Agonist treatment avoids hysterectomy in premenopausal

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: amperrone@libero.it
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

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

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

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.

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).

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.

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