Chapter 24: Pituitary & Thyroid Flashcards
HYPOTHALAMIC AND ANTERIOR
PITUITARY HORMONES
Choriogonadotropin alfa OVIDREL
Corticotropin H.P. ACTHAR
Cosyntropin CORTROSYN
Follitropin alfa GONAL-F
Follitropin beta FOLLISTIM
Goserelin ZOLADEX
Histrelin VANTAS
Leuprolide LUPRON
Menotropins MENOPUR, REPRONEX
Nafarelin SYNAREL
Octreotide SANDOSTATIN
Pegvisomant SOMAVERT
Somatropin HUMATROPE
Urofollitropin BRAVELLE
HORMONES OF THE POSTERIOR
PITUITARY
Desmopressin DDAVP
Oxytocin PITOCIN
Vasopressin (ADH) PITRESSIN
DRUGS AFFECTING THE THYROID
Iodine and potassium iodide LUGOL’S
SOLUTION
Liothyronine CYTOMEL
Levothyroxine LEVOXYL, SYNTHROID
Methimazole TAPAZOLE
Propylthiouracil (PTU)
Liotrix THYROLAR
Anterior pituitary hormones
Growth
hormone
ACTH
TSH
FSH
LH (F)
LH(M)
Prolactin
Adrenocorticotropic hormone (corticotropin)
Corticotropin-releasing hormone (CRH) is responsible for the synthesis
and release of the peptide pro-opiomelanocortin by the pituitary.
Adrenocorticotropic hormone (ACTH) or corticotropin
[kor-ti-koe-TROE-pin] is a product of the posttranslational processing
of this precursor polypeptide. [Note: CRH is used diagnostically to differentiate
between Cushing syndrome and ectopic ACTH-producing
cells.] Normally, ACTH is released from the pituitary in pulses with
an overriding diurnal rhythm, with the highest concentration occurring
in the early morning and the lowest in the late evening. Stress
stimulates its secretion, whereas cortisol acting via negative feedback
suppresses its release.
1. Mechanism of action: ACTH binds to receptors on the surface
of the adrenal cortex, thereby activating G protein–coupled processes
that ultimately stimulate the rate-limiting step in the adrenocorticosteroid
synthetic pathway (cholesterol to pregnenolone;
Figure 24.3).This pathway ends with the synthesis and release of
the adrenocorticosteroids and the adrenal androgens.
2. Therapeutic uses: The availability of synthetic adrenocorticosteroids
with specific properties has limited the use of corticotropin
mainly to serving as a diagnostic tool for differentiating between primary
adrenal insufficiency (Addison disease, associated with adrenal
atrophy) and secondary adrenal insufficiency (caused by the inadequate
secretion of ACTH by the pituitary). Therapeutic corticotropin
preparations are extracts from the anterior pituitaries of domestic animals
or synthetic human ACTH. The latter, cosyntropin [ko-sin-TROEpin],
is preferred for the diagnosis of adrenal insufficiency. ACTH is
also used in the treatment of infantile spasm (West syndrome).
3. Adverse effects: Short-term use of ACTH for diagnostic purposes
is usually well tolerated. With longer use, toxicities are similar to those
of glucocorticoids and include hypertension, peripheral edema,
hypokalemia, emotional disturbances, and increased risk of infection.**
Growth hormone (somatotropin) P1
Somatotropin is a large polypeptide that is released by the anterior
pituitary in response to growth hormone (GH)-releasing hormone
produced by the hypothalamus (Figure 24.4). Secretion of GH is inhibited
by another hypothalamic hormone, somatostatin (see below). GH
is released in a pulsatile manner, with the highest levels occurring
during sleep. With increasing age, GH secretion decreases, accompanied
by a decrease in lean muscle mass. Somatotropin influences
a wide variety of biochemical processes (for example, cell proliferation
and bone growth are promoted). Synthetic human GH (somatropin
[soe-mah-TROE pin]) is produced using recombinant DNA technology.
1. Mechanism of action: Although many physiologic effects of GH
are exerted directly at its targets, others are mediated through the
somatomedins—insulin-like growth factors 1 and 2 (IGF-1 and
IGF-2). [Note: In acromegaly (a syndrome of excess GH due to
hormone-secreting tumors), IGF-1 levels are consistently high,
reflecting elevated GH.]
2. Therapeutic uses: Somatropin is used in the treatment of GH deficiency
or growth failure in children. Somatropin is also indicated for
growth failure due to Prader-Willi syndrome, management of AIDS wasting syndrome, and GH replacement in adults with confirmed
GH deficiency. [Note: GH administered to adults increases lean
body mass, bone density, and skin thickness, whereas adipose tissue
is decreased. Many consider GH an “antiaging” hormone. This
has led to off-label use of GH by older individuals and by athletes
seeking to enhance performance.] Somatropin is administered by
subcutaneous or IM injection. Although the half-life of GH is short
(approximately 25 minutes), it induces the release of IGF-1 from
the liver, which is responsible for subsequent GH-like actions.
3. Adverse effects: Adverse effects of somatropin include pain at
the injection site, edema, arthralgias, myalgias, flu-like symptoms,
and an increased risk of diabetes. Somatropin should not be used
in pediatric patients with closed epiphyses, patients with diabetic
retinopathy, or obese patients with Prader-Willi syndrome.
Somatostatin (Growth hormone-inhibiting hormone) P2
In the pituitary, somatostatin binds to receptors that suppress GH
and thyroid-stimulating hormone release. Originally isolated from the
hypothalamus, somatostatin is a small polypeptide that is also found
in neurons throughout the body as well as in the intestine, stomach,
and pancreas. Somatostatin not only inhibits the release of GH but
also that of insulin, glucagon, and gastrin. Octreotide [ok-TREE-ohtide]
and lanreotide [lan-REE-oh-tide] are synthetic analogs of somatostatin.
Their half-lives are longer than that of the natural compound,
and depot formulations are available, allowing for administration once
every 4 weeks. They have found use in the treatment of acromegaly
and in diarrhea and flushing associated with carcinoid tumors. An
intravenous infusion of octreotide is also used for the treatment of
bleeding esophageal varices. Adverse effects of octreotide include
diarrhea, abdominal pain, flatulence, nausea, and steatorrhea.
Gallbladder emptying is delayed, and asymptomatic cholesterol gallstones
can occur with long-term treatment. [Note: Acromegaly that is
refractory to other modes of therapy may be treated with pegvisomant
(peg-VIH-soe-mant), a GH receptor antagonist.]
Gonadotropin-releasing hormone
Pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the
hypothalamus is essential for the release of the gonadotropins folliclestimulating
hormone (FSH) and luteinizing hormone (LH) from the
anterior pituitary. However, continuous administration of GnRH inhibits
gonadotropin release through down-regulation of the GnRH receptors
on the pituitary. Continuous administration of synthetic GnRH analogs,
such as leuprolide [loo-PROE-lide], goserelin [GOE-se-rel-in], nafarelin
[NAFF-a-rel-in], and histrelin [his-TREL-in], is effective in suppressing
production of the gonadotropins (Figure 24.5). [Note: Several of these
agents are available as implantable formulations that provide convenient
continuous delivery of the drug.] Suppression of gonadotropins,
in turn, leads to reduced production of gonadal steroid hormones
(androgens and estrogens). Thus, these agents are effective in the
treatment of prostate cancer, endometriosis, and precocious puberty.
In women, the GnRH analogs may cause hot flushes and sweating,
as well as diminished libido, depression, and ovarian cysts. They are contraindicated
in pregnancy and breast-feeding. In men, they initially
cause a rise in testosterone that can result in bone pain. Hot flushes,
edema, gynecomastia, and diminished libido may also occur.
Gonadotropins
Gonadotropins
The gonadotropins (FSH and LH) are glycoproteins that are produced
in the anterior pituitary. The regulation of gonadal steroid hormones
depends on these agents. They find use in the treatment of infertility.
Menotropins [men-oh-TROE-pinz] (also known as human menopausal
gonadotropins or hMG) are obtained from the urine of postmenopausal
women and contain both FSH and LH. Urofollitropin [yoor-ohfol-
li-TROE-pin] is FSH obtained from postmenopausal women and
is devoid of LH. Follitropin [fol-ih-TROE-pin] alfa and follitropin beta
are human FSH products manufactured using recombinant DNA technology.
Human chorionic gonadotropin (hCG) is a placental hormone
that is excreted in the urine of pregnant women. The effects of hCG
and choriogonadotropin [kore-ee-oh-goe-NAD-oh-troe-pin] alfa (made
using recombinant DNA technology) are essentially identical to those
of LH. All of these hormones are injected via the IM or subcutaneous
route. Injection of hMG or FSH products over a period of 5 to 12 days
causes ovarian follicular growth and maturation, and with subsequent
injection of hCG, ovulation occurs. Adverse effects include ovarian
enlargement and possible ovarian hyperstimulation syndrome, which
may be life threatening. Multiple births are not uncommon.
Prolactin
Prolactin
Prolactin is a peptide hormone that is also secreted by the anterior
pituitary. Its primary function is to stimulate and maintain lactation.
In addition, it decreases sexual drive and reproductive function. Its
secretion is inhibited by dopamine acting at D2 receptors. [Note: Drugs
that act as dopamine antagonists (for example, metoclopramide and
antipsychotics such as risperidone) can increase the secretion of
prolactin.] Hyperprolactinemia, which is associated with galactorrhea
and hypogonadism, is treated with D2 receptor agonists, such
as bromocriptine
and cabergoline. Both of these agents also find use
in the treatment of pituitary microadenomas. Bromocriptine is also
indicated for the treatment of type 2 diabetes. Among their adverse
effects are nausea, headache and, sometimes, psychiatric problems
HORMONES OF THE POSTERIOR PITUITARY
Oxytocin
Oxytocin [ok-se-TOE-sin] is used in obstetrics to stimulate uterine
contraction and induce labor. Oxytocin also causes milk ejection by contracting the myoepithelial cells around the mammary alveoli.
Although toxicities are uncommon when the drug is used properly,
hypertension, uterine rupture, water retention, and fetal death have
been reported. Its antidiuretic and pressor activities are much less
pronounced than those of vasopressin.
Vasopressin
Vasopressin
Vasopressin [vas-oh-PRESS-in] (antidiuretic hormone) is structurally
related to oxytocin. Vasopressin has both antidiuretic and vasopressor
effects (Figure 24.6). In the kidney, it binds to the V2 receptor to
increase water permeability and reabsorption in the collecting tubules.
Thus, the major use of vasopressin is to treat diabetes insipidus. It also
finds use in the management of cardiac arrest and in controlling bleeding
due to esophageal varices. Other effects of vasopressin are mediated
by the V1 receptor, which is found in liver, vascular smooth muscle
(where it causes constriction), and other tissues. The major toxicities
of vasopressin are water intoxication and hyponatremia. Abdominal
pain, tremor, and vertigo can also occur. Desmopressin [des-moe-
PRESS-in], an analog of vasopressin, has minimal activity at the V1
receptor, making it largely free of pressor effects. This analog is longer
acting than vasopressin and is preferred for the treatment of diabetes
insipidus and nocturnal enuresis. For these indications, desmopressin
may be administered intranasally or orally. [Note: The nasal spray
should not be used for enuresis due to reports of seizures in children
using this formulation.] Local irritation may occur with the nasal spray.
Thyroid hormone synthesis and secretion
The thyroid gland is made up of multiple follicles that consist of a
single layer of epithelial cells surrounding a lumen filled with thyroglobulin,
which is the storage form of thyroid hormone. A summary
of the steps in thyroid hormone synthesis and secretion is shown in
Figure 24.7. Thyroid function is controlled by thyroid-stimulating hormone
(TSH; thyrotropin), which is synthesized by the anterior pituitary
(Figure 24.2). [Note: TSH generation is governed by the hypothalamic
thyrotropin-releasing hormone (TRH).] TSH action is mediated by
cAMP and leads to stimulation of iodide (I−) uptake by the thyroid
gland. Oxidation to iodine (I2) by a peroxidase is followed by iodination
of tyrosines on thyroglobulin. [Note: Antibodies to thyroid peroxidase
are diagnostic for Hashimoto thyroiditis, a common cause of hypothyroidism.]
Condensation of two diiodotyrosine residues gives rise to T4,
Biosynthesis of thyroid hormones.
1.Uptake of
iodide ion
2. Synthesis of
thyroglobulin
3. Iodination (PTU /METHIMAZOLE)
4. Condensation (PTU /METHIMAZOLE)
5.Proteolytic release
of hormones
Treatment of hyperthyroidism (thyrotoxicosis)
Graves disease, an autoimmune disease that affects the thyroid, is the
most common cause of hyperthyroidism. In these situations, TSH levels
are reduced due to negative feedback. [Note: Feedback inhibition of TRH
occurs with high levels of circulating thyroid hormone, which, in turn,
decreases secretion of TSH.] The goal of therapy is to decrease synthesis
and/or release of additional hormone. This can be accomplished
by removing part or all of the thyroid gland, by inhibiting synthesis of the
hormones, or by blocking release of the hormones from the follicle.
1. Removal of part or all of the thyroid: This can be accomplished
either surgically or by destruction of the gland with radioactive
iodine (131I), which is selectively taken up by the thyroid follicular
cells. Most patients become hypothyroid as a result of this drug
and require treatment with levothyroxine.
2. Inhibition of thyroid hormone synthesis: The thioamides, propylthiouracil
[proe-pil-thye-oh-YOOR-ah-sil] (PTU) and methimazole
[me-THIM-ah-zole], are concentrated in the thyroid, where they inhibit
both the oxidative processes required for iodination of tyrosyl groups
and the condensation (coupling) of iodotyrosines to form T3 and T4
(Figure 24.7). PTU also blocks the peripheral conversion of T4 to T3.
[Note: These drugs have no effect on thyroglobulin already stored in
the gland. Therefore, clinical effects of these drugs may be delayed
until thyroglobulin stores are depleted (Figure 24.9).] Methimazole
is preferred over PTU because it has a longer half-life, allowing for
once-daily dosing, and a lower incidence of adverse effects. However,
PTU is recommended during the first trimester of pregnancy due to
a greater risk of teratogenic effects with methimazole. PTU has been
associated with hepatotoxicity and, rarely, agranulocytosis.
3. Blockade of hormone release: A pharmacologic dose of iodide
inhibits the iodination of tyrosines (“Wolff-Chaikoff effect”), but this
effect lasts only a few days. More importantly, iodide inhibits the
release of thyroid hormones from thyroglobulin by mechanisms
not yet understood. Iodide is employed to treat thyroid storm or
prior to surgery, because it decreases the vascularity of the thyroid
gland. Iodide is not useful for long-term therapy, because the
thyroid ceases to respond to the drug after a few weeks. Iodide is
administered orally. Adverse effects include sore mouth and throat, swelling of the tongue or larynx, rashes, ulcerations of mucous
membranes, and a metallic taste in the mouth.
4. Thyroid storm: Thyroid storm presents with extreme symptoms
of hyperthyroidism. The treatment of thyroid storm is the same as
that for hyperthyroidism, except that the drugs are given in higher
doses and more frequently. β-blockers, such as metoprolol or
propranolol,
are effective in blunting the widespread sympathetic
stimulation that occurs in hyperthyroidism.
