Abnormal Uterine Bleeding 8.

07
After an embarrassing incident last week while visiting a friend, Mrs Mary Freeman, aged 44, consults her family doctor
complaining that her periods are very heavy, with bad pelvic discomfort. She feels 'lousy' during them; and has passed large clots
on several occasions. She was particularly concerned six weeks ago to notice two episodes of bleeding between her usual periods.
History of Presenting Illness NORMAL UTERINE BLEEDING:
Increased volume of blood
Increased frequency of bleeding YOU ONLY WANT TO MENSTRUATE...
Irregular timing of periods - Every 24 to 35 days (mean 27-28)
Bleeding between periods - For 2 to 9 days at a time (mean 4-5)
Unusually painful menstruation - With only 1 or 2 heavy days
Passing of clots - Totalling less than 60 ml of blood
Differential Diagnoses What bleeding is abnormal?
Abortion intermenstrual bleeding
Adnexal Tumors MUST EXCLUDE bleeding in between normal periods
Adrenal Adenoma
Adrenal Carcinoma PREGNANCY !! menorrhagia
excessively heavy episodes (over 80 ml)
Cervicitis BEFORE YOU DO ANYTHING ELSE prolonged periods (over 7 days)
Endometrial Carcinoma metrorrhagia
Endometritis Coagulation disorders
irregular, frequent and variable periods
Hyperprolactinemia Endometrial polyps
postmenopausal bleeding (PMB)
Hyperthyroidism Genitourinary infection
postcoital bleeding
Hypothyroidism Intrauterine device
(often associated with intermenstrual bleeding)
Pelvic Inflammatory Disease Liver disease/failure precocious menstruation
Pituitary Microadenomas Medications (chemo?…) (usually a component of precocious puberty)
Uterine Cancer Renal disease/failure breakthrough bleeding
Vaginitis Steroid hormones [BTB; unscheduled bleeding with use of
Uterine fibroids hormonal contraception or hormone
Are they on any
HORMONE Findings on History replacement therapy (HRT)]
REPLACEMENT Is this the first time its happened?
THERAPY? Was it accompanied by pain? Estimates of VOLUME:
How much blood was there?

average tampon holds 5 mL
SEXUAL HISTORY: ask about STDs, average pad holds 5-15 mL of blood
Ask about sexual abuse Passing clots?
There must be over 80ml
Screen for HEMO + ENDOCRINOPATHY:
Has there been galactorrhoea, hirsuitism, cold intolerance, easy bruising?
Contraceptive History: recent cessation of the oral contraceptive pill?
- Intrauterine devices ever installed? Relationship to the THYROID GLAND:
AGE- DIRECTED SUSPICION:
Menarche
late teens:
- HYPO = MENORRHAGIA
most commonly have anovulatory bleeding - HYPER = AMENORRHOEA
due to the immaturity of their hypothalamic-pituitary axis. If bleeding does not respond to
usual therapy in this age group, a bleeding disorder must be considered.
(Undiagnosed von Willebrands Factor Deficiency is the most likely culprit )
IRREGULAR MENSES SINCE MENARCHE? Or… OBESE?
consider anovulation
30
50 yr olds:
Are there any SYMPTOMS OF ANAEMIA?
Organic or structural abnormalities.
Fibroids or polyps are frequent anatomical findings.
Organic causes can be anything from thyroid dysfunction to renal failure.
postmenopausal:
any uterine bleeding should receive an immediate workup for endometrial cancer.
Endometrial hyperplasia must be considered in women who are
obese, aged 70 or older, nulliparous, or have diabetes.
 Adipose tissue is a locale for
Findings on Examination estrogen conversion.
IMPORTANT STUFF TO LOOK FOR: Therefore, the larger the
Signs of severe volume depletion: ANAEMIC PALLOR? patient, the more increased
Obesity: = independent risk factor for |endometrial cancer | the risk (and the higher the
unopposed estrogen level on
Signs of androgen excess (eg, hirsutism, acne, virilisation):
the endometrium).
This usually points to polycystic ovarian syndrome (PCOS)
Ecchymosis+ Purpura: This also is a sign of trauma or a possible bleeding disorder.
Visual field exam (looking for pituitary bitemporal hemianopia)
Thyroid gland exam (looking for hypothyroid features)
Breast exam (galactorrhoea, or absence of secondary sexual characteristics)
Hepato or splenomegaly (clotting factor undersynthesis or aplastic thrombocytopeniuc anaemia)

The PELVIC EXAM: FOUND SOME SORT OF MASS?

Look for external genital lesions
Look for infectious discharge
immediate ultrasound!
Confirm the site of the bleeding
HALLMARK of Dysfunctional Uterine Bleeding
(DUB) is a completely NEGATIVE PELVIC EXAM
The UTERINE EXAM: (i.e no pathology
diagnosis by exclusion)
Uterine size, shape, and contour:
enlarged irregularly shaped uterus = fibroids if you’re in the 30-50 age group
enlarged uterus (regular or not) in the elderly = CANCER until proven otherwise
Cervical motion tenderness
= symptom of pelvic inflammatory disease (PID); gonorrhea or chlamydia.
Adnexal tenderness or masses
VERY SCARY if presents in the over-50s:
Ovarian cancer may present with intermenstrual bleeding as its only symptom.

Tests and Investigations BIOPSY:always the gold standard

Human Chorionic Gonadotropin Blood or Urine Test
Exclude Pregnancy
Full blood count
Exclude ANAEMIA and THROMBOCYTOPENIA
Iron studies
Exclude IRON DEFICIENCY
Imaging of the genital tract:
transvaginal and abdominal ultrasound
sonohysterography
hysteroscopy
endometrial sampling (biopsy or curettage)
Cervical PAP smear
Histology of the cervix may uncover horrible problems

but only 40% of the time
Other tests only if indicated by physical + history findings:
Liver function to investigate coagulopathy
coagulation screen to investigate coagulopathy
thyroid function to investigate hypothyroidism
pituitary hormone assay to investigate endocrinopathy
(particularly interested in PROLACTIN)
plus LH, FSH if it looks like polycystic ovaries
CT / MRI of abdomen for staging of malignancy
Urine protein, BUN and Creatinine – rule out nephrotic syndrome
SOFT AND FLUFFY MANAGEMENT
Prostaglandin synthetase inhibitors
inhibit the synthesis of prostaglandin
interfere with the myometrial binding of prostaglandin E2 (particularly the fenamates)
= 20-40% reduction in menstrual blood loss
= decrease in the number of days of bleeding.
Antifibrinolytic drugs
- act by inhibiting plasminogen activator,
THUS = reduce the accelerated endometrial fibrinolytic activity found in menorrhagic women.
Tranexamic acid reduces menstrual blood loss by about 50% in cases of DUB
Cyclical progestogen therapy
- most effective in cases of anovulatory dysfunctional uterine bleeding
- has less effect in cases of ovulatory menorrhagia.
Agents used include medroxyprogesterone acetate, norethisterone or dydrogesterone
- should be used for at least 2 weeks of each treatment cycle
- total treatment duration of about 6 months.
Combined oestrogen-progestogen formulations
= oral contraceptive pill incorporating the synthetic oestrogen ethinyloestradiol
= give a significant decrease in menstrual blood loss of between 40 and 50%.
!! The first cycle may show little change and patients must be encouraged to persist.
= safe in older women up to the age of the menopause providing that they do not have a
history of hypertension, cigarette smoking or venous thromboembolic disorders.
Danazol, (a derivative of 17 alpha ethinyl testosterone) DANAZOL IS A SQUATTER:
= ? inhibits endometrial proliferation displaces oesterogen
= thus
causes endometrial atrophy from its own receptors!
= ALSO reduces pituitary gonadotrophin secretion
= ALSO inhibits enzymes involved in ovarian steriodogenesis. (? Aromatase? )
= BUT :ANDROGENIC SIDE EFFECTS
GnRH agonists
= Eg. goserelin and nafarelin
= initially increases GnRH, but then “exhausts” the pituitary
= hypogonadotrophic hypogonadism resulting in amenorrhoea or oligoamenorrhoea.
= Longterm use is complicated by decreasing bone mass and should be limited to 6 months.
Progestogen releasing intrauterine system
= decrease in menstrual loss of 80-90% after 12 months
= not yet licensed in Australia!
HARD AND SCALY MANAGEMENT
Endometrial ablation
= destruction of the endometrium under hysteroscopic visualisation
= an electro-cautery, laser or a microwave technique.
= procedure is performed under general anaesthetic using glycine or similar non-conducting
media to distend the endometrial cavity. MUST DESTROY THE BASALIS LAYER
= a short stay in hospital and only short term morbidity postoperatively.
= long term amenorrhoea is achieved in 50% of patients
= significant reduction of blood loss in another 40% of patients.
= this is not for people with painful menorrhagia (DYSMENORRHOEA)
Myomectomy
= may be performed as an open procedure or laparoscopically to resect
submucous myomas from within the endometrial cavity, as a separate procedure
or as part of endometrial ablation.
Hysterectomy: major operation with all the risks thereof Most often performed operation!
= provides definitive cure for menorrhagia.
= The mortality rate ranges from 0.1-1.1 cases per 1000 procedures.
= The morbidity rate usually is 40%.
Disease Aetiology
Intermenstrual bleeding:
Usually the result of benign or malignant lesions of the inner surfaces of the
genital tract (especially cervix and endometrium)
Menorrhagia:
pelvic pathology
[eg myomata (fibroids); adenomyosis; polyps;
endometriosis, endometrial carcinoma;
generalised medical diseases
- RARE (coagulation disorders; SLE;
hypothyroidism; etc)
dysfunctional uterine bleeding:
(definition of DUB: excessive uterine bleeding
which is not due to complications of pregnancy or
to pelvic pathology or generalised medical
diseases)
- anovulatory or ovulatory
Metrorrhagia:
hypothalamic - pituitary effects on
ovarian function
surface lesions of the genital tract
polycystic ovarian disease
Postmenopausal:
- BTB with HRT
- atrophic vaginitis
- endometrial adenocarcinoma

Menorrhagia is the most common cause of

Epidemiology anaemia in premenopausal women
Frequency:
• menorrhagia = leading reason for gynecologic office visits
• BUT only 10-20% of all menstruating women experience blood loss severe enough
• DUB is a common diagnosis, making up 5-10% of cases in the outpatient clinic setting.

Mortality/Morbidity:
Loss of more than 80 mL of blood = serious medical sequelae.

iron-deficiency anemia

patients may experience shortness of breath, fatigue, palpitations

Age: Any woman of reproductive age who is menstruating may develop menorrhagia.
Most patients with menorrhagia are older than 30 years.
This is because the most common cause of heavy menses in the younger population is
anovulatory cycles, in which bleeding does not occur at regular intervals.
ADOLESCENTS may present with a disorder of haemostasis masquerading as
menorrhagia (in up to 20% of cases)

DIRE PREDICTIONS:
About 1-2% of women with improperly managed anovulatory bleeding eventually might
develop endometrial cancer.
Women who use estrogen HRT for 5 years or longer have approximately a 3.5-fold increase in
risk compared with that of women who have never used such therapy
Uterine bleeding in menstruation: the ENDOMETRIAL CYCLE
first day of bleeding is described as day 1 of the menstrual cycle.
Pre ovulation = proliferative phase (thickening endometrium)
Post Ovulation: Secretory phase : glands dilate, become tortuous;

begin secreting glycogen rich mucus)
Stroma cells become oedematous
No fertilised ovum to care for? That means…
The thick blood-rich nutrient-crammed endometrium is USELESS
Thus;
• The endometrium shrinks in height.
• The spiral arterioles supplying the endometrium go into spasm causing ischaemia and stasis.
• There is an influx of inflammatory white blood cells initiating release of
prostaglandins of the F series and E series.
• Finally the tissue collapses leading to bleeding and shedding of the spongiosum layer of the
endometrium.
The average volume of menstrual blood loss during menstruation is 30mL with a range of 10 to 80mL.

Normal menstrual blood does not clot because of the presence of fibrinolytic substances.
HEMNOSTASIS IS ACHIEVED BY:
• the partial occlusion of spiral arterioles with platelet and fibrin plugs;
• the predominance of F series prostaglandins (vasoconstrictors)
over E series prostaglandins (vasodilators) during menstruation;
• normal ovarian follicle growth supplying oestrogen to regenerate the endometrium.
Sex Steroids in General:
oestrogen receptor = activated by oestradiol, (E2)
Uterine action of sex hormones by various synthetic oestrogens
to a lesser extent, by oestriol
In the glands of the endometrium, progesterone receptor= activated by progesterone,
by various synthetic progestogens
progesterone is androgen receptor = activated by dihydrotestosterone
to a small extent the progestogens
antagonistic to oestrogen. (of the 19-nortestosterone type).

Oestrogen @ endometrium: Progesterone @ endometrium:

- Increases mitosis - INHIBITS mitosis
- UPREGULATES ITS OWN RECEPTORS - DOWNREGULATES ITS OWN RECEPTORS
AND PROGESTERONE RECEPTORS - Downregulates oesterogen receptors
- Thus oestrogen is needed to prime the uterus - Stimulates cell differentiation
for the secretory phase (else it wont respond to -
leads to a well-ordered sequence of
the progesterone from the corpus luteum) cessation of mitosis, subnuclear vacuolation,
- supranuclear vacuolation and glandular secretion,
stromal edema and stromal cell decidualisation

WITHDRAWAL OF PROGESTERONE @ ENDOMETRIUM

activates LYSOSOMES


the endothelium dies and is shed
TOO MUCH OF PROGESTERONE @ ENDOMETRIUM:

the endothelium STILL DIES! It inhibits its own receptors, so after a while
the endothelium wont detect it AS IF IT HAD BEEN WITHDRAWN

SO: THE ENDOCRINE BASIS OF ORAL CONTRACEPTION: you give progesterone EARLY in
the proliferative phase to STOP THE OESTROGEN-INDUCED THICKNENING
…a thin under-developed endometrium wont bleed as much, or harbour a foetus.
Risk factors for uterine cancer
Causal risk factors Casual risk factors

• Late menopause • Hypertension

• Nulliparity • Diabetes

• Prolonged • Mellitus

• Unopposed Factors associated with decreased disk

• Estrogen exposure • Oral Contraceptive Pill

• Obesity • Alcohol

• Other cancers • Progestogens

• Familial Cancer Syndromes

• Polycystic ovarian disease

Hormone Replacement Therapy: Why would anyone ever do that to a patient?

If you’re a HYPOGONADAL MAN
Acute oestrogen withdrawal? If you’re MENOPAUSAL WOMAN
- hot flushes, If you’ve HAD BOTH YOUR OVARIES REMOVED
- night sweats,
- insomnia, HRT: Oestrogen orally or transdermally
- difficulty in concentration, + Progesterone cyclically
- loss of short term memory, (cant just give oestrogen, or the
- lethargy, endometrium will not know
- depression, when to stop growing!)
- anxiety, …of course, if you have no uterus
- loss of libido, its OK to give oesterogen alone.
- skin itchiness, Supplemental vaginal oestrogen (tablets or creams) can be
- dry vagina given to women with symptoms of vaginal atrophy.
- superficial dyspareunia? the only way to sensibly stop HRT is to
Then you need HRT! gradually reduce the dose over 4-6 months
* Loss of libido may also require testosterone (or symptoms recur - often dramatically)
WHAT ELSE DOES IT DO:
prevents loss of calcium salts from bone (with reduction in risk of osteoporotic fractures),
slows development of artherosclerosis (with reduction in risk of myocardial infarction),
reduces changes in large bowel mucosa (with reduction in risk of colon cancer),
reduces changes in brain function (with reduction in risk of Alzheimer's dementia)
prevents a number of adverse changes…
in the pelvic floor, bladder and vagina, joints (osteoarthritis), skin, teeth, hair and eyes.

!! WARNING !!
causes slight increase in breast cancer risk;

causes small increase in the risk of (non-fatal) venous thrombo-embolism and of
some arterial thrombosis in the first year of use of HRT
Many other reproductive and lifestyle factors have a much greater influence on breast cancer risk than HRT.
PATHOGENESIS of Leiomyoma 8.07
OBESITY: hence
many adipocytes Hormone Phytoestrogens (from
Replacement green leafy vegies)
Therapy

High levels of Genetics (eg. being African=

peripheral aromatase higher levels of oestradiol naturally

Androstenedione HIGH OESTRADIOL (E2)

UPREGULATES Oestrogen and

Normal menstrual progesterone receptors of the
oestradiol (from follicle) MYOMETRIUM
(both types of receptor exert a
TROPHIC EFFECT)
Normal menstrual
PROGESTERONE
(from corpus luteum) THUS: myometrium is both
HYPER-RESPONSIVE
Early menarche And
(thus many cycles) OVERSTIMULATED each cycle

HYPERTROPHY OF
MYOMETRIUM OCCURS:
The cells are too far from the
capillaries to be properly
perfused, and thus…

WITHDRAWAL OF PROGESTERONE:

MENSTRUATION: ISCHAEMIC INJURY occurs:
Prostaglandin F closes up the arterioles Myometrium responds like any self-
respecting smooth muscle would:
by secreting GROWTH FACTORS:
- TFG-beta (tissue growth factor)
- BFGF (basic fibroblast growth factor)
- VEGF (vascular endothelial growth factor)
- PDGF (platelet-derived growth factor)

A FIBROID LUMP FORMS

- the growth factors attract enough fibroblasts to
lay down some extracellular matrix; hence
“fibroid”
- angiogenesis takes place, with new vessels
(being extremely thin walled and fragile) breaking
every once in a while
- more endometrium is required to cover the new
protuberance, and thus there is more sloughing off
each ovulatory cycle