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CASE 33
A 44-year-old woman presents to her gynecologist with complaints of not having had a period for the last 8 months. She reports a negative pregnancy test at
home. Upon further questioning, she reports a daily headache, changes in
vision, and a milky discharge from the breast. She has no medical problems
and is not taking any medications. On physical examination, she is noted to
have galactorrhea and diminished peripheral vision bilaterally. The remainder
of her examination is normal. A pregnancy test is repeated and is negative. A
thyroid-stimulating hormone (TSH) level is drawn and is normal. Her serum
prolactin level is elevated significantly. After a thorough workup is completed,
she is found to have a prolactin-secreting pituitary adenoma.
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How does hyperprolactinemia cause amenorrhea?
Why would a physician need to check thyroid studies in patients
with hyperprolactinemia?
Where are the posterior pituitary hormones synthesized?
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CASE FILES: PHYSIOLOGY
ANSWERS TO CASE 33: PITUITARY ADENOMA
Summary: A 44-year-old woman has secondary amenorrhea, galactorrhea,
headache and visual changes, and hyperprolactinemia. She is diagnosed as
having a pituitary prolactinoma.
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Elevated prolactin and amenorrhea: Elevated prolactin levels inhibit
pulsatile gonadotropin-releasing hormone (GnRH) secretion.
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Thyroid disease and elevated prolactin: Hypothyroidism is associated
with an elevated thyrotropin-releasing hormone (TRH) level that
increases the secretion of prolactin.
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Synthesis of the posterior pituitary hormones: Hypothalamic
nuclei—hormones are synthesized in nerve cell bodies, packaged in
secretory granules, and transported down the nerve axon to the posterior
pituitary.
CLINICAL CORRELATION
An elevated prolactin level can be seen in numerous conditions. Patients
should be screened initially with a pregnancy test and thyroid studies. Many
different medications can cause an elevated prolactin level, including birth
control pills, metoclopramide, and many antipsychotic medications. Patients
present with amenorrhea secondary to inhibition of GnRH and/or galactorrhea.
When adenomas are present, a patient may present with symptoms of
headache or even changes in vision. The visual changes (bitemporal hemianopia) and headache usually are related to the prolactinoma compressing the
optic chiasm. Normally, prolactin inhibits its own secretion by stimulating the
release of dopamine from the hypothalamus. However, when pituitary adenomas are present, prolactin is secreted without inhibition from normal feedback
mechanisms. Treatment of microadenomas that are not symptomatic is usually
medical with bromocriptine (a dopamine agonist). However, when microadenomas are symptomatic or do not respond to medical management, surgical
intervention is often necessary. Macroadenomas usually are treated surgically.
APPROACH TO THE PITUITARY GLAND
Objectives
1.
2.
3.
Discuss the synthesis and secretion of the hormones of the anterior and
posterior pituitary.
Describe the role of the hypothalamus in the synthesis and secretion of
the hormones of the anterior and posterior pituitary.
Know the factors that increase and decrease prolactin secretion.
CLINICAL CASES
273
Definitions
Hypothalamohypophysial portal system: The vasculature that allows for
peptides secreted by hypothalamic cells to travel to, and act on, cells in
the pituitary.
Arcuate nucleus: The region of the hypothalamus whose cells secrete
growth hormone-releasing hormone and gonadotropin-releasing hormone,
Paraventricular nucleus: The region of the hypothalamus whose cells
secrete thyrotropin-releasing hormone and corticotropin-releasing
hormone.
DISCUSSION
The pituitary gland is composed of two lobes that are derived embryonically
from the primitive gut (anterior lobe) and the brainstem (posterior lobe). The
pituitary secretes a large number of peptide hormones into the blood that affect
the growth and secretions of other endocrine glands and/or the function of
many end organs directly. Although it plays a major role in regulating many
body functions, the pituitary itself is regulated in large part by the hypothalamus and/or by secretory products of other endocrine glands.
Concerning the posterior pituitary, nerves extend from the supraoptic
and paraventricular nuclei of the hypothalamus to end in the posterior pituitary. Cell bodies in the hypothalamus, not in the posterior pituitary, synthesize and package peptide hormones in secretory granules that then undergo
axonal transport to be stored in nerve endings in the posterior pituitary until
they are released. The major hormones released from the posterior pituitary are antidiuretic hormone (ADH), also known as vasopressin, and oxytocin. These hormones are released from nerve endings in the pituitary when
their nerve cells bodies in the hypothalamus receive stimulatory input. Input
for the secretion of ADH comes from hypothalamic osmoreceptors responding to the osmotic pressure of the blood and from receptors located within
the cardiovascular system (eg, the right atrium) responding to blood volume
(pressure). Input for secretion of oxytocin comes from receptors in the cervix
and in mammary glands. Stretching of the cervix during labor and delivery
stimulates secretion of oxytocin, which stimulates uterine contractions that
result in further stretching of the cervix. This is an example of a positive feedback loop. In nursing females, oxytocin also is released in response to suckling and often as a conditioned reflex in response to the thought of nursing. In
this case, oxytocin stimulates milk ejection from the mammary gland. The
release of ADH and oxytocin does not appear to be under direct negative feedback from circulating levels of the hormones.
The situation for the anterior pituitary differs. Peptide hormones of the anterior
pituitary are synthesized and stored in secretory cells in the pituitary itself.
Communication with the hypothalamus is via the hypothalamohypophysial
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CASE FILES: PHYSIOLOGY
portal system, one of only two portal systems in the body. Capillaries in the
median eminence of the hypothalamus and in the infundibular stem converge to form portal vessels that travel to the anterior lobe, where they branch
into a second set of capillaries that supply the anterior pituitary. Thus, mediators released by cells in the hypothalamus can circulate to and affect pituitary
secretory cells.
The major peptide hormones released from the anterior pituitary are
growth hormone (GH); thyroid-stimulating hormone (TSH), also known
as thyrotropin; follicle-stimulating hormone (FSH); luteinizing hormone
(LH); adrenocorticotropic hormone (ACTH); and prolactin (PRL). The
secretion of all these hormones is regulated in large part by mediators secreted
into the hypothalamohypophysial portal system by cells in the hypothalamus.
In addition, secretion of most of the anterior pituitary hormones is modulated
by feedback inhibition from hormones released from the endocrine glands
they influence.
Secretion of GH is stimulated by growth hormone-releasing hormone
(GHRH), and perhaps by ghrelin, which is secreted by cells in the arcuate
nucleus. GH secretion is modulated in a complex fashion. In peripheral tissues, GH stimulates the production of insulin-like growth factor-1 (IGF-1).
IGF-1 in turn inhibits GH release at the level of the pituitary and the level of
the hypothalamus by inhibiting the release of GHRH and stimulating the
release of somatostatin, which in turn inhibits the release of GH from pituitary
cells. Secretion of TSH is stimulated by the tripeptide TRH secreted by
hypothalamic cells in the paraventricular nucleus. At the level of the thyroid
gland, TSH stimulates growth of the thyroid and the synthesis and secretion
of the thyroid hormones T3 and T4. As part of their actions, circulating T3 and
T4 exert feedback inhibition primarily at the level of the pituitary and perhaps
also at the hypothalamus. Secretion of FSH and LH is stimulated by the
secretion of gonadotropin-releasing hormone (GnRH) from cells in the arcuate nucleus. Unlike the other hypothalamic hormones, to be effective, GnRH
must be secreted in a pulsatile manner at a frequency of around 1 pulse per
hour. Frequencies much higher or lower than that are not effective at stimulating FSH and LH secretion. Also, GnRH, and hence FSH and LH, secretion
is very low during childhood. Starting at puberty and continuing during reproductive life, pulsatile GnRH secretion occurs and FSH and LH are secreted
from the pituitary to influence the maturation and function of the reproductive
organs. In addition to the control exerted by GnRH, FSH and LH secretion are
influenced by both positive and negative feedback.
In females, estrogen secreted by the developing graafian follicle suppresses FSH and LH secretion at the level of the pituitary. However, before
ovulation, estrogen levels are reached that trigger a surge in secretion of
FSH and LH. After ovulation, rising levels of progesterone suppress FSH
and LH secretion through actions on both the pituitary and the hypothalamus.
In males, testosterone secreted from the testes suppresses LH secretion
CLINICAL CASES
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through actions on both the pituitary and the hypothalamus. FSH secretion
is suppressed by inhibin, which also is secreted by the testes and acts at the
level of the pituitary. Secretion of ACTH is stimulated by the peptide
corticotropin-releasing hormone (CRH), which is secreted by cells in the
paraventricular nucleus. At the level of the adrenal gland, ACTH stimulates
growth of the adrenal cortex and the synthesis and secretion of cortisol, corticosterone, and small amounts of adrenal androgens and estrogens. ACTH
secretion exhibits a diurnal rhythm that peaks early in the morning. The mechanisms controlling this rhythm are not understood completely. As part of their
actions, circulating cortisol (mainly) and corticosterone exert feedback inhibition at the level of both the pituitary and the hypothalamus.
The regulation of prolactin secretion differs from that of the other pituitary
hormones in that PRL secretion is under tonic inhibition from the hypothalamus. If the hypothalamohypophysial portal system is disrupted, PRL
secretion increases rather than decreases as is the case for the other pituitary
hormones. Most evidence points to dopamine rather than a peptide as being
the prolactin inhibitory hormone. In addition to this inhibitory pathway,
PRL secretion can be stimulated by TRH. The main target of PRL is the
mammary gland, where it promotes the secretion of colostrum and milk. PRL
levels rise during pregnancy. After parturition, basal levels fall, but there are
spikes in PRL levels during and after periods of nursing. The spikes in PRL
secretion are because of neural signals from the breast acting at the level of the
hypothalamus to decrease dopamine release into the hypothalamohypophysial
portal system. This reflex and the high levels of PRL suppress the hypothalamic secretion of GnRH, thus inhibiting the menstrual cycle.
COMPREHENSION QUESTIONS
[33.1]
A 45-year-old woman is noted to have fatigue and cold intolerance
and is diagnosed with hypothyroidism. Her physician suspects a pituitary etiology. Which of the following laboratory findings is most
consistent with this condition?
A.
B.
C.
D.
Low TSH, low free thyroxine
Elevated TSH, low thyroxine
Elevated TSH, elevated thyroxine
Low TRH
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[33.2]
CASE FILES: PHYSIOLOGY
A 35-year-old woman experiences anterior pituitary hemorrhagic
necrosis (Sheehan syndrome) after a postpartum hemorrhage. She
feels light-headed, dizzy, and weak. Which of the following hormones
most likely is responsible for her symptoms?
A.
B.
C.
D.
E.
[33.3]
ACTH
GnRH
Prolactin
TSH
GH
A 25-year-old woman is undergoing ovulation induction for infertility. She is given an injection of GnRH on Monday. Serum estradiol is
low, and ovarian ultrasound reveals small follicles on Wednesday and
Friday. What is the most likely explanation?
A.
B.
C.
D.
Ovarian failure
Pituitary failure
Need for pulsatile hormone
More time needed to see an effect
Answers
[33.1]
A. Usually, hypothyroidism is diagnosed by an elevated TSH,
because the vast majority of cases of hypothyroidism involve a primary gland (thyroid) failure. A much less common etiology is a pituitary etiology, which would be reflected by a low TSH. This would
lead to a low free thyroxine but elevated hypothalamic secretion of
TRH.
[33.2]
A. This female with anterior pituitary failure after postpartum hemorrhage has symptoms of dizziness and light-headedness. This probably is because of lack of ACTH and thus lack of mineralocorticoids
such as aldosterone. The inability to retain sodium leads to hypovolemia and the symptoms of hypotension.
[33.3]
C. Unlike the other pituitary hormones, GnRH needs to be secreted
in a pulsatile fashion to effect gonadotropin (FSH and LH) secretion
from the pituitary.
CLINICAL CASES
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PHYSIOLOGY PEARLS
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The posterior pituitary secretes two hormones: antidiuretic hormone
(also known as vasopressin) and oxytocin.
The anterior pituitary secretes six hormones: GH, TSH, ACTH,
FSH, LH, and PRL.
Posterior pituitary hormones are released from endings of nerves
that originate in the hypothalamus.
The secretion of hormones by cells of the anterior hypothalamus is
regulated by factors released from the hypothalamus into a portal
venous system that runs from the hypothalamus to the anterior
pituitary.
The secretion of all the anterior pituitary hormones except prolactin
requires stimulatory peptide factors to be released from the hypothalamus. Prolactin secretion is tonically inhibited by dopamine
secreted by the hypothalamus.
Peripheral neural and humoral inputs that regulate posterior pituitary
hormone secretion act at the level of the hypothalamus.
Peripheral neural and humoral inputs that regulate anterior pituitary
hormone secretion act at the level of the hypothalamus and the
pituitary.
REFERENCES
Genuth SM. Hypothalamus and pituitary gland. In: Levy MN, Koeppen BM, and
Stanton BA, eds. Berne & Levy, Principles of Physiology. 4th ed. Philadelphia,
PA: Mosby; 2006:647-662.
Goodman HM. Pituitary gland. In: Johnson LR, ed. Essential Medical Physiology.
3rd ed. San Diego, CA: Elsevier Academic Press; 2003:573-585.
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