Hypothalamic and Pituitary Hormones Flashcards
- required during childhood and adolescence
- Effects mediated mainly by IGF-1
- Mediates effects via cell surface receptors that activate JAK/STAT signaling cascades
Growth Hormone: Somatotropin
Physiological effects of somatotropin
- Stimulation of longitudinal growth of bones
- Increased bone mineral density
- Increased muscle mass (in GH deficient persons)
- Increased GFR (Glomerular filtration rate)
- Stimulation of preadipocyte differentiation into adipocytes
- Anti-insulin actions (decreased glucose utilization & increased lipolysis)
- Development & increased function of the immune system
Criteria for Diagnosis with growth hormone deficiency
(1) A growth rate < 4cm per year, and
(2) the absence of a serum GH response to two GH secretagogues
Recombinant growth hormones
Somatropin: Recombinant GH
Somatrem: GH analog
- Active blood levels = persist for ~ 36 h
- Given subcutaneously 3-7 times a week
Clinical Use of Recombinant Growth Hormone
Adverse effects of recombinant growth hormone in children
- Scoliosis (during rapid growth)
- Diabetic syndrome (chronic use)
- Intracranial hypertension (rare)
- Otitis media (increased risk for Turner Syndrome patients)
- Pancreatitis, gynecomastia & nevus growth
- Hypothyroidism
Adverse effects of recombinant growth hormone in adults
- Peripheral edema, myalgias & arthralgias (hands & wrists especially)
- Carpal tunnel syndrome
- Proliferative retinopathy (rare)
Contraindications of Recombinant Growth Hormone
- Cytochrome P450 inducer
* Patients with a known malignancy
IGF-1 deficiency in children is due mutations in gene that encodes for GH receptor and development of neutralizing antibodies to GH. Which drug should be used ?
IGF-1 Analog: Mecasermin: Complex of recombinant human IGF-1 and recombinant human IGF-binding protein-3
AE of mecasermin
- Hypoglycemia (eat 20 minutes before or after administration)
- Intracranial hypertension (rare)
- Asymptomatic elevation of liver enzymes (rare)
Growth Hormone Secreting Tumors
- Acromegaly (abnormal growth of cartilage, bone tissue, skin, muscle, heart, liver & GI tract)
- Gigantism (if occurs before long bone epiphyses close)
Small GH-secreting adenomas can be treated with
- GH receptor antagonists- Pegvisomant
- Somatostatin analogs- Octreotide
- Dopamine receptor agonists- Bromocriptine and Cabergoline
• Larger pituitary adenomas require surgery or radiation
- Reduces symptoms caused by hormone-secreting tumors: acromegaly, carcinoid syndrome, gastrinoma, glucagonoma, nesidioblastosis, watery diarrhea, hypokalemia, achlorhydria syndrome & diabetic diarrhea.
- Localizing neuroendocrine tumors
- Acute control of bleeding from esophageal varices
Somatostatin Analog: Octreotide
- 45x more potent in inhibiting GH release than somatostatin
- 2x more potent in reducing insulin secretion
- t 1⁄2 = ~ 80 min (30x somatostatin)
- Octreotide acetate long-acting suspension can be given at 4-week intervals
AE OF Octreotide
*****Vit B 12 deficiency
- Nausea, vomiting, abdominal cramps, flatulence, steatorrhea (with bulky bowel movements)
- Constipation
- Biliary sludge & gallstones (20-30% patients after 6-month use)
- Sinus bradycardia (25%) & conduction disturbance (10%)
Treatment of hyperprolactinemis and acromegaly
Dopamine Agonists: Bromocriptine and Cabergoline
- Dopamine agonists shrink pituitary prolactin- secreting tumors, lower circulating prolactin levels, and restore ovulation in ~70% of women with microadenomas & ~30% with macroadenomas
- Oral or as vaginal inserts
- Bromocriptine t1/2 = ~7 h
- Cabergoline t1/2 = ~65 h
AE OF Dopamine Agonists: Bromocriptine and Cabergoline
- Nausea (bromocriptine>cabergoline), headache, light-headedness, orthostatic hypotension, fatigue
- Psychiatric manifestations occasionally occur
- High doses = cold-induced peripheral digital vasospasm • Chronic high-dosage therapy = pulmonary infiltrates
Gonadotropins in women
FSH: ovarian follicle development
• FSH & LH: ovarian steroidogenesis
• Luteal stage of menstrual cycle: estrogen & progesterone production is primarily under control of LH. (During pregnancy hCG takes over.)
Gonadotropins in men
• FSH: Spermatogenesis, conversion of testosterone to estrogen.
- Maintains high local androgen concentrations in vicinity of developing cells
• LH: Stimulus for production of testosterone
Act through GPCRs and is used for
- ovulation induction
- male infertility
- female infertility
Gonadotropins
Male Infertility
• Treatment of hypogonadal men requires both FSH and LH.
- Treatment can consist of hCG alone or alternative protocols using urofollitropin, rFSH and rLH
• Stimulate spermatogenesis
Female Infertility: induce ovulation in women (IVF)
Gonadotropins
AE OF GONADOTROPINS IN WOMEN
- Ovarian hyperstimulation syndrome
- Multiple pregnancies (15-20%)
- Headache
- Depression
- Edema
- Precocious puberty
AE OF GONADOTROPINS IN MEN
Gynecomastia
gonadotropin-releasing hormone
synthetic human GnRH
Given IV or SC
Half life of 4 mince
Gonadorelin
gonadotropin-releasing hormone analogs
more potent & longer-lasting than gonadorelin
Given SC, IM, nasal spray (Nafarelin) or as SC implant
Gonadotropin analogs- Goserelin, leuprolide, nafarelin
Continuous administration of Gonadotropin-Releasing Hormone & Analogs gives biphasic response:
- First 7 days = agonist response ‘flare’
* Chronic effects (> 1 week) = inhibitory action (due to receptor down-regulation & changes in signaling pathways)
Gonadotropin-Releasing Hormone & Analogs stimulates
- Female infertility
- Male infertility: In men with hypothalamic hypogonadotropic hypogonadism (pulsatile gonadorelin)
- Diagnosis of LH responsiveness: Whether delayed puberty is due to constitutional delay or hypogonadotropic hypogonadism
• Controlled ovarian hyperstimulation : Critical to suppress endogenous LH surge that could prematurely trigger ovulation
leuprolide, nafarelin
Endometriosis: Pain often decreased by abolishing exposure to cyclical changes in estrogen & progesterone concentrations during menstrual cycle.
- Treatment limited to 6 months
(leuprolide, goserelin, nafarelin)
Uterine Leiomyomata (fibroids): - Can reduce fibroid size and combined with supplemental iron can improve anemia
(leuprolide, goserelin, nafarelin)
Prostate Cancer:
- Combined therapy with continuous GnRH agonist and an androgen receptor antagonist is effective as castration in reducing serum testosterone
(leuprolide, goserelin)
Gonadotropin-Releasing Hormone & Analogs other suppression effects
- Central Precocious Puberty (leuprolide, nafarelin)
- Advanced Breast & Ovarian Cancer
- Treatment of Amenorrhea in women with Polycystic Ovary Disease
- Thinning of Endometrial lining: Preparation for endometrial ablation procedure in women with dysfunctional uterine bleeding
Adverse effects of Gonadotropin-Releasing Hormone & Analogs
- Headache, light-headedness, nausea, flushing
- Swelling at SC injection site
- Generalized hypersensitivity dermatitis (long-term administration)
- Rare acute hypersensitivity reactions
- Sudden pituitary apoplexy & blindness
Adverse effects of Gonadotropin-Releasing Hormone & Analogs for continuous treatment
Women
• Menopausal symptoms (hot flushes, sweats, headaches)
• Depression, diminished libido, generalized pain, vaginal dryness & breast atrophy can occur
• Ovarian cysts (generally resolve)
• Reduced bone density & osteoporosis (long treatment)
Contraindications
- Pregnant and breast-feeding women
Men
• Hot flushes, sweats, edema, gynecomastia, decreased libido, decreased hematocrit, reduced bone density, asthenia, & injection site reactions
These drugs suppress Gonadotropin Production: Prevent LH surge during controlled ovarian hyperstimulation
Cetrorelix, ganirelix = Competitive antagonists of GnRH receptors
These drugs
- Act via MC2R (GPCR → cAMP) to stimulate adrenal cortex to secrete glucocorticoids, mineralocorticoids & androgen precursor
• Diagnostic tool for differentiating between primary adrenal insufficiency (Addison’s disease) and secondary adrenal insufficiency (inadequate ACTH secretion)
• Infantile spasm (West Syndrome) treatment
Corticotropin, cosyntropin = ACTH analogs
- Acts on GPCRs → stimulates release of prostaglandins & leukotrienes that augment uterine contraction
- Small doses increase force & frequency of contractions
- Higher doses evoke sustained contractions. Weak antidiuretic & pressor activity (vasopressin R activation)
- Contraction of myoepithelial cells surrounding mammary alveoli → milk ejection
Oxytocin
- IV: initiation & augmentation of labor
- IM: control of postpartum bleeding
- t1/2=5min
Clinical applications of oxytocin
• Labor Induction: When early vaginal delivery is required
(Rh problems, maternal diabetes, preeclampsia, ruptured membranes)
• Augment Normal Labor: When labor is protracted or displays arrest disorder
• Control of uterine hemorrhage
AE of oxytocin
- Excessive stimulation of uterine contractions
- Inadvertent activation of vasopressin receptors: Excessive fluid retention, water intoxication → hyponatremia, heart failure, seizure, death
- Bolus injections can lead to hypotension: Administer IV as dilute solution at a controlled rate
Oxytocin contraindications
- Fetal distress
- Prematurity
- Abnormal fetal presentation
- Cephalopelvic disproportion
- Uterine rupture predisposition
Oxytocin antagonist used for treatment of preterm labor
Atosiban
Long-acting synthetic analog of vasopressin
Minimal V1 activity
Antidiuretic-to-vasopressor ratio 4000 x vasopressin
Desmopressin (Vasopressin (ADH) Agonists)
V1R
vascular smooth muscle→vasoconstriction
V2R
renal tubule cells→increased water permeability & water reabsorption
Drugs of choice for Diabetes Insipidus
Vasopressin (ADH) Agonists
Used for Esophageal variceal bleeding & colonic diverticular bleeding
Vasopressin
Used for Coagulopathy treatment in Hemophilia A and von Willebrand’s disease
Desmopressin
This drug is • Approved for use in patients with hyponatremia (due to elevated vasopressin)
• High affinity for V1 & V2 R’s
Conivaptan
Adverse effects of vassopressin agonists
- Headache, nausea, abdominal cramps, allergic reactions
* Overdosage = hyponatremia & seizures
