Leiomyomas (1 of 6)

No

Yes

Yes

No

Medically Surgically

1Patient presents w/ symptoms suggesting leiomyoma or asymptomatic leiomyoma is discovered upon pelvic exam or imaging

2DIAGNOSIS

Do pelvic exam & diagnostic tests confirm leiomyoma?

Is the leiomyoma growing rapidly?

CLINICAL DECISION

Should patient be managed medically

or surgically?

CLINICAL DECISION

Is uterine size <16 weeks & other causes of pelvic mass

have been excluded?

ALTERNATIVE DIAGNOSIS

EXPERT REFERRAL

A Pharmacological therapy

C Patient observation

Yes No

MEDICAL MANAGEMENT

See next page

SURGICAL MANAGEMENT

See next page

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Leiomyomas (2 of 6)

Not all products are available or approved for above use in all countries.Specifi c prescribing information may be found in the latest MIMS.

MEDICAL MANAGEMENT OF LEIOMYOMA

SURGICAL MANAGEMENT OF LEIOMYOMA

A Pharmacological therapy• Gonadotropin releasing

hormone (GnRH) agonist w/ or without estrogen-progestogen add-back therapy

• Selective progesterone receptor modulator (SPRM)

A Surgical pretreatment• GnRH agonist x

2-4 months• Ulipristal acetate x

3 months

Should patient receive pre-

surgical pharmacological therapy?Yes No

1 LEIOMYOMAS

• Also called fi broids, these are benign tumors of the uterus that consist of smooth muscle & extracellular matrix collagen & elastin- � ough pathogenesis is not yet well defi ned, fi broids are thought to develop from the myometrium after a smooth

muscle cell’s neoplastic transformation followed by the formation of a connective tissue component & a pseudocapsule

- Malignant transformation is extremely rare • Most common solid pelvic tumors & one of the most frequent clinical conditions encountered in gynecologic practice• Based on location, fi broids can be submucosal (protruding into the uterine cavity), intramural (found within

the myometrium), or subserosal (protruding outside the uterus) - Fibroid classifi cation may use the European Society for Gynecological Endoscopy (ESGE) or the International

Federation of Gynecology and Obstetrics (FIGO) classifi cation wherein the degree of uterine cavity distortion &/or intramural extension are taken into account

• Tend to grow during reproductive years & usually regress during menopause - Development is stimulated by estrogen & progesterone

• Fibroids occur more often in women of African descent than in Caucasian or Asian women • Factors that increase the risk of uterine fi broids include age >40 years old, early menarche <10 years old, family

history of uterine fi broids, obesity, nulliparity, race (African descent), genetic factors, alcohol & caff eine intake Signs & Symptoms• About 50% of fi broids are asymptomatic• Symptoms vary depending on size, number, & location of the fi broids • Abnormal uterine bleeding clinically manifests as menorrhagia leading to iron-defi ciency anemia • Pelvic mass & pelvic pressure symptoms: Increased abdominal girth, urinary frequency & urgency, urinary

incontinence or retention, dysuria, hydronephrosis, constipation, tenesmus, rectal pressure, low back pain • Infertility, non-cyclic pelvic pain, dyspareunia & dysmenorrhea • Obstetric complications: Rapid growth of the fi broid, red degeneration & pain, spontaneous miscarriage, breech

presentation, preterm delivery, primary cesarean section, low birthweight infants

2 DIAGNOSIS

Physical Exam• Pelvic exam may reveal a palpable enlarged, fi rm, & irregular uterus

- A pelvic mass that moves w/ the uterus is suggestive of fi broids• Myomatous uterus’ size is reported in menstrual week as is a pregnant uterus

- Size of >12 to 20 weeks may be palpated on abdominal exam• Diagnosis can be diffi cult in obese womenLaboratory Test• A CBC to evaluate hemoglobin (Hb) will detect iron-defi ciency anemia in patients w/ heavy menstrual bleeding

B Surgery• Hysterectomy1

• Myomectomy2, 3

• Myolysis3

• Endometrial ablation3

Other interventional therapies:• Uterine artery embolization (UAE)3

• Magnetic resonance-guided focused ultrasound surgery (MRgFUS)3

1Patient who does not wish to retain fertility & uterus2Patient who wishes to retain fertility3Patient who wishes to retain uterus

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Leiomyomas (3 of 6)

Not all products are available or approved for above use in all countries.Specifi c prescribing information may be found in the latest MIMS.

A PHARMACOLOGICAL THERAPYIndications for Medical Treatment• Preserve fertility in women w/ large leiomyomas prior to attempting conception

- May include infertile women of reproductive age who wish to conceive or symptomatic women of reproductive age who wish to preserve their fertility but have no immediate desire for pregnancy

• Symptomatic patients who do not wish future fertility but want to preserve the uterus • Treatment of women near menopause in an eff ort to avoid surgery • Women w/ medical contraindications to surgery• Personal or medical indications for delaying surgery• Option as stand-alone treatment for temporary symptom relief• Can be given as a preoperative adjunct to reduce the size of fi broids, control bleeding & improve Hb levelsGonadotropin Releasing Hormone (GnRH) Agonists• Eg Goserelin, Leuprorelin (Leuprolide), Triptorelin • Given to women in the perimenopausal or preoperative periods; operative & recovery time are both reduced• Actions: Down-regulate GnRH receptors at the pituitary level resulting in signifi cant reductions in follicle

stimulating hormone (FSH), luteinizing hormone (LH) & ovarian steroids, thus producing a hypoestrogenic state• Eff ects: Decrease uterine & myoma volume & improve menorrhagia

- Maximal diminution of uterine & myoma size is achieved within the 1st 12 weeks of therapy- Menorrhagia or related anemia is controlled after the 1st month of treatment - Pressure symptoms are usually relieved in the 1st 2 months- May induce amenorrhea in some women depending on the duration of use

• Approximately half of the women treated will experience leiomyoma regrowth within a few months after treatment cessation

• Treatment duration should be no more than 6 months • Signifi cant side eff ects stem from the state of hypoestrogenism manifesting clinically as hot fl ushes, headaches,

vaginal dryness, depression & bone demineralization • Side eff ects can be alleviated by add-back therapy using estrogen, progestin, or both; however, addition of

hormones may limit the eff ectiveness in treating myoma- Add-back therapy has not been shown to compromise the effi cacy of GnRH agonists

Selective Progesterone Receptor Modulators (SPRMs) • Eg Mifepristone, Ulipristal acetate • Mifepristone reduces heavy menstrual bleeding & uterine & leiomyoma volume • Ulipristal acetate is used for preoperative management of women w/ moderate to severe symptoms of uterine fi broids

- Signifi cantly reduces bleeding & volume of leiomyoma - Patients w/ heavy menstrual bleeding may be off ered up to 4 courses (long-term intermittent therapy) of

Ulipristal acetate if w/ fi broids of ≥3 cm in diameter & Hb level of ≤102 g/L • Benign & reversible changes occur in the endometrial tissue [progesterone receptor modulator associated

endometrial changes (PAEC)] w/ SPRM therapy • Data showed SPRMs are non-inferior to GnRH agonist w/ less bone loss & menopausal side eff ects but w/

higher risk of amenorrhea Pretreatment to Surgery• Pretreatment w/ GnRH agonist for 2-4 months for uterine fi broids is recommended for patients w/ large uterus

(>18 weeks' size) or pre-op anemia - May be given in combination w/ oral iron therapy

• Eff ects: Preoperative Hb is increased, & fi broid & uterine volume is decreased; in hysterectomy, blood loss, duration of operation & complication rates are also decreased

• Ulipristal acetate is given preoperatively for 3 months - Should also be considered in anemic patients prior to surgery

2 DIAGNOSIS (CONT’D)

Diagnostic Tests• Transvaginal ultrasound (TVS): Helpful in assessing the adnexae & growth of myoma • Transvaginal sonohysterography (TVSH): Should be considered if submucosal fi broids & polyps are suspected

- TVSH may avoid the need for diagnostic hysteroscopy in approximately 47% of women who can then proceed to planned operative hysteroscopy

• Magnetic resonance imaging (MRI): May be considered in women in whom the location & nature of the fi broids remain unclear after TVS & TVSH - May also be used in those who wish to avoid discomfort of TVSH- MRI predictors of malignancy include age >45 years, menopausal status, thickening of the endometrium,

presence of intratumoral hemorrhage, nonmyometrial origin, & T2-weighted signal heterogeneity Alternative Diagnosis• Pregnancy, ectopic pregnancy, adenomyosis, ovarian neoplasm, endometriosis, uterine sarcoma, endometrial polyp

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Leiomyomas (4 of 6)

Not all products are available or approved for above use in all countries.Specifi c prescribing information may be found in the latest MIMS.

A PHARMACOLOGICAL THERAPY (CONT’D)Other Medical Treatments of LeiomyomasGnRH Antagonists• Eg Abarelix, Cetrorelix, Ganirelix• Used as injectables, usually at doses of 5 mg twice daily for the initial 2 days followed by 0.8 mg twice daily for

at least 3 months• Action: Directly compete w/ endogenous GnRH for pituitary binding sites suppressing gonadotropin release• Eff ect: Result in a rapid decrease in myoma & uterine volume w/ minor side eff ects; lacks the initial “fl are”

eff ect observed w/ GnRH agonist stimulation Androgenic Agonists• Eg Danazol, Gestrinone• Can treat symptoms of fi broids but are related to frequent side eff ectsAntifi brinolytic Drug• Eg Tranexamic acid• Decreases uterine bleeding, including menorrhagia related to fi broids, but does not reduce volume of fi broidsAromatase Inhibitors• Eg Letrozole, Anastrozole, Fadrozole• Clinical trials have shown reduction in size & symptoms of leiomyomas, though additional studies are needed

to determine its cost eff ectiveness & duration of response Hormonal Contraceptives • Eg Levonorgestrel-releasing intrauterine system, exogenous progestins• Reduce bleeding related to leiomyoma & provide contraception • Do not appear to be eff ective in reducing bulk symptoms Nonsteroidal Anti-Infl ammatory Drugs (NSAIDs)• Used to treat pain, reduce blood loss from fi broids, but do not reduce volume of fi broids Selective Estrogen Receptor Modulator (SERM)• Eg Raloxifene• May be given to women in the perimenopausal or preoperative periods Other � erapeutic Options • � e following are undergoing clinical trials & laboratory investigations to determine their role in the management

of leiomyomas: Elagolix, Relugolix, Asoprisnil, Telapristone, epigallocatechin gallate, Pirfenidone, Tranilast, curcumin, & vitamin D

B SURGERYType of surgery will depend on patient’s age, symptoms & preference, position, size, & number of fi broids & patient’s desire to retain reproduction potential. Asymptomatic leiomyomas do not usually need surgery.Indications for Surgical Treatment• Unresponsiveness to medical treatment• Worsening vaginal bleeding or anemia from abnormal uterine bleeding• Chronic pain (severe dysmenorrhea, dyspareunia or lower abdominal pressure/pain)• Acute pain (prolapsing submucosal leiomyoma or torsion of pedunculated leiomyoma)• Infertility w/ fi broids as the only abnormal fi nding

- Treatment of interstitial or intramural fi broids does not improve fertility • Compression symptoms or discomfort from enlarged uterus• Urinary symptoms (hydronephrosis after complete evaluation)• Rapidly enlarging fi broids in the premenopausal patient or after menopause; enlarging myoma raises the risk

of leiomyosarcoma even though it remains very rare - Other risk factors for leiomyosarcoma are increasing age, pelvic radiation & Tamoxifen use

Hysterectomy• Treatment of choice for patients who have completed childbearing & do not wish to retain their uterus &

fertility or when leiomyosarcoma is detected • May be considered in women w/ severe symptoms uncontrolled by other therapies & informed perimenopausal

women w/ symptomatic fi broids • � e least invasive approach must be chosen for patients who will be undergoing hysterectomy• Increases the risk for urinary stress incontinence & pelvic prolapse• Hormone therapy is needed to prevent premature menopauseAbdominal Hysterectomy• Subtotal hysterectomy (uterus removed & cervix preserved) is a potential alternative to total hysterectomy

(both uterus & cervix are removed) because of reduced complications• Associated w/ prolonged hospital stayLaparoscopic Hysterectomy• Preferred over laparotomy for fi broids appearing typical on imaging • Benefi ts include less postoperative pain & faster recovery

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Leiomyomas (5 of 6)

B SURGERY (CONT’D)Laparoscopic Hysterectomy (Cont’d)• Use of laparoscopic power morcellation should be limited to reproductive-aged women who cannot undergo en

bloc uterine resection- Inform patient about the risks & complications of the procedure including spread of cancer from a rare

fi broid w/ an unexpected malignancy, though there are now containment systems for power & manual morcellation wherein tissue fragmentation can be done inside an enclosed container

Vaginal Hysterectomy• Has less blood loss & shorter surgery time, paralytic ileus time & hospitalization as compared w/ laparoscopically

assisted vaginal hysterectomy or total laparoscopic hysterectomy • Use is limited by the size of the myomatous uterusMyomectomy• Recommended in symptomatic women who wish to preserve fertility or symptomatic women who do not wish

preservation of fertility but want to preserve the uterus • Size & location of fi broids determine the most appropriate approach• Approximately 10% of women treated w/ myomectomy would eventually undergo hysterectomy within 5-10 years• Leiomyomas in pregnancy are not an indication for myomectomy

- Exception are women who have had a previous pregnancy w/ complications related to fi broidsAbdominal Myomectomy • Used to remove large or multiple fi broids that have grown deep into the uterine wall• Requires the longest hospital stay & recovery timeLaparoscopic Myomectomy• May be used to remove isolated fi broids ≤8 cm in diameter that have grown on the outside of the uterus• Preferable over abdominal myomectomy in women who wish to preserve their reproductive potential• Provides more rapid recovery & less postoperative complications • No signifi cant diff erence is noted in the reproductive outcomes when laparoscopic & abdominal myomectomy

are compared Hysteroscopic Myomectomy• Preferred therapy to remove symptomatic fi broids that have grown from the uterine wall into the uterine cavity

or submucosal fi broids <4 cm in length in women who want to preserve their fertility • Least invasive & has the shortest recovery timeMyolysis & Cryomyolysis• Considered a uterine-sparing alternative to myomectomy in select patients ≥40 years who do not desire future fertility• Myolysis employs a high-frequency electric current while cryomyolysis uses extreme cold to destroy the blood

supply to the fi broids- Recent development is the ultrasound-guided radiofrequency myolysis for myoma treatment

• Cannot be performed if leiomyomas are >10 cm or <3 cmEndometrial Ablation• Surgical procedure to destroy the entire uterine lining w/ electricity, laser, freezing, microwaves or radiofrequency

energy; needs surgical priming• Second generation techniques may be used to treat submucosal fi broids • May be employed when abnormal uterine bleeding is the main symptom w/ uterine fi broids <3 cm, & fertility

is no longer desired Other Interventional � erapiesUterine Artery Embolization (UAE)• Percutaneous procedure that involves no general anesthesia or surgical incision• Option for symptomatic women of reproductive age who are not interested in childbearing but wish to preserve

the uterus &/or avoid surgery• May be off ered to patients as a validated option to hysterectomy & myomectomy• Action: Occlusion of uterine arteries disrupts the blood supply to fi broids leading to infarction• Eff ects: Improvement in fi broid-associated symptoms, preservation of the uterus & obviation of the potential

complications & lengthy recovery associated w/ surgery - Studies w/ patient follow-up after 5-7 years have shown that UAE provides durable symptom relief & improves

quality of life Magnetic Resonance-Guided Focused Ultrasound Surgery (MRgFUS)• Uses focused high-energy ultrasound waves to destroy fi broid tissue • A noninvasive approach w/ shorter recovery time • Volume reduction is less than the mean levels seen after both myomectomy & UAE• May be considered in symptomatic women who do not wish preservation of fertility but want to preserve the uterus All surgical alternatives to hysterectomy allow the formation of new leiomyomas & rapid growth of preexisting leiomyomas, which may eventually require hysterectomy

C PATIENT OBSERVATION• Record location of palpable leiomyomas• Re-assess if new symptoms occur • Periodically repeat exams to ensure tumors are not growing rapidly• Medical preoperative therapy causes regression in the size of the fi broids so much so that in some cases, surgery

may not be required • As most fi broids decrease in size during menopause, asymptomatic patients may have expectant management

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Leiomyomas (6 of 6)

Dosage Guidelines

DRUGS ACTING ON THE UTERUS

Drug Dosage Remarks

Ulipristal acetate

5 mg PO 24 hrly for up to 3 mth before surgeryTreatment should be started during the 1st wk of the menstrual cycleRe-treatment courses should start at the earliest during the 1st wk of the 2nd menstruation following completion of previous treatment course Max dose: 4 courses

Adverse Reactions• GI eff ects (abdominal pain, nausea); CNS eff ects

(headache, dizziness, myalgia, fatigue); Other eff ects (pelvic pain, skin reactions, hot fl ushes, breast tenderness, amenorrhea, endometrial thickening)

Special Instructions• Monitor LFTs before, during & after stopping

treatment • Use w/ caution in patients w/ severe renal or

hepatic impairment• Avoid in patients w/ severe asthma uncontrolled by

oral glucocorticoids, uterine, cervical, ovarian or breast cancer, genital bleeding of unknown etiology

• Patients on Ulipristal acetate should avoid any progestin within 12 days of stopping Ulipristal acetate

TROPHIC HORMONES & RELATED SYNTHETIC DRUGS

Drug Dosage Remarks

Gonadotropin Releasing Hormone Analogues

Goserelin 3.6 mg depot inj SC into the anterior abdominal wall every 28 daysAdminister w/ Fe supplement Duration: Up to 3 mth prior to surgery

Adverse Reactions• Hypoestrogenism (transient vaginal bleeding, hot

fl ushes, vaginal dryness, decreased libido, breast tenderness, insomnia, depression, irritability & fatigue, decreased elasticity of the skin, headache, osteoporosis after several wk of treatment); GI eff ects (nausea, abdominal discomfort); Other eff ects (transient increase in menstrual bleeding, reduction in glucose tolerance can develop, changes in serum lipids & hepatic eff ects, hypersensitivity reactions)

Special Instructions• Add-back strategy w/ estrogen/progesterone can

eliminate most of these side eff ects• OCs should be discontinued prior to therapy &

other non-hormonal methods of birth control should be used- In later stages of treatment, pregnancy is

unlikely as long as recommended doses are administered

Leuprorelin 1.88 mg inj SC/IM once mthly or 3.75 mg depot inj SC/IM once mthly or 11.25 mg depot inj IM as a single dose every 3 mthStart therapy during the 1st 5 days of the menstrual cycleAdminister w/ Fe supplementDuration: Up to 6 mth may be used up to 3 mth prior to surgery

Triptorelin 3.75 mg depot inj SC/IM every 28 days or 0.5 mg SC inj/day for 7-10 days, followed by 0.1 mg SC inj/day Start therapy during the 1st 5 days of the menstrual cycleDuration: Up to 6 mth

Please see the end of this section for the reference list.

All dosage recommendations are for non-elderly adults w/ normal renal & hepatic function unless otherwise stated.Not all products are available or approved for above use in all countries.

Products listed above may not be mentioned in the disease management chart but have been placed here based on indications listed in regional manufacturers’ product information.

Specifi c prescribing information may be found in the latest MIMS.

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