Endocrinology Tutorial_3: Anterior Pituitary

Marc Imhotep Cray, M.D. 04-16

Buja LM & Krueger GR. Netters Illustrated Human Pathology, Updated Edition. Saunders , 2014.

Chromophobe adenomas
Chromophobe adenomas, most common pituitary tumors, constitute approximately
15% of all intracranial tumors
They occur in both sexes, usually in later life (sixth decade)
Chromophobe adenomas, which may remain microscopic for long periods, most often
compress optic chiasm, causing subsequent bitemporal hemianopsia when they expand
Vision impairment is often initial clinical sign
Functioning chromophobe adenomas produce a variety of hormones, including
Prolactin (lactotrophic adenomas)
Somatotropin (somatotropic adenomas)
LH and FSH (gonadotropic adenomas), and, rarely,
TSH (thyrotropic adenomas)
Clinical features differ according to adenoma type with signs of hypogonadism and
virilization, acromegaly, hypothyroidism, and others
Some adenomas produce more than 1 hormone including corticotropins
Marc Imhotep Cray, MD

Case
A 32-year-old woman complains of recent visual problems and slight
breast discharge (galactorrhea). She has not had her period for the
past 6 months (secondary amenorrhea) and is upset that she has
been unable to become pregnant, despite trying for the past year
with her husband. She denies any history of schizophrenia or of
being treated with neuroleptics (antipsychotics). Laboratory workup
reveals a negative pregnancy test result, normal TSH level, and
significantly elevated levels of prolactin. Magnetic resonance
imaging (MRI) of the head shows enlargement of the structure
located in the sella turcica.

Marc Imhotep Cray, MD

Tutorial Queries
1. What is the diagnosis?
2. What are the normal physiologic functions of prolactin preceding,
during, and following pregnancy?
3. Hyperprolactinemia can also occur in men. What symptoms might
be expected in men?
4. How does elevated prolactin prevent pregnancy (i.e., what is the
mechanism of infertility and amenorrhea in this patient)?
5. Why is asking about a history of schizophrenia and use of
antipsychotic medications a relevant question in the diagnostic
workup of this patient?
6. How can head trauma with a severed pituitary stalk cause a similar
increase in prolactin (assuming the anterior pituitary itself was not
Marc damaged)?
Imhotep Cray, MD

1. What is the diagnosis?

Prolactinoma: A pituitary adenoma caused by abnormal proliferation of
lactotrophs; it is most common type of hypersecreting pituitary adenoma
Note that the pituitary is situated in the sella turcica

Marc Imhotep Cray, MD

Effects of Pituitary Tumors on Visual Apparatus

Optic chiasm lies above the diaphragma sellae
Most common sign that a pituitary tumor has extended beyond
confines of sella turcica is a visual defect caused by growth
pressing on optic chiasm
Most frequent disturbance is a bitemporal hemianopsia, which
is produced by tumor pressing on crossing central fibers of
chiasm and sparing the uncrossed lateral fibers
Earliest changes are usually enlargement of blind spot; loss of
color vision, especially for red; and a wedge-shaped area of
defective vision in upper-temporal quadrants, which gradually
enlarges to occupy whole quadrant and subsequently extends to
include lower temporal quadrant as well

Young WF. The Netter Collection of Medical Illustrations, Vol 2.

The Endocrine System, 2nd Edn. Philadelphia: Saunders, 2011.

Pituitary macroadenoma, MRI

Pituitary macroadenoma, MRI this
T1-weighted sagittal MRI image
shows a large bright pituitary mass
larger than 1 cm
Overall, the most common types of
pituitary adenomas (and their clinical
outcomes) include prolactinoma
(amenorrhea-galactorrhea in women,
decreased libido in men)

About 3% of pituitary adenomas are

associated with multiple endocrine
neoplasia type 1 (MEN 1)
Marc Imhotep Cray, MD

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed.

Philadelphia: Saunders, 2015.

Pituitary macroadenoma, MRI and diagram

This T1-weighted MRI image in axial view shows a bright pituitary macroadenoma ( ).
Macroadenomas by their size can erode the sella turcica to produce headaches and impinge on the optic
chiasm to produce visual field defects, most commonly bitemporal hemianopsia, as shown by the diagram.
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

Anatomy & Relationships of Pituitary Gland

Pituitary gland is reddish-gray and ovoid, measuring about 12
mm transversely, 8 mm in its anteriorposterior diameter, and 6
mm in its vertical dimension
It weighs approximately 500 mg in men and 600 mg in women

It is contiguous with end of infundibulum and is situated in

hypophysial fossa of sphenoid bone

A circular fold of dura mater, diaphragma sellae, forms the

roof of this fossa In turn, the floor of hypophysial fossa forms
part of roof of sphenoid sinus
Diaphragma sellae is pierced by a small central aperture
through which pituitary stalk passes, and it separates anterior
part of upper surface of gland from optic chiasm
Young WF. The Netter Collection of Medical Illustrations, Vol 2.
The Endocrine System, 2nd Edn. Philadelphia: Saunders, 2011.

2. What are normal physiologic functions of PL

preceding, during, and following pregnancy?
Preceding pregnancy: Prolactin levels are normal due to tonic hypothalamic
inhibition via dopamine and to the absence of stimulatory factors such as
suckling or high estrogen
It has numerous physiologic functions in countless organ systems in nonpregnant
woman, all of which are beyond the scope of this presentation

During pregnancy: Prolactin levels are high secondary to high estrogen levels
(secreted by placenta), which stimulate breast maturation and lactogenesis
However, actual lactation is prevented by high estrogen and progesterone (which
antagonize actions of prolactin on breast)

Following pregnancy: Estrogen levels drop, and prolactin levels also will drop
unless stimulation by suckling occurs; levels increase and lactation occurs
with suckling stimulation
It is important for you to know that prolactin will also inhibit GnRH secretion, often (but
not always!) resulting in anovulatory infertility while nursing
Marc Imhotep Cray, MD

10

3. Why does this patient have galactorrhea, whereas

pregnant women with similar levels of serum prolactin
generally do not have this problem?
Although prolactin stimulates milk production, high concentrations of
estrogen and progesterone that are present during pregnancy inhibit
lactation, and therefore, galactorrhea
In contrast
This patient has hyperprolactinemia in absence of elevated levels of estrogen
and progesterone, which is causing her galactorrhea
Note: Milk letdown occurs after childbirth because, during pregnancy, placenta makes most
of estrogen and progesterone. Levels of both hormones decrease after this structure is
expelled in delivery. Additionally, oxytocin is secreted in response to suckling, and this
hormone stimulates contraction of myoepithelial cells around glandular tissue of breast,
causing milk ejection.
Marc Imhotep Cray, MD

11

4. Hyperprolactinemia can also occur in men. What

symptoms might be expected in men?
In men, inhibition of GnRH secretion by prolactin decreases
gonadotropin-mediated testosterone production low testosterone
may lead to erectile dysfunction (impotence) and loss of sex drive (libido)
Galactorrhea can also rarely occur in men in response to certain stimuli
such as severe stress and prolonged starvation
Of note, be suspicious of hyperprolactinemia in men presenting with
malaise and depression

Marc Imhotep Cray, MD

12

5. How does elevated prolactin prevent pregnancy (i.e., what

is the mechanism of infertility and amenorrhea in this
patient)?
Prolactin inhibits hypothalamic release of GnRH, which is a
stimulus for FSH and LH secretion consequent reduction of
FSH and LH eliminates ovulatory cycle, resulting in infertility and
amenorrhea
Note that hyperprolactinemia in men can cause impotence and
infertility through a similar mechanism, except in this case
testosterone is lowered as a result of decreased LH

Marc Imhotep Cray, MD

13

6. What is the mechanistic basis for using bromocriptine

(used to treat Parkinsons disease) in the treatment of a
prolactinoma?
Bromocriptine is a dopamine agonist (recall that Parkinsons disease is
caused by a lack of dopamine) that inhibits prolactin secretion by
anterior pituitary

7. Why is asking about a history of schizophrenia and use of

antipsychotic medications a relevant question in the
diagnostic workup of this patient?
Several antipsychotics (particularly the typical antipsychotics) can cause
hyperprolactinemia.
This is not a fact you have to memorize if you simply recall that
antipsychotics are dopamine antagonists, and that hypothalamic dopamine is
the major inhibitor of pituitary prolactin secretion
Marc Imhotep Cray, MD

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8. How can head trauma with a severed pituitary stalk cause a

similar increase in prolactin (assuming the anterior pituitary
itself was not damaged)?
This increase is due to disruption of the tuberoinfundibular tract,
which runs from hypothalamus through the pituitary stalk and is
the source of dopamine, which inhibits prolactin release.
Note: Plasma levels of all other anterior pituitary hormones (e.g.,
TSH, ACTH) will decrease with a severed pituitary stalk.

Marc Imhotep Cray, MD

15

Physiologic actions of prolactin

Marc Imhotep Cray, MD

Brown TA: Rapid Review Physiology. Philadelphia, Mosby, 2007

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Key Points
Hyperprolactinemia can be caused by a prolactinoma,
antipsychotics (via inhibition of hypothalamic dopamine
secretion), hypothyroidism (via increased thyrotropin-releasing
hormone [TRH]), and breast feeding or excessive nipple
stimulation.
The increase in prolactin secretion that occurs with suckling is
important in allowing for lactation. It can also inhibit
gonadotropin-releasing hormone (GnRH) secretion and cause an
anovulatory infertility, explaining why nursing women may have
difficulty becoming pregnant.
Marc Imhotep Cray, MD

Key Points (2)

In women, in addition to causing infertility, hyperprolactinemia
can cause galactorrhea. It can also cause malaise and
depression.
In men, hyperprolactinemia can cause impotence and lack of
libido but only rarely will cause galactorrhea.
Treatment for prolactinoma includes the use of dopamine
agonists (for small adenomas) or, less commonly, surgical
resection (for larger adenomas).
Marc Imhotep Cray, MD

Prolactin and Related Drugs

Prolactin contains 198 amino acids and acts on mammary gland to
stimulate tissue growth and promote lactation (milk production) in
presence of adequate levels of estrogens, progestins
Prolactin does not have any current clinical use

Secretion of PRL is inhibited by dopamine [(the prolactin-inhibiting

hormone (PIH)] and is stimulated by hypothalamic prolactin-releasing
factors (PRF or TRH)
Excessive prolactin secretion causes hyperprolactinemia leads to
galactorrhea (excessive milk production), hypogonadism, and infertility
In some cases, hyperprolactinemia occurs secondary to prolactinsecreting pituitary adenomas
Marc Imhotep Cray, MD

Prolactin-releasing factor (PRF)

Secretion of prolactin from pituitary is controlled by both inhibition
(mediated by PIF, which is dopamine) and stimulation (mediated by PRF)
PRF
o Several peptides, including thyrotropin-releasing hormone (TRH), that
increase synthesis and release of prolactin have been identified in
hypothalamus and placenta
their physiologic role is unclear
Drugs that reduce central nervous system (CNS) dopaminergic activity cause
an increase in prolactin secretion, as will dopamine antagonists
These include
o Antipsychotics, including chlorpromazine and haloperidol
o Antidepressants, including imipramine
o Antianxiety agents, including diazepam
Marc Imhotep Cray, MD

Prolactin-inhibiting factor (PIF)

PIF
Inhibition of prolactin secretion can be produced by a
number of dopamine agonists
o Bromocriptine
o Cabergoline

Marc Imhotep Cray, MD

Prolactin and Related Drugs (2)

Both idiopathic and secondary forms of hyperprolactinemia can be
treated with a dopamine agonist such as cabergoline or bromocriptine
Bromocriptine and cabergoline are both ergot alkaloid derivatives
Effects and Use
Each drug mimics action of dopamine and thereby reduces prolactin
secretion
In patients with prolactin-secreting adenomas, treatment with either
drug also produces a significant reduction in tumor size
MOA
Bromocriptine acts as an agonist of dopamine D2-receptors and an
antagonist of D1-receptors
Cabergoline is a potent D2 agonist with greater D2 selectivity
Marc Imhotep Cray, MD

Prolactin and Related Drugs (3)

In comparison with bromocriptine, cabergoline appears to be more
effective and better tolerated in patients with hyperprolactinemia
MOA
Cabergoline selectively activates dopamine D2 receptors in pituitary gland
and thereby suppresses secretion of prolactin
Other Use
It is also useful in persons with a mixed growth hormone and prolactin
secreting pituitary adenoma
Pharmacokinetics
drug has an elimination half-life of about 65 hours provides a long
duration of action permits twice-weekly dosing
Adverse Effects
most common adverse effects of cabergoline are nausea, headache, and
dizziness
Marc Imhotep Cray, MD

Question
3. By which mechanism does cabergoline relieve symptoms of
hyperprolactinemia in persons with a prolactin secreting pituitary
adenoma?
(A) blocks prolactin receptors
(B) blocks receptors for prolactin-releasing hormone
(C) has a cytotoxic effect on pituitary adenoma cells
(D) activates receptors for prolactin-inhibiting hormone
(E) stimulates the breakdown of prolactin

Marc Imhotep Cray, MD

Answer
The answer is D: activates receptors for prolactin inhibiting
hormone. Prolactin secretion is ordinarily restrained by tonic
secretion of prolactin-inhibiting hormone (PIH or dopamine).
Cabergoline and bromocriptine are dopamine receptor agonists
that act to mimic the effect of endogenous prolactin-inhibiting
hormone and thereby reduce excessive prolactin secretion in
persons with prolactin-secreting pituitary adenomas.

Marc Imhotep Cray, MD

---THE END--Case Source:

Modified from: Brown TA, Brown D. USMLE Step 1 Secrets, 3rd Ed.
Philadelphia. Saunders, 2013, Case 8-2; pgs. 207-10
Further learning:
Disorders of the Hypothalamus & Pituitary Gland (Ch.19), Hypopituitarism.
Pgs. 560-62. In: Hammer GD, McPhee SJ, eds. Pathophysiology of Disease:
An Introduction to Clinical Medicine, 7th Edn. New York: McGraw-Hill, 2014
Young WF. Pituitary and Hypothalamus, Postpartum Pituitary Infarction
(Sheehan Syndrome), pg. 19. In: The Netter Collection of Medical
Illustrations Vol 2- The Endocrine System 2nd Edn. Philadelphia: Saunders,
2011.
Endocrine and Reproductive System Pharmacology eNotes
Marc Imhotep Cray, MD