MIOMI IN RIPRODUZIONELe terapie mediche

Prof. R. MarciDpt. of Morphology Surgery and Experimental Medicine

Uterine fibroids are prevalent in adult females

Estimated cumulative incidenceof fibroids

Cum

ulat

ive

inci

denc

eof

fibr

oids

1.0

0.8

0.6

0.4

0.2

0.036 38 40 42 44 46 48

Age (years)

Black

White

Prev

alen

ce o

f clin

ical

lyre

leva

nt fi

broi

ds 0.8

0.4

0.2

0.036 38 40 42 44 46 48

Age (years)

Black

White

Uterine fibroids affect 24 million women in Europe

Estimated prevalence of clinicallyrelevant fibroids

•Age •Race

•Nulliparity•Obesity

REASONS FOR TREATING FIBROIDS

Menorrhagia

Anemia

Pressure symptom

Pelvic pain

Pain on intercourse

Bladder Frequency/incontinence

Planning pregnancy/subfertility

QoLQoL

40% of women with fibroids have significant symptoms

The choice of therapy is influenced by the patient’s

Severity of symptoms

Clinical features of myoma (e.g. volume, localisation)

Age

Uterine preservation wishes

Fertility preservation wishes

THERAPEUTIC APPROACH

Mass effectsrelated to the size

and locationof fibroids 

Pregnancycomplications 

Bleedingcomplaints

These symptoms and consequenceshave been shown to diminish quality of life3

When symptomatic, fibroids can be linkedto at least three major problems3

What are the symptoms?

●Not all fibroids are symptomatic

●However, for the 50% of women with symptomatic fibroids, the condition is debilitating.1

●Symptoms can include:●Abnormal or heavy menstrual bleeding1, 2●Pain,1,2 pressure symptoms1,2 and urinary symptoms2

●Impairment of Quality of Life 2

1. Tropeano G, Amoroso S, Scambia G. Hum. Reprod. Update (2008) 14 (3): 259-274. 2. Downes E, Sikirica V, Gilabert-Estelles J. et al. Eur J Obstet Gynecol Reprod Biol. 2010; 152(1): 96-102.3. Viswanathan M, Hartmann K, McKoy N. et al. Evid Rep Technol Assess (Full Rep). 2007 Jul;(154):1-122. Review.

THERAPEUTIC APPROACH

Currently, therapies are intended to reduce or eliminate

uterine fibroid symptoms through one of the following

options:

Reduction of the size of tumours

Reduction of the amount of bleeding

Removal of the uterine fibroids or uterus

Miller CE, Journal of Minimally Invasive Gynecology 2009; 16:11–21

FIGO Classification

ASYMPTOMATIC FIBROIDS WILL NOT REQUIRE THERAPY

FIBROIDS AND INFERTILITY

Uterine myomas may be identified in approximately 5%–

10% of infertile women

but

only 2%–3% of infertility may be attributed to the effects of

myomas when all other causes are excluded

Myomas and Reproductive Function. The Practice Committee of the American Society for Reproductive Medicine in collaborationwith The Society of Reproductive Surgeons. Fertil Steril 2008;90:S125–30.

Focus on the four features that can possibly impair fertility:

1. Position

2. Size

3. Number

4. Distance from the endometrium

Do all fibroids affect fertility?

Critical and still unsolved question

Uterine fibroids are detected in 5‐10% of women with infertility

impaired gamete transport reduced embryo implantation chronic endometrial inflammation anatomic distortion of the endometrial cavity increased uterine contractility abnormal local hormonal milieu

Fibroids and Infertility

Somigliana et al; Human Reprod Update 2007

Location and size

Do all fibroids affect fertility?

Women presenting fibroids were found to have infertility experience at least 2years.

Buttramand Reiter 1981; Hassan et al., 1990

Submucous fibroids (5-18% of all fibroid cases) are a causal factor of infertility.

Buttramand Reiter 1981; Bernard et al., 2000

Both intramural and subserous fibroids negatively influence patient’s fertilityand pregnancy outcomes.

Seracchiolli et al, 2000; Campo et al, 2003

→ 11% of women with myomas conceived without interven on, compared with 25% of those without myomas and with 42% of women who underwent laparoscopic myomectomy

As shown by published data, the critical factor seems to be the distortion of the uterine cavity:

Donnez & Jadoul (2002)

Do all fibroids affect fertility?POSITION

Fibroid (n) PR/ET (%)

Distorted cavity (65) 9

Not distorted cavity (487) 34

Control (1636) 40

• SM fibroid shows the most detrimental effect

• IM displays a modest impact

• SS has the least impact on PR

Do all fibroids affect fertility?POSITION

Bajekal & Li (2000)

Fibroid (n) PR/ET (%)

Submucous (27) 9

Intramural (44) 16

Subserous (158) 37

Control (2413) 30

all locations

Do all fibroids affect fertility?POSITION

Submucous

Intramural

No intracavitary involvement

Do all fibroids affect fertility?POSITION

Do all fibroids affect fertility?DISTANCE FROM THE ENDOMETRIUM

Somigliana et al. (2007) → updated meta‐analysis of studies investigating the influence of fibroids located at different sites in IVF cycles although based on a small number 

of studies,submucosal lesions appear to strongly interfere with the chance of pregnancy

the impact of intramural myomas is less dramatic even if also statistically significant

• Most investigators did not include size of fibroids as a variable when data analysis wasperformed.

• Five investigators did, however, report fibroid size and stratified their analysis accordingly.Categoric thresholds were 2, 3, 4, 5, and 6 cm.

• None of these studies found any significant difference in fertility outcomes comparedwith groups of infertile women without myomas

Do all fibroids affect fertility?SIZE

Narayan R. J Am Assoc Gynecol Laparosc 1994;1: 307–11Bulletti C. J Am Assoc Gynecol Laparosc 1999;6:441–5Check JH. Hum Reprod 2002;17: 1244–8.Oliveira FG. Fertil Steril 2004;81:582–7Bulletti C. Ann N YAcad Sci 2004;1034:84–92

Feliciani et al, 2003

Do all fibroids affect fertility?NUMBER

Number of fibroids PR (%)

<3 37

>3 28

Control 41

Clinical management

Medical treatment

Expectant Management

Surgical treatment

Hysteroscopic Myomectomy Abdominal Myomectomy Laparoscopic Myomectomy Uterine Artery Embolization Hysterectomy

Pharmacological APPROACH

●Oral contraceptives, Progestogens

●Intrauterine Device (IUD)

●Gonadotrophin-releasing hormone (GnRH) agonist

Benefits Disadvantages

Non-invasive

Uterine fibroid related symptomsreoccur after therapy has ceased

Adverse events Not suitable for long-term therapy

ORAL CONTRACEPTIVES / PROGESTINS

• Treatment of bleeding disorders

• No reduction of myoma size (effect on associated pain is limited)

• Off-label use

• Contraindications in patients with risk factors (age >35 years and

additional risk factor)

OC: a treatment option for irregular menstrual bleeding when not related to fibroids

Not indicated

INTRAUTERINE DEVICE (IUD)

Insertion of an IUD is contraindicated in case of submucosalfibroids

Levonorgestrel-IUD can be used to reduce symptoms in patients without a large uterus distorted by fibroids

However:

– high risk of IUD expulsion (up to 20%)

– the impact on fibroid volume reduction is controversial

Ardaens-Boulier K, Réalités en gynécologie-obstétrique Mars 2011; 152:1-6Zapata LB, Whiteman MK, Tepper NK, Jamieson DJ, Marchbanks PA, Curtis KM. Intrauterine device use among women with uterine fibroids: a

systematic review. Contraception. 2010 Jul;821(1):41-55. Epub 2010 Mar 29

Not indicated

GnRH-AGONIST

Indicated for the preoperative treatment of uterine fibroids size reduction

Used in perimenopausal women to reduce uterine fibroid bulk before the onset of menopause, when uterine fibroids normally decline

The GnRH therapy effects are not immediate and can be associated with symptom worsening due to “the flare-up effect”

Miller CE, Journal of Minimally Invasive Gynecology 2009; 16:11–21

Repeated administration GnRH-a suppresses pituitary stimulation of ovarian oestrogen production

Friedman et al. Obstet Gynecol 1991;77:720–725Lethaby et al. BJOG 2002;109:1097–1108

• This leads to a reduction in:

Bleeding

Fibroid volume

Uterine volume

• However, fibroids return to the pretreatment size 24 weeks after cessation of therapy

Randomised trial: GnRHa vs placeboChange in uterine volume (n=128)[Friedman, 1991]

GnRH-AGONIST

Progesterone receptor ligands can possess activity ranging from pure antagonist activity through mixed antagonist/agonist activity to pure agonist activity

SPRMs are progesterone receptor ligands with mixed antagonist/agonist activity

SELECTIVE PROGESTERONE RECEPTOR MODULATORS (SPRMS)

Progesterone antagonist Progesterone antagonist/agonist

O

CH3

NCH3

H3CC

OHC CH3

RU-486 (Mifepristone)

OH

H

H

N

OCH3

HO

CH2OCH3

J-867 (Asoprisnil)

O

N

CH3

H3C OCH3

OCCH3

O

Ulipristal acetate

O

OOMe

N

OAc

CH3

H3C

Telapristone acetate

N

O

OH OH

ZK98299 (Onapristone)

UPA modulates progesterone effect primarily by targeting fibroids, endometrium and the pituitary gland

UPA exerts direct action on fibroids, reducing their size through the inhibition of cell proliferation and induction of apoptosis

UPA MECHANISMS

OF ACTION

UPA exerts a direct effect on the endometrium and stops uterine bleeding, resulting in benign and reversible changes in the endometrial tissue termed “Progesterone Receptor Modulator Associated Endometrial Changes” (PAEC)

UPA acts on the pituitary gland, inducing amenorrhea by inhibiting LH surge and ovulation and maintaining mid-follicular phase levels of oestradiol

Study design

● Patients with menorrhagia due to uterine fibroids● 4 Courses of 12 weeks of UPA (5 mg or 10 mg)● The “off” period is about 2 months

UPA UPA UPA UPA

UPA 5 mg or 10 mg (double-blind) Menses

Efficacy: Amenorrhoea

p = NS

Percentage of patients in amenorrhoea

UPA 5mgUPA 10mg

Efficacy: Controlled bleeding

p = NS

UPA 5mgUPA 10mg

Efficacy: Fibroid volume reductionMedian change from screening in total fibroid volumea

aVolume of 3 largest fibroids combined* After treatment course + 1 bleed

• Control symptoms in severe bleeders and painfulpatients

• Reduce volume and restore anemia before surgerytrying to reduce the invasiveness in patientcandidate to surgery

• Control the symptoms until the onset of spontaneous menopause and avoid hysterectomy in pre-menopausal women

• Reduce the invasiveness of surgery or allow to postpone surgery after childbearing in Infertile patients and IVF candidates

Donnez J, et al. Hum. Reprod. Update 2016

MEDICAL TERAPY:  TO TREAT SYMPTOMS TO POSTPONE OR AVOID SURGERY

Medical therapy HOW?

Donnez J, et al. Hum. Reprod. Update 2016

• 31 years old, nulliparous

• Primary infertility

• Known myoma already detected (2 years prior)

• No abnormal uterine bleeding

CASE STUDY 1Infertile patient

MRI showedFIGO 2 myoma 37 x 32 x 25

vol 21 cm3

ULIPRISTAL ACETATE 5 mg/day FOR THREE MONTHS

POST TREATMENT RESULTS

Fibroids volume reduction about 66 %

Fibroids volume reduction about 66 %

HyisteroscopyConfirmed an empy uterine cavity

NO IMPACT ON THE MUCOSA

HyisteroscopyConfirmed an empy uterine cavity

NO IMPACT ON THE MUCOSA

MRI showedFIGO-3 myoma 28 x 10 x 12

vol. 7 cm3

Fibroma mygration

- At the hysteroscopy: normal cavity without myoma’s impact on the mucosa

EFFECT ON FIBROID VOLUME REDUCTION

Donnez J, et al. N Engl J Med 2012;366:421−32

PEARL II

POSSIBLE THERAPEUTIC WINDOW TO OBTAIN PREGNANCY

EOT

FIBROID VOLUME REDUCTION IS MAINTAINED DURING FOLLOW-UP AT 6 MONTHS

3-mo

*

-70

-60

-50

-40

-30

-20

-10

0EOT

Follow-upEOT

Follow-up3-mo 6-mo 6-mo 3-mo 6-mo

Follow-up

Changement of surgical approach: hysteroscopylaparoscopy

Decrease in size of myomas- Increases of cleaved caspase 3 inducing proapoptotic effect- Reduces expression of VEGF (suppression of Neovascolaritation and

cell proliferation)- Reduce collagen deposition in the extracellular matrix

• 32 years old

• Primary infertility

• Repeated episodes of menorrhagia

• Pelvic pain unresponsive to common

analgesic treatments

• Asthenia and anemia

CASE STUDY 2Infertile patient with less invasive surgery

Uterine cavity markedly distorted Several submucosal myomas (biggers with size 37 x33 mm and 30 x 28 mm) (FIGO2) Intramural myoma 31 x 40 mm (FIGO3)

ULIPRISTAL ACETATE 5 mg/day FOR THREE MONTHS

POST-TREATMENT RESULTS

Abnormal uterine bleeding and pelvic pain disappeared after 8 days of treatment

AFTER 3 MONTHS

BLEEDING CONTROL IN MORE THAN 90% OF WOMEN – VERY FAST ONSETPEARL II

Donnez J et. al N Engl J Med 2012;366;421-432 (PEARL II)Donnez J et al. N Engl J Med 2012;366;409-420 (PEARL I)

0

20

40

60

80

100

0 10 20 30 40 50 60 70 80 90100

UPA 5 mgUPA 10 mgGnRHa

7 days 

Patie

nts (%)

POST-TREATMENT RESULTS

Abnormal uterine bleeding disappeared after 8 days of treatment

AFTER 3 MONTHS

Fibroids reduction about40 %

Fibroids removal by resectoscopy procedure

Regular endometrial layer no presence of thickeningRegular endometrial layer no presence of thickening

Sonohyisterography Uterine cavity and myometrial echostructure almost regular

Sonohyisterography Uterine cavity and myometrial echostructure almost regular

POST TREATMENT RESULTS

Lo Monte et al. Eur. Rev. Med Pharmacol Sci. 2016: 20:202-207

Other 3 months UPA treatment to reduce the size

of others submucous myoma

Infertile patient with less invasive surgery

Prompt symptoms relief

Fibroids volume significant reduction

Hysteroscopic myomectomy easily performed

Avoidance of invasive surgical approach (laparotomy/laparoscopy)

Improvement of the whole anatomy of the uterus cavity

IVFIVF

Pre‐ART treatment with UPA

IndicationMyomasRecurranceMultipleAdenomyosis

UPA 5mg/day for 3x28Day Wash out ART

PLACE IN THERAPY

UPA may be a good option

for women seeking pregnancy or preserving their fertility

for women who wish to avoid surgery

or before surgery to reduce the invasiveness of the procedures

Conclusion 

• The evidence regarding effect of fibroids on infertility and reproductive outcomes is weak and mostly inconclusive

• Appropriate evaluation and classification of fibroids, particularly those involving or suspected to be in-volving the endometrial cavity is essential

• Submucosal fibroids (FIGO 0-2) should be treated hysteroscopically (or laparoscopic for large 2) to improve conception rates

Recommendations

- Evaluate and classify fibroids

- Preoperative assessment of submucosal fibroids

- Submucosal fibroids are managed hysteroscopically and should be always removed (unexplained infertility)

- Management of intramural fibroids should be individualized

- Laparoscopic approach to myomectomy may be limited by the technicaldifficulty of this procedure.

- Women, fertile or infertile, seeking future pregnancy should not generallybe offered uterine artery embolization.