Endocrinology lecture 2

Hyperprolactinemia, Diabetes Insipidus

Manal Kh. Aladhadh
Professor of Internal Medicine
Department of Medicine
College of Medicine - University of Baghdad
 Objectives
By the end of this lecture, the student should be
able to:
• List causes of hyperprolactinemia.
• Outline the clinical consequences of pituitary adenoma
producing prolactin.
• Assess clinically a case of hyperprolactinemia.
• Recognize the action of ADH.
• Define diabetes insipidus (DI).
• Mention types of DI.
• Evaluate and manage a case of diabetes insipidus and
interpret water deprivation test.
 CASE SCENARIO 1
• A 40-year-old obese woman with type 2 DM
and hypertension presented because of
hirsutism, galactorrhea and amenorrhea for
the last 4 months.
• What additional questions should be asked of
this patient?
• What diagnostic tests should be ordered as
part of the work-up of galactorrhea and
amenorrhea in this patient?
 PROLACTINOMA
❑ Most common functional pituitary tumor.
❑ 10/100,000 in men and 30/100,000 in women.
❑ Mixed tumors that secrete combinations of GH
and PRL, ACTH and PRL are also seen.
❑ The female: male ratio for microprolactinomas
is 20:1, whereas the sex ratio is near 1:1 for
macroadenomas.
 OTHER CAUSES OF HYPERPROLACTINEMIA
❑Physiological: breast feeding, sexual activity, sleep,
stimulation of mammary gland.
❑Interruption of inhibitory control of the
hypothalamus over pituitary, stalk compression by
other tumors, hypothalamic tumors.
❑Empty Sella syndrome.
❑Drugs: Antipsychotics, antidepressives (SSRI), α-
methyl-DOPA, 5HT2 inhibitors, estrogen, H2 receptor
antagonist, anticonvulsants.
❑Hypothalamic diseases: sarcoidosis, hysticytosis.
❑Polycystic ovarian disease, acromegaly,
hypothyroidism, kidney failure, liver cirrhosis.
❑ Head trauma (Pituitary stalk section, suprasellar
surgery).
 Major physiologic and pathologic causes of hyperprolactinemia
Physiological Pathological
Pituitary disorders CNS disorders Systemic diseases
Severe
Pregnancy Prolactinomas Tumors
Hypothyroidism
Breast feeding Mixed pituitary Granulomatous Liver cirrhosis
Breast stimulation adenomas diseases Chronic renal
Sleep Cushing’s disease Vascular disorders failure
Autoimmune
Stress Acromegaly
disorders Polycystic ovary
Not secreting syndrome
Hypothalamic
adenomas
tumours or
Empty sella syndrome metastasis Estrogen-secreting
tumours
Pituitary stalk section Cranial irradiation
or tumours Seizures Pseudocyesis
Lymphoid
Chest wall trauma
hypophysitis
Herpes zoster
 Prolactinomas, Hyperprolactinemia
Clinical presentation
❖ Prolactin excess inhibits gonadotropins secretion
(GnRH release is decreased in direct response to elevated
prolactin, leading to decreased production of LH and FSH).

IN WOMEN:
❑ Secondary amenorrhea, oligomenorrhea, infertility
❑ Galactorhea
❑ Hirsutism
❑ Weight gain
❑ Signs of estrogen deficiency with genital atrophy
❑ Osteoporosis
❑ Pituitary failure in large prolactinomas

Most prolactinomas in women are microadenomas.

 Prolactinomas, Hyperprolactinemia
In men: decreased testosterone secretion with:
❑ Decreased libido
❑ Erectile dysfunction
❑ Infertility
❑ Pituitary failure
In men most prolactinomas are macroprolactinomas and
are associated with “pituitary tumor syndrome”

✓ Serum PRL levels rise transiently after exercise, meals,

sexual intercourse, minor surgical procedures, general
anesthesia, chest wall injury, acute myocardial infarction,
and other forms of acute stress.
Microprolactinoma

Macroprolactinoma
❑What additional diagnostic tests should be ordered as
part of the work-up of galactorrhea and amenorrhea
in this patient?
• Repeat serum prolactin test.
• TSH and free T4.
• Pregnancy test.
• Serum testosterone level in men.
• If the results came normal and other diagnoses are
excluded, the most likely diagnosis is a prolactinoma.
Then pituitary MRI should be done.
• Visual field testing/ in individuals with loss or
impairment of peripheral vision.
 ASSESSEMENT OH HYPERPROLACTINEMIA
❑ Prolactin values:
Prolactin levels correlates with tumor size:
– Normal adult serum PRL levels are about 10–25µg/L in
women and 10–20µg/L in men. PRL secretion is pulsatile,
with the highest secretary peaks occurring during rapid eye
movement (REM) sleep.
– Peak serum PRL levels (up to 30 g/L) occur between
4:00 and 6:00 a.m.
- (below 200 ng/ml with less than 1 cm, 200 ng/ml to 1000 ng/ml
with 1 cm to 2 cm and more than 1000 ng/ml with tumor sized
more than 2 cm in diameter).
❑ Bromocriptine test:
– 2,5 mg bromocriptine must reduce prolactin levels
❑ CT, MRI should be performed in all patients with
hyperprolactinemia.
 Diagnosis
❑ Assess hypersecretion:
• Basal, fasting morning PRL levels (normally <20 ug/L)
❑ Multiple measurements may be necessary:
• Pulsatile hormone secretion
• levels vary widely in some individuals with
hyperprolactinemia
❑ Both false-positive and false-negative results may be
encountered
• May be falsely lowered with markedly elevated PRL
levels (>1000 ug/L)
– sample dilution is required to measure these high
values accurately
• May be falsely elevated by aggregated forms of
circulating PRL, which are biologically inactive
(macroprolactinemia)
❑ Hypothyroidism should be excluded
 Macroprolactinemia
• Big variants of 50 kDa and prolactin-IgG
complexes of 150 kDa, with high immunogenic
properties but poor biological effects, can
circulate in large amount (up to 85% of total
prolactin).
• This condition, is characterized by normal
levels of biological prolactin and lack of clinical
symptoms.
 TREATMENT OF PROLACTINOMAS
A. Pharmacotherapy – dopamine agonists
• First choice treatment in microprolactinomas and
pre treatment in macroprolactinomas in order to
reduce tumor size and facilitate surgery
– Bromocriptine: 2,5 – 20 mg /day (start with
0.625–1.25 mg/ day at night)
– Cabergoline: 0,5 – 1 mg twice weekly orally

• Effects of pharmacotherapy:
- menses occur again
- fertility is restored
- shrinks 70% of macroprolactinomas.
 TREATMENT OF PROLACTINOMAS
B. Surgery
❑ For large tumors with compressive symptoms that fails
to improve after drug treatment.
❑ Dopamine resistance or intolerance.
❑ Effects of surgery:
- in best cases gonadotropin secretion occurs again.
- hyperprolactinemia recurs in up to 20% of patients
within the first year after surgery; long-term
recurrence rates exceed 50% for macroadenomas.
- residual disease may be controlled with dopamine
agonists.
C. External irradiation is reserved for patients with
aggressive tumors that do not respond to maximally
tolerated dopamine agonists and/or surgery.
 Quick Quiz!!!
❑What type of tumors are most prolactinomas?
❑Prolactin levels >200 almost always indicate
what?
❑Do prolactin levels correlate with tumor size?
• A 38-year-old lady presented to the
endocrine clinic with a 2-year history of
irregular menses and 1-year history of
both right sided headaches and blurring of
vision. There is associated galactorrhea,
weight gain and loss of libido.
• Examination of the cardiovascular, chest,
abdomen and thyroid glands are not
remarkable.
 DIABETES INSIPIDUS
CASE SCENARIO
• A 23 y old male was admitted to the ICU
after having a concussion and head trauma
from a car accident. He had CT scan that
revealed cerebral edema but was otherwise
normal. During the 2nd day he had polyuria
(UOP= 5L in last 24h), he had not been
given diuretics. His urine osmolarity was
low.
❑What is the most likely diagnosis?
 ADH
❑ADH is produced in cells in
the supraoptic and
paraventricular nuclei
❑It is transported to and
osmoreceptors paraventricular
released from the posterior
neurons
pituitary baroreceptor
supraoptic input
• A decrease in osmolality of
neurons
1-2% will rapidly suppress
ADH levels to allow diuresis
• ADH is released in response
ant. pons
to decrease in blood volume
pituitary
or arterial pressure. post.
• ADH release is inhibited by ADH
atrial natriuretic
peptide (ANP).
 Diabetes Insipidus
– Decreased secretion or action of AVP.
– A large volume of urine (diabetes).
– That is hypotonic, dilute and tasteless (insipid).
• The 24-hour urine volume is >50 mL/kg body weight, and the
osmolarity is <300 mosmol/L.
• The polyuria produces symptoms of urinary frequency,
enuresis, and/or nocturia.
• It results in a slight rise in plasma osmolarity that stimulates
thirst and polydipsia.
• Overt clinical signs of dehydration are uncommon unless fluid
intake is impaired.
 Etiology
• Four distinct defects:
❑Central DI, a primary deficiency of ADH.
❑Nephrogenic DI, caused by an inappropriate renal
response to ADH.
❑Gestational DI of pregnancy, caused by
vasopressinase produced by placenta.
❑Primary Polydipsia, in which pathology is secondary
to ingestion, rather than elimination of, fluid
 Central DI
• Most common.
• Usually secondary to irreversible destruction
of >80% ADH producing neurons.
• Genetic forms caused by accumulation of
poorly folded precursor proteins.
Genetic Congenital Acquired
Chromosome 20 –dominant Septo-optic dysplasia Head trauma including pit. surgery

X linked (Xq28) Midline craniofacial defects Neoplasms

craniopharyngioma, adenoma, leukemia,
lymphoma, Meningioma, metastatic
Autosomal recessive Wolfram Holoprosencephaly Granulomas ( Sarcoidosis, Histiocytosis)
syndrome

Agenisis/hypogenisis of Infections
pit meningitis, encephalitis, toxoplasmosis
Autoimmune
lupus, scleroderma, Wegener’s
Toxins (snakes)

Vascular (sheehan’s, Aneurysm, Hypoxic

encephalopathy

Idiopathic
 Nephrogenic DI
• Caused by a poor response of the kidney to
ADH, most common form is congenital
Genetic Acquired
X linked recessive (V2 Drugs
gene) lithium, ampho B, rifampin, cisplatin,
foscarnet, demeclocycline
Autosomal Recessive Metabolic
(aquaporin gene) hypercalcemia, hypercalcuria, hypokalemia
Autosomal dominant Vascular
sickle cell disease& trait, ischemia/ ATN
Granuloma/ Sarcoidosis
Neoplasm/ Sarcoma
Amyloidosis, Pregnancy, Idiopathic
 Primary polydipsia
• They are divided into three subcategories:
Dipsogenic DI-- Inappropriate thirst (reduction in
the set of the osmoregulatory mechanism) due to
multifocal diseases of the brain such as
neurosarcoid, tuberculous meningitis, and multiple
sclerosis but is often idiopathic.
Psychogenic polydipsia, is not associated with thirst,
and the polydipsia seems to be a feature of
psychosis or obsessive compulsive disorder.
Iatrogenic polydipsia, results from
recommendations to increase fluid intake for its
presumed health benefits.
 Pathophysiology
❑ Lack of ADH, or ADH response, leads to a deficiency
in urine concentration
– decrease in TBW, and a rise in plasma osmolality
and Na (thirst response, which, if intact, stabilizes
osmo’s and Na)
❑ Increased osmolarity, water exits cells, and moves
down its concentration gradient into the plasma,
stimulates the osmoreceptors cells to contract,
results in afferent signals being sent from the
hypothalamus to the posterior pituitary gland to
increase the release of ADH.
❑ Baroreceptors in the left atrium, carotid artery and aortic
arch detect changes in arterial blood volume.
❑ If BP reduces, baroreceptors relay this to the vagus
nerve, which sends afferent signals that directly stimulates
the release of ADH. Conversely, in a hypervolemic state, the
release of ADH will be reduced.
❑ Polyuria further impairs concentrating ability through
washout of medullary concentration gradient.
❑ Gradient washout is a depletion of interstitial medullary
sodium or urea that reduces water reabsorption, despite
the presence of functioning ADH (secondary nephrogenic
DI).
 Diagnosis
❑Urinary frequency, enuresis, nocturia, and/or
persistent thirst are present, the possibility of DI
should be evaluated after excluding glucosuria and
hyperglycemia
❑CLINICAL SUSPICION
Bad brain injury, neurosurgery post-op
❑High or increasing urine output, exceeds 50 mL/kg
per day and Urine Osmolarity usually < 300mOsm/kg
❑Increasing serum Na
– Implies free water loss in excess of sodium loss,
which implicates ADH as the culprit
Laboratory Findings
❑Na >145 mEq/L
❑Posm > 285 mOsm/kg
❑Uosm < 300 mOsm/kg
❑Urine Na low
❑Urine Specific Gravity < 1.005
❑UOP > 3ml/kg/h
 For Differential Diagnosis
Fluid deprivation test.
• Should be started in the morning and continued with
hourly monitoring of body weight, plasma osmolarity
and/or sodium concentration, urine volume, and
urine osmolarity until either of two endpoints is
reached.
• If fluid deprivation does not result in urine
concentration (osmolarity >300 mosmol/L, specific
gravity >1.010) before body weight decreases by 5%
or plasma osmolarity/sodium rise above the upper
limit of normal, the patient has severe pituitary or
severe nephrogenic DI.
• These disorders can be distinguished by
administering desmopressin (0.03 g/kg SC or IV) and
repeating the measurement of urine osmolarity 1–2
hours later.
• An increase of >50% indicates severe pituitary DI,
whereas a smaller or absent response is strongly
suggestive of nephrogenic DI.
• If fluid deprivation results in concentration of the
urine, severe defects in AVP secretion and action are
excluded and the question becomes whether the
patient has partial pituitary DI, partial nephrogenic
DI, or primary polydipsia.
MRI of the pituitary and hypothalamus.
• In most healthy adults and children, the posterior
pituitary emits a hyperintense signal in T1-
weighted midsagittal images.
• This "bright spot" is almost always present in
patients with primary polydipsia but is invariably
absent or abnormally small in patients with
pituitary DI.
• It is usually also small or absent in nephrogenic DI
presumably because of high secretion of AVP.
• Thus, a normal bright spot strongly suggests
primary polydipsia.
Normal post pituitary bright spot
MRI of the brain revealed the loss of posterior pituitary
bright spot, suggesting the diagnosis of central DI.
 Treatment
❑If central DI
• DDAVP (a synthetic analogue of AVP)
– For chronic correction
– More resistant than vasopressin to degradation&
longer duration of action.
– 1–2 µg qd or bid by injection, 10–20 µg bid or tid
by nasal spray, or 100–400 µg bid or tid orally.
❑If nephrogenic DI
– Thiazide diuretic and/or amiloride in conjunction
with a low-sodium diet and a prostaglandin
synthesis inhibitor (e.g., indomethacin) usually
reduces the polyuria and polydipsia by 30–70%
and may eliminate them completely in some
patients.
– Gene therapy
❑Primary polydipsia cannot be treated safely
with desmopressin because eliminating the
polyuria does not eliminate the urge to drink
and it produces hyponatremia and/or other
signs of water intoxication.
• Patient education to eliminate iatrogenic
polydipsia.
• In psychogenic or dipsogenic DI, avoid the use
of drugs that can impair urinary free-water
excretion directly or indirectly.
• FURTHER READINGS
Davidson’s Principles of Internal Medicine.
Harrison’s Principles of Internal Medicine.