Hypothalamic and Pituitary Agents Fall 23.2 PDF

Hypothalamic and Pituitary agents  Neuroendocrine system Regulates many functions Growth, metabolism, reproduction Endocrine system Releasing hormones from hypothalamus Trigger release of tropic hormones from Anterior pituitary Cause release of hormone from t...

Hypothalamic and Pituitary agents  Neuroendocrine system Regulates many functions Growth, metabolism, reproduction Endocrine system Releasing hormones from hypothalamus Trigger release of tropic hormones from Anterior pituitary Cause release of hormone from target gland EX: TRH causes release of TSH which causes the release of thyroid hormone Exceptions: GH and Prolactin are regulated differently Hypothalamus and anterior pituitary communicate via portal system Posterior pituitary hormones Produced in hypothalamus Stored in posterior pituitary Release regulated by neural activation of hypothalamic neurons Oxytocin and ADH  Common theme of Endocrine Axes Releasing hormone from hypothalamus regulates release of pituitary hormone Pituitary hormone (stimulating hormones) acts on target gland to stimulate release of its hormone Negative feedback control End product inhibits releasing and stimulating hormones GH and prolactin are exceptions GHRH stimulates release of GH, somatostatin inhibits Prolactin is normally inhibited by dopamine  Most hypothalamic and pituitary hormones are available A small fraction used clinically Uses Large percentage used for diagnostic purposes Replacement for deficiencies Treatment of disorders Most are peptides Act via cell surface receptors Activate downstream signaling RTK pathways GH and prolactin Others are GPCR mediated 7 transmembrane serpentine receptors Activate enzyme systems and second messenger generation Differing subtypes Adenyl cyclase Protein kinase Growth hormone Required for growth during childhood and adolescence Affects carbohydrate and lipid metabolism, lean body mass, bone density Mediates growth promoting effects through IGF-1 (somatomedin C) Childhood deficiency Short stature, low muscle mass, increased fat deposition Adult deficiency Low lean body mass Also associated with diminished bone mineral density, Dyslipidemia , and reduced cardiac output 191 Amino acid peptide Structure similar to prolactin Cadaver derived not used Increased incidence of CJD due to prion contamination Recombinant form – Somatotropin- Genotropin, Humatrope, Norditropin, Nutropin, Omnitrope, Saizen, Serostim, Zomacton, Zorbtive Identical structure to native GH Endogenous GH has a half life of 20 min Recombinant form administered subcu 6-7 times per week Peak levels in 2-4 hours GH actions Works through Jak/Stat system Effects concerned primarily with growth and metabolism Stimulates bone lengthening, muscle growth and fat breakdown Mediates most of its growth promoting actions through IGF-1 Mixed effects on carbohydrate metabolism GH and IGF-1 have opposite effects on insulin sensitivity GH reduces insulin sensitivity Mild hyperinsulinemia and elevated blood glucose IGF-1 has insulin like effects on glucose transport  Approved uses Growth failure in kids Due to GH deficiency Noonan syndrome ( genetic mutation in multiple genes) Prader-Willi syndrome ( chromosome 15 abnormalities) Turner syndrome (missing X chromosomes) Height benefits in girls Must be combined with gonadal steroids for full height benefits Lack functional ovaries Idiopathic short stature Somewhat controversial Requires monitoring to assess proper dosing Improved metabolic state and body composition Adults with GH deficiency Increased lean body mass, weight and physical endurance Wasting in HIV patients Improving GI function Short bowel syndrome in patients receiving nutritional support  Adverse effects Pancreatitis, gynecomastia, intracranial hypertension, muscle aches, scoliosis, edema Contraindicated in active malignancy  GH antagonists Used to treat symptoms of GH secreting tumors Acromegaly, gigantism, carcinoid tumor and other GH secreting tumors Somatostatin Short duration of action limits use Octreotide ( sandostatin) subcu. form. Sandostatin LAR depot given i.m. Analog of somatostatin with much longer duration of action ( 80 minutes) Increased potency at reducing GH Less potency at inhibiting insulin release Hyperglycemia rare S/E n/v , gallstones, sinus bradycardia ( 25%), conduction abnormalities , vitamin B12 deficiency with long-term use Lanreotide is a long acting form Dopamine receptor agonists Reduce GH production GH receptor blockers Pegvisomant (somavert) Used to treat acromegaly Does not reduce GH levels, and may cause GH increases and possible adenoma growth monitoring required IGF levels and MRI of anterior pituitary  GnRH and analogs Acts via GPCRS on gonadotrophs in pituitary Pulsatile secretion required for FSH and LH release Sustained non-pulsatile administration will inhibit FSH and LH release Used for prostate cancer treatment in men women who benefit from ovarian suppression Leuprolide (Leupron depot, Elegard) Also goserelin acetate ( Novadex), nefarelin(Synarel), histrelin(Vantas), and triptorelin, (Trelstar)( increased potency and duration) Leuprolide Nonapeptide GnRH analog Administered continuously Initially stimulates FSH And LH , then inhibits Clinical uses : Palliative treatment of advanced prostatic cancer Breast cancer Uterine fibroids Endometriosis Precocious puberty Analogs induce hypogonadism when given continuously  Leuprolide (Lupron Depot) & GnRH analogs Given s.c., i.m. or intranasally Half-life of 3 hr Adverse effects Hot flashes, headaches and sweats in females , depression, diminished libido and breast atrophy ( all menopausal symptoms) Osteoporosis with prolonged use Contraindicated during pregnancy and breast-feeding GnRH antagonist Ganirelix(Antagon) and Cetrorelix (Cetrotide) Used in IVF Oocyte harvest Controlled ovarian stimulation to stop premature LH surge Elagolix(Orlissa) Endometriosis Chiara Melloni, Susan F. Slovin, Allan Blemings, Shaun G. Goodman, Christopher P. Evans, Jan Nilsson, Deepak L. Bhatt, Konstantin Zubovskiy, Tine K. Olesen, Klaus Dugi, Noel W. Clarke, Celestia S. Higano, Matthew T. Roe,Cardiovascular Safety of Degarelix Versus Leuprolide for Advanced Prostate Cancer: The PRONOUNCE Trial Study Design,JACC: CardioOncology,Volume 2, Issue 1,2020,Pages 70-81,  Gonadotropins FSH, LH and hCG FSH stimulates oocyte maturation in females, estrogen production from androgen conversion LH stimulates androgen synthesis by theca cells during follicular phase, converted to estrogen by aromatase in granulosa cells under action of FSH sperm production in males LH stimulates ovulation in females Estrogen and progesterone production during luteal phase ( indirect as LH maintains corpus luteum) hCG will maintain corpus luteum if pregnancy results, Testosterone production in males Uses Stimulate sperm production in men , follicle development and ovulation in females ( especially for IVF) Menotropin (menopure) Gonadotropins derived from urine of postmenopausal females (HMGs) Both FSH and LH  FSH Follitropin alfa(Gonal-F) and follitropin beta (Follistim Aq) Recombinant forms Identical in sequence to native FSH Treatment of infertility in combination with hCG ( males and females) Treatment of secondary hypogonadism in combin. With hCG Adverse effects: ovarian enlargement, gynecomastia in men , and multiple births Contraindicated in hormone dependent prostate cancer Circulating levels correlated with reduced time to CRPC LH Lutropin alfa Recombinant form that has been withdrawn from market hCG used instead Production of progesterone/testosterone, Triggers ovulation , Maintains placenta hCG Choriogonadotropin alfa Recombinant form Used in combination with FSH to stimulate ovulation, treatment of infertility, stimulates testosterone production in men All exert effects through GPCRs Used to induce follicle development and ovulation in women Anovulation secondary to : Hypogonadotropic hypogonadism, PCOS or other causes Controlled ovarian stimulation and other reproductive technologies Multiple pregnancies and ovarian hyperstimulation syndrome are adverse effects OHSS can be associated with ovarian enlargement, hypovolumenia, pulmonary edema, electrolyte imbalances , and thromboemboli Increased risk when HcG and gonadotropins are used Risk can be diminished by GnRH agonists in lieu of HcG Used for male infertility Requires action of both FSH and LH Prolactin No prolactin preparation in use for prolactin deficiency Prolactin inhibition Dopamine agonists Dopamine is PIH but is not used due to peripheral effects and need for IV administration Agonists are used instead Bromocriptine (Parlodel) , Cabergoline (dostinex) Cabergoline more active at D2 receptors and longer half life, cost higher Dopamine D2 receptor agonists given p.o. effective in decreasing prolactin secretion Uses: Management of hyperprolactinemia Treatment of prolactinoma  Adverse effects : Nausea and GI upset , Psychiatric disturbances , Hypotension (Postural) Headache, dizziness and fatigue Ergotism (rare) : Associated with severe vasospasm, tissue ischemia and necrosis Hyperprolactinemia Dopamine agonists are used first line Were used historically to reduce milk production when breast feeding not desired Now discouraged due to adverse effects Dopamine receptor antagonists : Haloperidol , Phenothiazines , Chlorpromazine , Fluphenazine May cause hyperprolactinemia due to dopamine inhibition ACTH Corticotropin (Acthar H.P. Acthar Gel) 39 amino acid peptide hormone Cosyntropin (Cortrosyn) Synthetic derivative (ACTH1-24) Mechanism of action GPCR Works via adenyl cyclase , results in increased activity of cholesterol esterase Production of Pregnenolone Stimulates adrenocortical production of glucocorticoids, mineralocorticoids and adrenal androgens Cosyntropin (Cortrosyn) Diagnostic use Used to delineate between primary and secondary hypoadrenocorticosteroidism (Addison’s disease) Primary Addison’s disease adrenal cortex is defective ACTH does not stimulate Cortisol release Secondary Addison’s disease ACTH is deficient ACTH increases Cortisol secretion Cosyntropin Pharmacokinetics (i.v.) Half-life of 20 min Adverse effects limited Posterior Pituitary hormones Vasopressin ( ADH) and Oxytocin Oxytocin (Pitocin) Peptide hormone-9 amino acids Sequence only differs slightly from ADH Stimulates uterine contraction and myoepithelial contraction in breast tissue Involved in labor and milk let down Used to induce labor IV administration Used for reduction of postpartum bleeding IM administration Half life of 5 minutes Acts via GPCRs Works via Phosphoinositide system Releases intracellular calcium causing smooth muscle contraction Also stimulates prostaglandin release which reinforces uterine contraction Fetal monitoring required Contraindicated in fetal distress , placental abruption, fetal malpresentation, and predisposition to uterine rupture High concentrations will have ADH-like effects Toxicity rare, but due to this action when it occurs  Oxytocin Receptor antagonist Atosiban (tractrocile, Antocin) Preterm labor treatment Not approved in the US Vasopressin (ADH) Peptide hormone Nine amino acids Acts via GPCRs Increases distal nephron water permeability Also increases platelet activation via non renal receptors Released in response to osmoreceptor stimulation or reduced BP Deficiency is central to diabetes insipidus V1 receptors mediate cardiovascular effects Vasoconstriction Platelet aggregation V2 receptors responsible for renal tubule effects Desmopressin Analog Desmopressin administered IV, subcu, intranasally, or oral Half life of 1-2 hours  Vasopressin and Desmopressin Indications Used to treat diabetes insipidus Bedwetting Desmopressin at bedtime Hemophilia A and Vonwillebrands disease Desmopressin High dose Vasopressin bolus useful as an alternative to epinephrine for pulseless arrest Vasopressin but not desmopressin can cause widespread vasoconstriction CI in coronary artery disease Adverse effects Headache n/v, abdominal cramps, and hyponatremia and seizures in high doses  Vasopressin antagonists Conivaptan (Vaprisol) Dual V1 and V2 receptor antagonist Administered IV Tolvaptan (Samsca, Jynarque) Selective V2 receptor antagonist Oral administration Treatment limited to 30 days due to severe hepatotoxicity Increase sodium and free water clearance Use: Hyponatremia with normal or increased fluid volume SIADH Tolvaptan used in heart failure Adverse effects Hypernatremia Thirst Infusion site reaction