CLINICAL SCIENCE SESSION

UTERINE FIBROID

Supervised by:

dr. Bogie Prabowo SpOG(K)

Presented by:

Dwiki Wahyu Pratama

Muhammad Faisal

DEPARTMENT OF OBSTETRIC AND GYNECOLOGY

FACULTY OF MEDICINE UNIVERSITAS PADJADJARAN

RSUD WALED KABUPATEN CIREBON

PERIOD: FEBRUARY 25th – MARCH 2nd 2019

 CONTENT

DEFINITION .................................................................................................................................3

CLASSIFICATION .......................................................................................................................3

INCIDENCE ...................................................................................................................................4

ETIOLOGY ....................................................................................................................................4

RISK FACTOR ..............................................................................................................................5

SIGN & SYMPTOMS ...................................................................................................................7

DIAGNOSIS .................................................................................................................................10

FIBROIDS AND PREGNANCY ................................................................................................12

TREATMENT ..............................................................................................................................14

NEW APPEARANCE OF FIBROID .........................................................................................17

REFERENCES .............................................................................................................................20

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 DEFINITION

Uterine fibroid also known as leiomyomas or uterine myomas, is a benign and monoclonal
tumors of the smooth muscle cells of the myometrium and contain large aggregation of ECM
composed of collagen, elastin, fibronectin, and proteoglycan.

CLASSIFICATION

Based on its location, FIGO classified it as 4 fibroids:

1. Submucosal fibroids
2. Intramural fibroids
3. Subserosal fibroids
4. Transmural fibroids

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 INCIDENCE

Fibroids are remarkably common. Fine serial sectioning of uteri from 100 consecutive
women subjected to hysterectomy discovered fibroids in 77%, some as small as 2 mm. A random
sampling of women ages 35 to 49, screened by self-report, medical record review, and sonography,
found that among African American women by age 35 the incidence of fibroids was 60%, and it
was over 80% by age 50. White women have an incidence of 40% at age 35 and almost 70% by
age 50.

ETIOLOGY

Genetic

Fibroids are monoclonal and about 40% have chromosomal abnormalities that include,
- translocations between chromosomes 12 and 14,
- deletions of chromosome 7, and
- trisomy of chromosome12.
Cellular, atypical, and large fibroids are most likely to show chromosomal abnormalities. The
remaining 60% may have as yet undetected mutations.
More than 100 genes were found to be up- or down-regulated in fibroid cells. Many of
these genes appear to regulate cell growth, differentiation, proliferation, and mitogenesis. Collagen
types I and III are abundant, but collagen fibrils are in disarray, much like the collagen found in
keloid formation.
Genetic differences between fibroids and leiomyosarcomas indicate that leiomyosarcomas
do not result from the malignant degeneration of fibroids. Cluster analysis of 146 genes found that
the majority is down-regulated in leiomyosarcomas but not in fibroids or myometrium.
Comparative genomic hybridization did not find specific anomalies shared by fibroids and
leiomyosarcomas.

Hormonal

Both estrogen and progesterone appear to promote the development of fibroids. Fibroids are,
- rarely observed before puberty,
- are most prevalent during the reproductive years, and

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 - regress after menopause.
Factors that increase overall lifetime exposure to estrogen, such as obesity and early menarche,
increase the incidence and decreased exposure to estrogen found with smoking, exercise, and
increased parity is protective.

Growth Factor

Growth factors, proteins, or polypeptides, produced locally by smooth muscle cells and
fibroblasts, appear to stimulate fibroid growth primarily by increasing extracellular matrix. Many
of these growth factors are overexpressed in fibroids and either increase smooth muscle
proliferation (TGF-β, bFGF), increase DNA synthesis (EGF, PDGF), stimulate synthesis of
extracellular matrix (TGF-β), promote mitogenesis (TGF-β, EGF, IGF, PRL), or promote
angiogenesis (bFGF, VEGF).

RISK FACTOR

Age

The incidence of fibroids increases with age,

- 4.3 per 1,000 woman-years for 25 to 29 year olds and

- 22.5 per 1,000 woman-years for 40 to 44 year olds.

African American women develop fibroids at an earlier age than white women.

Endogenous Hormonal Factor

Greater exposure to endogenous hormones, as found with early menarche (younger than
10 years of age) increases and late menarche decreases the likelihood of having uterine fibroids.
Fibroids are smaller, less numerous, and have smaller cells in hysterectomy specimens from
postmenopausal women, when endogenous estrogen levels are low.

Family History

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 First-degree relatives of women with fibroids have a 2.5 times increased risk of developing
fibroids. Monozygous twins are reportedly hospitalized for treatment of fibroids more often than
heterozygous twins, but these findings may be the result of reporting bias.

Ethnicity

African American women have a 2.9 times greater risk of having fibroids than white
women, unrelated to other known risk factors. African American women have fibroids develop at
a younger age and have more numerous, larger, and more symptomatic fibroids. It is unclear
whether these differences are genetic or result from known differences in circulating estrogen
levels, estrogen metabolism, diet, or environmental factors.
Weight

A prospective study found that the risk of fibroids increased 21% with each 10 kg increase
in body weight, and with increasing body mass index (BMI). Similar findings were reported in
women with greater than 30% body fat. Obesity increases conversion of adrenal androgens to
estrone and decreases sex hormone binding globulin. The result is an increase in biologically
available estrogen, which may explain an increase in fibroid prevalence and/or growth.

Diet

Few studies examined the association between diet and the presence or growth of fibroids.
A diet rich in beef, other red meat, and ham increased the incidence of fibroids, while a diet rich
in green vegetables decreased this risk. These findings are difficult to interpret because calorie and
fat intake were not measured.

Exercise

Women in the highest category of physical activity (approximately 7 hours per week) were
significantly less likely to have fibroids than women in the lowest category (less than 2 hours per
week).

Oral Contraceptive

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 There is no definite relationship between oral contraceptives and the presence of fibroids.
An increased risk of fibroids with oral contraceptive use was reported, but a subsequent study
found no increased risk with use or duration of use. Studies in women with known fibroids who
were prescribed oral contraceptives showed no increase in fibroid growth. The formation of new
fibroids does not appear to be influenced by oral contraceptive use.

Pregnancy

Increasing parity decreases the incidence and number of clinically apparent fibroids. The
remodeling process of the postpartum myometrium, a result of apoptosis and dedifferentiation,
may be responsible for the involution of fibroids. Another theory postulates that the vessels
supplying fibroids regress during involution of the uterus, depriving fibroids of their source of
nutrition.

Smoking

Smoking reduces the incidence of fibroids. Reduced conversion of androgens to estrone,

caused by inhibition of aromatase by nicotine, increased 2-hydroxylation of estradiol, and
stimulation of higher levels of sex hormone–binding globulin (SHBG) decrease bioavailability of
estrogen.

Tissue Injury

Cellular injury or inflammation resulting from an environmental agent, infection, or

hypoxia was proposed as a mechanism for initiation of fibroid formation. Repetitive tissue injury
to the endometrium and endothelium might promote the development of monoclonal smooth
muscle proliferations in the muscular wall. Frequent mucosal injury with stromal repair
(menstruation) may release growth factors that promote the high frequency of uterine fibroids.

SIGN AND SYMPTOMS

Abnormal Bleeding

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 The association of fibroids with menorrhagia is not clearly established. Therefore, other
possible etiologies, including coagulopathies such as von Willebrand’s disease, should be
considered in a woman with heavy menstrual bleeding. A random sample of women aged 35 to 49
was evaluated by self-reported bleeding patterns and by abdominal and transvaginal sonography
to determine the presence, size, and location of fibroids.
Of the 878 women screened, 564 (64%) had fibroids and 314 (36%) did not. Forty-six
percent of women with fibroids reported, “gushing blood” during menstrual periods, compared
with 28% without fibroids. Gushing blood and length of periods were related to the size of fibroids
but not to the presence of submucous fibroids or multiple fibroids.
Another study found that women with fibroids used 7.5 pads or tampons on the heaviest
day of bleeding compared with 6.1 pads or tampons used by women without fibroids. Women with
fibroids larger than 5 cm had slightly more gushing and used about three more pads or tampons on
the heaviest day of bleeding than women with smaller fibroids.
However, several theories have been proposed to account for the bleeding that is seen in
association with fibroids. These include
- Increase in the uterine surface area
- Increased vascularity and vascular flow into the uterus
- Reduction in myometrial contractility particularly of the inner junctional zone,
- Endometrial ulceration over a submucosal leiomyoma, and
- Compression of the venous plexus within the myometrium leading to congestion of
myometrium and endometrium
There is limited objective evidence for many of these suggested pathogenetic mechanism. There
is no consistent relationship between the size and location of fibroids and abnormal bleeding. Some
other theories include , dysregulation of normal vascular function and angiogenic growth factor,
and composition of the leukocytes in overlying endometrium.

Urinary Symptoms

Fibroids may cause urinary symptoms, although few studies examined this association.
Following uterine artery embolization with a 35% reduction in mean uterine volume, frequency
and urgency were greatly or moderately improved in 68% of women, slightly improved in 18%,

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and unchanged or worse in only 14%. This finding suggests that increased uterine volume
associated with fibroids is related to urinary symptoms.

Fourteen women with large fibroids and urinary symptoms were given six monthly
injections of GnRH agonist (GnRH-a) with a resulting 55% decrease in uterine volume. Following
therapy, urinary frequency, nocturia, and urgency decreased. There were no changes in urge or
stress incontinence as measured by symptoms or urodynamic studies. It is not clear whether these
findings are related to a decrease in uterine volume or to other effects of GnRH treatment.

Pain

Women with fibroids are only slightly more likely to experience pelvic pain than women
without fibroids. Transvaginal sonography was performed on a population-based cohort of 635
non-care-seeking women with an intact uterus to determine the presence of uterine fibroids.
Dyspareunia, dysmenorrhea, or noncyclic pelvic pain was measured by visual analog scales.
The 96 women found to have fibroids were only slightly more likely to report moderate or
severe dyspareunia or noncyclic pelvic pain and had no higher incidence of moderate or severe
dysmenorrhea than women without fibroids. Neither the number nor the total volume of fibroids
was related to pain. However, women who present for clinical evaluation for fibroid-associated
pain may be different from those in the general population.
Fibroid degeneration may cause pelvic pain. As fibroids enlarge, they may outgrow their
blood supply, with resulting cell death. Types of degeneration determined both grossly and
microscopically include hyaline degeneration, calcification, cystic degeneration, and hemorrhagic
degeneration. The type of degeneration appears to be unrelated to the clinical symptoms. Pain from
fibroid degeneration is often successfully treated with analgesics and observation. Torsion of a
pedunculated subserosal fibroid may produce acute pelvic pain that requires surgical intervention.
There is such thing called red degeneration, occasionally seen as a complication of
pregnancy (during pregnancy or immediate postpartum period). The pathogenesis is unknown,
may be the result of the accumulation of blood in the tumour because of venous obstruction. The
cut surface resembles raw meat. Some clinical features include, acute pain, fever, rapid growth,
and tenderness

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 DIAGNOSIS

Gynecology Examination

Clinically significant subserosal and intramural fibroids can usually be diagnosed by pelvic
examination based on findings of an enlarged, irregularly shaped, firm and nontender uterus.
Uterine size assessed by bimanual examination, even for most women with BMI greater than 30,
correlates well with uterine size and weight at pathological examination.
Routine sonographic examination is not necessary when the diagnosis is almost certain.
However, a definite diagnosis of submucous fibroids often requires saline-infusion sonography,
hysteroscopy, or magnetic resonance imaging (MRI).

Fibroid Location

The FIGO fibroid classification system categorizes submucous, intramural, subserosal, and
transmural fibroids.
Type 0 - intracavitary (e.g., a pedunculated submucosal fibroid entirely within the cavity)
Type 1 - less than 50% of the fibroid diameter within the myometrium
Type 2 - 50% or more of the fibroid diameter within the myometrium
Type 3 - abut the endometrium without any intracavitary component
Type 4 - intramural and entirely within the myometrium, without extension to either the
endometrial surface or to the serosa
Type 5 - subserosal at least 50% intramural
Type 6 - subserosal less than 50% intramural
Type 7 - subserosal attached to the serosa by a stalk
Type 8 - no involvement of the myometrium; includes cervical lesions, those in the round
or broad ligaments without direct attachment to the uterus, and “parasitic” fibroids Transmural
fibroids are categorized by their relationship to both the endometrial and the serosal surfaces, with
the endometrial relationship noted first, e.g., type 2–3.

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Imaging/USG

For symptomatic women, consideration of medical therapy, noninvasive procedures, or

surgery often depends on an accurate assessment of the size, number, and position of fibroids.
Transvaginal sonography (TVS), saline-infusion sonography (SIS), hysteroscopy, and MRI were
all performed on 106 women scheduled for hysterectomy and the findings were compared to
pathologic examination.
Submucous fibroids were best identified with MRI (100% sensitivity, 91% specificity).
Identification was about equal with transvaginal sonography (sensitivity 83%, specificity 90%),
saline-infusion sonography (sensitivity 90%, specificity 89%), and hysteroscopy (sensitivity 82%,
specificity 87%). MRI is not technique dependent and has low interobserver variability for
diagnosis of submucous fibroids, intramural fibroids, and adenomyosis when compared with TVS,
SIS, and hysteroscopy.
MRI allows evaluation of the number, size, and position of submucous, intramural, and
subserosal fibroids and can evaluate their proximity to the bladder, rectum, and endometrial cavity.
MRI helps define what can be expected at surgery and might help the surgeon avoid missing
fibroids during surgery.
For women who wish to preserve fertility, MRI to document location and position relative to the
endomyometrium may be helpful prior to hysteroscopic, laparoscopic, or abdominal
myomectomy.
Sonography is the most readily available and least costly imaging technique to differentiate
fibroids from other pelvic pathology and is reasonably reliable for evaluation of uterine volume

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less than 375 cc and containing four or fewer fibroids. Sonographic appearance of fibroids can be
variable, but often they appear as
- symmetrical,
- well-defined,
- hypoechoic and
- heterogenous masses.
Areas of calcification or hemorrhage may appear hyperechoic, while cystic degeneration
may appear anechoic. SIS utilizes saline inserted into the uterine cavity to provide contrast and
better defines submucous fibroids.

FIBROIDS AND PREGNANCY

Incidence
The prevalence of fibroids among pregnant women is,
- 18% in African American women,
- 8% in white women, and
- 10% in Hispanic women,
based on first trimester sonography. Mean size of the fibroids was 2.5 cm. Clinical examination
detects 42% of fibroids greater than 5 cm during pregnancy, but only 12.5% when they are less
than 5 cm.

Effect of Pregnancy on Fibroids

Most fibroids do not increase in size during pregnancy. Pregnancy has a variable, and
unpredictable, effect on fibroid growth, likely dependent on individual differences in fibroid gene
expression, circulating growth factors, and fibroid-localized receptors.
A prospective study of 36 pregnant women with a single fibroid discovered during routine
first trimester sonographic screening and examined by sonography at 2- to 4-week intervals found
that 69% of the women had no increase in fibroid volume throughout pregnancy. In the 31% of
women noted to have an increase in volume, the greatest increase occurred before the 10th week
of gestation. There was no relationship between initial fibroid volume and fibroid growth during

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gestational periods. A reduction in fibroid size toward baseline measurements was observed 4
weeks after delivery.

Fibroids Degeneration during Pregnancy

In women noted to have fibroids during pregnancy, clinical symptoms and sonographic
evidence of fibroid degeneration occurs in about 5%.
Among 113 women followed during pregnancy with serial sonography, 10 (9%) developed
anechoic spaces or coarse heterogenous patterns consistent with fibroid degeneration. Seven of 10
women had severe abdominal pain requiring hospitalization, consistent with clinical symptoms of
degeneration.
No sonographic changes were noted in the other 103 women, and only 11.7% had similar
abdominal pain. A small study of women with fibroid-associated pain during pregnancy found use
of ibuprofen shortened the hospital stay and decreased the rate of readmission.

Influence of Fibroids during Pregnancy

Very rarely does the presence of a fibroid during pregnancy lead to an unfavorable
outcome. Research was conducted on large populations of pregnant women examined with routine
second trimester sonography with follow-up care and delivery at the same institution. In a study
of 12,600 pregnant women, the outcomes of 167 women with fibroids were no different with
regard to the incidence of preterm delivery, premature rupture of membranes, fetal growth
restriction, placenta previa, placental abruption, postpartum hemorrhage, or retained placenta.
Cesarean section was more common among women with fibroids (23% vs. 12%).
The other study of 15,104 pregnancies, including 401 women with fibroids, found no
increased risk of premature rupture of membranes, operative vaginal delivery, chorioamnionitis,
or endometritis. However, there were increased risks of
- preterm delivery (19.2% vs. 12.7%),
- placenta previa (3.5% vs. 1.8%), and
- postpartum hemorrhage (8.3% vs. 2.9%).
- Cesarean section was again more common (49.1% vs. 21.4%).
Fetal injury attributed to mechanical compression by fibroids is uncommon. A search of
the PubMed database from 1980 to 2010 revealed one case of fetal head anomalies with fetal

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growth restriction, one case of a postural deformity, one case of a limb reduction, and one case of
fetal head deformation with torticollis.
Any decision to perform a myomectomy in order to prevent problems during pregnancy
should take into account the risks of surgery, anesthesia, postoperative adhesions, and an increased
likelihood of subsequent cesarean delivery, along with concerns about discomfort, expense, and
time away from work or family.

TREATMENT

Watchful Waiting

Not having treatment for fibroids rarely results in harm, except for women with severe
anemia from fibroid-related menorrhagia or hydronephrosis from ureteric obstruction from an
massively enlarged fibroid uterus. Predicting future fibroid growth or onset of new symptoms is
not possible.
During observation, the average fibroid volume increases 9% per year with a range of
−25% to +138%. A nonrandomized study of women with uterine size 8 weeks or greater who
chose watchful waiting found that 77% of women had no significant changes in the self-reported
amount of bleeding, pain, or degree of bothersome symptoms at the end of 1 year. Furthermore,
mental health, general health, and activity indexes were also unchanged. Of the 106 women who
initially chose watchful waiting, 23% opted for hysterectomy during the course of the year.
Therefore, for women who are mildly or moderately symptomatic with fibroids, watchful
waiting may allow treatment to be deferred, perhaps indefinitely. As women approach menopause,
watchful waiting may be considered, because there is limited time to develop new symptoms and
after menopause, bleeding stops and fibroids decrease in size. Although not specifically studied,
the incidence of hysterectomy for fibroids declines considerably after menopause, suggesting that
there is a significant decline in symptoms.

Medical Therapy

- Non-Steroidal Anti-Inflammatory Medication

- Gonadotropin-Releasing Hormone Agonist

- Gonadotropin-Releasing Hormone Antagonist

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 - Progesterone-mediated Medical Treatment

- Progesterone-Releasing Intrauterine Device

- Alternative Medicine Treatment

Surgical Therapy

- Abdominal Myomectomy

- Laparoscopic Myomectomy

- Hysteroscopic Myomectomy

- Endometrial Ablation

- Abdominal, Vaginal, or Laparoscopic Hysterectomy

Uterine Artery Embolization

- Candidate (some criteria*):

o Women who have bothersome enough symptoms to warrant hysterectomy or

myomectomy

o Women who not consider fertility (Some Radiologist)

o Woman accept hysterectomy as life-saving necessite from complication

Unfortunately, embolization used on large fibroids can result in die-off and expulsion of
the fibroid tumor, which can result in an infection. Material from the fibroid sloughing off from
the lining of the uterus can provide a site for bacterial growth and lead to infection of the uterus
(endomyometritis). While many uterine infections can be treated with antibiotics, in extreme cases,
the infection if unresponsive to antibiotics may require a hysterectomy.

- Contraindications (some criteria*):

o Active genital infection

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 o Genitral Tract Malignancy

o Diminished immune status

o Severe vascular disease that limit access to uterine arteries

o Contrast allergy

o Impaired renal fuction

Focused Ultrasound

Ultrasound energy can be focused to create sufficient heat at a focal point so that protein
is denatured and cell death occurs. Concurrent MRI allows precise targeting of tissue and
monitoring of therapy by assessing the temperature of treated tissue. The advantages of this
procedure are a very low morbidity and a very rapid recovery, with return to normal activity in
one day.
The procedure is not recommended for women wishing future fertility. Initial studies had
treatment limited by the U.S. Food and Drug Administration to approximately 10% of fibroid

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volume, and while a 15% reduction in fibroid size was reported 6 months following treatment,
only a 4% reduction was noted at 24 months. More recent studies with larger treatment areas
reported better results; 6 months after treatment, the average volume reduction was 31% (+/−28%).

NEW APPEARANCE OF FIBROID

Although new fibroids may sometimes develop following myomectomy, most women will
not require additional treatment. If the first surgery is performed in the presence of a single fibroid,
only 11% of women will need subsequent surgery. If multiple fibroids are removed during the
initial surgery, only 26% will need subsequent surgery (mean follow-up 7.6 years). Individual
fibroids, once removed, do not grow back. Fibroids detected after myomectomy, often referred to
as “recurrence,” result either from failure to remove fibroids at the time of surgery or they are
newly developed fibroids.
Perhaps this circumstance is best designated “new appearance” of fibroids. Sonography
found that 29% of women had persistent fibroids 6 months after myomectomy. Additionally, the
background formation of new fibroids in the general population should be considered. As
previously noted, a hysterectomy study found fibroids in 77% of specimens from women who did
not have a preoperative diagnosis of fibroids. Incomplete follow-up, insufficient length of follow-
up, the use of either transabdominal or transvaginal sonography (with different sensitivity),
detection of very small clinically insignificant fibroids, or use of calculations other than life-table
analysis confound many studies of new fibroid appearance.

Clinical Follow-Up

Self-reported diagnosis based on symptom questionnaires has reasonably good correlation

with sonographic or pathologic confirmation of significant fibroids and may be the most
appropriate method of gauging clinical evidence of new appearance. One study of 622 patients
ages 22 to 44 at the time of surgery and followed over 14 years found the cumulative new
appearance rate based on clinical examination and confirmed by ultrasound was 27%. An excellent
review of life-table analysis studies found a cumulative risk of clinically significant new
appearance of 10% 5 years after abdominal myomectomy.

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Sonographic Follow-Up

Routine ultrasound follow-up is sensitive but detects many clinically insignificant fibroids.
One hundred forty-five women, mean age 38 (range, 21 to 52), were followed after abdominal
myomectomy with clinical evaluation every 12 months and transvaginal sonography at 24 and 60
months (sooner, with clinical suspicion of new fibroids).
However, no lower size limit was used for the sonographic diagnosis of fibroids and, thus,
the cumulative probability of new appearance was 51% at 5 years. A study of 40 women who had
a normal sonogram 2 weeks following abdominal myomectomy found that the cumulative risk of
sonographically detected new fibroids larger than 2 cm was 15% over 3 years.

Need for Subsequent Surgery

Meaningful information for a woman considering treatment for her fibroids is the approximate risk
of developing symptoms that would require yet additional treatment. A study of 125 women
followed by symptoms and clinical examination after a first abdominal myomectomy found that a
second surgery was required during the follow-up period (average 7.6 years) for 11% of women
who had one fibroid removed initially and for 26% of women who had multiple fibroids removed.
Crude rates of hysterectomy after myomectomy vary from 4% to 16% over 5 years.

Prognostic Factors Related to New Appareance of Fibroid

Age - Given that the incidence of fibroids increases with increasing age, 4 per 1,000 woman-years
for 25- to 29-year-olds and 22 per 1,000 for 40- to 44-year-olds, new fibroids would be expected
to form as age increases, even following myomectomy.

Subsequent Childbearing - The 10-year clinical new appearance rate for women who subsequently
gave birth was 16%, but for those women who did not the rate was 28%.
Number of Fibroids Initially Removed - After at least 5 years of follow-up, 27% of women who
initially had a single fibroid removed had clinically detected new fibroids and 59% of women with
multiple fibroids initially removed had new fibroids.
Gonadotropin Releasing Hormone Agonist - Preoperative treatment with GnRH-a decreases
fibroid volume and may make smaller fibroids harder to identify during surgery. A randomized
study found that 3 months following abdominal myomectomy, 5 (63%) of 8 women in the GnRH

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group had fibroids less than 1.5 cm detected sonographically, while only 2 of 16 (13%) untreated
women had small fibroids detected.
Laparoscopic Myomectomy - New appearance of fibroids is not more common following
laparoscopicmyomectomy when compared with abdominal myomectomy. Eighty-one women
randomized to either laparoscopic or abdominal myomectomy were followed with transvaginal
sonography every 6 months for at least 40 months. Fibroids larger than 1 cm were detected in 27%
of women following laparoscopic myomectomy compared to 23% in the abdominal myomectomy
group, and no woman in either group required any further intervention.

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 REFERENCES

Berek, Jonathan S., and Emil Novak. Berek & Novak's Gynecology. 14th ed. Philadelphia:
Lippincott Williams & Wilkins, 2007.

Hapangama DK, Bulmer JN. Pathophysiology of heavy menstrual bleeding. Womens Health
(Lond). 2016;12(1):3-13.

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