hypothalamic &amp; pituitary hormones

controls the metabolism, growth, and reproduction
1. drugs that mimic/block the effects of the hypothalamus & pituitary homones:
  1. act as replacement therapy for hormone deficient states
  2. act as antagonists for diseases that result from excess production of pituitary homones
  3. act as diagnosistic tools for identifying endocrine abnormalities
anterior pituitarty & hypothalmic receptors
1. all hormones except prolactin (PRL) are key participants in the hormonal systems they regulate
2. classified by hormone structure & types of receptors they activate
  1. growth hormone (GH) & PRL
    1. single chain protien
    2. activate receptors of the JAK/STAT group
    3. GH stim by growth hormone releasing hormone (GHRH)
      1. inhib by the peptide somatostatin (SST) & insulin-like growth factor (IGF-1)
    4. PRL inhib by dopamine
  2. Thyroid-stimulating hormone (TSH/thyrotropin), follicle stim hormone (FSH), luteinizing hormone (LH)
    1. dimeric orotiens that acivate G protien-coupled receptors
    2. share a common alpha chain
    3. beta chains differ to target specific receptors
    4. TSH release is reg by thyrotropin releasing hormone (TRH)
      1. inhib by thyroxine & triiodothyroxine
    5. LH & FSH (aka gonadotropins) release is stimulated by gonadotropin-releasing hormone (GnRH)
      1. inhib in women by estrogen and progesterone, men by androgens
  3. adrenocorticotropic hormone (ACTH)
    1. a single peptide, cleaved from a larger precursor that contains beta-endorphon
    2. acts through a G protien-coupled receptor
    3. release stim by corticotropin-releasing hormone (CRH)
      1. inhib by cortisol
Growth hormone (Somatotropin)
1. prod by anterior pituitary
2. req'd during childhood/adolescense for attainment of normal adult size
3. req'd thoughout life for lipid & carb metabolism and on lean body mass
4. SST effects are mediated by IGF-1, somatomedin C, and IGF-2 (less)
5. indiv w/ congenitial/acquired deficiency during childhood fail to reach adult height and have increased body fat and dec myo mass
6. adults with deficiency have low lean body mass
7. chemistry & pharmacokinetics
  1. GH is a 191 AA peptide w. 2 sulfhydryl bridges
    1. resembles prolactin
    2. was isolated from cadavers but assoc poisons caused Creutzfeldt-Jakob disease
  2. Somatotropin, recombinant form of GH (rhGH), has 191 AA sequence identical to GH
  3. ciculating GH has t1/2 of 20-25 min and is cleared predominately by the liver
  4. rhGH is admin subQ 3-7x/wk...peak 2-4 hrs...DOA 36hrs
8. clinical pharmacology
  1. growth hormone deficiency
    1. genetic or acquired by damage to pituitary/hypothalamus by a tumor, infection, surgery, or radiation therapy
    2. children have short stature & adiposity (neonates are normal size)
      1. another early sign is hypoglycemia
    3. criteria
      1. growth rate < 4 cm/yr
      2. absence of serum GH response to 2 GH secretagogues
    4. tx w/ rhGH should allow child to reach normal height
    5. adults have obesity, dec myo mass, asthenia, dec CO
      1. tx with GH shows reversal of sx
  2. GH tx of peds w/ short stature
    1. Prader-Willi syndrome- autosomal dominant genetic disease assoc w/ growth failure, obesity, & carb intolerance
      1. in children GH tx dec body fat, inc lean body mass, linear growth, & energy
    2. Turner syndrome
      1. GH has strong benefit on final height (10-15 cm)
      2. must be combined w/ gonadal steroids for max effect
      3. critical to start GH b4 lone bone epiphyses have closed
      4. chronic renal failure
      5. small for gestional age
      6. idiopathic short stature aka non-growth hormone deficient short stature
      7. ht < 2.25+ standard deviation for the norm in same age children
    3. other uses
      1. approved tx in pts w/ waisting assoc w/ AIDS
      2. short bowel syndrome dependent on TPN
      3. intestinal resection or bypass
      4. anti-aging remedies
      5. inc myo mass- athletes
    4. tox & contraindications
      1. children well tolerated
      2. intracranial HTN
      3. sx: vision changes, HA, N/V
      4. scoleosis during rapid growth- children
      5. inc otitis media- Turner syn
      6. hypothyoidism
      7. measure thyroid func
      8. pancreatitis, gynomastia, neuro growth
      9. peripheral edema, myalgias, arthralgias (esp hands & wrists), carpel tunnel syn, proliferative retinopathy
      10. inc activ of P450
      11. contraind in pts w/ known malignancy
      12. GH tx of critically ill pts inc mortality
Mecasermin
1. tx sever IGF-1 deficiency not responsive to GH
2. drug is complex of recomb human IGF-1 (rhIGF-1) & recomb human insulin-like growth factor binding protien 3 (rhIGFFBP-3)
3. admin subQ BID
4. ADR
  1. hypoglycemia
    1. avoid by eating 20 min b4 or apter admin
  2. HTN
  3. inc liver enzymes
Growth hormone antag
1. acromegaly
  1. abnormal growth of cartelage and bone tissue & organs
  2. affects skeletal, myo, cardio, resp, & metabolic systems
2. when GH secreting adenoma occurs b4 epiphyses close --> gigantism
3. somatostatin analogs & DA receptor agonists dec production of GH
4. larger adenomas (produce greater amts of GH) impair visual & CNS func
  1. are tx w/ spenoidal surgery or radiation
5. drugs
  1. pegvisomant
    1. prevents GH from activating its receptor
    2. polyethylene glycol deriv of a mutant GH b2036
      1. inc affinity for one GH recptor site, but reduced affinity at 2nd site
      2. allows for dimerization of the receptor but blocks conformational changees req'd for signal transduction
      3. less potent at GH recptor than B2036, but peg dec clearance & improves effectiveness
    3. makes serum levels of IGF-1 fall into normal range
      1. low incidence of GH secreting tumors & inc liver enzymes
  2. somatostatin analogs
    1. somatostatin
      1. inhib release of GH, glucagon, insulin, & gastin
      2. found in hypothalamus, cns, pancreas, and GI tract
      3. metab & excreted by kidney
      4. t1/2 is 1-3 min
      5. limited therapeutic use bc short DOA and multiple effects
    2. octreotide
      1. 45x more potent in inhib GH release
      2. 2x as potent in dec insulin secretion
      3. hypoglycemia rarely occurs
      4. elim t1/2 of 80 min
      5. dec sx cause by hormone secreting tumors: acromegaly, carcinoid syn, gastrinoma, nesudioblastosis, watery diarrhea, hypokalemia, achlorhydria (WDHA syn), diabetic diarrhea
      6. somatostatin receptor scintigraphy, using radiolabeled octreotide, is usefule in localizing neuroendocrine tumors having somatostain receptors & help predict response to octreotide therapy
      7. useful for acute control of bleeding from esophageal varices
      8. ADR
      9. N?V, abd cramps, flatulence, steatorrhea w/ bulky bowel movements, biliary sludge & gallstones, bradycardia & condition disturbances, inj site pain, vit b12 def
    3. lanreotide
      1. tx acromegaly
  3. Topic
The Gonadotropins (FSH & LH) & human chorionic gonadotropin (hCG)
1. prod by a single type pituitary cell
2. in women FSH directs ovarian follicle level
  1. FSH & LH- ovarian steroidogenesis
  2. in the ovary- LH stim androgen production by theca cells in the follicular stage of menstrual cycle, FSH stim conv of grandular cells of androgens to estrogens
  3. in the luteal phase of the m.cycle E & P are under control of LH, then if prego under hCG
    1. placental protien identical to LH
3. in men FSH reg spermatogenesis, maintain inc local androgen conc, conversion og T to E
  1. LH stim for production of T
4. used for infertility
5. menotropins aka human menopausal gonadotropins (hMG)
  1. extracted from urine of postmenopausal women
6. FSH
  1. urofollitropin (uFSH)
  2. 2 recomb forms (rFSH)
    1. follitropin alpha
      1. identical to FSH
    2. follitropin beta
7. LH
  1. lutropin alpha
    1. recomb LH
    2. t1/2 10 hrs
    3. used in combo with rFSH alpha
      1. stim follucular level in infertile women w. LH deficiency
    4. not apv'd for use w. other FSH preperations nor for stim LH surge necc to complete follicular devel and facilitate ovulation
8. hCG
  1. prod by human placenta and excreted into urine
    1. IM inj
  2. glycoprotien that has 92 AA alpha chain
    1. identical to FSH,LH, and TSH
  3. beta chain 145 AA
    1. resembles LH
  4. Choriogonadotropin alfa (rhCG) is recomb form of hCG
    1. packaged & dosed on basis of wt rather than units of sctiv
    2. sub Q inj
9. pharmacodynamics
  1. exert effects through G protien coupled receptors
10. clinical pharmacology
  1. ovulation induction
    1. used to induce ovulation in women w. anovulation 2ary to hypogonadotropic hypogonadoism, polycystic ovary syn, obesity, other
    2. $$$
      1. usu used after trying clomid
    3. usu on day 3, daily inj of FSH are begun for 7-12 days
    4. in women w/ hypogonadotropic hypogonadism, follicle devel req's FSH + LH
      1. they dont produce the basal level of LH req'd for adeqyate ovarian estrogen production & normal follicle devel
    5. dose and duration is based on response measured by serum estradiol conc & ultrasound eval
    6. risk of premature endogenous surge in LH
      1. admin w/ drug that blocks the effects of endogenous GnRH
    7. when appropriate follucilar maturation has occured FSH+ GnRH agonist or GnRh antag inj are d/c
      1. the next day hCG is admin to induce final follicular mautration & ovulation followed by insemination in ovulation induction & oocyte retrieval
      2. must provide exogenous hormonal support of the luteal phase (bc LH production is suppressed)
      3. exogeneous progesterone, hCG or the 2 combined are effective
      4. progesterone is preferred bc hCG carries higher risk of ovarian hyperstimulation syn
  2. male infertility
    1. signs & sx
      1. delayed puberty
      2. no prepubertal 2ary sex characteristics after puberty
      3. tx w/ androgen
    2. tx w/ LH and FSH
    3. conventional therpay
      1. hCG inj x 8-12 wks
      2. takes 4-6 months for sperm to show in ejaculate
    4. more current therpay
      1. rFSH & rLH
      2. intracytoplasmic sperm inj (ICSI)
      3. a single sperm is inj into mature oocyte
  3. tox & contraindications
    1. women
      1. controlled ovarian hypestimulation
      2. possible ovarian enlargement that usu resolves spontaneously
      3. characterized by ovarian enlargement, ascities, hydrothorax, hypovolemia (resulting in shock), hemoperitoneum (from ruptured ovarian cyst), fever, arterial thrombolism
      4. multiple pregnancies
      5. 15-20 % vs normal rate of 1%
      6. carry inc risk of complications
      7. gestational diabetes, preeclampsia, & preterm labor
      8. in vitro- risk determined by # of embryos transferred to pt
      9. SE
      10. HA, depression, edema, precocious puberty, and production of antibodies to hCG (rare)
      11. ovarian cancer
    2. men
      1. gynecomastia
      2. related to the level of T produced in response to tx
gonadotropin-releasing hormone & its analogs
1. secreted by neurons in the hypothalamus
2. travels through the hypothalamic-pituitary evnous portal plexus to the anterior pituitary and binds to G-protien coupled receptors on the plasma membranes of gonadotroph cells
3. pulsatile GnRH secretion is req'd to stim gonadrotroph cell to produce and release LH and FSH
4. sustained non-pulsatile admin of GnRH or GnRH analogs inhib release of FSH and LH by the pituitary
  1. results in hypogonadism
5. GnRH are used to prduce gonadal supression in men w/ prostrate cancer
6. used in women undergoing assisted reproduction technology proced. or who have a problem benefited by ovarian suppression
7. Chemistry & pharmacokinetics
  1. decapeptide
  2. Gonadorelin
    1. acetate salt of synthethic human GnRH
    2. tox
      1. HA, lightheadedness, nausea, flushing
      2. local swelling at inj site& hypersensitivity, bronchospasm, anaphylaxis
      3. pituitary apoplexy & blindness
      4. after admin of GnRH to pt w/ gonadotropin-secreting pituitary tumor
    3. analogs
      1. Goserelin
      2. tx endometriosis (depot), uterine fibroids, prostate cancer
      3. contin tx causes menopause
      4. Histrelin
      5. tx prostate cancer
      6. Leuprolide
      7. tx supress LH surge that triggers ovulation, endometrriosis (depot), uterine fibroids, prostate cancer, central precocious puberty (depot)
      8. contin tx causes menopause
      9. Nafarelin (nasal)
      10. tx supress LH surge, endometriosis, uterine fibroids, central precocious puberty
      11. contin tx causes menopause
      12. tox: may cause/ aggravate sinusitis
      13. Triptorelin
      14. tx prostate cancer
      15. usu admin w/ bicalutamide or androgen receptor agonists- avoid tumor plares
      16. other tx: adv ovarian/ breast cancer, thinning of endometrial lining with dysfunct uterine bleeding, amenorrhea, and infertility assoc w/ polycystic ovary disease
      17. tox in wm: ovarian cysts, depression, dec libido, generlaized pain, vag dryness, breast atrophy, red bone density/osteoporosis
      18. tox in men: hot flashes, edema, gynecomastia, dec libido, dec hematocrit, red bone density, asthenia, inj site rxns
      19. have D-amino acids at #6 & have ethylamide sub'd for glycine at # 10 (except nafarelin)- make more potent and longer lasting
  3. admin IV or subQ
  4. analogs admin subQ, IM, nasal spary (nafarelin) or as subQ implant
  5. t1/2 of IV gonadorelin is 4 min
  6. t1/2 of subQ & intranasal GnRH analogs are approx 3 hrs
  7. duration of use ranges from day for ovulation induction to years for tx of metastatuc prostate cancer
    1. preparations devel with range of DOA from several hrs (daily admin) to months (depot forms)
8. pharmacology
  1. used for stim of gonadotropin production & suppression of gonadotropin release
  2. supression of gonadotropin production
Main Topic 8