L22: Hyperprolactinemia, Galactorrhea, Pituitary Adenomas

Dr. LV Barrot-Gler | May 10, 2021

OUTLINE: o Polymeric
PROLACTIN o 50,000D
NEUROMODULATORS o Dimer
HYPERPROLACTINEMIA o Inactive
GALACTORRHEA
PROLACTINOMAS BIG-BIG
REFERENCES o Larger
APPENDIX o >100,000 D
o Aggregation of monomeric

PROLACTIN The larger forms also contain added sugar moieties

(glycosylation), which decreases biologic activity

Functions

1. Stimulate the growth of mammary tissue

2. Produce & secrete milk into the alveoli
- Mammogenic & lactogenic

• Polypeptide hormone
NEUROMODULATORS
• Synthesized and stored by the chromophobe cells
(lactotrophs)
• Inhibiting Factors
• Lateral areas of the pituitary gland
• Stimulating and Releasing Factors
• Circulates in different molecular sizes
• Involves:
• N° 8 ng/ml
o Dopamine
• Release is episodic o Serotonin
• Circulates in unbound form o Thyroid Releasing Hormone
• Receptor sites: breast, ovaries, liver, testes, prostate
• PRL levels normal fluctuate throughout the day Prolactin-inhibiting factor
o Maximal during night time while asleep
o Smaller increase in the early afternoon Dopamine
• Extra pituitary sites of synthesis: • Neurotransmitter
1. Decidua • Acts directly on the receptors on the lactotrophs of the
2. Hypothalamus pituitary gland
3. Lungs • Major inhibiting factor
4. Intestinal tract cells
5. Kidneys Secreting & Releasing Factor

ß Has a 20-minute half-life Thyroid-releasing hormone (TRH)

• Principal stimulating factor of prolactin
• Cleared by liver and kidneys
• Contains 198 amino acids
Serotonin
• MW = 22,000 daltons
• Principal releasing factor (PRF)
• Different molecular sizes: small, big, big-big
• Hypothalamic prolactin releasing factor
SMALL
o Monomeric Hormone Estrogen
o 22,000 D • Enhances the effects of TRH
o Biologically active • Inhibits the effects of dopamine
o 80%
HYPERPROLACTINEMIA
BIG

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 L22: Hyperprolactinemia, Galactorrhea, Pituitary Adenomas
Dr. LV Barrot-Gler | May 10, 2021

• High prolactin level in non-pregnant

• 20-25 ng/ml (Normal: 8ng)

Causes:

• Physiologic
• Pathologic

Physiologic Stimuli

• Nipple stimulation
• Exercise (when you exercise, These
serotonin increases) physiologic
• Stress – most frequent factors can
cause false- CAUSES:
• Sleep
positive results
• Following ingestion of noonday meal
o Renal Disease
Pathologic Causes
• Decreased metabolic clearance of prolactin
• Increased production rate – cause is unknown
Pituitary Disease
• Prolactinomas o CNS Disorders
• “Empty Sella syndrome” Hypothalamic Causes
• Acromegaly • Alters the normal portal circulation of dopamine
• Lymphocytic hypophysitis • Ex:
• Cushing’s disease - Craniopharyngioma
- Hypothalammic sarcoidosis
Hypothalamic Diseases - Histiocytosis
- Leukemia
• Craniopharyngiomas
- Carcinoma
• Meningiomas
• Dysgerminomas
Pituitary Causes
• Pituitary tumors
- Alteration in the normal portal circulation of
- 80% prolactin secreting
dopamine
- Prolactinoma – most common
- Ex:
▪ Microadenoma: <1cm
1. Craniopharyngioma
▪ Maroadenoma: >1cm
2. Hypothalamic sarcoidosis
- GH & ACTH producing adenomas
3. Histiocytosis
▪ Cushing Syndrome (25%)
4. Leukemia
▪ Acromegaly (10%)
5. Carcinoma

Medications • Lactotroph hyperplasia

- Pituitary enlargement with suprasellar
Neurogenic extension
- Can’t be distinguished from those with
• Chest wall lesions
microadenoma
• Spinal cord lesions
- Diagnosed by pituitary exploration
• Breast stimulation
- 8%
Other
• Functional Hyperprolactinemia
• Hypothyroidism
- Clinical diagnosis for women with ↑PRL
• Chronic Renal Disease
▪ No adenoma
• Liver cirrhosis ▪ Adenoma is too small to be visualized
• Adrenal Insufficiency ▪ Due to decreased dopamine inhibition
• Pseudocyesis
• PCOS • Empty Sella Syndrome
• Idiopathic - Defect in the sella diaphragm that allows
subarachnoid membrane to herniate into the
sella turcica

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 L22: Hyperprolactinemia, Galactorrhea, Pituitary Adenomas
Dr. LV Barrot-Gler | May 10, 2021

- Results in compression of pituitary gland & ▪ Oligomenorrhea

enlarged sella turcica ▪ Amenorrhea
- Distortion of the infundibulary stalk leads to 2. Anovulation
decreased dopamine reaching the pituitary 3. Inappropriate lactation/galactorrhea
gland
- Defect is congenital or acquired Gonadotropin-sex Steroid Functions Disorders
(radiation/surgery)
- N° pituitary function but hyperprolactinemia
- 5% of individuals have amenorrhea, CONDITIONS WITH HYPERPROLACTINEMIA
galactorrhea or both o Primary hypothyroidism
- Benign course • 3-5%
- Dx: CT Scan • ↓T4
MRI - best • ↓ negative feedback to the hypothalamic-pituitary
• ↑TRH & TSH: stimulates PrL secretion
o Pharmacologic Agents • Dx:
TSH determination – most sensitive indicator for
PSYCHOACTIVE hypothyroidism
Phenothiazines Fluphenazine T3, T4
Diazepam Chlorpromazine
Haloperidol SSRIs
TCA Opiates
Chlordiazepoxide Amphetamines
GALACTORRHEA
ANTI-HYPERTENSIVE
• Non puerperal secretion from the breast of watery or
Propranolol
milky fluid; contains no pus or blood
Phentolamine
Cyproheptadine • 30% to 80% of individuals with hyperprolactinemia
Reserpine
Methyldopa Diagnosis
Propranolol
1. Sample collection
Breast palpation – express any secretion
HORMONE
(+) multiple fat globules/droplets under LPF
Estrogen
2. MRI
OCP
3. CT Scans
TRH
4. Prolactin – all women with galactorrhea, oligorrhea, or
amenorrhea who do not have an elevated FSH level
PROLACTIN STIMULATORS
AGENT ACTION
Management
Anesthetics • Deplete hypothalamic circulation of
Psychoactive/ dopamine
• Expectant Treatment
Transquilizers • Block binding sites thus ↓
dopamine action - For those who do not wish to conceive:
Antidepressant Block dopamine uptake 1. Prolactin levels measured yearly
Anti-hypertensives 2. Exogenous estrogen for those with low
Reserpine Depletes catecholamines estrogen levels
Methyldopa Blocks the conversion of tyrosine to 3. Progesterone for those with adequate
dihydroxyphenylalanine (dopa) estrogen
Propranolol Blocks hypothalamic dopamine • Medical Therapy
receptors - For those with:
OCP ↑estrogen 1. Macroadenoma
2. Anovulatory
PROLACTIN INHIBITORS 3. Wish to conceive
Pharmacologic Agents - Give dopamine receptor agonist
• L Bromocriptine-Dopa ▪ Bromocriptine, methysergide
• Bromocriptine ▪ Metergoline, cabergoline
• Pergolide - Bromocriptine
• Cabergoline ▪ Dopamine receptor agonist
▪ Directly stimulate dopamine receptors
EFFECTS: ▪ Inhibit prolactin secretion & release
1. Menstrual Cycle Derangement ▪ Peak blood levels 1-3H later
▪ Gonadotropin-sex steroid function disorders ▪ Depresses PRL levels for 14 H after
single dose

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 L22: Hyperprolactinemia, Galactorrhea, Pituitary Adenomas
Dr. LV Barrot-Gler | May 10, 2021
▪ BID dose
▪ Reduce tumor size by 80-90%
▪ Used as initial management with PRL-
secreting macroadenomas → operative
treatment
▪ Side effects: hypotension, nausea,
vomiting, nasal congestion, diarrhea,
fatigue, constipation
• Operative Approaches
- Recommended in patients:
▪ Macroadenoma who fail with medical
therapy
▪ Poor compliance
- Transsphenoidal microsurgical resection of
prolactinoma
▪ Minimal risk; mortality < 0.5%
▪ Cure rate & normal PRL level is
achieved in
o 65-85% with microadenomas
o 20-40% macroadenomas
- Cure rate is related to pretreatment levels of PRL
▪ <100ng/ml = 85% prognosis
▪ > 200 ng/ml = 35%
- Poor prognosis:
▪ PRL levels > 200 ng/ml
▪ >26 years old, with amenorrhea for 6
months
• Radiation Therapy
- Not the primary mode of treatment
- Used as adjunct mgt following incomplete
removal of large tumors
- Can cause damage to normal pituitary tissue
↓ cause have hyperprolactinemia
- Abnormal anterior pituitary function (diabetis
insipidus)
- Damage to optic nerves may also occur
PROLACTINOMAS
• Adenoma
• Arise from single cell mutations, with clonal
proliferation occurring subsequently
• Seen in 50% of women with hyperprolactinemia
• Incidence: higher if the PRL > 100 ng/ml & almost all if
PRL > 200 ng/ml
• Radiologic evidence of pituitary tumors is seen in:
- 20% of individuals with galactorrhea
- 35% of women with amenorrhea-galactorrhea
• Incidence greater if with a more profound H-P-O
function disturbance
• May also secrete other hormones
• Enlargement is uncommon
• May regress spontaneously
ß May also secrete other hormones with GH being the
most common companion.
Also, up to 40% of primarily GH-secreting adenomas
also secrete PRL. Combinations of PRL and ACTH,
PRL and TSH, and PRL and FSH have been
described.
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Even “nonfunctioning” adenomas have been found to
secrete isolated α and β subunits of gonadotropins.
Prognosis
• Hyperprolactinemia with or without microadenoma is
benign
• Therapy is unnecessary unless:
a. Pregnancy is desired: Bromocriptine
b. Low estrogen level: OCP
• Following pregnancy:
o PRL levels decreased to normal in 36%
• Adenoma
o PRL levels decreased to normal in 17%
PREGNANCY
• Bromocriptine crosses the placenta
• Long term effects on fetus are unknown
• Discontinue use during pregnancy
• Reinitiated only when symptoms of visual
disturbances or severe headaches occur.
• With macroadenomas: monthly visual field
examination & neurological testing recommended
Summary
- PRL
- Normal: 8 ng
- The most common pathologic cause is ingestion
of medication
- 15% of all anovulatory women have
hyperprolactinemia
- 20% of women with amenorrhea of undetermined
- 60% of all women with galactorrhea have
hyperprolactinemia
ß Key Points
• The main symptoms of hyperprolactinemia
are galactorrhea and amenorrhea, the
latter caused by alterations in normal GnRH
release.
• Pathologic causes of hyperprolactinemia
include pharmacologic agents (e.g.,
tranquilizers, narcotics, antihypertensive
drugs), hypothyroidism, chronic renal
disease, chronic neurostimulation of the
breast, hypothalamic disease, and pituitary
tumors (e.g., prolactinoma, acromegaly,
Cushing disease).
• Autopsy studies reveal that prolactinomas
are present in approximately 10% of the
population.
• Approximately 70% of women with
hyperprolactinemia, galactorrhea, and
amenorrhea with low estrogen levels will
have a prolactinoma.
• Most macroadenomas enlarge with time;
almost all microadenomas do not.
• The initial operative cure rate for
microadenomas is approximately 80% and
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 L22: Hyperprolactinemia, Galactorrhea, Pituitary Adenomas
Dr. LV Barrot-Gler | May 10, 2021

30% for macroadenomas, but the long-term

recurrence rate is at least 20% for each.
• In women with hyperprolactinemia and no
macroadenoma, bromocriptine or
cabergoline treatment returns PRL levels to
normal in 90%, induces ovulatory cycles in
80%, and eradicates galactorrhea in 60%.
• The dopamine agonist of choice is
cabergoline, because of increased efficacy
and fewer side effects.
• Without prior treatment, 2.7% of women with
microadenomas develop symptoms,
whereas 22.9% of women with a
macroadenoma will develop symptoms.
Estrogen therapy or oral contraceptives will
not stimulate the growth of PRL-secreting
microadenomas and can be used for
treatment of hyperprolactinemia and
hypoestrogenism.
• Surgical treatment of prolactinomas is
recommended only for patients who fail to
respond or do not comply with medical
management.

END OF TRANSCRIPTION

REFERENCES
● Comprehensive Gynecology 7th edtn
● Dr. Barrot-Gler’s Lecture and PPT

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