Agonist treatment avoids hysterectomy in premenopausal

Single or repeated gonadotropin-releasing hormoneagonist treatment avoids hysterectomy in premenopausalwomen with large symptomatic fibroids with no effectson sexual function

Anna Myriam Perrone1, Federica Pozzati1, Barbara Di Marcoberardino1, Martina Rossi1,Martina Procaccini1, Alice Pellegrini1, Donatella Santini2 and Pierandrea De Iaco1

1Unit of Oncologic Gynaecology and 2Unit 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 medicalmanagement with gonadotropin-releasing hormone agonist (GnRHa) in women of more than 45 years oldcompared to surgical management.Methods: Women with symptomatic uterine fibroids were enrolled to participate to the present open-labelstudy. 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 surgicaltherapy on sexual life was evaluated.Results: No significant differences were found in population characteristics between the two groups. GnRHatreatment was efficient in reducing symptoms in 88% of patients but 22% of patients needed adjunctive cyclesof medical therapy. After 24 months, 16% of the patients did not complete the study. The failure percentage ofthe 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 domainbetween the medical and surgical groups, with total scores of 18.94 � 10.16 and 22.00 � 8.86, respectively(mean � standard deviation), and the prevalence of dysfunction was 12% and 22%, respectively, similar to thegeneral population of the same age.Conclusion: We found that medical therapy with GnRHa is a satisfactory alternative to surgery for fibroids inwomen of more than 45 years old.Key words: fibroids, GnRHa, medical treatment, peri-menopausal women, surgery.

Introduction

Uterine fibroids are benign monoclonal tumors of thesmooth muscle cells of the myometrium most commonin 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 typesof 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, 40138Bologna, Italy. Email: [email protected] of interest: The authors declare no conflict of interest.

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doi:10.1111/jog.12135 J. Obstet. Gynaecol. Res. Vol. 40, No. 1: 117–124, January 2014

© 2013 The Authors 117Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology

mailto:[email protected]

approach in young women who want to preserve theirfertility whereas hysterectomy is generally proposed inperimenopausal women.3,4

Recently, medical management, androgens, anti-progestogens, raloxifene and gonadotropin-releasinghormone agonist (GnRHa) and antagonist is an attrac-tive strategy for many gynecologists in the manage-ment of uterine fibroids.5–10 These drugs have someadvantages when compared with surgery as they areeasily administrated and lack postoperative complica-tions (pelvic organ adhesion, postoperative bleedingand pain), but published work reports a high recur-rence rate 6–12 months after discontinuation oftreatment.11–14 Due to the high relapse rate, medicaltherapy does not appear to represent a definitivechoice in young patients with symptomatic uterinefibroids, but in women who are near menopausal status(age �45 years, defined as perimenopausal) medicaltreatment may be definitive and the patients may avoidhysterectomy.15

Among the drugs currently used for uterine fibro-matosis, GnRHa appear to be the most effective in theshortest time, but the use is limited in time by side-effects related to hypoestrogenism as vasomotor insta-bility, vaginal dryness and bone loss, which precludethe long-term use of these compounds.16 Only onestudy has evaluated the possibility that after 45 yearssome perimenopausal women may transit to naturalmenopause in an unexpectedly short period, andwaiting for menopause, medical therapy may avoidhysterectomy.15 The use of a GnRHa in premenopausalwomen 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 offibroids; (ii) there is the possibility of administration ofGnRHa for short period of time; and (iii) the possibilityto repeat administration after a period free fromtreatment.

Bleeding and other symptoms related to fibroids cancompromise women’s sexuality.17,18 Few studies haveexplored the effects of uterine fibroids on female sexualfunction. Some authors found an increased prevalenceand incidence of dyspareunia and non-cyclic pelvicpain19 but others do not confirm this data.20 Somestudies report the impact of pelvic surgery andhypoestrogenism on sexual function,21–24 but no datahas evaluated the effects of GnRHa treatment forfibroid on sexual function in perimenopausal women.

The aim of our study was to explore the effective-ness, limitations and female sexual function effects ofthe conservative medical management with GnRHa in

perimenopausal women aged 45 years or olderwith symptomatic fibroids compared to the surgicalapproach (hysterectomy).

Methods

Between 2005 and 2009, among women with aged 45years or older with symptomatic uterine fibroids thathad been referred to our center to be scheduled forhysterectomy, we invited 100 consecutive patients toparticipate in the present open-label study: somepatients received medical treatment with depot GnRHa(group A) and the others received surgical manage-ment (group B). The study was approved by the localethics committee and all patients signed an informedconsent.

Inclusion criteria were: the presence of one or moreintramural/subserosal, intramural, intramural/submucosal, submucosal fibroids larger than 4 cm, andsymptoms such as abnormal uterine bleeding, anemia(�12 g/dL), pelvic pain, compression syndrome andbulge-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 90days (leuprolide acetate 11.25 mg; Takeda Pharmaceu-ticals, Osaka, Japan) for at least 6 months. The group Bpatients were submitted to hysterectomy by laparo-scopic or laparotomic route according to the surgeon’sexperience and the uterine volume. All patients agreedto be evaluated for a period of 2 years.

Exclusion criteria were: small submucosal fibroidwith uterine longitudinal diameter of 20 cm or more,malignancies, chronic disease such as diabetes andrenal failure, interstitial cystitis, irritable bowel syn-drome, endometriosis and antidepressant medicationsknown to affect sexual function.

At baseline, the patients were submitted to physicalexamination and pelvic transvaginal ultrasound.Symptom assessment such menorrhagia, pain, com-pression syndrome and a bulge-like sensation weremeasured using a 4-point scale: 0, none; 1, mild; 2,moderate; and 3, severe symptoms. The volume of thelargest fibroid was calculated by measuring the threemain diameters (D1, D2, D3) and applying the formulaof the ellipsoid (length ¥ height ¥ width ¥ 0.52).

Group A patients were reviewed at 6, 12 and 24months after GnRHa administration, and any medicalor surgical treatment or the need for repeated use ofGnRHa treatment were recorded. Failure of themedical treatment included: (i) the need for hysterec-tomy or myomectomy; and (ii) discontinuation of

A. M. Perrone et al.

118 © 2013 The AuthorsJournal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology

GnRHa treatment (treatment for <6 months) due topoor patient compliance or complications.

To evaluate the impact of the medical and surgicaltherapy on sexual life, patients were interviewed abouttheir sexual activity 24 months after treatment. Weadministrated 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 DistressScale (FSDS).27,28 All patients were interviewed abouttheir sexuality before the treatment. Sexually inactivepatients 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 meanand standard deviation of the mean and range.Unpaired Student’s t-test was performed to investigatecontinuous variable differences between the groups.Pearson’s c2-test, calculated by the Monte Carlomethod, was performed to investigate the relationshipsbetween grouping variables. For all tests, P < 0.05 wasconsidered significant. Statistical analysis was carriedout by means of the Statistical Package for the SocialSciences software ver. 9.0.

ResultsCharacteristics of the two groups at baseline

The characteristics of the population (groups A and B)are shown in Tables 1 and 2. No significant differenceswere found between the two groups in the severity ofsymptoms, except for mild bulge-like sensation whichwas more common in group B (P < 0.05).

First follow-up after 6 months ofmedical treatment

Forty-six out of 50 patients (92%) completed medicaltreatment with GnRHa injection for at least 6 monthswithout additional hormonal supplement. Vaginalspotting was noted in 26 of the patients (57%) after thefirst injection and 35 (76%) were in amenorrhea afterthe second dose. Hemoglobin (Hb) levels and symp-toms such menorrhagia, pain and bulge-like sensationsdecreased significantly and a 53% reduction in fibroidsvolume from baseline was noted in this group after 6months of therapy (Table 3).

Four patients did not complete the treatment: two(4%) were lost to follow-up, while two (4%) interruptedGnRHa treatment after the first dose because ofclimacteric symptoms, refused add-back therapy andrequired hysterectomy. Apart from these patients, themenopausal 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 ofmedical treatment

Ten out of 46 (22%) patients required a second cycle ofGnRHa because of recurrence of mild and moderatemenorrhagia. Adjunctive medical treatments such astranexamic acid and progestins were administrated ineight out of 46 (17%) patients. Fourteen out of 46 (30%)were in amenorrhea (10 patients received the secondcycle of GnRHa treatment). Hb levels and the intensityof symptoms such menorrhagia, pain and bulge-likesensations were similar to those reported at firstfollow-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 PMean � SD n (%) Mean � SD n (%)

Age (years) 48.7 � 3.2 — 49.5 � 2.0 — nsBody mass index

(kg/m2)27.7 � 5.3 — 28.2 � 2.0 — ns

Parity0 — 17/50 (34) — 15/50 (30) ns1 — 19/50 (38) — 21/50 (42) ns2 — 14/50 (28) — 12/50 (24) ns�3 — — — 2/50 (4) ns

Baseline hemoglobinlevel (g/dL)

9.5 � 1.5 — 9.8 � 2.0 — ns

P � 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


Table 2 Severity of symptoms and fibroids characteristic in the two groups. Dataare presented as number or percentage (%)

Symptoms Group A Group B Pn (%) n (%)

Pain 20/50 (40) 25/50 (50) nsMild 17/20 (85) 18/25 (72) nsModerate 3/20 (15) 6/25 (24) nsSevere 0 1/25 (4) ns

Menorrhagia 45/50 (90) 49/50 (98) nsMild 13/45 (29) 15/49 (31) nsModerate 14/45 (31) 15/49 (31) nsSevere 18/45 (40) 19/49 (38) ns

Bulge-like sensation 14/50 (28) 17/50 (34) nsMild 3/14 (21) 6/17 (35) <0.05Moderate 5/14 (36) 6/17 (35) nsSevere 6/14 (43) 5/17 (30) ns

Volume of larger fibroid 427.46 � 293.05 460.33263.03 nsNo. of fibroids for each patient

1 18/50 (36) 15/50 (30) ns2 10/50 (20) 15/50 (30) ns�3 22/50 (44) 20/50 (40) ns

Location of fibroids for each patientSubserosal 0 0 nsIntramural/subserosal 15/50 (30) 14/50 (28) nsIntramural 17/50 (34) 18/50 (36) nsIntramural/submucosal 13/50 (26) 12/50 (24) nsSubmucosal 5/50 (10) 6/50 (12) ns

P � 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-up0 months 6 months 12 months 24 monthsMean � SD Mean � SD Mean � SD Mean � SD

Hemoglobin level (g/dL) 9.16 � 2.18 12.87 � 0.55* 11.22 � 0.22* 11.16 � 0.27*Volume of larger myoma cm3 427.46 � 293.05 201.35 � 172.88* 224.00 � 154.03* 218.05 � 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 � standard deviation (SD) or n (%). The definitions of symptoms (pain, menorrhagia, bulge sensation) areavailable in the text. *Compared with baseline, all P < 0.005. †Lost to follow-up. ‡Climacteric symptoms. §Uterine sarcoma. ¶Did not respondto therapy: hysterectomy.



controlled by the leuprolide and the volume of thefibroid was unchanged. The final diagnosis was uterinesarcoma.

Third follow-up after 24 months ofmedical treatment

No adjunctive cycles of GnRHa were recorded. Threeout of 10 patients, who in the second follow-up weresubmitted to a second cycle of GnRHa, underwent hys-terectomy because of persistent symptoms such asmenorrhagia, pain and bulge-like sensation. Eightpatients were in menopause; the diagnosis was madeafter 12 months of amenorrhea without medical hor-monal therapy. Hb levels and the intensity of symp-toms such menorrhagia, pain and bulge-like sensationswere similar to first and second follow-up in 42patients. After 24 months, the percentage of failure ofthe medical treatment was 12% (two patients did notcomplete medical treatment and were submitted tosurgery and four patients were submitted to hysterec-tomy after at least one cycle of treatment with GnRHa).

Sexual function after 24 months of medical andsurgical treatment

All 42 patients in group A (we excluded the six patientssubmitted to hysterectomy) and all 50 patients in groupB completed the FSFI and FSDS questionnaires. Allpatients 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. Amongthe two groups, no significant difference was observedin the FSFI score in each domain (desire, arousal, lubri-cation, orgasm, satisfaction, pain, and total score)(Table 4). When considered alone, the average FSDSscore was 7.16 � 8.76 and 11.27 � 11.39 for group Aand group B, respectively (P = 0.2). Among womenwho 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 �26.5 and FSDS >15) was five of 42 (12%) and 11of 50 (22%) women in groups A and B, respectively(P = 0.5).

Discussion

Our study shows that, in women over 45 years old withlarge symptomatic uterine fibroids, GnRHa, adminis-trated once or via repeated cycles over 6 months, iseffective in significantly reducing the volume offibroids, leading to a significant improvement in symp-toms. The administration of GnRHa does not affect thequality of the sex life of these women in comparison tothose who have undergone hysterectomy.

Ours is one of the few studies to have evaluated thelong-term efficacy of GnRHa therapy on large fibroidsin women over 45 years with the intent of avoiding orreducing the number of hysterectomies for this condi-tion in women approaching menopause.15 We offeredthis therapeutic strategy to patients without assessingtheir hormonal milieu. In fact, follicle-stimulatinghormone and other hormones such as anti-Müllerianhormone are considered to be less effective in assessingthe menopausal status of women after 45 years.29,30 Thedecision for therapy is therefore based on clinicalparameters, such as menorrhagia, budge-like sensationand absence of menopausal symptoms.

Data in the published work show that hysterectomyis one of the most commonly practiced procedures ingynecological 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 beendescribed. Hysterectomy requires a variable convales-cence period which depends on the type of surgicalaccess and complexity added to the fact that it is anoperation 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 afteronly three months of therapy, however, the effects aretransient and, as is described in the published work,fibroids return to their original size approximately 6months after discontinuation the drug, although thepositive effects on symptoms tend to last longer.35–37

In our study, we observed that the positive effectsof GnRHa administration on volume and clinical

Table 4 Female Sexual Function Index scores after24 months of the medical and surgical treatment

Domains Group A Group B P � 0.05

Desire 2.82 � 1.26 3.16 � 1.31 nsArousal 2.87 � 1.77 3.49 � 1.56 nsLubrication 3.40 � 2.15 3.82 � 1.69 nsOrgasm 3.14 � 1.98 3.70 � 1.62 nsSatisfaction 3.33 � 1.90 3.99 � 1.79 nsPain 3.36 � 2.33 3.83 � 2.08 nsTotal 18.94 � 10.16 22.00 � 8.86 ns

Data are presented as mean �standard deviation. P � 0.05 t-test.Group A, gonadotropin-releasing hormone analog treatment.Group B, surgical treatment (hysterectomy).



symptoms were maintained over time (24-monthfollow-up, Table 3); the therapeutic effect was probablyenhanced by the proximity of menopause for somewomen and repetition of a second course of therapy.This type of treatment option, although less invasivethan surgery, is different because it is not definitive andoften requires two cycles of GnRHa (22% of patients) orthe administration of additional therapies (18% ofpatients) as norethisterone for 3 months. In case ofsevere menopausal symptoms, add-back therapy withestrogens can be administrated, although in our studythis was never necessary. However, at the end of the24-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% ofpatients) this treatment was definitive. This indicatesthat adequate counseling and repeated check-ups mayimprove the clinical management of patients withfibroids reserving hysterectomy for difficult caseswhere poor results had been obtained after repeatedcourses of medical therapy.

However, the use of GnRHa can delay the diagnosisand treatment of leiomyosarcoma and thus mayincrease the risk of morbidity and affect the treatmentoutcome of patients with this tumor.38 In fact, in thecase of no response to medical treatment, it is necessaryto carefully re-evaluate the clinical picture of the patientin order to investigate the possibility of the presence ofneoplastic disease such as uterine sarcoma.

Female sexual function has multiple aspects, emo-tional and psychological. In our study, we administeredthe validated FSFI and FSDS questionnaires to comparethe occurrence of sexual problems and sexually relatedpersonal distress among patients with uterine fibroidssubmitted to medical and surgical therapy. Other stud-ies20,39 have considered only selected aspects of sexualfunction but, to obtain a complete picture, we includedthe FSDS questionnaire which was intended to appraisethe distress related to sexual life.

This is the first study that evaluated the sexual func-tion in women affected by uterine fibroids submittedto GnRHa therapy compared to women submitted tohysterectomy. Previous studies have showed thatfibroids do not impact on sexual function and womenwith uterine myomas do not have an increased preva-lence or severity of dyspareunia.20 Our data demon-strated that the presence of hypoestrogenism inducedby GnRHa did not alter sexual function compared tohysterectomy. In our study, we found that both groups(groups A and B) showed a relatively low score (�26.5)but only in 12% of group A and 22% of group B was

sexual dysfunction identified. Both groups showedsimilar sexual function impairment (score FSFI �26.5,considered as cut-off for normal sexual function), butonly in 12% of group A and 22% of group B were theseresults felt by the patients as a real sexual dysfunction(FSDS score >15). These percentages of dysfunctionwere comparable to those reported in previous studieson the general population in Europe and the USA ofthe same age and confirm the data in the publishedwork that this gynecological condition does not impairsexual function.20,40,41 In addition, the GnRHa therapyleading to a similar clinical improvement of symptoms,did not result in a worsening of sexual function inrespect to those women undergoing surgery in any ofthe domains evaluated.

One of the main limitations of our study was the lackof baseline sexual function assessment, but our aim wasnot a prospective evaluative effect of GnRHa but acomparative post-treatment analysis of the effect ofmedical and surgical treatment. The sexual functionevaluation at 24 months has been considered a correctevaluation of the mid-term effect of the therapy. Ashorter evaluation would have been too close toGnRHa injection; on the contrary, a much longerfollow-up would have been influenced by the naturalonset of the menopausal status. Another possible limi-tation of the study was the lack of baseline hormonalmilieu, but we considered it unreliable as a specificendocrine marker of early or late menopausal transi-tion, being the diagnosis of menopause based on clini-cal parameters.29 Because leuprolide does not interferewith estrogen synthesis in adipose tissue, the effect ofmedical 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 largerseries studies.

In conclusion, we found that medical therapy withGnRHa is a satisfactory alternative to surgery forfibroids in women over 45 years. It avoids surgery in88% of patients who are candidates for hysterectomy.GnRHa therapy has to be repeated in 18% of patientsand it needs a careful follow-up to evaluate theefficacy of the therapy and exclude the presence ofleiomyosarcoma.

Medical therapy does not modify sexual function inperimenopausal women compared with hysterectomy.

The less invasive nature of medical treatment needsto be balanced against the need of re-intervention inalmost 18% of patients. The choice should lie with theinformed patient.



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