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PITUITARY HORMONESPITUITARY HORMONES

Yulia Komarova, Ph.D.Yulia Komarova, Ph.D.

ykomarov@uic.eduykomarov@uic.edu

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The Hypothalamic-Pituitary-Endocrine Axis

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Anterior Pituitary Hormone Hypothalamic Hormone Target Organ Primary Target Organ Hormone or Mediator

Growth hormone (GH, somatotropin)

Growth hormone-releasing hormone (GHRH) (+) Somatostatin (–)

Liver, muscle, bone, kidney, and others

Insulin-like growth factor-1 (IGF-1)

Thyroid-stimulating hormone (TSH)

Thyrotropin-releasing hormone (TRH) (+)

Thyroid Thyroxine, triiodothyronine

Adrenocorticotropin (ACTH) Corticotropin-releasing hormone (CRH) (+)

Adrenal cortex Glucocorticoids, mineralocorticoids, androgens

Follicle-stimulating hormone (FSH) Luteinizing hormone (LH)

Gonadotropin-releasing hormone (GnRH) (+)2

 

Gonads Estrogen, progesterone, testosterone

Prolactin (PRL) Dopamine (–) Breast —

Hormones that Integrate

the Hypothalamic-Anterior Pituitary-Endocrine Axis

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Hypothalamic Hormone Clinical Uses

Growth hormone-releasing hormone (GHRH) Used rarely as a diagnostic test for GH responsiveness

Thyrotropin-releasing hormone (TRH, protirelin) Used rarely to diagnose hyper- or hypothyroidism

Corticotropin-releasing hormone (CRH) Used rarely to distinguish Cushing's disease from ectopic ACTH secretion

Gonadotropin-releasing hormone (GnRH) Used rarely in pulses to treat infertility caused by hypothalamic dysfunction

  Analogs used in long-acting formulations to inhibit gonadal function in men with prostate cancer and women undergoing assisted reproductive technology (ART) or women who require ovarian suppression for a gynecologic disorder

Dopamine Dopamine agonists used for treatment of hyperprolactinemia

Clinical Uses of Hypothalamic Hormones and Their Analogs

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HORMONE MASS (daltons)

PEPTIDE CHAINS

AMINO ACID RESIDUES

CHROMOSOMAL LOCATION

Somatotropic hormones         

  Growth hormone (GH) 22,000 1 191 17q22-24

  Prolactin (PRL) 23,000 1 199 6p22.2-21.3

  Placental lactogen (PL) 22,125 1 190 17q22-24

Glycoprotein hormones         

  Luteinizing hormone (LH) 29,400 2 α-92

β-121

6q12.q21

19q13.3

  Follicle-stimulating hormone (FSH)

32,600 2 α-92

β-111

6q12.q21

11p13

  Human chorionic gonadotropin (hCG)

38,600 2 α-92

β-145

6q12.q21

19q13.3

  Thyroid-stimulating hormone (TSH), thyrotropin

28,000 2 α-92

β-118

6q12.q21

1p13

POMC-derived hormones* 

       

Adrenocorticotropic hormone (ACTH)

4500 1 39 2p22.3

α-Melanocyte-stimulating (α-MSH) 

1650 1 13  

Classification of Anterior Pituitary Hormones

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Somatotropic Hormone Family: Growth Hormone

Structure and Pharmacokinetics

1.GH, a single polypeptide chain of 22 kDa and 20kDa, is secreted by

the pituitary cells somatotropes as a heterogeneous mixture of peptides

2.Daily GH secretion varies throughout life; high in children, peaks

during puberty, and then decreases in an age-related manner in

adulthood.

3.GH is secreted in discrete but irregular pulses. The amplitude of

secretory pulses is greatest at night, and the most consistent period of

GH secretion is shortly after the onset of deep sleep.

4.GH has a half-life of 20–25 minutes and is predominantly cleared by

the liver.

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Molecular and Cellular Bases of GH Action

hGH receptor contains 620 amino acids, approximately 250 of which are extracellular, 24 of which are transmembrane, and 350 of which are cytoplasmic.JAK2, a cytoplasmic tyrosine kinase of the Janus kinase family; STAT (Signal Transducers and Activators of Transcription), Shc (an adapter protein that regulates the Ras/MAPK signaling pathway), and IRS-1 and IRS-2 (insulin-receptor substrate proteins that activate the PI3K pathway).

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Somatotropic Hormone Family: Growth Hormone

Developmental Actions:

GH is required during childhood and adolescence for attainment of normal adult size and body composition;

GH increases the production of IGF-1 in the liver, bone, cartilage, muscle, and the kidney.

GH stimulates longitudinal bone growth

Metabolic Effects:

GH controls lipid and carbohydrate metabolism, and lean body mass.

GH has anabolic effects in muscle and catabolic effects in lipid cells adipocytes.

GH reduces insulin sensitivity, which results in mild hyperinsulinemia.

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Positive Regulators of GH

GH-RH, produced by hypothalamic neurons found predominantly in the arcuate nucleus, binds to and activates specific GPCR on somatotropes;

GH-RH receptor → Gs activation → cAMP and Ca2+→ GH secretion and release

Ghrelin, a 28-amino acid peptide that is octanoylated at Ser3.

Ghrelin is synthesized in endocrine cells in the fundus of the

stomach.

Ghrelin activates the GH secretagogue receptor and directly

stimulates GH release.

Both fasting and hypoglycemia stimulate circulating ghrelin levels.

Regulation of GH Biosynthesis and Secretion

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Negative Regulators of GH

Insulin-like growth factor 1 (IGF-1), acts in a negative feedback

loop.

IGF-1 inhibits GH by effecting GH release from the anterior

pituitary gland.

Somatostatin (SST) is synthesized in widely distributed neuronsas as

a 92–amino acid precursor; proteolytic cleavage products are: SST-28

and SST-14.

SST binds to and activates a family of five related GPCRs that signal

through Gi to inhibit cyclic AMP accumulation and to activate K+

channels and protein phosphotyrosine phosphatases.

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Regulation of GH Biosynthesis and Secretion

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Growth Hormone Deficiency

GH deficiency is a result of a genetic mutations or damage to

the pituitary or hypothalamus by a tumor, infection, surgery, or

radiation therapy. In most patients, the deficiency is idiopathic,

with normal production of other pituitary hormones and no

obvious structural abnormalities.

Children with GH deficiency present with short stature, delayed

bone age, a low age-adjusted growth velocity, hypoglycemia

and adiposity.

Criteria for diagnosis are: (1) a growth rate below 4 cm per year

and (2) the absence of a serum GH response to two GH

secretagogues.

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Growth Hormone Treatment

Primary Therapeutic Objective Clinical Condition

Growth Growth failure in pediatric patients associated with:

    Growth hormone deficiency

    Chronic renal failure

    Noonan syndrome

    Prader-Willi syndrome

    Short stature homeobox-containing gene deficiency

    Turner syndrome

    Small for gestational age with failure to catch up by age 2

    Idiopathic short stature in pediatric patients

Improved metabolic state, increased lean body mass, sense of well-being

Growth hormone deficiency in adults

Increased lean body mass, weight, and physical endurance

Wasting in patients with HIV infection

Improved gastrointestinal function Short bowel syndrome in patients who are also receiving specialized nutritional support;malabsorption syndrome

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Indications for Growth Hormone Treatment (rhGH)

•Treatment of children with short stature

•Children with Turner syndrome, Noonan's syndrome, Prader-Willi

syndrome, or chronic renal insufficiency, children born small for

gestational age, and children with idiopathic short stature

•In 2004, GH was approved for treatment of patients with short bowel

syndrome. In this case, GH is administered with glutamine, which also

has trophic effects on the intestinal mucosa.

•GH is a popular component of anti-aging programs by athletes for a

purported increase in muscle mass and athletic performance. GH is one

of the drugs banned by the Olympic Committee.

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Recombinant Human Growth Hormone (rhGH)

Human GH is produced by recombinant DNA technology

• Somatropin refers to the many GH preparations whose sequences match that of native 22 aa peptide GH (ACCRETROPIN, GENOTROPIN, HUMATROPE, NORDITROPIN, NUTROPIN, OMNITROPE, SAIZEN, SEROSTIM, TEV-TROPIN, VALTROPIN, and ZORBTIVE);

• Somatrem refers to a derivative of GH with an additional methionine at the N-terminus that is no longer available in the U.S.

• Sermorelin (GEREF) is a synthetic form of human GHRH that corresponds in sequence to the first 29 amino acids of human GHRH (a 44–amino acid peptide) and has full biological activity. Sermorelin was withdrawn from the U.S. market in late 2008.

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Therapeutic Uses of Somatropin

• GH is administered subcutaneously, with a bioavailability of 70%. t1/2 of

GH is only 20 minutes, its biological t1/2 is considerably longer, and once-

daily administration is sufficient.

• In GH-deficient children, somatropin typically is administered in a dose

of 25-50 g/kg per day subcutaneously in the evening; higher daily doses

(e.g., 50-67 g/kg) are employed for patients with Noonan's syndrome or

Turner's syndrome, who have partial GH resistance

• For adults, a typical starting dose is 150-300 g per day, with higher

doses used in younger patients transitioning from pediatric therapy;

lower doses are used in older patients (e.g., >60 years of age).

• Because estrogen inhibits GH action, women taking oral—but not

transdermal—estrogen may require larger GH doses to achieve the

target IGF-1 level.

• In the setting of AIDS-related wasting, considerably higher doses (e.g.,

100 g/kg) have been used.

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Somatropin Toxicity & Contraindications

Children:

• rarely intracranial hypertension, which may manifest as vision

changes, headache, nausea, or vomiting.

• scoliosis as a result of rapid growth

• patients with Turner syndrome have an increased risk of otitis media.

• hypothyroidism , pancreatitis, gynecomastia, and nevus growth

Adults:

• peripheral edema, myalgias, and arthralgias (especially in the hands

and wrists) occur commonly but remit with dosage reduction.

• carpal tunnel syndrome can occur.

• GH treatment is contraindicated in a patient with a known

malignancy.

• proliferative retinopathy is rare

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Recombinant Human IGF-1 (mecasermin)

Therapeutic Uses

• for patients with impaired growth secondary to mutations in the GH

receptor or postreceptor signaling pathway,

• patients with GH deficiency who develop antibodies against GH that

interfere with its action,

• and the very rare patients with IGF-1 gene defects that lead to primary

IGF-1 deficiency

• 40-80 g/kg per dose twice daily by subcutaneous injection, with a

maximum of 120 g/kg per dose twice daily.

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Excess Production of Growth Hormone

Clinical Manifestations

•Acromegaly , a result GH-secreting pituitary adenomas, which

is characterized by abnormal growth of cartilage and bone

tissue, and many organs including skin, muscle, heart, liver, and

the gastrointestinal tract.

•Gigantism is a result of GH-secreting adenoma occurring before

the long bone epiphyses close.

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Somatostatin analogs: octreotide, octreotide acetate, lanreotide, vapreotide

Pegvisomant , high affinity antagonist of GH receptor, prevents activation of GH receptor downstream signaling.

Growth Hormone Antagonists

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Octreotide

• the amino acid residues in positions 7-10 of the SST-14 peptide (Phe-

Trp-Lys-Thr) are the major determinants of biological activity. Trp8 and

Lys9 are essential, whereas conservative substitutions at Phe7 and Thr10

are permissible.

• active SST analogs retain this core segment constrained in a cyclic

structure by a disulfide bond

• octreotide and lanreotide bind to the SST subtypes with the following

order of selectivity:

SST2 > SST5 > SST3 SST≫ 1 and SST4.

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Therapeutic Uses of Octreotide

• octreotide (100 g) administered subcutaneously three times daily is virtually 100% bioactive, peak effects are seen within 30 min, serum t1/2 is 90 min, and duration of action is 12 hour.

• a long-acting, slow-release form (SANDOSTATIN-LAR DEPOT) in which the active species is incorporated into microspheres is administered intramuscularly in a dose of 20 or 30 mg once every 4 week. A lower dose of 10 mg per injection should be used in patients requiring hemodialysis or with hepatic cirrhosis.

• octreotide has been used to treat symptoms associated with metastatic carcinoid tumors (e.g., flushing and diarrhea) and adenomas secreting vasoactive intestinal peptide (e.g., watery diarrhea).

• octreotide is used for treatment of acute variceal bleeding and for perioperative prophylaxis in pancreatic surgery.

• octreotide has significant inhibitory effects on TSH secretion, and it is the treatment of choice for patients who have thyrotrope adenomas that oversecrete TSH.

• octreotide labeled with indium or technetium has been used for diagnostic imaging of neuroendocrine tumors such as pituitary adenomas and carcinoids (OCTREOSCAN);

• modified forms labeled with emitters such as 90Y have been used in selective destruction of SST2 receptor-positive tumors.

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Toxicity & Contraindications of SST analogs

• GI side effects—including diarrhea, nausea, and abdominal pain—occur in

up to 50% of patients

• 25% of patients develop gallbladder sludge or even gallstones,

presumably due to decreased gallbladder contraction and bile secretion.

• cardiac effects include sinus bradycardia (25%) and conduction

disturbances (10%).

• octreotide reduces insulin secretion to a lesser extent as SST and only

infrequently affects glycemic control.

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Growth Hormone Antagonists, Pegvisomant

• Pegvisomant (SOMAVERT) is a GH receptor antagonist that is FDA-approved for the treatment of acromegaly..

• Pegvisomant is the polyethylene glycol (PEG) derivative of a mutant GH, B2036, which has increased affinity for one site of the GH receptor but a reduced affinity at its second binding site.

•Pegvisomant binds to the GH receptor but does not activate JAK-STAT signaling or stimulate IGF-1

•Pegvisomant is administered subcutaneously as a 40-mg loading dose under physician supervision, followed by self-administration of 10 mg per day.

•Based on serum IGF-1 levels, the dose is titrated at 4- to 6-week intervals to a maximum of 40 mg per day.

•Pegvisomant should not be used in patients with an unexplained elevation of hepatic transaminases.

•Pegvisomant differs structurally from native GH and induces the formation of specific antibodies in 15% of patients.

•Pegvisomant provides a highly effective alternative for use in patients who have not responded to SST analogs.

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Somatotropic Hormone Family: Prolactin

•Human prolactin is a 23 kDa peptide hormone produced in the anterior pituitary.

•It is synthesized by lactotropes and presents in dimeric and polymeric forms in circulation.

•Prolactin is the principal hormone responsible for lactation. Milk production is stimulated by prolactin when appropriate circulating levels of estrogens, progestins, corticosteroids, and insulin are present.

•A deficiency of prolactin—which can occur in rare states of pituitary deficiency—is manifested by failure to lactate .

•Hyperprolactinemia is developed as a result of impaired transport of dopamine (prolactin-inhibiting hormone) to the pituitary or more commonly, as a result of prolactin-secreting adenomas.

•Hyperprolactinemia produces a syndrome of amenorrhea and galactorrhea in women, and loss of libido and infertility in men.

•Hypogonadism and infertility associated with hyperprolactinemia result from inhibition of GnRH release.

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Regulation of Prolactin Secretion

• Hypothalamic regulation of prolactin secretion is predominantly inhibitory.

• The major regulator of prolactin secretion is DA, which is released by tuberoinfundibular neurons and interacts with the D2 receptor on lactotropes to inhibit prolactin secretion

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Dopamine Agonists

•Quinagolide, a drug approved in Europe, is a nonergot agent with similarly high D2 receptor affinity.

•Bromocriptine and cabergolineare ergot derivatives with a high affinity for dopamine D2 receptors.

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Therapeutic Uses of Dopamine Agonists

•Dopamine agonists suppress prolactin release very effectively in patients with hyperprolactinemia.

•Dopamine agonists reduce GH release in patients with acromegaly, although not as effectively.

•Cabergoline and bromocriptine are also used in Parkinson's disease to improve motor function and reduce levodopa requirements

Pharmacokinetics

•All dopamine agonists are oral preparations, which are eliminated by metabolism.

•Cabergoline, with a half-life of approximately 65 hours, has the longest duration of action.

•Quinagolide has a half-life of about 20 hours, whereas of

•Bromocriptine has the half-life about 7 hours.

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• dopamine agonists are the standard medical treatment for hyperprolactinemia. •they shrink pituitary prolactin-secreting tumors, lower circulating prolactin levels, and restore ovulation in approximately 70% of women with microadenomas and 30% of women with macroadenomas •Cabergoline is initiated at 0.25 mg twice weekly orally or vaginally. It can be increased gradually up to a maximum of 1 mg twice weekly. •Bromocriptine is generally taken daily after the evening meal at the initial dose of 1.25 mg; the dose is then increased as tolerated. Most patients require 2.5–7.5 mg daily.

Hyperprolactinemia

Acromegaly•A dopamine agonist alone or in combination with pituitary surgery, radiation therapy, or octreotide administration can be used to treat acromegaly

•The doses are 20–30 mg/d of bromocriptine unless the pituitary tumor secretes prolactin as well as GH.

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Toxicity & Contraindications of Dopamine Agonists

• nausea, headache, light-headedness, orthostatic hypotension, and fatigue.

• occasional psychiatric manifestations

•high dosages of ergot-derived preparations can cause cold-induced peripheral digital vasospasm.

• pulmonary infiltrates have occurred with chronic high-dosage therapy.

• therapy during the early weeks of pregnancy has not been associated with an increased risk of spontaneous abortion or congenital malformations.

•patients with very large adenomas continue a dopamine agonist treatment throughout pregnancy.

•rare reports of stroke or coronary thrombosis in postpartum women taking bromocriptine to suppress postpartum lactation.

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The Glycoprotein Hormones: TSH and the Gonadotropins

• Thyroid-stimulating hormone(TSH) release is regulated by thyrotropin-releasing hormone (TRH) and inhibited by thyroid hormones, thyroxine and triiodothyronine

•The gonadotropins include LH, FSH, and hCG

•LH and FSH are synthesized and secreted by a single type of pituitary cell, the gonadotroph, which make up 10% of the hormone-secreting cells in the anterior pituitary

•hCG is synthesized by the syncytiotrophoblast of the placenta.

•In women, FSH directs ovarian follicle development. FSH stimulates the conversion by granulosa cells of androgens to estrogens. •LH stimulates androgen production by theca cells in the follicular stage of the menstrual cycle•In the luteal phase of the menstrual cycle, estrogen and progesterone production is primarily under the control first of LH and then, if pregnancy occurs, under the control of human chorionic gonadotropin (hCG). •hCG is a placental protein nearly identical with LH; its actions are mediated through LH receptors.

•In men, FSH is the primary regulator of spermatogenesis, whereas LH is the main stimulus for the production of testosterone by Leydig cells. •FSH helps to maintain high local androgen concentrations in the vicinity of developing sperm by stimulating the production of androgen-binding protein by Sertoli cells. •FSH also stimulates the conversion by Sertoli cells of testosterone to estrogen.

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Thyroid-stimulating hormone (TSH) Thyrotropin is used for diagnostic thyroid function in patients who have been treated surgically for thyroid carcinoma, to test for recurrence by assessing TSH-stimulated whole-body 131I scans and serum thyroglobulin determinations

Follicle-Stimulating Hormone

•Urofollitropin, also known as uFSH, is a purified preparation of human FSH

that is extracted from the urine of postmenopausal women.

•Recombinant forms of FSH (rFSH): follitropin alfa and follitropin beta.

Luteinizing Hormone•Lutropin alfa, the recombinant form of human LH, has only been approved

for use in combination with follitropin alfa for stimulation of follicular

development in infertile women with profound LH deficiency.

Human Chorionic Gonadotropin (hCG) •Choriogonadotropin alfa (rhCG) is a recombinant form of hCG.

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Ovulation Induction

•Gonadotropins are used to induce ovulation in women with anovulation that is secondary to hypogonadotropic hypogonadism, polycystic ovary syndrome, obesity.

•Gonadotropins are also used for controlled ovarian hyperstimulation in assisted reproductive technology procedures.Toxicity & Contraindications

•the ovarian hyperstimulation syndrome and multiple pregnancies.

•the ovarian hyperstimulation syndrome is a serious complication that occurs in 0.5–4% of patients. It is characterized by ovarian enlargement, ascites, hydrothorax, and hypovolemia, sometimes resulting in shock.

the risk of multiple pregnancy is estimated to be 15–20%, whereas the percentage of multiple pregnancies in the general population is closer to 1%.

headache, depression, edema, precocious puberty, and (rarely) production of antibodies to hCG.

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Male Infertility

•treatment of infertility in hypogonadal men requires the activity of both LH and FSH.

•initial treatment for 8–12 weeks with injections of 1000–2500 IU hCG several times per week following hMG injection at a dose of 75–150 units three times per week.

•In men with hypogonadal hypogonadism, it takes an average of 4–6 months of such treatment for sperm to appear in the ejaculate.

•an advance that has indirectly benefited gonadotropin treatment of male infertility is intracytoplasmic sperm injection (ICSI), in which a single sperm is injected directly into a mature oocyte that has been retrieved after controlled ovarian hyperstimulation of a female partner.

Toxicity & Contraindications•the risk of gynecomastia is directly correlated with the level of testosterone produced in response to treatment.

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Regulation of Gonadotropin Synthesis and Secretion

• the hypothalamic peptide GnRH is the predominant regulator of gonadotropin synthesis and secretion.

•GnRH is a decapeptide with blocked amino and carboxyl termini derived by proteolytic cleavage of a 92–amino acid precursor peptide.

• GnRH release is pulsatile and is governed by a neural pulse generator in the hypothalamus, primarily in the arcuate nucleus, that controls the frequency and amplitude of GnRH release.

• The GnRH pulse generator is active late in fetal life and for 1 year after birth but decreases considerably thereafter, presumably secondarily to CNS inhibition.

•Shortly before puberty, CNS inhibition decreases and the amplitude and frequency of GnRH pulses increase, particularly during sleep.

•The intermittent release of GnRH is crucial for the proper synthesis and release of the gonadotropins; the continuous administration of GnRH leads to desensitization and down-regulation of GnRH receptors on pituitary gonadotropes and forms the basis for the clinical use of long-acting GnRH agonists to suppress gonadotropin secretion

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Regulation of Gonadotropin Synthesis and Secretion

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Structures of GnRH and GnRH Analogs

AMINO ACID RESIDUE

GnRH CONGENER (TRADE NAME) 

1 2 3 4 5 6 7 8 9 10 DOSAGE FORMS

Agonists                       

GnRH (FACTREL, LUTREPULSE) 

PyroGlu His Trp Ser Tyr Gly Leu Arg Pro Gly-NH2

 

IV, SC

Goserelin (ZOLADEX)  — — — — — D-Ser(tBu) — — — AzGly-NH2

 

SC implant

Nafarelin (SYNAREL)  — — — — — D-Nal — — — — IN

Triptorelin (TRELSTAR DEPOT, LA) 

— — — — — D-Trp — — — — IM depot

Buserelin* (SUPREFACT)  — — — — — D-Ser(tBu) — — Pro-NHEt   IN, SC

Deslorelin* — — — — — D-Trp — — Pro-NHEt   , depot

Histrelin (VANTAS, SUPPRELIN LA) 

— — — — — D-His(Bzl) — — Pro-NHEt   SC implant

Leuprolide (LUPRON, ELIGARD) 

— — — — — D-Leu — — Pro-NHEt   , depot

Antagonists                       

Abarelix* (PLENAXIS)  Ac-D-Nal D-Cpa D-Pal — Tyr(N-Me) D-Asn — (iPr) — D-Ala-NH2

 

SC depot

Cetrorelix (CETROTIDE)  Ac-D-Nal D-Cpa D-Pal — — D-Cit — — — D-Ala-NH2

 

SC

Ganirelix (ANTAGON)  Ac-D-Nal D-Cpa D-Pal — — D-hArg(Et)2

 

— D-hArg(Et)2

 

— D-Ala-NH2

 

SC

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Synthetic GnRH Agonists

•Gonadorelin is an acetate salt of synthetic human GnRH.

•Synthetic GnRH analogs: goserelin, histrelin, leuprolide, nafarelin, and triptorelin.

•These analogs all have D-amino acids at position 6, and all but nafarelin have ethylamide substituted for glycine at position 10.

•Both modifications make them more potent and longer-lasting than native GnRH and gonadorelin.

Pharmacokinetics•Gonadorelin can be administered intravenously or subcutaneously.

•GnRH analogs can be administered subcutaneously, intramuscularly, via nasal spray (nafarelin), or as a subcutaneous implant. The duration of clinical uses of GnRH agonists varies from a few days for ovulation induction to years for treatment of metastatic prostate cancer.

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Therapeutic Uses of Synthetic GnRH Agonists

• pulsatile intravenous administration of gonadorelin every 1–4 hours stimulates FSH and LH secretion.

• continuous administration of gonadorelin or its longer-acting analogs produces a biphasic response. The first 7–10 days, an agonist effect results in increased concentrations of gonadal hormones in males and females. The continued presence of GnRH results in an inhibitory action that manifests as a drop in the concentration of gonadotropins and gonadal steroids.

•Female and Male Infertility

•Diagnosis of LH Responsiveness

•Controlled Ovarian Hyperstimulation

•Endometriosis

•Uterine Leiomyomata (Uterine Fibroids)

•Prostate Cancer

•Central Precocious Puberty

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Toxicity

•headache, light-headedness, nausea, and flushing.

•local swelling at subcutaneous injection sites. Generalized hypersensitivity dermatitis has occurred after long-term subcutaneous administration.

In women, continuous treatment with a GnRH analog (leuprolide, nafarelin, goserelin) causes the symptoms of menopause including hot flushes, sweats, and headaches.

•Depression, diminished libido, generalized pain, vaginal dryness, and breast atrophy may also occur.

•Ovarian cysts may develop within the first 2 months of therapy and generally resolve after an additional 6 weeks

•Reduced bone density and osteoporosis may occur with prolonged use, so patients should be monitored with bone densitometry before repeated treatment courses.

•Contraindications to the use of GnRH agonists in women include pregnancy and breast-feeding.

•In men treated with continuous GnRH agonist administration, adverse effects include hot flushes and sweats, edema, gynecomastia, decreased libido, decreased hematocrit, reduced bone density, asthenia.

•GnRH analog treatment of children is generally well tolerated.

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Synthetic GnRH Receptor Antagonists

Ganirelix,cetrorelix, abarelix, and degarelix inhibit the secretion of FSH and LH in a dose-dependent manner.

•canirelix and cetrorelix are approved for use in controlled ovarian hyperstimulation procedures

•abarelix and degarelix are approved for men with advanced prostate cancer.

Pharmacokinetics•Administration of 0.25 mg of Ganirelix and cetrorelix daily maintains GnRH antagonism.

•A single 3.0-mg dose of cetrorelix suppresses LH secretion for 96 hours.

•Abarelix reaches a peak concentration 3 days after injection and has a half-life of 13 days. After three initial doses on days 1, 13, and 28, abarelix is administered every 4 weeks.

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Therapeutic Uses of Synthetic GnRH receptor Antagonists

•Suppression of Gonadotropin Production

GnRH antagonists are approved for preventing the LH surge during controlled ovarian hyperstimulation. GnRH antagonists produce an immediate antagonist effect, their use is shorter as compared to GnRH agonist and treatment can be delayed until day 6–8 of the in vitro fertilization cycle.

•Advanced Prostate Cancer

Abarelix is approved for the treatment of symptomatic advanced prostate cancer in men for whom a GnRH agonist is not appropriate and who decline surgical castration.

Abarelix and Degarelix reduce symptoms in patients with vertebral or skeletal metastasis, or bladder outlet obstruction.

Toxicity•ganirelix and cetrorelix are well tolerated when used for controlled ovarian hyperstimulation.

•nausea and headache.

•abarelix has elicited immediate-onset allergic responses that manifested as skin reactions or as hypotension and syncope, and it also prolonged the QT interval.

•abarelix leads to signs and symptoms of androgen deprivation, including hot flushes and sweats, gynecomastia, decreased libido, decreased hematocrit, and reduced bone density.

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Adrenocorticotropic hormone (ACTH)

• ACTH a single peptide that is cleaved from a larger precursor that also contains the peptide –endorphin

•ACTH release is stimulated by corticotropin-releasing hormone (CRH).

•Production of ACTH is inhibited by cortisol

Diagnostic Use

• ACTH is used test for a cortisol response in patients suspected of adrenal insufficiency

• ACTH is used to identify 21-hydroxylase deficiency, 11-hydroxylase deficiency, and 3 -hydroxy- 5 steroid dehydrogenase deficiency, in patients suspected of congenital adrenal hyperplasia

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Posterior Pituitary Hormones

Vasopressin and oxytocin are synthesized in neuronal cell bodies in the hypothalamus and transported via their axons to the posterior pituitary, where they are stored and then released into the circulation.

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Oxytocin

Oxytocin is a peptide hormone secreted by the posterior pituitary that participates in labor and delivery and elicits milk ejection in lactating women.

Oxytocin acts through G protein-coupled receptors and the phosphoinositide-calcium second-messenger system to contract uterine smooth muscle.

Oxytocin stimulates the release of prostaglandins and leukotrienes that augment uterine contraction.

Oxytocin causes contraction of myoepithelial cells surrounding mammary alveoli, which leads to milk ejection.

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Therapeutic Uses of Oxytocin

•Oxytocin is used to induce labor for conditions requiring early vaginal delivery such as Rh problems, maternal diabetes, preeclampsia, or ruptured membranes. •It is also used to augment abnormal labor that is protracted or displays an arrest disorder.

•Oxytocin is usually administered intravenously via an infusion pump with an initial infusion rate of 0.5–2 mU/min. •For induction of labor, rate is increased every 30–60 minutes until a physiologic contraction pattern is established. The maximum infusion rate is 20 mU/min. •For postpartum uterine bleeding, 10–40 units are added to 1 L of 5% dextrose, and the infusion rate is titrated to control uterine atony.

•Contraindications to oxytocin include fetal distress, prematurity, abnormal fetal presentation, cephalopelvic disproportion, and other predispositions for uterine rupture.

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Vasopressin (Antidiuretic Hormone, ADH)

•Vasopressin is a peptide hormone released by the posterior pituitary in response to rising plasma tonicity or falling blood pressure. •A deficiency of this hormone results in diabetes insipidus

•Vasopressin activates two subtypes of G protein-coupled receptors on vascular smooth muscle cells and mediate vasoconstriction. •V2 receptors are found on renal tubule cells and reduce diuresis through increased water permeability and water resorption in the collecting tubules. •Extrarenal V2-like receptors regulate the release of coagulation factor VIII and von Willebrand factor.

•Desmopressin acetate (DDAVP, 1-desamino-8-D-arginine vasopressin) is a long-acting synthetic analog of vasopressin with minimal V1 activity and an antidiuretic-to-pressor ratio 4000 times that of vasopressin. •Desmopressin is modified at position 1 and contains a D-amino acid at position 8.

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Therapeutic Uses of Vasopressin and Desmopressin

•Vasopressin and desmopressin are treatments of choice for pituitary diabetes insipidus.

•The dosage of desmopressin is 10–40 mcg (0.1–0.4 mL) in two to three divided doses as a nasal spray or, as an oral tablet, 0.1–0.2 mg two to three times daily.

•The dosage by injection is 1–4 mcg (0.25–1 mL) every 12–24 hours as needed for polyuria, polydipsia, or hypernatremia..

•Vasopressin infusion is effective in some cases of esophageal variceal bleeding and colonic diverticular bleeding.

•Desmopressin is also used for the treatment of coagulopathy in hemophilia A and von Willebrand's disease .

Toxicity & Contraindications•Headache, nausea, abdominal cramps, agitation, and allergic reactions occur rarely.

•Overdosage can result in hyponatremia and seizures.

•Vasopressin (but not desmopressin) can cause vasoconstriction and should be used cautiously in patients with coronary artery disease.

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Summary: Hypothalamic and Pituitary Hormones

Subclass Mechanism of Action Effects Clinical Applications Pharmacokinetics, Toxicities, Interactions

Growth hormone (GH) 

  Somatropin Recombinant form of human GH  acts through GH receptors to increase production of insulin-like growth factor-1 (IGF-1)

Restores normal growth and metabolic GH effects in GH-deficient individuals increases final adult height in some children with short stature not due to GH deficiency

Replacement in GH deficiency increased final adult height in children with certain conditions associated with short stature (see Table 37–4) wasting in HIV infection short bowel syndrome

SC injection 3–7 x/wk Toxicity: Scoliosis, edema, gynecomastia, intracranial hypertension, myalgia, arthralgia, carpal tunnel syndrome, increased CYP450 activity

IGF-1 agonist 

  Mecasermin Recombinant form of IGF-1 that stimulates IGF-1 receptors

Restores normal growth and metabolic IGF-1 effects in individuals with IGF-1 deficiency

Replacement in IGF-1 deficiency that is not responsive to exogenous GH

SC injection 2 x/d also contains recombinant human IGF-binding protein-3, which prolongs the half-life of the rIGF-1 Toxicity: Hypoglycemia, intracranial hypertension, increased liver enzymes

Somatostatin analogs 

  Octreotide Agonist of somatostatin receptors

Inhibits production of GH and, to a lesser extent, of glucagon, insulin, and gastrin

Acromegaly and several other hormone-secreting tumors acute control of bleeding from esophageal varices

SC injection 3–7 x/d long-acting formulation injected IM monthly Toxicity: Gastrointestinal disturbances, gallstones, bradycardia, and other cardiac conduction problems 

  Lanreotide: Similar to octreotide and available as a long-acting formulation for acromegaly 

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GH receptor antagonist 

  Pegvisomant Blocks GH receptors Ameliorates effects of excess GH production

Acromegaly SC injection 3–7 x/wk Toxicity: Increased liver enzymes 

Gonadotropins: Follicle-stimulating hormone (FSH) analogs 

  Follitropin alfa Activates FSH receptors Mimics effects of endogenous FSH

Controlled ovulation hyperstimulation in women infertility due to hypogonadism in men

SC injection 3–7 x/wk Toxicity: Ovarian hyperstimulation syndrome and multiple pregnancies in women gynecomastia in men headache, depression, edema in both sexes 

  Follitropin beta: A recombinant product with the same peptide sequence as follitropin alfa but differs in its carbohydrate side chains 

  Urofollitropin: Human FSH purified from the urine of postmenopausal women 

  Menotropins (hMG): Extract of the urine of postmenopausal women; contains both FSH and LH activity 

Gonadotropins: Luteinizing hormone (LH) analogs 

  Human chorionic gonadotropin (hCG)

Agonist of the LH receptor Mimics effects of endogenous LH

Initiation of ovulation during controlled ovulation hyperstimulation ovarian follicle development in women with hypogonadotropic hypogonadism

IM Toxicity: Ovarian hyperstimulation syndrome and multiple pregnancies in women gynecomastia in men headache, depression, edema in both sexes 

  Choriogonadotropin alfa: Recombinant form of hCG 

  Lutropin: Recombinant form of human LH 

  Menotropins (hMG): Extract of the urine of postmenopausal women that contains both FSH and LH activity 

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(GnRH) analogs 

  Leuprolide Agonist of GnRH receptors Increased LH and FSH secretion with intermittent administration reduced LH and FSH secretion with prolonged continuous administration

Ovarian suppression, controlled ovarian hyperstimulation, central precocious puberty advanced prostate cancer

Administered IV, SC, IM or intranasally depot formulations are available Toxicity: Headache, light-headedness, nausea, injection site reactions symptoms of hypogonadism with continuous treatment

  Gonadorelin is synthetic human GnRH 

  Other GnRH analogs: Goserelin, histrelin, nafarelin, and triptorelin 

Gonadotropin-releasing hormone (GnRH) receptor antagonists 

  Ganirelix Blocks GnRH receptors Reduces endogenous production of LH and FSH

Prevention of premature LH surges during controlled ovulation hyperstimulation

SC injection Toxicity: Nausea, headache 

  Cetrorelix: Similar to ganirelix and approved for controlled ovarian hyperstimulation 

  Abarelix, degarelix: Approved for advanced prostate cancer; can cause immediate-type hypersensitivity reactions 

Dopamine agonists 

  Bromocriptine Activates dopamine D2

receptors 

Suppresses pituitary secretion of prolactin dopaminergic effects on CNS motor control and behavior

Treatment of hyperprolactinemia and Parkinson's disease

Administered orally or vaginally Toxicity: Gastrointestinal disturbances, orthostatic hypotension, headache, psychiatric disturbances, vasospasm and pulmonary infiltrates in high doses

  Cabergoline: Another ergot derivative with similar effects 

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  Oxytocin Activates oxytocin receptors Increased uterine contractions Induction and augmentation of labor control of uterine hemorrhage after delivery

IV infusion Toxicity: Fetal distress, placental abruption, uterine rupture, fluid retention, hypotension 

Oxytocin receptor antagonist 

  Atosiban Blocks oxytocin receptors Decreased uterine contractions Tocolysis for preterm labor IV infusion Toxicity: Concern about rates of infant death 

Vasopressin receptor agonists 

  Desmopressin Activates vasopressin V2

receptors much more than V1

receptors 

Acts in the kidney to decrease the excretion of water acts on

extrarenal V2 receptors to

increase factor VIII and von Willebrand factor 

Pituitary diabetes insipidus hemophilia A and von Willebrand disease

Oral, IV, SC, or intranasal Toxicity: Gastrointestinal disturbances, headache, hyponatremia, allergic reactions 

  Vasopressin: Available for treatment of diabetes insipidus and sometimes used to control bleeding from esophageal varices 

Vasopressin receptor antagonist 

  Conivaptan Antagonist of vasopressin V1a

and V2 receptors

 

Reduced renal excretion of water in conditions associated with increased vasopressin

Hyponatremia in hospitalized patients

IV infusion Toxicity: Infusion site reactions 

  Tolvaptan: Similar but more selective for vasopressin V2 receptors 

 

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Literature:

Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor Basic & Clinical Pharmacology, 11e, Chapter 37 Hypothalamic & Pituitary Hormones

Laurence L. Brunton, Bruce A. Chabner, Björn C. Knollmann Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e Chapter 38 Introduction To Endocrinology: The Hypothalamic-Pituitary Axis