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Photo: Colorized transmission electron micrograph of an endocrine cell from the anterior pituitary gland.

The secretory vesicles (brown) contain hormones.


From: Seeleys Anatomy & Physiology 10th ed New York, NY: McGraw-Hill 2010.

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

Some hormones and drugs affecting the


hypothalamus, pituitary, and thyroid
HYPOTHALAMIC AND ANTERIOR PITUITARY
HORMONES

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

HORMONES OF THE POSTERIOR PITUITARY

Desmopressin DDAVP
Oxytocin
Vasopressin (ADH)
DRUGS AFFECTING THE THYROID

Iodine and potassium iodide


Liothyronine
Levothyroxine
Methimazole
Propylthiouracil (PTU)

NB (note well [Lat. nota bene])


The ending relin indicates a hypothalamus-related hormone.
Drugs that end in tropin are related to the pituitary hormones.

Hypothalamic and
Pituitary Disorders

Marc Imhotep Cray, MD

Marc Imhotep Cray, MD

Baron SJ and Lee CI. Lange Pathology Flash Cards. New York: McGraw-Hill, 2009

Hormones secreted by anterior


pituitary include:
FSH, LH, ACTH, TSH, prolactin, and GH
FLAT P(i)G is a useful mnemonic to
remember these hormones

Marc Imhotep Cray, MD

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

Marc Imhotep Cray, MD

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Sanders, 2014

Regulation of Hypothalamic & Pituitary Hormones


Hypothalamus and pituitary control a complex neuroendocrine system that
governs metabolism, growth, and reproduction
Hypothalamus produces both inhibitory and releasing neuropeptides and
hormones which reach pituitary via a hypophysial portal system
Hypothalamic hormones trigger release of anterior pituitary hormones
which are sent to target organs where they induce hormone synthesis
Endocrine-organ systems function via negative feedback,
o eg, hypothalamic CRH stimulates pituitary ACTH secretion
stimulates adrenal cortisol secretion which in turn inhibits CRH
and ACTH secretion

Marc Imhotep Cray, MD

Hypothalamic and pituitary hormones (2)


Hypothalamic and pituitary hormones are used as tools in
stimulation tests to diagnose hypofunctioning or
hyperfunctioning endocrine states
For example, ACTH and CRH, which target adrenal cortex, aid adrenal
insufficiency diagnosis
Pituitary hormones are also used as replacement therapy for
deficiencies such as hypopituitarism

Marc Imhotep Cray, MD

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Marc Imhotep Cray, MD

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

Clinical signs depend on degree and rapidity of onset of deficiency


For example, basal cortisol secretion is normal in partial ACTH
deficiency, but during an illness, adrenal insufficiency may occur
In complete ACTH deficiency, cortisol secretion is always subnormal

Marc Imhotep Cray, MD

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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

Marc Imhotep Cray, MD

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Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Sanders, 2014

Growth Hormone (somatotropin)


normal physiologic functions and regulation
GH secretion occurs primarily at night and in response to various stressors
such as starvation and hypoglycemia
When released during a good night of sleep, its anabolic actions on
muscle and bone are of primary importance
When released in response to physiologic stressors such as starvation
and hypoglycemia, its metabolic actions to conserve carbohydrate fuels
(for use by the central nervous system [CNS] and other glucose-dependent
tissues) and maintain protein stores (to preserve muscle strength needed
for mobility) take center stage
GH secretion is inhibited by elevated somatostatin, glucose levels, emotional
stress, illness, malnutrition, obesity, glucocorticoids, and decreased thyroid
hormone
Triiodothyronine (T3) is required for normal function of GH
Marc Imhotep Cray, MD

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Physiologic actions
of growth hormone

Marc Imhotep Cray, MD

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

Three forms include:


somatomedin A, another name for insulin-like growth factor 2 (IGF-2)
somatomedin B, derived from vitronectin
somatomedin C, another name for insulin-like growth factor 1 (IGF-1)
Marc Imhotep Cray, MD

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Growth Hormone Deficiency and Treatment


Growth hormone promotes linear growth by regulating endocrine and
paracrine production of IGF-1 (insulin-like growth factor 1)
Besides disruption in growth, GH deficiency also causes

increased subcutaneous visceral fat


reduced muscle mass
reduced bone density and
Reduced exercise performance

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

Marc Imhotep Cray, MD

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GH Deficiency and Treatment (2)


GH therapy goals differ in children and adults
In adults, they are to improve conditioning and strength, restore
normal body composition, and improve quality of life
In children, therapy promotes linear growth and restores body
composition
Synthetic Growth hormone is effective for children with GH deficiency as
long as epiphyses are not closed
Side effects include
o
o
o
o
o
o
o

edema
muscle and joint pain
benign intracranial hypertension
hair loss
hypothyroidism
hypoglycemia or hyperglycemia, and
risk of cancer

Marc Imhotep Cray, MD

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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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GH Excess (Acromegaly) and Treatment


Acromegaly is a disfiguring hormonal disorder caused by excessive GH
secretion from a pituitary tumor
Signs of Acromegaly include
coarse facial features and
enlarged hands, feet, tongue, and internal organs (which lead to heart
disease, hypertension, diabetes, arthralgias)
Treatments includes
surgical removal of tumor and (or)
radiation, or
subcutaneous use of octreotide a GH inhibitor, available in a longacting depot form or
pegvisomant (growth hormone receptor antagonist)
Marc Imhotep Cray, MD

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Marc Imhotep Cray, MD

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Sanders, 2014

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A. A 26-year-old attractive woman prior to acromegaly changes.


B. Facial changes 20 years later in the same woman.
Note the coarse facial features with large nose, lips, and chin.
Protrusion of lower jaw is visible.

Marc Imhotep Cray, MD

Usatine RP etal. (Eds.) The Color Atlas of Family Medicine. McGraw-Hill, 2013

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GH Excess (Acromegaly) and Treatment (2)


Octreotide effects mimic those of natural hormone somatostatin (GHIF), ie.,
inhibition of GH and IGF-1 levels
suppression of response of LH to GnRH
By normalizing levels of GH and IGF-1-both markers for acromegalyoctreotide controls clinical signs and symptoms
Common adverse effects of octreotide are
gastrointestinal
more serious effects include
cardiac arrhythmias
hypoglycemia or hyperglycemia
suppression of thyrotropin
pancreatitis and
biliary tract abnormalities
Marc Imhotep Cray, MD

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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.

Marc Imhotep Cray, MD

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THE END

See next slide for further study.


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Sources and further study:


eLearning
Endocrine cloud folder tools and resources
MedPharm Guidebook:
Unit 5 Drugs Used In Disorders of Endocrine System
Endocrine and Reproductive System Pharmacology eNotes
Clinical Pharmacology Cases 39 to 44 (Learning Triggers)
Textbooks
Brunton LL, Chabner BA , Knollmann BC (Eds.). Goodman and Gilmans The Pharmacological
Basis of Therapeutics. 12th ed. New York: McGraw-Hill, 2011
Katzung, Masters, Trevor. Basic and Clinical Pharmacology, 12th ed. New York: McGraw-Hill,
2012
Mulroney SE. and Myers AK. Netter's Essential Physiology. Philadelphia: Saunders, 2009
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition.
Philadelphia: Sanders, 2014
Toy E C. et.al. Case Files-Pharmacology Lange 3rd ed. New York: McGraw-Hill 2014.
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