Pituitary and Hypothalamic Hormones

Akrum Hamdy

Introduction

Most pituitary and hypothalamic hormone are trophic hormones. This and other factors limit their use as drugs.

Exceptions – growth hormone and gonadotropins

Growth HormoneGH or Somatotropin Chemistry – a single chain polypeptide. Significant differences in amino acid

sequence between humans and other species prevent use of non-human hormone

Growth HormonePhysiological Actions

Growth Hormone

Physiological actions Mechanism – GH receptor stimulation activates an

intracellular tyrosine kinase, JAK2, resulting in phosphorylation of proteins and gene regulation.

Growth – almost all body tissues stimulated to grow Nitrogen metabolism – increased nitrogen retention,

amino acid transport into tissues, and incorporation into protein

Carbohydrate and lipid metabolism – GH appears to promote use of lipids as energy source instead of carbohydrates

GH has a diabetogenic effect in diabetics

Growth Hormone

Physiological actionsConserves muscle at the expense of fat

during stress Insulin-like growth factor (IGF, somatomedins)

– peptides produced by liver and other tissues in response to GH; appear to mediate many GH effects. rhIGF-1 (mecasermin, Increlix) now available for treatment of growth failure in GH-resistant patients

Growth Hormone Clinical applications – one of the few

pituitary hormones with long-term therapeutic utility. Recombinant human growth hormone (rh-GH) is used clinically. There are two forms, somatotropin and somatrem. Hypopituitary dwarfism – in children with

insufficient GH secretion, GH will generally produce an increased growth rate over several years. Recently, FDA approved use in children with idiopathic, non-GH-deficient short stature.

Growth Hormone Clinical applications

Treatment of AIDS – associated wastingTreatment of adult onset growth hormone

deficiencyTurner’s syndrome

Anti-aging supplements – OTC supplements which suggest they contain hGH. Contain amino acids that are supposed to release GH.

Growth Hormone

Problems associated with therapy – possibility of intracranial hypertension and visual changes exist, so fundascopic exams needed.

Also possibility of type 2 diabetes and respiratory difficulties in patients with obesity or sleep apnea due to Prader-Willi syndrome.

Possible contamination of human-derived GH with Creutzfeldt-Jakob virus.

Growth Hormone

Acromegaly – hypersecretion of GH may result in acromegaly.

Octreotide (Sandostatin) or other somatostatin analogs are most commonly used to decrease GH secretion.

Dopamine agonists such as bromocryptine will inhibit GH secretion from some GH secreting tumors.

Pegvisomant (Somavert), a GH receptor antagonist, is now available to treat acromegaly in patients who have not responded to other treatment. Pegvisomant prevents GH stimulation of IGF.

Gonadotropins

Luteinizing hormone (LH, interstitial cell stimulating hormone)Chemistry – glycoprotein hormone with 2

peptide chains. Physiological actions

Mechanism – LH receptor stimulation activates Gs Ovary – promotes ovulation and luteinization of

ovarian follicles; stimulates synthesis and secretion of estrogen and progesterone from corpus luteum.

Gonadotropins

Luteinizing hormonePhysiological actions

Testis – stimulate interstitial (leydig) cells to secrete androgens

Figure 56-4. The hypothalamic-pituitary-gonadol axis

A single hypothalamic releasing factor, gonadotropin-releasing hormone (GnRH), controls the synthesis and release of both gonadotropins (LH and FSH) in males and females. Gonadal steroid hormones (androgens, estrogens, and progesterone) cause feedback inhibition at the level of the pituitary and the hypothalamus. The pre-ovulatory surge of estrogen also can exert a stimulatory effect at the level of the pituitary and the hypothalamus. Inhibin, a polypeptide hormone produced by the gonads, specifically inhibits FSH production by the pituitary.

Gonadotropins

Luteinizing hormoneClinical application

Infertility – menotropins (a mixture of urinary LH and FSH) and chorionic gonadotropin have been used to induce ovulation. Recombinant human LH lutropin alpha (Luveris) is now available.

Hyperstimulation of ovary may occur May also increase fertility in men Kits available to predict time of ovulation by measuring

urinary LH

Gonadotropins

Follicle stimulating hormone (FSH) Chemistry – glycoprotein with 2 peptide chains.

Agents available are recombinant human FSH, follitropin (Gonal-F and Follistim), and urinary human FSH, urofollitropin

Physiological actions of FSH Mechanism – activates Gs Ovary – promote follicular development Testis – stimulate testicular growth and maintain

seminiferous tubules Clinical application – promote ovulation

Gonadotropins

Chorionic gonadotropin (HCG) – not a pituitary hormone but is similar to the pituitary gonadotropinsChemistry – glycoprotein with 2 polypeptide

chains. Synthesized by syncytiotrophoblasts of placenta. Recombinant human HCG, choriogonadotropin alfa (Ovidrel) is used clinically.

Physiological actions – stimulate and sustain function of corpus luteum

Gonadotropins

Chorionic gonadotropin (HCG)Clinical application – induction of ovulation,

promote descent of testes in cryptorchismPresence of HCG in urine used to confirm

diagnosis of pregnancy

Prolactin - PRL Chemistry – single chain polypeptide

hormone Physiological actions

Lactation – causes growth and development of breasts, and increased synthesis of milk proteins

Decreases release or effectiveness of gonadotropins

Hypersecretion – hyperprolactinemia may cause galactorrhea, amenorrhea and infertility. Bromocriptine, pergolide (Permax), and cabergoline (Dostinex) are useful in suppressing PRL secreting tumors.

Thyrotropin (TSH)

Chemistry – glycoprotein with 2 polypeptide chains. Thyrotropin alpha, human recombinant TSH, is used clinically.

Physiological actions – Receptor stimulation activates Gs which increases function of thyroid gland Increases uptake of iodine by thyroid, synthesis and

release of hormone, and growth of gland.

Thyrotropin (TSH)

Clinical application Increases uptake of radioactive iodine. Used

as a diagnostic tool for serum thyroglobulin testing or whole body scanning in the follow-up of patients with thyroid cancer.

Corticotropin(Adrenal cortex trophic hormone, ACTH)

Chemistry – natural hormone is a single chain polypeptide of 39 amino acids. A synthetic form containing amino acids 1-24 is available.

Physiological actions – stimulates adrenal cortex to synthesize and secrete cortisol, corticosterone, and aldosterone (slightly). Prevents atrophy of adrenal cortex. Mechanism – receptor interaction results in

activation of adenylate cyclase and synthesis of cAMP. cAMP activates enzymes involved in steroid synthesis.

CorticotropinAdrenal cortex trophic hormone, ACTH)

Clinical useDiagnosis of adrenal insufficiency Treatment of infantile spasms (epilepsy)

Hypothalamic Hormones Peptides synthesized in hypothalamus and

transported to the anterior pituitary via portal circulation Gonadotropin releasing hormone and analogs – drugs

available include Gonadorelin (natural hormone) and Long-acting analogs histrelin (Suprelin), leuprolide

(Leupron), gosrelin (Zoladex), triptoreline (Trelstar), and nafareline (Synarel).

Gonadorelin is used for induction of ovulation. Long acting analogs are used for treatment of PMS,

endometriosis, prostate cancer, and central precocious puberty. Experimental use as male contraceptive.

Hypothalamic Hormones GnRH antagonists – ganirelix (Antagon)

and cetrorelix (Cetrotide) Used to inhibit premature LH surges prior to

harvesting eggs for in vitro fertilizationAlso abarelix (Plenaxis) – a GnRH receptor

antagonist used to treat advanced prostate cancer. Danger of life-threatening allergic reactions in 4% of patients.

Hypothalamic Hormones

Somatostatin – an analog, octreotide acetate (Sandostatin) used to treat acromegaly, carcinoid, and VIP secreting tumors. Long acting form now available (once per month).

Growth hormone releasing hormone – Semorelin (Geref), a synthetic form of GHRH, has been approved for treatment of GH deficiency. Will only work in patients with functioning pituitary.