Medical Management of Fibroids

 Chairperson ICOG –Indian College of OB/GY
 National Corresponding Editor-Journal of OB/GY of India JOGI
 National Corresponding Secretary Association of Medical Women, India
 Founder Patron & President –ISOPARB Vidarbha Chapter 2019-21
 Chairperson-IMS Education Committee 2021-23
 President-Association of Medical Women, Nagpur AMWN 2021-24
 Nagpur Ratan Award @ hands of Union Minister Shri Nitinji Gadkari
 Received Bharat excellence Award for women’s health
 Received Mehroo Dara Hansotia Best Committee Award for her work as
Chairperson HIV/AIDS Committee, FOGSI 2007-2009
 Received appreciation letter from Maharashtra Government for her work in the
field of SAVE THE GIRL CHILD
 Senior Vice President FOGSI 2012
 President Menopause Society, Nagpur 2016-18
 President Nagpur OB/GY Society 2005-06
 Delivered 11 orations and 450 guest lectures
 Publications-Thirty National & Eleven International
 Sensitized 2 lakh boys and girls on adolescent health issues
Dr. Laxmi Shrikhande
MBBS; MD(OB/GY);
FICOG; FICMU; FICMCH
Medical Director-
Shrikhande Fertility Clinic
Nagpur, Maharashtra

Medical Management
of Fibroids

Uterine Fibroids - Introduction
• “A benign tumor of muscular and fibrous
tissues, typically developing in the wall of the
uterus”1
• Prevalence varies among studies and countries
(4.5-68.6%)2
• Nearly 20-30% Indian women in reproductive
age group have fibroid uterus3
• At any given time, nearly 15-25 million Indian
women have fibroid uterus3
1. Best Pract Res Clin Obstet Gynaecol. 2008 Aug;22(4):643-54
2. Int J Obstet Gynecol 2020;149(1):3-9.
3. StandardTreatment Guidelines Obstetrics & Gynaecology; Ministry of Health & Family Welfare Govt. of India; Pg:4

Etiology of Uterine Fibroids
Int. J. Mol. Sci. 2018, 19, 2051
Estrogen Progesterone Genetic predisposition
It has been implicated in
growth of myomas. Studies
show that:
• Myomas contain estrogen
receptors in higher
concentration than
surrounding myometrium
• Myomas may increase in
size with estrogen
therapy & in pregnancy
• They are not detectable
before puberty
• Regress after menopause
due to fall in estrogen
levels
Increase mitotic activity &
reduce apoptosis
Fibroids are monoclonal &
about 40% have
chromosomal abnormalities
that include:
• Translocations between
chromosomes 12 & 14
• Deletions of
chromosomes 60% may
have yet undetected
mutations

Functional role of Estrogen &
Progesterone
Fibroids overexpress Estrogen & Progesterone receptors
J Tumor Res 2017, 3:3

Pathophysiology of Uterine Fibroids

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Etiology of Uterine Fibroids: Newer
Perspective

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Pathophysiology of Uterine Fibroids: Newer
Perspective
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Pathophysiology of Uterine Fibroids: Newer
Perspective

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Pathophysiology of Uterine
Fibroids: Newer Perspective

Uterine fibroids & Infertility
• Interference with sperm or ovum transport.1
• Enlargement and deformity of the uterine cavity2
• Distortion or obstruction of the tubal ostia. 2
• Increase the chance of miscarriage3
• Increase the risk of obstetrical complications 3
1. J Gynecol Endosc Surg. 2011 Jan-Jun; 2(1): 36–42 ; 2. Semin Reprod Med. 2007 Nov;25(6):483-9
3. Tochie, J. N. , Badjang, G. T. , Ayissi, G. , Dohbit, J. S. . Physiopathology and Management of Uterine Fibroids. In: Abduljabbar, H. , editor. Fibroids [Internet]. London: IntechOpen;
2020 [cited 2022 Nov 23]. Available from: https://www.intechopen.com/chapters/73825 doi: 10.5772/intechopen.94162

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Diagnosis

11. Medical
Management
Treatment Algorithm
3b) Uterus >14
weeks in size

Treatment Algorithm
Medical Therapy / Surgical
Therapy
Medical Therapy / Surgical
Therapy
Surgical Therapy

Treatment Options for Uterine Fibroids
Uterine artery
embolization
Magnetic resonance
guided focused
ultrasound surgery
Laparoscopic
Hysterectomy
Hysteroscopic
Myomectomy

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•
•
•
•
•
Limitations of Surgical Management

Medical Management Options
Hormonal Therapy
• GnRH Agonists
• GnRH Antagonists
• Androgens e.g. Danazol
• Levonorgestrel – releasing
intrauterine system
• SPRMs
• Ulipristal Acetate
• Mifepristone
Non-Hormonal Therapy
• Tripterygium wilfordii
• Epigallocatechin gallate [EGCG]
• Vitamin D
 Ulipristal Acetate
 Mifepristone

GnRH Agonists
• Synthetic peptides that are structurally analogous to natural GnRH hormone1
• Used primarily as preoperative therapy1
• Reduce uterine and fibroid volume by as much as 30–40%1
• Given before myomectomy, apparently to render the operation easier and
reduce operative blood loss, thus 87% use GnRH agonist2
• Challenge of GnRH agonist therapy involves adverse effects, such as1:
Exacerbation of symptoms
Development of vasomotor symptoms
Decreased bone mineral density
• Commercially available GnRH agonists include, Goserelin, Leuprolide acetate,
Nafarelin, Buserelin, and Triptorelin1
1. Cochrane Database Syst Rev. 2017 Oct; 2017(10): CD012846
2. J Obstet Gynaecol India. 2012 Oct; 62(5): 506–510

• Objective: To assess the effects of depot injections of Goserelin (Zoladex), a GnRH-
agonist analogue, on the management of uterine fibroids
• Study Design:
 Randomized controlled study
 N=40 premenopausal women aged 26-50 years
 Dosage:
o Goserelin 3.6mg administered subcutaneously every 28 days
 Duration: 26 weeks
1
Trop J Obstet Gynaecol, 22 (2), October 2005.
Goserelin
CLINICAL EVIDENCE

RESULTS
There was a statistically significant difference between the uterine and fibroid
volume from the baseline
(p<0.05)
(p<0.05)
Conclusion: Goserelin treatment, prior to surgery, demonstrated benefit in terms of uterine
and fibroids volumes, symptoms reduction and improvement of hematological profile in
Nigerian patients with uterine leiomyoma
Trop J Obstet Gynaecol, 22 (2), October 2005.

• Objective: To assess the efficacy and side-effect profile of Ulipristal acetate as
compared with those of Leuprolide acetate for the treatment of symptomatic uterine
fibroids before surgery
• Study Design:
 Double-blind noninferiority trial
 N=307 patients
 Dosage:
o Ulipristal acetate 5mg or 10mg OD
o Leuprolide acetate 3.75mg IM monthly
 Duration: 3 months
2
N Engl J Med 2012;366:421-32
Leuprolide

RESULTS
• 10mg dose of Ulipristal was
superior to Leuprolide acetate in
controlling the bleeding
• Leuprolide acetate was
associated with a significantly
greater reduction in uterine
volume
• Amenorrhea was induced more
rapidly in patients receiving 10
mg of ulipristal acetate than in
those receiving leuprolide acetate
Conclusion: Goserelin treatment, prior to surgery, demonstrated benefit in terms of uterine
and fibroids volumes, symptoms reduction and improvement of hematological profile in
Nigerian patients with uterine leiomyoma
N Engl J Med 2012;366:421-32
(p=0.03)

Current Status in Therapy
• Cochrane systematic review has demonstrated that their use can
improve both preoperative and postoperative hemoglobin levels,
reduce operative time, and shorten the duration of hospital stay.
• GnRH agonists decreases menstrual bleeding and reducing fibroid
volume by approximately 50%
Cochrane Database of Systematic Reviews 2017, Issue 10. Art. No.: CD012846
GnRH agonists

GnRH agonists
Dr. Nandita Palshetkar, A FOGSI President’s Initiative, Key Practice Points on Fibroids, Indian Perspective, 2019

GnRH Antagonists
• Compete with endogenous GnRH for pituitary binding sites1
• Due to the lack of any intrinsic activity of GnRH-antagonists, the characteristic
initial flare-up observed with GnRH-agonist treatment is absent1
• Rapidly suppress gonadotropin release within 4-8 h, while GnRH-agonists
show clinical effects after 2 or 3 weeks of treatment1
• Activity is dose-dependent so dose adjusted to obtain levels of inhibition1
• Side-effects include flushes and head-ache1
• After stopping therapy with both drugs, leiomyomas rapidly achieve their
original size while side-effects disappear1
• Elagolix and Relugolix are the only GnRH antagonists approved by the USFDA
to treat Abnormal Uterine Bleeding-Leiomyoma2
1. Minerva Ginecol. 2006 Dec;58(6):553-60.; 2. Mil Med. 2022 Mar 28;usac078

• Objective: To determine the effectiveness of Elagolix treatment in women with heavy
menstrual bleeding associated with uterine fibroid by comparing: elagolix versus
placebo and Elagolix versus estradiol/norethindrone acetate.
• Study Design:
 4 randomized controlled trials
 N=1949 premenopausal women from 323 locations
 Dosage:
o Group 1: Elagolix versus placebo
o Group 2: Elagolix versus estradiol/norethindrone acetate
 Duration: 3 to 6 months
1
Muhammad et al. BMC Women’s Health (2022) 22:14
Elagolix
CLINICAL EVIDENCE

RESULTS
Elagolix increased
the no. of patients
with a reduction of
menstrual blood
loss of >50%
No difference in
menstrual blood
loss of >50% from
baseline
Conclusion: Elagolix appeared to be effective in reducing heavy menstrual bleeding caused
by uterine fibroid and combination with estradiol/norethindrone acetate was able to
alleviate the hypoestrogenism side effects in premenopausal women.
Muhammad et al. BMC Women’s Health (2022) 22:14

• Objective: To evaluate the efficacy of in women with uterine fibroids and
heavy bleeding while avoiding hypoestrogenic effects
• Study Design:
2 replicate international (L1 and L2), double-blind, 24-week, phase 3 trial
N=388 in L1; 382 in L2
Dosage:
o 1:1:1 ratio Placebo, Relugolix combination therapy (40 mg of Relugolix, 1 mg of
estradiol, and 0.5 mg of norethindrone acetate), or delayed Relugolix
combination therapy (40 mg of Relugolix monotherapy, followed by Relugolix
combination therapy) OD
Duration: 24 weeks
2
N Engl J Med 2021;384:630-42.
Relugolix

RESULTS
Participants with Reduction in Heavy Menstrual Bleeding
Conclusion: OD Relugolix combination therapy resulted in significant reduction in
menstrual bleeding, as compared with placebo, and preserved bone mineral density in
women with uterine fibroids.
N Engl J Med 2021;384:630-42.
In the Relugolix combination therapy groups, 73% of the participants in trial L1 and 71% of
those in trial L2 had a significant to reduction in heavy menstrual bleeding response, as
compared with 19% and 15%, respectively in placebo

• Objective: to confirm the efficacy and safety of Linzagolix with or without hormonal
add-back therapy compared with placebo for the treatment of symptomatic uterine
fibroids.
• Study Design:
 52-week, randomised, parallel, double-blind, placebo controlled, phase 3 trial
 PRIMROSE 1=511 women
 PRIMROSE 2=501 women
 Dosage: 1:1:1:1:1 ratio to one of five masked treatments-
(1) Placebo; (2) 100 mg Linzagolix per day alone; (3) 100 mg Linzagolix per day with
once-per-day hormonal add-back therapy (1 mg estradiol and 0·5 mg norethisterone
acetate); (4) 200 mg Linzagolix per day alone or (5) 200 mg Linzagolix per day with
once-per-day hormonal add-back therapy (1 mg estradiol and 0·5 mg norethisterone
acetate).
• Duration: 24 weeks
3
Prof David Archer, MD et. al. Volume 400, Issue 10356, P896-907, September 17, 2022
Linzagolix

RESULTS
Conclusion: Linzagolix (100 mg or 200 mg) with or without add-back therapy significantly
reduced heavy menstrual bleeding
Prof David Archer, MD et. al. Volume 400, Issue 10356, P896-907, September 17, 2022
In both trials, significantly higher proportion of women had a reduction in heavy menstrual
bleeding in all Linzagolix (with or without add-back therapy) treatment groups compared
with the placebo group
56.40% 56.70%
66.40%
77.20%
71.40%
77.70%
75.50%
93.90%
35%
29.40%
PRIMROSE 1 PRIMROSE 2
% Reduction in heavy menstrual bleeding
100mg 100mg plus ABT 200mg 200mg + ABT Placebo
(p≤0·003)

Relugolix–estradiol–norethisterone acetate is recommended, within its
marketing authorisation, as an option for treating moderate to severe
symptoms of uterine fibroids in adults of reproductive age.
NICE May 2022

Androgens
Isoxazole derivative of 17·-ethynyltestosterone & a synthetic steroid
Clinical application was based on its antigonadotropic properties
Effects are mainly androgenic together with moderate progestogenic,
antiprogestogenic and antiestrogenic activity
Reduces release of GnRH, FSH & LH, alteration of the normal growth process of
the ovarian follicle & specific suppression of endometrial growth &
endometriosis
Produces amenorrhea, blockade of ovarian steroid production and blockade of
gonadotropin release by the pituitary
Gynecol Obstet Invest 1999;47:258–262
Danazol

Objective: To evaluate the effects of danazol in reducing the volume of fibromyomas and in
treatment of associated symptoms
Study Design:
• 20 women with uterine fibromyomas
• Treatment: Danazol 400 mg/day
• Duration: 4 months
1
CLINICAL EVIDENCE

• Average reduction of fibromyoma
volume after 4 months was 23.6+5%
• After 6 months of end of treatment
fibromyoma volume increased slightly
Conclusion: Danazol at a dose of 400 mg/day for 4 months effectively
reduced the volume of fibromyomas and associated symptoms
• All patients experienced partial or complete relief of symptoms
• Plasma levels of E2 were significantly reduced
RESULTS

Objective: To evaluate results of administration of danazol after suspension of GnRHa
therapy for uterine myomas
Study Design:
• 21 women with uterine myomas
• Treatment: 100 mg danazol per day after GnRHa (goserelin/triptorelin) therapy
Human Reproduction vol.12 no.2, pp. 357–360
2

• Rebound of uterine volume about
30% less than in controls at end of
danazol therapy
• Menstrual cyclicity returned after
65+3 days in 16 patients, rest 5
remained amenorrhoeic
Results
Conclusion: Results show the utility of Danazol in prolonging the therapeutic
effects of GnRHa
Higher reduction of myoma volume
was seen in GnRHa+ Danazol
Human Reproduction vol.12 no.2, pp. 357–360

Objective: To compare danazol & gestrinone treatment as preoperative
endometrial preparation for operative hysteroscopy
Study Design:
• Prospective, randomized clinical study
• 35 patients with endouterine pathologies (endometrial polyps, sub mucous
myoma, septate uterus)
• Group I: Gestrinone 2.5 mg twice weekly (n=68) & Group II: Danazol 200 mg
T.I.D (n=67) before operative hysteroscopy
Fertil Steril. 2006 Apr;85(4):1027-31.
3

Higher rate of endometrial
response & lower incidence
of moderate bleeding seen
in Gestrinone group
97.10%
83.60%
Gestrinone Group Danazol Group
Rate of Endometrial Response
Conclusion: Both treatments are good ways to prepare the endometrium for
operative hysteroscopy. However, the results suggest that gestrinone
pretreatment is preferable to Danazol.
Fertil Steril. 2006 Apr;85(4):1027-31.
3%
22.40%
Gestrinone Group Danazol Group
Incidence of moderate
bleeding
Patients personal satisfaction was in favor of Gestrinone
RESULTS

Current status on therapy
Authors' conclusions:
• Despite benefits, various undesirable side effects have also been reported. These
include acne, hirsutism, weight gain, irritability, musculoskeletal pain, hot flushes,
liver damage, and breast atrophy, which many women may not tolerate
• There is no evidence from randomized controlled trials demonstrating that the
benefits of Danazol outweigh its risks in treating uterine fibroids
Cochrane Database Syst Rev. 2009 Jul 8;2009(3):CD007692.
Danazol

Levonorgestrel
releasing-Intrauterine
System (LNG-IUS)

Levonorgestrel releasing-Intrauterine
System (LNG-IUS)
• Consists of a T-shaped polyethylene frame (32 mm × 32 mm) with a
levonorgestrel-containing reservoir around its vertical stem1
• Contains a 1:1 mixture of 52 mg of LNG and polydimethylsiloxane as the
carrier polymer
• An alternative to hysterectomy for menorrhagia1
• Used in patients having fibroids, adenomyosis and endometriosis2
• Reduces the amount of bleeding by over 90% due to its continuous
progestogenic effect on the endometrium2
1. Int J Reprod Contracept Obstet Gynecol. 2014 Sep;3(3):671-677 2. J Mid-life Health 2013;4:31-5.

Objective: To assess the clinical effectiveness of LNG-IUS in treatment of
menorrhagia due to either DUB or fibroid
Study Design:
• Prospective observational study
• Sixty women with menorrhagia, 30 due to fibroid and 30 due to DUB
• Treatment: LNG-IUS
LNG-IUS=Levonorgestrel releasing-Intrauterine system DUB: Dysfunctional Uterine Bleeding
Int J Reprod Contracept Obstet Gynecol. 2014 Sep;3(3):671-677
1
CLINICAL EVIDENCE

Patients satisfied or very satisfied
were higher in DUB group
66.70%
82.80%
Fibroid Group DUB Group
Patients satisfied or very
satisfied
LNG-IUS=Levonorgestrel releasing-Intrauterine system DUB: Dysfunctional Uterine Bleeding
Int J Reprod Contracept Obstet Gynecol. 2014 Sep;3(3):671-677
Haemoglobin & serum ferritin levels significantly increased in both groups
367
8.5
Baseline After 9 months
PBAC Score
95% reduction in PBAC score at
9 months
Conclusion: LNG-IUS is a useful treatment option in non-submucosal small
fibroids for symptoms of menorrhagia, can reduce uterine volume & can help
avoid hysterectomy, but there is no effect on fibroid volume
RESULTS

Objective: To determine efficacy of LNG IUS in treatment of AUB in
women >35 years & also to determine satisfaction of users
Study Design:
• Multicentric, retrospective, and observational study
• 80 women inserted with LNG-IUS
• Fibroids and adenomyosis were the most common pathology of AUB
J Mid-life Health 2013;4:31-5.
2

• 27.5% had amenorrhea by 18 month
• 14 women in whom device was
expelled or removed due to persistent
symptoms, underwent hysterectomy
• Patient satisfaction was high at about
80%
Conclusion: LNG IUS seems to be a viable and effective treatment option for
AUB in women after 35 years. There is a high rate of patient satisfaction in
appropriately selected patients.
24%
65.20%
Baseline At 10 months
Patients with no complaint/reduced bleeding
Patients with no complaint/reduced
bleeding were high at 18 month
J Mid-life Health 2013;4:31-5.
RESULTS

Objective: To evaluate effectiveness of LNG-IUS in treatment of menorrhagia
and/or frequent irregular uterine bleeding in women with uterine myomas
Study Design:
• Prospective study
• 102 women with intramural myomas inserted with LNG-IUS
Eur J Contracept Reprod Health Care. 2011 Dec;16(6):480-7.
3

231.7
17.6
PBAC Score
PBAC score & uterine
volume reduced
significantly at 12 month
Eur J Contracept Reprod Health Care. 2011 Dec;16(6):480-7.
p<0.001
Conclusion: LNG-IUS is effective in controlling heavy menorrhagia and/or
frequent irregular uterine bleeding related to presence of myomas, but has no
significant effect on the size of the tumours.
145
129
Uterine Volume (cm3)
p<0.00
1
Changes in the volume of the myomas were not statistically significant
RESULTS

Objective: To determine efficacy of LNG-IUD insertion in menorrhagic patients
who have at least one type II myoma according to the European Society of
Hysteroscopy
Study Design:
• Prospective investigation
• Experimental arm: 32 patients inserted with LNG-IUS
• Control arm: Historical group of 32 patients underwent TBA
TBA: Thermal Ballon Ablation
4

Significant decrease in PBAC score
in LNG-IUS and TBA group
Conclusion: This prospective controlled trial demonstrates the effectiveness of
LNG-IUD in this setting and equivalent results are obtained as compared to TBA.
Significant increase in hemoglobin
levels in LNG-IUS and TBA group
TBA: Thermal Ballon Ablation
RESULTS

LNG-IUS

Combined Oral Contraceptives
• Combined hormonal (estrogen-progestin) contraception offers many non-
contraceptive benefits.1
• COCs primarily act by inhibiting ovulation through a negative feedback to the
hypothalamus & pituitary gland, resulting in decreased secretion of FSH and
LH, and in decreased ovarian production of sex steroids (estrogen and
progesterone).2
• COCs inhibit ovarian secretion of sex steroids, but exert agonistic effects on
estrogen and progesterone receptors themselves.2
• Due to these effects, COCs have already been considered a risk factor for the
development or growth of leiomyomas.2
1. Austin J Obstet Gynecol. 2017; 4(3): 1077
2. Gynecol Obstet Invest. 2015;79(3):145-52
FSH= Follicular Stimulating Hormone; LH= Luteinizing Hormone

• Objective: To assess the efficacy of combined oral contraceptives (COC) in
treating women with uterine leiomyomata and heavy menstrual bleeding.
• 2 studies were reviewed.
• Study 1: Open, randomized, controlled study,
• Study 2: Quasi-randomized, controlled study with blinding of the participants
• Interventions:
Study 1: EE 30 μg + levonorgestrel 150 μg administered daily for 21 days/month
with a levonorgestrel-releasing intrauterine system (LNG-IUS)
Study 2: EE 20 μg + gestodene 75 μg daily for 21 days/month with placebo
Gynecol Obstet Invest. 2015;79(3):145-52
1
CLINICAL EVIDENCE

Gynecol Obstet Invest. 2015;79(3):145-52
Control of heavy menstrual bleeding: COCs were less effective than LNG-IUSs
COCs were less effective than LNG-IUSs in achieving QoL improvement
COCs were less effective than LNG-IUSs
COC versus LNG-IUS: 1 RCT (Sayed 2012)
RESULTS

Conclusion: Evidence regarding the use of COCs as treatment for women
with symptomatic fibroids is very scarce and of low quality, and we are very
uncertain about the real efficacy of such treatment.
COC versus Placebo: 1 Quasi-Randomized Controlled Study (Driak 2012)
COCs were better than placebo
1. Gynecol Obstet Invest. 2015;79(3):145-52
RESULTS

Arch Gynecol Obstet (2013) 288:139–148
• Objective: Review the epidemiological and clinical evidence for the association
between oral contraceptives (OCs) and uterine leiomyoma (UL).
• 11 literatures involving 8,990 UL patients and 1,31,055 participants were
included from 3,017 studies
• Influence of OCs on UL risk was assessed by comparing ‘‘ever’’, ‘‘current’’ or
‘‘former’’ users and ‘‘never’’ users
2

Random-effects meta-analysis of case–control and cohort studies that examined OCs use and UL risk
Arch Gynecol Obstet (2013) 288:139–148
Conclusion: Although role of potential bias & evidence of heterogeneity should be
carefully evaluated, the study suggests that uterine leiomyoma (UL) should not be
considered a contra-indication for OCs use.
 Meta-analysis indicated that
OCs use did not increase UL
morbidity.
 Dose–response analysis
showed the risk of UL
morbidity was reduced by 17
% in ‘‘ever’’ users for 5 years
or more.
RESULTS

• Objective: Compared the efficacy of a Levonorgestrel-releasing intrauterine system
(LNG-IUS) with that of a low-dose combined oral contraceptive (COC) in reducing
fibroid-related menorrhagia
• Intervention: 58 women with menorrhagia who desired contraception were
randomized to receive a LNG-IUS or COC
• Outcomes: Treatment failure; menstrual blood loss (MBL) & pictorial assessment chart
(PBAC); hemoglobin levels; and “lost days
International Journal of Gynecology and Obstetrics 112 (2011) 126–130
3

Study endpoints as percentage reduction
 Treatment failed in 6 women (23.1%) in LNG IUS group & 11 (37.9%) in COC group
 Reduction of MBL was significantly greater in the LNG-IUS group.
 PBAC scores: Reduction was also significantly greater in the LNG-IUS group.
 Hemoglobin levels increased from 9.7±1.9 g/dL to 11.7± 1.2 g/dL (Pb0.001) & Lost
days decreased from 8.2±3.3 days to 1.3±1.5 days (P=0.003) in the LNG-IUS group.
International Journal of Gynecology and Obstetrics 112 (2011) 126–130
Conclusion: Although the rate of treatment failure was similar in both groups, the LNG-IUS
was more effective in reducing MBL than the COC in women with fibroid-related menorrhagia
RESULTS

Austin J Obstet Gynecol. 2017; 4(3): 1077
• Randomized, controlled, single-blind, prospective observational study
• 129 patients were randomly divided into 2 groups:
 97 women with 1 or multiple uterine fibroids treated conservatively
with monophasic hormonal pills containing 20mcg of Ethinyl estradiol
and 75mcg of Gestodene were observed for a period of 2 to 4 years.
 32 women in the control group
4

• 74/97 patients (76.3%) treated with monophasic
COC, regression or no changes in growth were
registered, and then were followed-up for 2
years.
26
28
30
32
34
36
Baseline At 2 years
Reduction in Myoma Volume
Myoma Volume
Austin J Obstet Gynecol. 2017; 4(3): 1077
• 13/97 patients (13.4%) growth of fibroids as well
as problems like menorrhagia, anemia, abdominal
pain and dysmenorrhea continued or increased.
• 10 patients: Severe uterine bleeding (approximate blood loss of 300ml), 3 suffered from
abdominal and pelvic pain
• Myoma volumes dropped significantly (p=0.040)
Conclusion: Use of low-dose hormonal contraceptives with progestin dominancy can lead
to significant reduction in myoma volume.
RESULTS

COCs, Tranexamic acid & NSAIDs

Anti-fibrinolytic agents:
• Tranexamic acid is useful in treatment of idiopathic heavy menstrual
bleeding, but has not been well studied in leiomyoma-related heavy
menstrual bleeding
NSAIDs:
• NSAIDs have not been extensively studied in leiomyoma-related heavy
menstrual bleeding. They can be useful in this population as they decrease
painful menses
Other Agents

Selective Progesterone
Receptor Modulators
(SPRMs)

Selective Progesterone Receptor Modulators
(SPRMs)
Steroid progesterone receptor ligands able to induce
agonistic or antagonistic activities.1
Very effective in range of biological activity including
contraception, preoperative treatment of uterine
leiomyomas.2
Mifepristone & Ulipristal acetate have consistently
demonstrated efficacy, & Vilaprisan is currently under
investigation, while studies of Asoprisnil & Telapristone
were halted for safety concerns.3
Treatment needs to be initiated between 1st & 7th day of
menstrual cycle
1. Climacteric. 2018 Aug;21(4):375-379; 2. Sci Rep. 2019 Nov 21;9(1):17279; 3. Endocrine Reviews, October 2020, 41(5):1–52

Mifepristone is well known for
antiglucocorticoid activity & has
beneficial effects, such as decreased
volume & symptoms of uterine
fibroids, but also detrimental effects
including endometrial hyperplasia.1
Ulipristal acetate can effectively
control bleeding, reduce fibroid size,
and improve quality of life without
showing significant adverse events
except for endometrial hyperplasia
without evidence of atypia2
Approved in Canada and Europe as a
presurgical therapy for patients with
uterine fibroids as well as for
emergency contraception in the
United States2
Selective Progesterone Receptor Modulators
(SPRMs)
1. Endocrine Reviews, October 2020, 41(5):1–52; 2. Endocrine Reviews, October 2020, 41(5):1–52

Systematic Review of Mifepristone for the Treatment of
Uterine Leiomyomata
Obstetrics & Gynecology.2004 Jun;103(6):1331-6
OBJECTIVES: To systematically review the effect of Mifepristone on uterine leiomyoma size
and symptoms.
6 studies involving 166 women with symptomatic uterine leiomyomata
The subjects received 5 to 50 mg/d of Mifepristone for 3 to 6 months
RESULTS:
• Mifepristone reduced uterine volumes by 27-49%.
• Mifepristone reduced leiomyoma volume by 26-74%.
• Mifepristone reduced the prevalence and severity of Dysmenorrhea, Menorrhagia, &
Pelvic Pressure.
• Rates of Amenorrhea ranged from 63-100%.
.
Conclusion: Published trials of Mifepristone showed reduction in leiomyoma size &
improvement in symptoms.
1
Mifepristone
CLINICAL EVIDENCE

Meta-analysis of 11 randomized trials with a total of 780 premenopausal
women having leiomyomas
Treatment: Mifepristone 2.5-25 mg for 3-6 months
Results: Mifepristone was effective in
• Reducing fibroid volume and uterine volume
• Alleviating the symptoms
No significant difference in the rate of atypical endometrial hyperplasia
between Mifepristone and placebo
.
Conclusion: We recommend daily treatment with Mifepristone for 3-6
months as optimum clinical treatment for leiomyoma. There is insufficient
evidence of endometrial hyperplasia with Mifepristone.
Effects of mifepristone on uterine
leiomyoma in premenopausal women: a
meta-analysis
Fertility & Sterility.2013;100:1722-6
2

Role of low dose mifepristone in management of
uterine fibroid
• A clinical study in 100 patients with uterine fibroids
• Aged 18-49 years
• Patients were treated with Mifepristone 25 mg/day
• Outcomes: Uterine volume, fibroid volume, PBAC score, numeric pain rating scale
score
Int J Clin Obstet Gynecol 2021;5(1):397-400. PBAC: Pictorial Blood Loss Assessment Chart
3

193.06 191.15
170.45
150
160
170
180
190
200
Baseline Month 1 Month 3
Uterine Volume
66.13
57.42
38.32
0
20
40
60
80
Fibroid Volume
Significant reduction in uterine volume and fibroid volume at 1 month
& 3 months
Int J Clin Obstet Gynecol 2021;5(1):397-400. PBAC: Pictorial Blood Loss Assessment Chart
Significant reduction in PBAC score & Numeric Pain Rating Scale score at 1
month & 3 months
237.69
53.83
14.42
0
50
100
150
200
250
PBAC Score
P<0.001 vs. Baseline
& Month 1
5.17
3.86
1.4
0
2
4
6
Numeric Pain Rating Scale
Score
Conclusion: At the end of 3 months, there was a significant reduction in the amount of
menorrhagia, dysmenorrhea, uterine and fibroid volumes and improvement in Hb levels
Hemoglobin level increased significantly at 1 month and 3 months
P<0.001 vs.
baseline & month 1
RESULTS

• Group 1: Patients treated with Tablet Mifepristone 25mg once daily for 3 months
• Group 2: Patients treated with Inj. Leuprolide acetate depot preparation 3.75mg IM
once a month for 3 months
2019 Study
A marked relief with significant decrease in visual analog scale score in both
the groups (p <0.001)
Treatment with Mifepristone 25 mg daily for three months significantly
reduced bleeding, uterine volume and myoma volume
Asian J Med Res 2019; 8(2) PC01-PC04
4

Conclusion: Treatment with Ulipristal acetate for 13 weeks effectively controlled excessive
bleeding due to uterine fibroids & reduced the size of the fibroids.
Phase III randomized, parallel-group, double-blind trial in 6 countries
Endpoints Controlled
Uterine
Bleeding
Rate of
Amenorrhea
Fibroid
Volume
Ulipristal
5 mg
91% 73% -21%
Ulipristal 10
mg
92% 82% -12%
Placebo+
concomitant
iron (80 mg)
19% 6% +3%
N Engl J Med 2012; 366:409-420
5
RESULTS
Ulipristal Acetate
CLINICAL EVIDENCE

N Engl J Med 2012; 366:421-432
Phase III randomized, parallel-group, double-blind trial
Endpoints Controlled
Uterine
Bleeding
Times of
Amenorrhea
Incidence
of Hot
flashes
Ulipristal
5 mg
90% 7 days 11%
Ulipristal 10
mg
98% 5 days 10%
Leuprolide
Acetate
3.75mg
89% 21 days 40%
Conclusions: Both the 5-mg and 10-mg daily doses of Ulipristal acetate were non-inferior
to once-monthly Leuprolide acetate in controlling uterine bleeding and were significantly
less likely to cause hot flashes
RESULTS
6

UPA= Ulipristal Acetate; NETA= Norethisterone Acetate
Fertil Steril. 2014 Jun;101(6):1565-73.e1-18
Conclusion: Repeated 3-month UPA courses effectively control bleeding and shrink
fibroids in patients with symptomatic fibroids.
Long-term, Phase III open-label trial; Conducted at 21 investigation centers in 4 countries
• 209 women with symptomatic fibroids
including heavy menstrual bleeding.
• Received up to 4; 3-month courses of UPA
10 mg daily, immediately followed by 10-
day double-blind treatment with NETA
(10 mg daily) or placebo
Endpoints Amenorrhea Onset of
Amenorrhea
Change in
fibroid
Volume
1st UPA course 79% 4 days -45%
2nd UPA
course
89% 2 days -63%
3rd UPA
course
88% 3 days -67%
4th UPA
course
90% 3 days -72%
RESULTS
7

RESULTS
8
PEARL IV Study: Phase III multicenter, randomized, double-blind, parallel group,
long-term trial; Conducted at 46 study sites across 11 countries
• 451 patients with symptomatic uterine
fibroid(s) and heavy bleeding.
• 2 repeated 12-week treatment
courses of daily 5 or 10 mg of
Ulipristal acetate
Conclusion: Repeated 12-week courses of daily oral Ulipristal acetate (5 and 10 mg)
effectively control bleeding and pain, reduce fibroid volume, and restore QoL in patients
with symptomatic fibroids.
Endpoints Amenorrhea Reduction in
fibroid
Volume
Ulipristal 5mg 62% 54%
Ulipristal 10mg 73% 58%
Fertil Steril. 2015 Feb;103(2):519-27.e3

• Multicenter, randomized,
double-blind, double-dummy,
parallel-group study
• Patients assigned to 2 arms,
 82 patients: 10 mg of
UPA OD for 12 weeks
 79 patients: 1.88 mg or
3.75 mg of LEU S.C at
weeks 0, 4, and 8
UPA=Ulipristal Acetate; LEU=Leuprorelin Acetate
Fertil Steril. 2021 Jul;116(1):189-197
Efficacy and safety endpoints of Japanese women with symptomatic uterine
fibroids at week 12 of treatment with either ulipristal or leuprorelin.
RESULTS
9

Conclusion
• Effect of UPA on heavy menstrual bleeding was shown to be comparable with that of
LEU in Japanese patients with symptomatic UFs.
• No notable AEs occurred because of the UPA treatment, & the incidence of AEs in the
UPA was comparable with that of AEs in the LEU group.
UPA=Ulipristal Acetate; LEU=Leuprorelin Acetate
Fertil Steril. 2021 Jul;116(1):189-197
• % of patients with amenorrhea for 35
days was 87.0% in the UPA & 81.8% in the
LEU.
• Efficacy of UPA for causing amenorrhea
for 35 days was confirmed to be
noninferior to that of LEU.
• AEs occurred in 78.0% in the UPA & 88.8%
of the patients in the LEU group
RESULTS

SPRMs
J Obstet Gynaecol Can 2015;37(2):157–178

Low dose Mifepristone

Ulipristal acetate (UPA)

Non-Hormonal Therapy
Other important pathways exist which are independent of hormones
Growth factors, early life exposure & inflammation are key factors
Need to take care of all etiological factors of uterine fibroid with non-hormonal
therapy
Hit the newer target of fibroid that is Catechol-O-Methyltransferase (COMT) &
Transforming growth factor-β (TGF-β3)
Acts on both progesterone & estrogen receptors
Treatment can be initiated on any day of menstrual cycle
Curr Opin Obstet Gynecol. 2020 Oct; 32(5): 361–370.

• Objective: To observe the therapeutic effect of Tripterygium wilfordii Hook.
f. on patients with uterine leiomyoma
• Study Design:
N=65 patients
1
Zhonghua Fu Chan Ke Za Zhi. 2000 Jul;35(7):430-2
Tripterygium wilfordii
CLINICAL EVIDENCE

RESULTS
Zhonghua Fu Chan Ke Za Zhi. 2000 Jul;35(7):430-2
Conclusion: Tripterygium wilfordii Hook. f. may be an effective therapeutic agent
for leiomyomas with fewer side effects
• Significant decrease in leiomyoma volume was observed.
• Decrease in mean estradiol & progesterone levels
60%
70%
10%
20%
30%
40%
50%
60%
70%
80%
After 3-4 months After 5-6 months
% of patients showing significant
decrease in Myoma Volume

• Objective: To evaluate the efficacy and safety of green tea extract
(epigallocatechin gallate [EGCG]) on UF burden and quality of life in women
with symptomatic UF
• Study Design:
double-blinded, placebo-controlled randomized study
N=39 reproductive age women
• Dosage:
• 800mg green tea extract OD (45% EGCG) or placebo (800 mg of brown rice)
2
Int J Womens Health. 2013; 5: 477–486
Epigallocatechin gallate [EGCG]

RESULTS
• Epigallocatechin gallate (EGCG) treatment decreases symptom-severity (SS) score
and increases health-related quality-of-life (HRQL) score in patients with uterine
fibroids.
• SS score dramatically decreased and HRQL score dramatically increased with 4
months

RESULTS
• EGCG was associated with significant improvements in the menstrual bleeding
pattern
• Mean hemoglobin levels increased in the treatment group from 11.7 to 12.4 g/dL,
while levels decreased in the placebo group
72 71
88
45
Placebo EGCG
Blood Loss (mL/month)
Before Treatment After Treatment
12.95
11.7
12.5 12.4
Placebo EGCG
Hemoglobin (g/dL)
Before Treatment After Treatment
(P = 0.001)
(P = 0.083)
(P = 0.03)
(P = 0.02)
Conclusion: EGCG shows promise as a safe and effective therapeutic agent for women with
symptomatic UFs. Such a simple, inexpensive, and orally administered therapy can improve
women’s health globally.

• Objective: To evaluate the effect of vit D supplementation on the size of
uterine leiomyoma in women with vit D deficiency.
• Study Design:
double-blinded prospective study
N=69 patients
• Dosage:
• Group A (n=35): Vit. D 50,000 IU every 2 weeks
• Group B (n=34): Placebo
• Duration: 10 weeks
3
Caspian J Intern Med. 2019 Spring; 10(2): 125–131
Vitamin D

RESULTS
• After a 10-week intervention, 25-
hydroxyvitamin D3 levels were
significantly higher in group receiving
vitamin D
• Leiomyomas size in vit D group
significantly decreased as compared
to placebo group
16.25
61.11
36.08
52.58
Vit. D3 Levels Leiomyomas size
Placebo Vit. D
(P < 0.001)
Conclusion: Administration of Vit. D3 may reduce the size of leiomyoma. It seems
that vitamin D administration is the effective way to treat leiomyoma.

• Objective: To verify the effect of combined oral vitamin D and EGCG
supplementation in symptomatic women with myomas
• Study Design:
Pilot study
N=30 patients
• Dosage:
• Group A (n=15): 25mcg Vit. D + 150mg EGCG + 5mg Vit. B6 BID
• Group B (n=15): Placebo
4
Combined Vitamin D + EGCG

RESULTS
• A significant reduction was
observed in the volume of
myomas after 4 months
• The reduction of volume was
independent of the type of
myomas
10.84
10.17
8.04
10.94
0
2
4
6
8
10
12
14
Vit D + EGCG Control
Before treatment After treatment
(P < 0.0001)
-34.8%
Conclusion: The combined supplementation of vitamin D and EGCG seems to be
an optimal approach for the management of myomas and correlated symptoms
(P < 0.001)
+6.9%

Key Takeaways
• Uterine Fibroids: A benign tumor of muscular and fibrous tissues, typically developing
in the wall of the uterus
• Newer prespective of etiology: Increased number of progesterone and estrogen
receptors, increase COMT expression and TGF-β3
• Uterine fibroids can be treated either surgically or medically, however surgical
approach has its own limitations
• Medical therapies for treatment of uterine fibroids are hormonal and non-hormonal
• Treatment of fibroids must be individualized depending on factors, such as patient’s
age, signs & symptoms, sustained reduction of fibroid size, & maintenance or
improvement of fertility, while minimizing side effects.

The more you give, the more you
will get.
Then life will become a sheer dance
of love.
H. H. Sri. Sri. Ravishankar
The Art of Living
Thank you

Medical Management of Fibroids

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