HYPERPROLACTENEMIA

PROLACTIN

• Polypeptide hormone
• 198 amino acids
• MW: 22 kDA
• Synthesized & stored in the Pituitary
Gland & endometrium
PROLACTIN

• Stimulant:
• TRH –principal
• Estrogen

• Principal Suppressant:
• Dopamine
PROLACTIN

• Normal serum levels: 8 ng/ml

• 20 – minute half life
• Cleared by the Kidney and Liver
• Main Function:
• Stimulate growth of mammary
glands
• Produce and secrete milk
PROLACTIN:
PHYSIOLOGY
• Synthesis and release controlled by
the hypothalamus
• Main control mechanism: Inhibitory
• Prolactin Inhibiting Factor:
Dopamine
PROLACTIN:
PHYSIOLOGY
• Prolactin Stimulating Factor:
• Thyrotrophin Releasing Hormone
• Serotonin

• Manner of release:
• Episodic
PROLACTIN:
PHYSIOLOGY
• Increase Levels during puberty in
females
• Pregnancy induces hypertrophy &
hyperplasia of lactotrophs
• Inducing rising levels during
pregnancy
• Peaks at 200 ng/ml 3rd trimester
PROLACTIN:
PHYSIOLOGY
• Estrogens inhibits the action of
prolactin on the breast preventing
Lactation
• After delivery, estrogen & prolactin
decrease and lactation is initiated
PROLACTIN:
PHYSIOLOGY
• Non pregnant stimulant to prolactin
release:
• Nipple & breast stimulation
• Exercise
• Sleep
• Stress
• Ingestion of mid day meals
PROLACTIN: HYPERPROLACTINEMIA

• >20 – 25 ng/ml
• Must be taken midmorning hours
• If levels are increase the test is
repeated 1 hour after resting in a
quiet room
HYPERPROLACTINEMIA: EFFECTS

• Oligomenorrhea
• Amenorrhea
• Anovulation
• Galactorrhea
• Nonpuerperal secretion of water/ milky
fluid from breast that does not contain
pus nor blood
HYPERPROLACTINEMIA: CAUSES

• CNS disorders
• Pharmacologic agents
• Hypothyroidism
• Chronic Renal disease
• Chronic breast nerve stimulation
HYPERPROLACTINEMIA: CAUSES

• CNS disorders • Hypothalamic causes

• Pharmacologic agents • Pituitary causes
• Hypothyroidism
• Chronic Renal disease
• Chronic breast nerve stimulation
HYPERPROLACTINEMIA: CAUSES

• CNS disorders • Tranquilizers

• Pharmacologic agents • Narcotics
• Hypothyroidism • Antihypertensives
• Chronic Renal disease • Oral Contraceptive Steroids
• Chronic breast nerve stimulation
HYPERPROLACTINEMIA: CAUSES

• CNS disorders • Stop the medication

• Pharmacologic agents • Measure PRL levels a month later
• Hypothyroidism • If medication cannot be stopped
• Chronic Renal disease monitor PRL levels

• Chronic breast nerve stimulation • If >100 ng/ml r/o macroadenoma

HYPERPROLACTINEMIA: CAUSES

• CNS disorders • Decrease negative feedback

• Pharmacologic agents • Increase TRH levels
• Hypothyroidism • Increase PRL & TSH
• Chronic Renal disease
• Chronic breast nerve stimulation
HYPERPROLACTINEMIA: CAUSES

• CNS disorders • Decrease Metabolic clearance

• Pharmacologic agents
• Hypothyroidism
• Chronic Renal disease
• Chronic breast nerve stimulation
HYPERPROLACTINEMIA: CAUSES

• CNS disorders • Thoracic Operations

• Pharmacologic agents • Herpes Zoster
• Hypothyroidism • Chest Trauma
• Chronic Renal disease
• Chronic breast nerve stimulation
DIAGNOSTIC TECHNIQUE: IMAGING

• CT scan w/ IV contrast
• MRI w/ gadolinium enhancement
DIAGNOSTIC TECHNIQUE: IMAGING

• CT scan w/ IV contrast • Principally shows bony structural

• MRI w/ gadolinium enhancement abnormalities
DIAGNOSTIC TECHNIQUE: IMAGING

• CT scan w/ IV contrast • Better soft tissue definition

• MRI w/ gadolinium enhancement • Provides 1 mm resolution
DIAGNOSTIC TECHNIQUE:
RECOMMENDED DIAGNOSTIC
EVALUATION

• PRL levels be measured in cases

of:
• Galactorrhea
• Oligomenorrhea
• Amenorrhea
• … w/o elevated FSH levels
DIAGNOSTIC TECHNIQUE:
RECOMMENDED DIAGNOSTIC
EVALUATION

• If PRL level is elevated check the:

• TSH level to r/o: 1o Hypothyroidism
• Elevated: check T3 & T4
• T3 & T4 elevated: TSH – secreting
Pituitary adenoma
• T3 & T4 low: Hypothyroidism Treat
w/ thyroid replacement

• If Normal: request MRI or CT to r/o

adenomas
DIAGNOSTIC TECHNIQUE:
RECOMMENDED DIAGNOSTIC
EVALUATION

• If..
• PRL level is normal
• TSH level is normal
• BUT w/:
• Galactorrhea
• Normal menses

• no further test required

TREATMENT:
EXPECTANT
• If w/ microadenoma or functional
hyperprolactinemia w/o plans of
pregnancy
• Monitor PRL levels annually

• If w/ menstrual irregularities
• OCP
• Progesterone only pills
TREATMENT: MEDICAL

• Macroadenoma • Bromocriptine
• Hyperprolactinemia w/ • Dopamine 2 receptor stimulant
anovulatory cycles wishing to • Cabergoline
conceive • Long-acting dopamine agonist
TREATMENT:
OPERATIVE
• Trans-sphenoidal resection
• Minimal risk
• < .05% mortality rate
TREATMENT:
RADIATION THERAPY

• External beam:
• Cobalt
• Proton beam
• Brachytherapy
THANK YOU
FOR YOUR
ATTENTION
TRANQUILIZERS

• Phenothiazides • Action:
• Diazepam • Depletes hypothalamic
circulation of dopamine
• Blocks the binding site of
dopamine
NARCOTICS

• Tricyclic antidepressant • Action:

• Propranolol • Block dopamine uptake

• Haloperidol • Block hypothalamic dopamine

receptors
• Phentolamine
• Cyproheptadine
ANTIHYPERTENSIVES

• Reserpine • Action:
• Methyldopa • Depletes Cathecholamines
• Blocks conversion of tyrosine
to dihydroxyphenylalanine
(Dopa)
ORAL CONTRACEPTIVES

• Combination Pills • Hyperprolactinemia usually

occurs in higher estrogen
formulations
• But seldom seen clinically
HYPOTHALAMIC CAUSES

• Disease that interferes with the normal

portal circulation of dopamine
• Craniopharyngioma
• Infiltration of the hypothalamus by:
• Sarcoidosis
• Histiocytosis
• Leukemia
• Carcinoma
PITUITARY CAUSES

• Pituitary tumors • Prolactinomas

• Microadenoma
• Lactotrophs hyperplasia
• < 1 cm diameter

• Empty sella syndrome • Macroadenoma

• > 1 cm diameter
• Associated w/
• 25% of Acromegaly
• 10% of Cushing’s
PITUITARY CAUSES

• Pituitary tumors • Prolactinomas

• 50% of women w/ hyperprolactinemia
• Lactotrophs hyperplasia
• Higher possibility if PRL > 100 ng/ml
• Empty sella syndrome • Certain if PRL > 200 ng/ml are
PITUITARY CAUSES

• Pituitary tumors • Seen in 8% of autopsy reports

• Lactotrophs hyperplasia • Cannot distinguish from microadenoma

• Diagnosis made only after surgical
• Empty sella syndrome
procedure for microadenoma
• Functional hyperprolactinemia
• Clinical diagnosis for cases with elevated
PRL w/o imaging evidence of adenoma
PITUITARY CAUSES

• Pituitary tumors • 1o Empty Sella Syndrome

• Intrasellar extension of arachnoid space
• Lactotrophs hyperplasia compressing the pituitary and an
enlarged sella tursica
• Empty sella syndrome
• Congenital or acquired
• Defect in the sella diaphragm allowing
the subarachnoid membrane to
herniate into the sella tursica
• Normal pituitary function EXCEPT for
hyperprolactinemia
PITUITARY CAUSES

• Pituitary tumors • 1o Empty Sella Syndrome

• Intrasellar extension of arachnoid space
• Lactotrophs hyperplasia compressing the pituitary and an
enlarged sella tursica
• Empty sella syndrome
• Congenital or acquired
• Defect in the sella diaphragm allowing
the subarachnoid membrane to
herniate into the sella tursica
• Normal pituitary function EXCEPT for
hyperprolactinemia
OLFU MEDICINE 2020 GYNECOLOGY

Hyperprolactinemia  Ingestion of mid-day meals

Dr. Crisostomo Santos O. Ordoño
Comprehensive Gynecology 7th Edition + Lecture Notes
HYPERPROLACTINEMIA
November 15, 2018

PROLACTIN
 Polypeptide hormone
 198 amino acids
 MW: 22kDa
 Synthesized & stored in the anterior pituitary gland and
endometrium because during pregnancy they are able to detect
prolactin in amniotic fluid
 Prolactin is described as always being in a inhibitory state
 Stimulant:
 TRH (thyrotrophin releasing hormone) – principal
stimulant
 Estrogen
 Principal Suppressant:
 Dopamine  > 20-25 ng/mL
 Normal serum level: 8 ng/mL  If you are suspecting hyperprolactinemia in non-pregnant woman,
 20 minute half-life (short) her usual complain is nipple discharge. One of the differentials is
 Cleared by the kidney and liver hyperprolactinemia, of course need to rule out carcinoma and
 Main function: mastitis.
 Stimulate growth of mammary glands  Blood sample must be taken midmorning hours because during
 Produce and secrete milk sleep there is an increase in serotonin which initiates the release
of prolactin. Prolactin is normally high upon waking up.
PROLACTIN: PHYSIOLOGY  If levels are increase the test is repeated 1 hour after resting in a
quiet room

HYPERPROLACTINEMIA: EFFECTS
 Oligomenorrhea
 Amenorrhea
 Anovulation (infertility)
 Galactorrhea
o Nonpuerperal secretion of water/milky fluid from
breast that does not contain pus (abscess or mastitis)
nor blood (carcinoma)

HYPERPROLACTINEMIA: CAUSES
I. CNS disorders
a. Hypothalamic causes
b. Pituitary causes
II. Pharmacologic agents
a. Tranquilizers
 Synthesis and release controlled by the hypothalamus b. Narcotics
 Main control mechanism: inhibitory c. Antihypertensives
 Prolactin inhibiting factor: d. Oral Contraceptive Steroids
 Dopamine III. Hypothyroidism
 Prolactin stimulating factor: IV. Chronic renal disease
 Thyrotrophin Releasing Hormone V. Chronic breast nerve stimulation
 Serotonin
 Manner of release: CNS DISORDERS
 Episodic a. Hypothalamic Causes
 Increase levels during puberty in females  Disease that interfere with the normal portal
 Pregnancy induces hypertrophy and hyperplasia of lactotrophs circulation of dopamine can result in
(because these are the cells that produces prolactin) hyperprolactinemia
 Inducing rising levels during pregnancy (because of estrogen,  Craniopharyngioma – most common
pregnancy is in hyper-estrogenic state)  Infiltration of the hypothalamus by:
 Peaks at 200 ng/mL 3rd trimester  Sarcoidosis
 Estrogens inhibits the action of prolactin on the breast preventing  Histiocytosis
lactation  Leukemia
 After delivery, estrogen and prolactin decrease and lactation is  Carcinoma
initiated because of nipple suckling by the baby  These tumors arise from the remnants of Rathke’s
 Non pregnant stimulant to prolactin release: pouch along the pituitary stalk.
 Excessive nipple and breast stimulation  They are most frequently diagnosed during 2nd and 3rd
 Exercise decades of life and usually result in impairment of
 Sleep secretion of several pituitary hormones
 Stress

“IN MY DISTRESS I CALLED TO THE LORD, AND HE ANSWERED ME.” – PSALM 120:1|MMF 1
OLFU MEDICINE 2020 GYNECOLOGY

b. Pituitary Causes membrane to herniate into the

 It has been estimated that 80% of all pituitary sella turcica
adenomas secrete PRL.  The syndrome is usually
 Pituitary Tumors associated with normal pituitary
function, EXCEPT for
hyperprolactinemia
PHARMACOLOGIC AGENTS
 Tranquilizers
 Phenothiazides
 Diazepam

Action:
 Depletes hypothalamic circulation of dopamine
 Blocks the binding site of dopamine
 Narcotics
 Tricyclic antidepressant
Action: Block dopamine uptake
 Prolactinomas – most common
 Microadenoma  Propranolol
o < 1 cm diameter  Haloperidol
 Macroadenoma  Phentolamine
o > 1 cm diameter  Cyproheptadine
Action: Block hypothalamic dopamine receptors
 Associated with:
 Antihypertensives
o 25% of Acromegaly
 Reserpine
o 10% of Cushing’s
 Methyldopa
disease
 50% of women with
Action:
hyperprolactinemia
 Depletes catecholamines (dopamine is classified
 Higher possibility if PRL > 100
as catecholamine)
ng/mL
 Methyldopa blocks conversion of tyrosine to
 Certain if PRL > 200 ng/mL -
dihydroxyphenylalanine (DOPA) - precursor of
100%
dopamine
 Lactotrophs Hyperplasia
 Oral Contraceptive Pills
 Seen in 8% of autopsy reports
 Combination Pills
 Cannot distinguish from microadenoma by  Hyperprolactinemia usually occurs in higher dose of
any clinical, laboratory, or radiologic
estrogen, however newer brands of OCP has low dose
method
of estrogen.
 Diagnosis made only after surgical
 Galactorrhea does not usually occur during OCP
exploration of the pituitary gland
ingestion because the exogenous estrogen blocks the
 Functional hyperprolactinemia
binding of PRL to its receptors
 Term used for the clinical Action:
diagnosis of cases of elevated  Hyperprolactinemia usually occurs in higher
PRL levels w/o imaging evidence estrogen formulations
of adenoma  But seldom seen clinically
 Primary Empty Sella Syndrome
What to do with these pharmacologic agents?
 Discontinue the medication
 Measure PRL level 1 month thereafter to determine if the level
has returned to normal
 If medication cannot be discontinued, monitor PRL level
 If > 100 ng/mL, imaging of sella turcica should be performed to
rule out macroadenoma

 Sella turcica (means Turkish saddle) is the
body of sphenoid bone
 In MRI, sella turcica is black (radiolucent)
that is why it is called empty sella
 Intrasellar extension of subarachnoid space
results in compression of the pituitary gland
and an enlarged sella turcica
 Congenital or acquired (by radiation or
surgery)
 Defect in the sella diaphragm
allowing the subarachnoid
HYPOTHYROIDISM
 Can also produce hyperprolactinemia and galactorrhea because of
decreased negative feedback of T4on the hypothalamic-pituitary
axis.
 If T3 & T4 is decreased it will send signal to hypothalamus to
release TRH then signals the anterior pituitary to secrete TSH to
increase T3 & T4
 TRH is the primary stimulant for prolactin secretion
 The resulting increase TRH level stimulates PRL secretion and TSH
secretion from the pituitary
CHRONIC RENAL DISEASE
 Decrease metabolic clearance
CHRONIC BREAST NERVE STIMULATION
 Thoracic operation

“IN MY DISTRESS I CALLED TO THE LORD, AND HE ANSWERED ME.” – PSALM 120:1|MMF 2
OLFU MEDICINE 2020 GYNECOLOGY

 Herpes zoster  However, if estrogen is deficient, low estrogen levels in

 Chest trauma
DIAGNOSTIC TECHNIQUES
DIAGNOSTIC TECHNIQUE: IMAGING
 CT scan with IV contrast
o Principally beneficial
abnormalities
 MRI with gadolinium enhancement
o Better soft tissue definition
o Provides 1mm resolution and thus should be able to
detect all microadenomas
combination with hyperprolactinemia has been shown to be
associated with the early onset of osteoporosis; thus exogenous
estrogen should be administered. Hormonal theraphy, as is used
for postmenopausal women, or oral contraceptives may be used.
TREATMENT: MEDICAL
for bony structurally  The initial treatment for women with macroadenomas, as well as
for those women with hyperprolactinemia who are anovulatory
and wish to conceive, should be the administration of a dopamine
receptor agonist. Cabergoline, bromocriptine, and pergolide have
been used successfully; pergolide is currently not available.
 Macroadenoma – possible complain of patient is visual defect, if
there is a macroadenoma in the pituitary gland it may compress
the optic chiasm leading to bitemporal hemianopsia.
 Hyperprolactinemia with anovulatory cycles wishing to conceive
 Bromocriptine
o Semisynthetic ergot alkaloid developed to inhibit PRL
secretion.
o Dopamine 2 receptor stimulant
o Usually given to women who delivered dead babies to
stop milk production
 Cabergoline
o Long-acting dopamine agonist
TREATMENT: OPERATIVE
 Trans-sphenoidal resection
 Minimal risk: < 0.05% mortality rate

DIAGNOSTIC TECHNIQUE: RECOMMENDED DIAGNOSTIC

EVALUATION
 PRL level be measured in cases of women with the following
who do not have an elevated FSH level TREATMENT: RADIATION BEAM THERAPY
 Galactorrhea  External beam: there can be a possible involvement of normal
 Oligomenorrhea tissues in periphery
 Amenorrhea (r/o pregnancy first)  Cobalt
 If PRL level is elevated, a TSH assay should be performed to rule  Proton beam
out presence of hypothyroidism  Brachytherapy
 TSH levels
 If the TSH level is elevated, T3 & T4 should
be measured to rule out the rare possibility BLACK – POWERPOINT
of a TSH-secreting pituitary adenoma BLUE – RECORDING
 If TSH level is elevated and hypothyroidism GREEN – BOOK
is present, appropriate thyroid replacement
should begin and the PRL level will usually
return to normal.
 If the TSH level is normal and the woman
has a normal PRL level with galactorrhea, no
further tests are necessary if she has regular
menses.

TREATMENT
TREATMENT: EXPECTANT
 If with microadenoma or functional hyperprolactinemia who do
not wish to conceive may be followed without treatment by
measuring PRL levels once annually.

“IN MY DISTRESS I CALLED TO THE LORD, AND HE ANSWERED ME.” – PSALM 120:1|MMF 3