Professional Documents
Culture Documents
Learning Objectives
1. Neuroendocrine Pharmacology: Hypothalamic and Pituitary Hormones
1. The physiology of neuroendocrine hormonal regulation, including
a) Hypothalamus-Pituitary-Growth Hormone Axis,
b) Hypothalamus-Pituitary-Reproductive Axis,
c) Hypothalamus-Pituitary-Prolactin Axis
2. The use of specific neuroendocrine agents in treatment of following
neuroendocrine disorders:
a) growth hormone deficiency
b) growth hormone excess
c) infertility
d) hyperprolactinemia
3. The indications, mechanism of action, adverse effects, contraindications
and therapeutic considerations for the major neuroendocrine hormones
and pharmacological agents.
Marc Imhotep Cray, MD
HCG
Corticotropin
Cosyntropin
Follitropin alfa
Follitropin beta
Goserelin
Histrelin
Leuprolide
Menotropins
Nafarelin
Octreotide
Pegvisomant
Somatropin
Urofollitropin
Marc Imhotep Cray, MD
Corticorelin (CRH)
Gonadorelin
(GnRH)
Octreotide
Protirelin (TRH)
Sermorelin
Somatostatin
Triptorelin
GnRH antagonists
Ganirelix
Cetrorelix
Desmopressin DDAVP
Oxytocin
Vasopressin (ADH)
DRUGS AFFECTING THE THYROID
Hypothalamic and
Pituitary Disorders
Baron SJ and Lee CI. Lange Pathology Flash Cards. New York: McGraw-Hill, 2009
Modified from: Whalen K. Lippincott Illustrated Reviews: Pharmacology 6th Ed. Wolters Kluwer, 2015
Case 39
Drugs Active on the Hypothalamus and Pituitary Gland
A 67-year-old man complains of pain in his right hip for the past few weeks.
He has had no injury to the area and describes the pain as a bone ache that
does not radiate. Review of systems is positive only for some weakness of
urinary stream and having to get up twice a night to go to the bathroom.
His general physical examination is normal. His hip examination is normal with
a full range of motion and no tenderness. Examination of his prostate reveals it
to be firm, enlarged, and nodular. Blood tests show a markedly elevated
prostate-specific antigen (PSA), and biopsy of the prostate shows carcinoma.
A bone scan confirms the presence of metastatic disease in the right hip.
Along with other adjuvant therapies, a decision is made to start depot
leuprolide acetate.
_ Leuprolide acetate is an analog of which hypothalamic hormone?
_ What is the mechanism of action of leuprolide acetate?
_ Which pituitary hormones are affected by leuprolide acetate, and how are they affected?
Marc Imhotep Cray, MD
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Sanders, 2014
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Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Sanders, 2014
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Hypopituitarism
Hypopituitarism may be partial or complete and may result from
hypothalamic disease (leading to deficiency of hypothalamic releasing
hormones) or intrinsic pituitary disease (causing pituitary hormone
deficiency)
Patients may present with, for ex., adrenal insufficiency or hypothyroidism
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Hypopituitarism (2)
Diagnosis of complete deficiency is relatively easy:
most patients have symptoms, and
serum levels of target-organ hormone (eg, cortisol, thyroxine, and
testosterone in men) and
pituitary hormone (eg, ACTH, thyrotropin, and luteinizing hormone,
respectively) are low
Causes of hypopituitarism include
pituitary tumor (most common)
hypothalamic tumor or cyst
infiltrative and vascular disorders and
pituitary or cranial radiotherapy
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Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Sanders, 2014
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Physiologic actions
of growth hormone
Brown TA. Rapid Review Physiology 2nd Ed. Philadelphia: Mosby, 2012
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Somatomedins
Somatomedins are produced, predominantly by liver, when
growth hormones act on target tissue
Somatomedins inhibit release of growth hormones by acting
directly on anterior pituitary and by stimulating secretion of
somatostatin from hypothalamus
Somatomedins are a group of hormones that promote cell
growth and division in response to stimulation by growth
hormone (GH) also known as somatotropin (STH)
Somatomedins have similar biological effects to somatotropin
Marc Imhotep Cray, MD
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Somatomedins cont.
In addition to their actions that stimulate growth, somatomedins also
stimulate production of somatostatin, which suppresses growth hormone
release
Thus, levels of somatomedins are controlled via negative feedback
through intermediates of somatostatin and growth hormone
Somatomedins are produced in many tissues and have autocrine and
paracrine actions in addition to their endocrine action
liver is thought to be predominant source of circulating somatomedins
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Children have short stature and low growth velocity for age and pubertal
stage
Adults, who usually have had pituitary tumors or head trauma, show
low energy
reduced strength
weight gain
anxiety
reduced libido and
impaired sleep
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edema
muscle and joint pain
benign intracranial hypertension
hair loss
hypothyroidism
hypoglycemia or hyperglycemia, and
risk of cancer
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Question
A 38-year-old man presents complaining of gradually enlarging hands and feet
over the past several years. In comparison with a photo from 15 years ago, his
facial features have become obviously coarsened. Laboratory evaluation shows
mildly elevated plasma glucose, and MRI of the brain reveals an enlarged mass
in the sella turcica. Given the suspected diagnosis, specialized testing is
performed in which GH levels are measured following administration of an
oral glucose load; no measurable decrease is seen.
What is the diagnosis?
Note: One good way to diagnose this disorder is to look at an old picture
of the patient and compare it with the patients current appearance.
Because the physical changes take place over decades, family members
and friends often do not recognize them.
Marc Imhotep Cray, MD
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Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Sanders, 2014
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Usatine RP etal. (Eds.) The Color Atlas of Family Medicine. McGraw-Hill, 2013
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Case 39 Answers:
Drugs Active on Hypothalamus and Pituitary Gland
Summary: A 67-year-old man with metastatic prostate cancer is to
receive depot leuprolide acetate.
Leuprolide acetate is an analog of which hypothalamic hormone:
Gonadotropin releasing hormone (GnRH).
Mechanism of action of leuprolide acetate: Chronic
administration of GnRH analog results in the reduction of the
number of GnRH receptors in the pituitary
(downregulation), with resultant decreases in pituitary
gonadotropin production.
Pituitary hormones affected: Luteinizing hormone (LH) and
follicle-stimulating hormone (FSH) production is reduced.
Marc Imhotep Cray, MD
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Case 39 Answers:
Drugs Active on Hypothalamus and Pituitary Gland cont.
CLINICAL CORRELATION
The hypothalamic-pituitary-gonadal axis is a classic example of a hormonal
stimulation- negative feedback system. The hypothalamus produces GnRH,
which binds to specific receptors on pituitary gonadotropic cells. These cells
then produce LH and FSH, which act on the gonads. LH and FSH regulate the
female menstrual cycle by their effects on the ovarian follicles and the ovarian
production of estrogen and progesterone. In males, LH and FSH regulate
spermatogenesis and the production of testosterone in the testes. Estrogen,
progesterone, and testosterone then function as feedback signals for the
hypothalamic production of GnRH. Leuprolide acetate is a synthetic 9-amino
acid analog of GnRH.
Marc Imhotep Cray, MD
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Case 39 Answers:
Drugs Active on Hypothalamus and Pituitary Gland cont.
When initially administered, leuprolide acetate results in increases in
LH, FSH, and gonadal steroid production because of its action as a
GnRH agonist. However, with chronic administration, there is a
reduction in the number of GnRH receptors in the pituitary
gonadotropic cells. This causes a reduction in FSH or LH production
and a resultant reduction in gonadal hormone production. In women
this effect may be beneficial in conditions such as endometriosis,
where estrogen stimulates the growth and activity of the ectopic
endometrial tissue, which causes symptoms.
Marc Imhotep Cray, MD
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Case 39 Answers:
Drugs Active on Hypothalamus and Pituitary Gland cont.
The effect in men is to lower the production of testosterone to near castrate
levels. Because prostate cancer is often testosterone dependent, leuprolide
acetate can be used as a treatment for prostate cancer in those who are not
surgical candidates, do not desire surgery, or have metastatic disease.
Leuprolide acetate must be administered parenterally, and it has a depot form
which is active for up to 3 months. It commonly causes menopausal side
effects, such as hot flashes, as a result of the reduction in gonadal hormone
production. Other antiandrogenic drugs such as abiraterone, which blocks
conversion of pregnenolone to androgens by inhibiting CYP17, can be used in
combination with leuprolide or as sole therapeutic agents.
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THE END
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