ENDOCRINE DRUGS
HYPOTHALAMIC & PITUITARY HORMONES
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A combination of neural and endocrine systems
located in the hypothalamus and pituitary gland
control metabolism, growth, and reproduction.
The pituitary gland weighs about 0.6g and is
located near the optic chiasm and cavernous
sinuses in the bony sella turcica at the base of the
brain.
An anterior lobe(adenohypophysis) and a posterior
lobe(neurohypophysis) make up the pituitary
(Figure 37-1).

Drugs that mimic or block the effects of
hypothalamic and pituitary hormones have
pharmacologic applications in three areas:
(1) replacement therapy for hormone
deficiency;
(2) antagonists for diseases caused by
excessive pituitary hormone production; and
(3) diagnostic tools for identifying a variety of
endocrine abnormalities.
ANTERIOR PITUITARY HORMONES
& THEIR HYPOTHALAMIC REGULATORS

Except for prolactin, all of the hormones
produced by the anterior pituitary are important
players in hormonal systems, regulating
hormone and autocrine-paracrine factor
production by endocrine glands and other
peripheral tissues.
ANTERIOR PITUITARY &
HYPOTHALAMIC HORMONE RECEPTORS
 The anterior pituitary hormones can be
classified according to hormone structure and
the types of receptors that they activate.

a)
3 pituitary hormones:
thyroid-stimulating
hormone
b) follicle-stimulating
hormone, and
c) luteinizing hormone
— are dimeric proteins that
activate G protein-coupled
receptors

A stalk of neurosecretory fibers and blood vessels
connect it to the overlying hypothalamus, including
a portal venous system that drains the
hypothalamus and perfuses the anterior pituitary.
The portal venous system transports small
regulatory hormones from the hypothalamus to the
anterior pituitary (Figure 37-1, Table 37-1).
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
The regulation of TSH,
FSH, LH, and ACTH
release
from
the
pituitary is very similar.
Each is regulated by a distinct hypothalamic
peptide that acts on G protein-coupled
receptors to stimulate their production. TSH
production
is
regulated
by
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thyrotropin-releasing hormone, whereas pulses of
gonadotropin-releasing hormone stimulate the
production of LH and FSH (collectively known as
gonadotropins).
Corticotropin-releasing hormone stimulates ACTH
production.
The
thyroid
hormones
thyroxine
and
triiodothyronine inhibit the production of TSH and
TRH.
Estrogen and progesterone inhibit gonadotropin
and GnRH production in women, while testosterone
and other androgens inhibit it in men.
Cortisol inhibits the production of ACTH and CRH.
The hypothalamus secretes two hormones that
control GH production:
a) growth hormone-releasing hormone stimulates
GH production
b) somatostatin inhibits it.
Dopamine, a catecholamine, inhibits prolactin
production by acting on the D2 subtype of
dopamine receptors.
While all of the pituitary and hypothalamic
hormones mentioned above can be used in
humans, only a few are clinically significant.
The related hypothalamic and pituitary hormones
are used infrequently as treatments due to the
greater ease of administration of target endocrine
gland hormones or their synthetic analogs. Many of
them, including TRH, TSH, CRH, ACTH, GnRH,
and GHRH, are used in specialized diagnostic
testing.
Tables
37-2
and 37-3 detail
the
various
agents.
GH, SST, LH,
FSH, GnRH,
and dopamine
or analogs of
these
hormones, on
the other hand,
are frequently
used and are
discussed
in
the
following
text
.
GROWTH HORMONE (SOMATOTROPIN)
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Growth hormone, an anterior pituitary
hormone, is necessary for achieving normal
adult size during childhood and adolescence,
and it has important effects on lipid and
carbohydrate metabolism, as well as lean body
mass and bone density, throughout postnatal
life.
IGF-I is primarily responsible for its
growth-promoting effects.
Individuals who have a congenital or acquired
GH
deficiency
during
childhood
or
adolescence do not reach their midparental
target adult height and have disproportionately
higher body fat and lower muscle mass.
Adults with GH deficiency have a lower lean
body mass.
Chemistry & Pharmacokinetics
A. STRUCTURE
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Growth hormone is a 191-amino-acid peptide
with two sulfhydryl bridges in its structure.
Its structure is very similar to prolactin's.
Medicinal GH was previously extracted from
the pituitaries of human cadavers and it was
discovered to be contaminated with prions that
can cause Creutzfeldt-Jakob disease. As a
result, it is no longer in use.
The 191-amino-acid sequence of somatropin,
the recombinant form of GH, is identical to the
predominant native form of human GH.
B. ABSORPTION, METABOLISM, AND EXCRETION
 Endogenous GH in circulation has a half-life of
about 20 minutes and is primarily cleared by
the liver.
 6-7 times per week, recombinant human GH is
given subcutaneously.
 Peak levels are reached in 2-4 hours, and
active blood levels last for about 36 hours.
Pharmacodynamics
 The JAK/STAT cytokine receptor superfamily
mediates the effects of growth hormone on cell
surface receptors.
 IGF-I production is stimulated by growth
hormone in bone, cartilage, muscle, kidney,
and other tissues, where it plays an autocrine
or paracrine role. It promotes long-term bone
growth until the epiphyseal plates fuse near
puberty's end.
 GH has anabolic effects in muscle and
catabolic effects in adipose cells in both
children and adults, shifting the balance of
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body mass to an increase in muscle mass and a
decrease in adiposity.
Because GH and IGF-I have opposite effects on
insulin sensitivity, the direct and indirect effects of
GH on carbohydrate metabolism are mixed.
IGF-I has insulin-like effects on glucose transport,
whereas growth hormone reduces insulin
sensitivity, resulting in mild hyperinsulinemia and
elevated blood glucose levels.
Because of its insulin-like effects, recombinant
human IGF-I may cause hypoglycemia in patients
who are unable to respond to growth hormone due
to severe resistance (caused by GH receptor
mutations, post-receptor signaling mutations, or GH
antibodies).
Clinical Pharmacology
A. Growth Hormone Deficiency
 Growth hormone deficiency can be hereditary,
linked to midline developmental defect syndromes,
or acquired as a result of trauma to the pituitary or
hypothalamus, such as breech or traumatic
delivery, intracranial tumors, infection, infiltrative or
hemorrhagic processes, or irradiation.
 Though since prenatal growth is not dependent on
GH, neonates with isolated GH deficiency are
usually of normal size at birth. IGF-I, on the other
hand, is required for normal pre- and postnatal
development. IGF-I expression and postnatal
growth become GH-dependent during the first year
of life through mechanisms that are poorly
understood.
 Short stature and mild adiposity are common
symptoms of GH deficiency in children.
Hypoglycemia is another early sign of GH
deficiency, caused by the loss of GH's
counter-regulatory
hormonal
response
to
hypoglycemia; young children are especially
vulnerable to this condition due to their high insulin
sensitivity.
 A subnormal height velocity for age and a
subnormal serum GH response after provocative
testing with at least two GH secretagogues are
usually used to diagnose GH deficiency.
 SST is reduced by arginine and insulin-induced
hypoglycemia, which increases GH release. GH
deficiency affects about 1 in every 5000 people.
 Adults with GH deficiency, are more likely to have
generalized obesity, reduced muscle mass,
asthenia, decreased bone mineral density,
dyslipidemia, and reduced cardiac output,
according to more detailed studies.
B. Growth Hormone Treatment of Pediatric
Patients with Short Stature
 Exogenous GH has some effect on height in
children with short stature caused by
conditions other than GH deficiency, despite
the fact that patients with GH deficiency benefit
the most from it.
 Growth failure, obesity, and carbohydrate
intolerance are all symptoms of Prader-Willi
syndrome, an autosomal dominant genetic
disease.
 GH treatment reduces body fat and increases
lean body mass, linear growth, and energy
expenditure in children with Prader-Willi
syndrome and growth failure.
 Treatment with growth hormones has also
been shown to have a significant positive
impact on the final height of Turner syndrome
girls. In clinical trials, GH treatment increased
the final height of Turner syndrome girls by 10
to 15 cm.
 Seeing as Turner syndrome girls also have
either absent or rudimentary ovaries, gonadal
steroids must be used in conjunction with GH
to achieve maximum height.
 Slowing growth velocity in children should be
closely monitored, as it could indicate a need
to increase the dosage, the possibility of
epiphyseal plate fusion, or other problems
such as hypothyroidism or malnutrition.
 Growth hormone is approved for a number of
conditions (see Table 37-4) and has been used
experimentally or off-label in a number of
others.
Other Uses of Growth Hormone
 Growth hormone has an anabolic effect on many
organ systems. It's been tested in a variety of
conditions linked to a severe catabolic state, and
it's been approved for the treatment of wasting in
AIDS patients.
 In the clinical studies that have been published to
date, the benefits of GH treatment for patients with
short bowel syndrome and TPN dependency have
mostly been short-lived.
 Growth hormone is a common ingredient in
«anti-aging» treatments.
 Athletes also use GH for the purpose of increasing
muscle mass and athletic performance.
 The use of recombinant bovine growth hormone in
dairy cattle to increase milk production was
approved by the FDA in 1993.
Toxicity & Contraindications
 While taking GH, patients with Turner syndrome are
more likely to develop otitis media.
 Periodic testing of the other anterior pituitary
hormones in children with GH deficiency may
reveal concurrent deficiencies that require
treatment as well (ie, with hydrocortisone,
levothyroxine, or gonadal hormones).
 Pancreatitis, gynecomastia, and nevus growth have
occurred in patients receiving GH.
 Carpal tunnel syndrome can occur. Growth
hormone treatment raises the activity of
cytochrome P450 isoforms, which may lower drug
levels metabolized by that enzyme system in the
blood.
MECASERMIN
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The FDA approved mecasermin and mecasermin
rinfabate, two forms of recombinant human IGF-I, in
2005 for the treatment of severe IGF-I deficiency
that is not responsive to GH.
Mecasermin is a combination of rhIGF-I and
recombinant human insulin-like growth factor
binding protein-3, whereas mecasermin rinfabate is
a combination of rhIGF-I and recombinant human
insulin-like growth factor binding protein-3.
The circulating half-life of rhIGF-I is significantly
increased by this binding protein. The majority of
circulating IGF-I is normally bound to IGFBP-3,
which is primarily produced by the liver under the
control of GH.
Mecasermin rinfabate is not available for short
stature-related indications due to a patent
settlement.
Mecasermin is given subcutaneously twice daily at
a starting dose of 0.04 0.08 mg/kg per dose, which
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is gradually increased weekly up to a
maximum twice-daily dose of 0. 12 mg/kg per
dose.
Hypoglycemia is the most common side effect
associated with mecasermin. To avoid
hypoglycemia, the prescribing instructions call
for a carbohydrate-rich meal or snack to be
consumed 20 minutes before or after taking
mecasermin.
As well as intracranial hypertension,
adenotonsillar hypertrophy, and asymptomatic
elevations in liver enzymes.
GROWTH HORMONE ANTAGONISTS
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The effects of GH-producing cells in the
anterior pituitary that tend to form
GH-secreting tumors are reversed with GH
antagonists. Adults are more likely to develop
hormone-secreting pituitary adenomas.
Acromegaly is a condition in which
GH-secreting adenomas cause abnormal
growth of cartilage and bone tissue, as well as
many organs such as the skin, muscle, heart,
liver, and gastrointestinal tract.
Gigantism is a rare condition that occurs when
a GH-secreting adenoma develops before the
long bone epiphyses close.
Larger pituitary adenomas produce more GH
and, by encroaching on nearby brain
structures, can impair visual and central
nervous system function.
Endoscopic transsphenoidal surgery is the first
line of treatment for GH-secreting adenomas.
Somatostatin analogs and dopamine receptor
agonists, which reduce GH production, and
pegvisomant, a novel GH receptor antagonist
that prevents GH from activating GH signaling
pathways, are among these agents.
Somatostatin Analogs
 The hypothalamus, other parts of the central
nervous system, the pancreas, and other
gastrointestinal tract sites all contain
somatostatin, a 14-amino-acid peptide (Figure
37-2).
 Inhibits the
release of
GH, TSH,
glucagon,
insulin, and
gastrin and
acts as an
inhibitory
paracrine
factor.
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Half-life: 1-3 minutes, somatostatin is quickly
cleared from the bloodstream.
In terms of metabolism and excretion, the kidney
appears to play a significant role.
Octreotide
 Octreotide is a somatostatin analogs with a longer
time of action (Figure 37-2), 45 times more effective
than somatostatin at inhibiting GH release but only
twice as effective at reducing insulin secretion.
Hyperglycemia is uncommon during treatment due
to the treatment's relatively mild effect on
pancreatic beta cells.
 Octreotide has a plasma elimination half-life of
about 80 minutes, which is 30 times longer than
somatostatin.
 Acromegaly, carcinoid syndrome, gastrinoma,
glucagonoma,
insulinoma,
VIPoma,
and
ACTH-secreting tumor all benefit from octreotide,
which is given subcutaneously every 8 hours and
reduces symptoms.
 Other therapeutic indications: secretory diarrhea,
HIV-associated
diarrhea,
diabetic
diarrhea,
chemotherapy-induced
diarrhea,
and
radiation-induced diarrhea, as well as portal
hypertension.
 Adverse effects of octreotide: nausea, vomiting,
abdominal cramps, flatulence, and steatorrhea with
bulky bowel movements.
 Octreotide
acetate
injectable
long-acting
suspension is a microsphere formulation with a
slow release. After a short course of shorter-acting
octreotide has been shown to be effective and well
tolerated, it may be used. Injections of 10–40 mg
into alternate gluteal muscles are repeated every
four weeks.
 Long-term use of octreotide can lead to vitamin B12
deficiency.
Lanreotide
 Another
octapeptide
somatostatin
analog,
lanreotide, treatment for acromegaly in a
long-acting formulation.
 Lanreotide appears to have effects similar to
octreotide in terms of lowering GH levels and
restoring IGF-I levels.
Pegvisomant
 Pegvisomant is a GH receptor antagonist used to
treat acromegaly. It is the polyethylene glycol
(PEG) derivative of a mutant GH, B2036.
 Its clearance is reduced by pegylation, which
improves its overall clinical effectiveness.
 Pegvisomant, like native GH, has two GH receptor
binding sites. One of its GH receptor binding sites,
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on the other hand, has a higher affinity for the
GH receptor, whereas the other has a lower
affinity.
Pegvisomant does not inhibit GH secretion
and may lead to increased GH levels and
possible adenoma growth.
The initial step (GH receptor dimerization) is
enabled by the differential receptor affinity, but
the conformational changes required for signal
transduction are blocked.
Pegvisomant given subcutaneously to patients
with acromegaly in clinical trials, and daily
treatment for two months or more reduced
serum levels of IGF-I to normal levels in 97%
of the cases.
THE GONADOTROPINS (FOLLICLE-STIMULATING
HORMONE & LUTEINIZING HORMONE) & HUMAN
CHORIONIC GONADOTROPIN
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Gonadotroph cells, which make up 7 – 15
percent of the pituitary's cells, produce the
gonadotropins.
FSH, LH, and hCG has variety of
pharmaceutical forms, used to stimulate
spermatogenesis in men and induce follicle
development and ovulation in women in cases
of infertility.
Controlled ovarian stimulation, which is at the
heart of assisted reproductive technologies like
in vitro fertilization, is their most common
clinical application.
WOMEN:
The primary function of FSH in women is to
promote the development of ovarian follicles.
Ovarian steroidogenesis requires both FSH
and LH.
LH stimulates androgen production by theca
cells in the ovary during the follicular stage of
the menstrual cycle, whereas FSH stimulates
granulosa cell conversion of androgens to
estrogens.
Estrogen and progesterone production is
primarily controlled by LH during the luteal
phase of the menstrual cycle, and then by
human chorionic gonadotropin if pregnancy
occurs (hCG).
Human chorionic gonadotropin (HCG) is a
placental glycoprotein that functions similarly
to LH and is controlled by LH receptors.
MEN:
In men, FSH is the primary regulator of
spermatogenesis.
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FSH stimulates the production of androgen-binding
protein in Sertoli cells, which helps maintain high
local androgen concentrations in the vicinity of
developing sperm.
FSH also encourages Sertoli cells to convert
testosterone to estrogen, which is necessary for
spermatogenesis.
Leydig cells, LH is the primary stimulus for
testosterone synthesis.
Chemistry & Pharmacokinetics
 FSH, LH, and hCG are all heterodimers that share
an identical subunit as well as a distinct subunit that
confers receptor specificity.
 The subunits of hCG and LH are nearly identical,
they can be used interchangeably.
 All gonadotropin preparations are given by
injection, either subcutaneously or intramuscularly,
on a daily basis.
 Half-lives vary by preparation and route of injection
from 10 to 40 hours.
A. Menotropins
 FSH and LH were extracted from the urine of
postmenopausal women to create the first
commercial gonadotropin product.
 Menotropins,
or
human
menopausal
gonadotropins, are a purified extract of FSH and LH
(hMG). These preparations have been used to
stimulate follicle development in women.
 The bioactivity ratio of FSH to LH in these early
preparations was 1:1.
B. Follicle-Stimulating Hormone
 Purified FSH is available in three different forms.
 Urofollitropin, or uFSH, is a purified preparation
of human FSH extracted from postmenopausal
women's urine.
 Follitropin alfa and follitropin beta are two
recombinant forms of FSH (rFSH) that are also
available. These two products have amino acid
sequences that are identical to human FSH.
 The half-life of rFSH preparations is shorter than
that of preparations derived from human urine, but
they stimulate estrogen secretion just as well, if not
better, than preparations derived from human urine.
 rFSH preparations have less protein contamination,
less batch-to-batch variability, and may cause less
local tissue reaction when compared to
urine-derived gonadotropins and the rFSH
preparations are more costly.
C. Luteinizing Hormone
 Lutropin alfa, the first and only recombinant
form of human LH, was approved in 2004, but
was withdrawn in 2012.
 It has a half-life of about 10 hours when given
via subcutaneous injection.
 Lutropin is only approved for use in infertile
hypogonadotropic hypogonadal women with
profound LH deficiency (1.2 IU/L) in
combination with follitropin alfa for stimulation
of follicular development.
 Not recommended for use with other FSH
preparations or for ovulation induction.
D. Human Chorionic Gonadotropin
 The human placenta produces human
chorionic gonadotropin, which is excreted in
the urine and can be extracted and purified.
 It's a glycoprotein with a 92-amino-acid subunit
that's nearly identical to FSH, LH, and TSH,
and a 145-amino-acid subunit that's similar to
LH except for the presence of a carboxyl
terminal sequence of 30 amino acids that's not
found in LH.
 The
recombinant
form
of
hCG
is
choriogonadotropin alfa (rhCG). Because of its
more consistent biologic activity, rhCG is
packaged and dosed by weight while all of the
other gonadotropins, including rFSH, are
packaged and dosed according to their activity
units.
 Both hCG (purified from human urine) and
rhCG
(recombinant
human
chorionic
gonadotropin) can be injected subcutaneously
or intramuscularly.
Pharmacodynamics
 G
protein-coupled
receptors
are
responsible for the
effects
of
gonadotropins
and
hCG.
 These effects change
throughout a woman's
menstrual cycle.
 Normal
follicle
development,
ovulation,
and
pregnancy require a
coordinated pattern of
FSH and LH secretion
during the menstrual
cycle
(see Figure
40-1).

The ovarian corpus luteum produces the
progesterone and estrogen needed to keep the
pregnancy going during the first eight weeks of
pregnancy.
Clinical Pharmacology
A. Ovulation Induction
 Gonadotropins are used to stimulate follicle
development and ovulation in women who are
experiencing anovulation due to hypogonadotropic
hypogonadism, polycystic ovary syndrome, or other
factors.
 Gonadotropins are also used for controlled ovarian
stimulation.
 Currently, gonadotropins are used in a variety of
ovulation induction and controlled ovulation
stimulation protocols.
 Two main risks of ovulation induction: multiple
pregnancies
and
ovarian
hyperstimulation
syndrome.
 Controlled ovulation stimulation is discussed in
relation to a cycle that begins on the first day of a
menstrual bleed (Figure 37-3), just like a menstrual
cycle.
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
Daily injections of one of the FSH preparations
(hMG, urofollitropin, or rFSH) are started shortly
after the first day (usually on day 2) and continued
for approximately 8–12 days.
Gonadotropins are almost always combined with a
drug that blocks the effects of endogenous GnRH—
either continuous administration of a GnRH
agonist, which downregulates GnRH receptors, or
a GnRH receptor antagonist (see Figure 37–3)
(see below).
When follicular maturation is complete, the
gonadotropin and GnRH agonist or antagonist
injections are stopped, and hCG (3300–10,000 IU)
is given subcutaneously to induce final follicular
maturation and, in ovulation induction protocols,
ovulation.

Exogenous progesterone, hCG, or a
combination of the two has been shown to
provide adequate luteal support in clinical
trials.
B. Male Infertility
 Exogenous androgen can effectively treat
most signs and symptoms of hypogonadism in
males (e.g., delayed puberty, retention of
prepubertal secondary sex characteristics after
puberty); however, treatment of infertility in
hypogonadal men requires the activity of both
LH and FSH.
 In men with hypogonadal hypogonadism,
sperm can appear in the ejaculate after 4-6
months of treatment in up to 90% of cases, but
this is not always the case.
C. Outdated Uses