatment and sexual function © 2013 The Authors 121 Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology
  • 6. symptoms were maintained over time (24-month follow-up, Table 3); the therapeutic effect was probably enhanced by the proximity of menopause for some women and repetition of a second course of therapy. This type of treatment option, although less invasive than surgery, is different because it is not definitive and often requires two cycles of GnRHa (22% of patients) or the administration of additional therapies (18% of patients) as norethisterone for 3 months. In case of severe menopausal symptoms, add-back therapy with estrogens can be administrated, although in our study this was never necessary. However, at the end of the 24-month follow-up, only six of the initial 50 candi- dates for hysterectomy underwent the surgical proce- dure and for the eight menopausal women (17% of patients) this treatment was definitive. This indicates that adequate counseling and repeated check-ups may improve the clinical management of patients with fibroids reserving hysterectomy for difficult cases where poor results had been obtained after repeated courses of medical therapy. However, the use of GnRHa can delay the diagnosis and treatment of leiomyosarcoma and thus may increase the risk of morbidity and affect the treatment outcome of patients with this tumor.38 In fact, in the case of no response to medical treatment, it is necessary to carefully re-evaluate the clinical picture of the patient in order to investigate the possibility of the presence of neoplastic disease such as uterine sarcoma. Female sexual function has multiple aspects, emo- tional and psychological. In our study, we administered the validated FSFI and FSDS questionnaires to compare the occurrence of sexual problems and sexually related personal distress among patients with uterine fibroids submitted to medical and surgical therapy. Other stud- ies20,39 have considered only selected aspects of sexual function but, to obtain a complete picture, we included the FSDS questionnaire which was intended to appraise the distress related to sexual life. This is the first study that evaluated the sexual func- tion in women affected by uterine fibroids submitted to GnRHa therapy compared to women submitted to hysterectomy. Previous studies have showed that fibroids do not impact on sexual function and women with uterine myomas do not have an increased preva- lence or severity of dyspareunia.20 Our data demon- strated that the presence of hypoestrogenism induced by GnRHa did not alter sexual function compared to hysterectomy. In our study, we found that both groups (groups A and B) showed a relatively low score (Յ26.5) but only in 12% of group A and 22% of group B was sexual dysfunction identified. Both groups showed similar sexual function impairment (score FSFI Յ26.5, considered as cut-off for normal sexual function), but only in 12% of group A and 22% of group B were these results felt by the patients as a real sexual dysfunction (FSDS score >15). These percentages of dysfunction were comparable to those reported in previous studies on the general population in Europe and the USA of the same age and confirm the data in the published work that this gynecological condition does not impair sexual function.20,40,41 In addition, the GnRHa therapy leading to a similar clinical improvement of symptoms, did not result in a worsening of sexual function in respect to those women undergoing surgery in any of the domains evaluated. One of the main limitations of our study was the lack of baseline sexual function assessment, but our aim was not a prospective evaluative effect of GnRHa but a comparative post-treatment analysis of the effect of medical and surgical treatment. The sexual function evaluation at 24 months has been considered a correct evaluation of the mid-term effect of the therapy. A shorter evaluation would have been too close to GnRHa injection; on the contrary, a much longer follow-up would have been influenced by the natural onset of the menopausal status. Another possible limi- tation of the study was the lack of baseline hormonal milieu, but we considered it unreliable as a specific endocrine marker of early or late menopausal transi- tion, being the diagnosis of menopause based on clini- cal parameters.29 Because leuprolide does not interfere with estrogen synthesis in adipose tissue, the effect of medical treatment could have been altered by obesity; unfortunately, because of the small number of patients, body mass index and GnRHa failure could not be cor- related. These results should be validated by larger series studies. In conclusion, we found that medical therapy with GnRHa is a satisfactory alternative to surgery for fibroids in women over 45 years. It avoids surgery in 88% of patients who are candidates for hysterectomy. GnRHa therapy has to be repeated in 18% of patients and it needs a careful follow-up to evaluate the efficacy of the therapy and exclude the presence of leiomyosarcoma. Medical therapy does not modify sexual function in perimenopausal women compared with hysterectomy. The less invasive nature of medical treatment needs to be balanced against the need of re-intervention in almost 18% of patients. The choice should lie with the informed patient. A. M. Perrone et al. 122 © 2013 The Authors Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology
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