Menstrual cycle regulation.

Menstrual cycle disturbances.

Abnormal uterine bleeding.

Stelian Hodorogea
 Menstrual cycle
• The menstrual cycle describes the monthly
(cyclical) physiological changes that prepare
women for pregnancy and end in endometrial
shedding and bleeding should this not occur.

• Hormonal changes
• Ovarian changes
• Endometrial changes
• Other reproductive tract organs
Hypothalamus-pituitary-
ovarian hormonal axis

Ovarian changes

Endometrial changes
 Menstruation (menstrual
bleeding, periods)
• Menstruation is an external indicator of
ovarian events controlled by the
hypothalamic-pituitary axis
 What controls
follicular growth?

??????
Gonadotrophin
FSH
independent
+ LH

Menstruation
 FSH
+ LH

OESTRADIOL
As each follicle grows, it produces
Menstruation increasing amounts of oestradiol.
 Hypothalamus
Increasing
negative
feedback
_ GnRH
(gonadotrophin
releasing
Pituitary hormone)
INHIBIN
(suppresses FSH) Decreased
FSH
Increasing
amounts of +
oestradiol. Ovaries

Oestradiol (E2)

+
Reproductive tract
Other targets
 Why is only 1
selected and
becomes
Many follicles at
“dominant”?
the start of the
cycle

Ovulation

Menstruation
 Hypothalamus

GnRH
Pituitary

FSH
+
Ovaries

Small follicles: Large follicles: less

very dependent dependent on FSH
on FSHOestradiol (E2)
 Hypothalamus
_
Increasing
negative
feedback GnRH
Pituitary

INHIBIN Decreased
Oestradiol FSH
FSH
+
Ovaries
Large follicles: less


Small follicles:
very dependent dependent on FSH
on FSHOestradiol (E2)
Growth factors
Insufficient Oestradiol Dominant
FSH follicle
+ +
 What causes
ovulation?

0 4 8 12 16 20 24 28
 What causes
ovulation?

LH

0 4 8 12 16 20 24 28
 What effects
does it have?

What causes
the LH surge?

0 4 8 12 16 20 24 28
 Hypothalamus
For most of the cycle,
negative feedback
operates…
_
_ GnRH
Pituitary

LH Inhibited by
FSH oestradiol

Oestradiol
Ovary
BUT, with high
levels of E2
maintained for
Hypothalamus
long enough……
+
+ Pituitary
GnRH

LHLH
FSH
surge
Oestradiol
Ovary
Enzyme induction in the
follicle wall
Transformation of ruptured follicle into corpus luteum (CL)

• Ruptured follicle
becomes solid corpus
luteum
• Thecal cells and blood
vessels invade
• Granulosa cells
hypertrophy and
terminally differentiate
(“luteinisation”).

Steroid secretion changes – Progesterone

+
Oestradiol
What causes the onset of menstruation?

Steroid
levels
fall This is followed
by the onset of
menstruation
• Characteristics of normal menstrual cycle
• Disorders of menstrual cycle

• Abnormal uterine bleeding (AUB)

• PALM-COIEN classification of causes of
AUB
• Treatment of AUB
 Suggested Normal limits for
menstrual parameters
Clinical Parameter Descriptive term Normal limits (5–95th
percentiles)

Frequency of menses (days) Frequent <24

Normal 24–38
Infrequent >38

Regularity of menses, cycle Absent No bleeding

to cycle (Variation in days Regular Variation ± 2–20 days
over 12 months) Irregular Variation >20 days

Duration of flow (days) Prolonged >8.0

Normal 4.5–8.0
Shortened <4.5

Volume of monthly blood Heavy >80

loss (mL) Normal 5–80
Light <5
Characteristics of normal menstrual cycle
• Volume - Blood loss is usually about 35 mL and is
considered abnormal when it is greater than 80-130
mL
• Regularity – normal variation ± 2 to 20 days
• Frequency (ranging from 24(21) to 38 (35) days)
• Duration (range of 3-8 days).
• Also:
– Result in ovulation
– Not very painful
 Disorders of menstrual cycle
• Disorders of flow / volume
• Disorders of cycle regularity
• Disorders of cycle frequency
• Disorders of cycle duration
• Disorders of ovulation
• Dysmenorrhea
 Abnormal uterine bleeding
• Abnormal uterine bleeding (AUB) is
defined as bleeding from uterine corpus that
is abnormal in regularity, volume,
frequency, or duration and occurs in the
absence of pregnancy.
• Heavy menstrual bleeding is the most
common complaint of AUB. It has been
defined as “excessive menstrual blood loss
which interferes with the woman’s physical,
social, emotional, and/or material quality of
life . . . [that] can occur alone or in
combination with other symptoms.”
 Structural causes: Polyps
• Polyps (endometrial and
cervical) are classified as
absent, or present (AUB-P)
• Through imaging
(radiological or
hysteroscopic) or
histology.
 Structural causes: adenomyosis
• Diagnosis based on:
– Clinical sings
– Ultrasound
– MRI

• AUB-A
 Structural causes: leiomyoma
• Most relevant: sub-mucous leiomyoma
• Diagnosis:
– Bimanual exam
– Ultrasound
– Other radiological

• AUB – Lsm
• AUB – Lother
 Structural causes:
Malignancy and hyperplasia

• Despite a higher incidence of this condition in post-

menopausal women, atypical hyperplasia or frank
malignancy (AUB-M) should be considered in almost
all women suffering AUB, particularly those with a
high-risk profile, for example, raised body mass
index, persistent anovulation and older age.
• Diagnosis – histology
Non-structural causes: coagulopathy
• Initial screening for an underlining disorder of hemostasis in
patients with AUB should be by a structured history:
• 1. HMB since menarche
• 2. One of the following:
– Post-partum hemorrhage
– Surgical related bleeding
– Bleeding associated with dental work
• 3. Two or more of the following symptoms
– Bruising 1-2 times/months
– Epistaxis 1-2 times/months
– Frequent gum bleeding
– Family symptoms of bleeding symptoms
 Non-structural causes: Iatrogenic
• AUB-I comprises the spectrum of uterine bleeding
problems related to intrauterine contraceptive
systems, exogenous sex-steroid administration or
agents such as gonadotrophin releasing hormone
agonists that directly affect sex steroid production.
• Also include those related to changes in target
tissue drug bioavailability.
– Ex.: anti-epileptic or anti-tuberculous drugs such as
carbamazepine or rifampicin, respectively, significantly
altering hepatic enzyme activity.
Non-structural causes: Ovulatory disorders
1. Diseases causing deviation from normal ovulation and
regular progesterone withdrawal from the corpus
luteum such as hyperprolactinemia or polycystic ovarian
syndrome.
2. Anovulation, especially at the extremes of reproductive
life (adolescence or premenopausal).

• AUB-O
Non-structural causes: Ovulatory disorders
1. Diseases causing deviation from normal ovulation and
regular progesterone withdrawal from the corpus
luteum such as hyperprolactinemia or polycystic ovarian
syndrome.
2. Anovulation, especially at the extremes of reproductive
life (adolescence or premenopausal).

• AUB ranging from amenorrhea, to light sporadic bleeding,

to extreme blood loss requiring transfusion or surgery can
result.
• AUB-O
Non-structural causes: Endometrial
dysfunction
• AUB-E is presently reserved as a diagnosis
of exclusion among other causes of AUB,
and may represent a primary endometrial
disorder.
• Most AUB-E cases appear to be due to
disturbances of metabolic molecular
pathways, such as those involving tissue
fibrinolytic activity, prostaglandins, other
inflammatory or vasoactive mediators
 Non-structural causes:
Endometrial dysfunction
• To be confident of attributing AUB-E as the
primary cause of a woman’s symptoms, as
no validated tests are currently available for
clinical use, all other causes of AUB need to
be considered and then determined less
likely to be causative.
 Not otherwise classified
• AUB-N is reserved for those causes that
require further description or delineation in
their clinical relevance, such as uterine
arterio-venous malformations or chronic
endometritis.
 Investigation
• History and physical examination are the
first steps
• These methods will help:
– to establish the cause of the abnormal bleeding,
– to direct further investigations,
– and to guide options for management.
 What should be determined:
• the amount, frequency, and regularity of
bleeding,
• the presence of post-coital or intermenstrual
bleeding,
• any dysmenorrhea or premenstrual
symptoms.

This can help to distinguish anovulatory from

ovulatory bleeding or to suggest anatomic
causes such as cervical pathology or leiomioma.
 Ovulatory vs Anovulatory AUB
• Ovulatory AUB is usually regular and is
often associated with premenstrual
symptoms and dysmenorrhea.
• Anovulatory bleeding, which is more
common near menarche and the
perimenopause, is often irregular, heavy,
and prolonged.
– It is more likely to be associated with
endometrial hyperplasia and cancer.
Methods of diagnosis
 Management
• Stop heavy bleeding (emergency treatment)
• Prevention of recurrence
• Treatment of the cause

• Medical – initial treatment for most of the

patients. (COEIN)
• Surgical – based on clinical stability, severity of
the bleeding, lack of response or
contraindications to medical treatment, and
underlying medical condition. (PALM)
 1. Emergency treatment:
heavy bleeding
• 1. Intravenous estrogen at 25mg every 4 hours for 12
hours is said to be the treatment of choice
• OR
• 2. Intravenous conjugated equine estrogen
(Premarin) at 1.25mg every 4 hours is a good
alternative
• THEN
• Estrogen at 1.25mg per day of conjugated estrogen
can be administered for 7 to 10 days, PLUS a
progestational agent such as MPA 10 mg/day
 1. Emergency treatment:
moderate bleeding
• 1. Monophasic oral contraceptives (MOC) to be
taken 3 to 4 times per day for a week, then start a
new pack of pills one pill a day after this week
• OR
• MOC – 5 times per day first day, 4 times –
second, 3 times – third, 2 times – fourth and 1
pill per day till full 21 days course
• OR
• 2. MPA10 mg daily for 10 days
 2. Prevention of recurrence:
mild or recurrent bleeding
• 1. Monophasic oral contraceptive pills for 3 to 6 months at least
• OR
• 2. MPA10 mg daily for 10 days each month – not effective
• OR
• 3. Depo Provera intramuscularly 150mg every 3 months
• OR
• 4. Progestin IUD insertion
• OR
• 5. NSAIDs 10 to 15 days per month
• OR
• 6. Antiphybrinolitic drugs: tranexamic acid
 Choice of medical treatment
• Non-hormonal treatments such as non-steroidal
anti-inflammatory drugs and antifibrinolytics are
taken during menses to reduce blood loss, and thus
are effective mainly in the setting of heavy
menstrual bleeding when the timing of bleeding is
predictable.
 Choice of medical treatment
• Irregular or prolonged bleeding is most effectively
treated with hormonal options that regulate cycles,
decreasing the likelihood of unscheduled and potentially
heavy bleeding episodes.
• Combined hormonal contraceptives, and the
levonorgesterel-releasing intrauterine system are examples
of effective options in this group, providing more
predictable cycles while protecting the endometrium from
unopposed estrogen and the risk of hyperplasia or
carcinoma.
 Surgery

• Vacuum aspiration
• D&C
• Endometrial ablation
• Uterine artery embolization
• Polypectomy or miomectomy
• Hysterectomy

• Not only in PALM, but also in COEIN