Endocrinology (EXAM 2 MATERIAL)Cells releasing hormones in the Anterior Pituitary-The anterior pituitary contains cells that express receptors that bind to hypothalamic hormones released via the hypothalamic-hypophyseal portal system- Cell types in the anterior pituitary that respond to hypothalamic hormones to synthesize/release other hormones- The target cells are themselves--- autocrines1. Somatotrophs are the target cells for GHRH (growth hormone releasing hormone) and GHIH (growth hormone inhibiting hormone)a. Under the influence of GHRH, the somatotrophs respond to GHRH to synthesize and release Growth Hormone (GH)b. GHIH inhibits the somatotrophs from synthesizing and releasing GHi. GHIH is also referred to as a somatostatin2. Lactotrophs stimulated to synthesize release the hormone prolactina. Lactotrophs are inhibited by prolactin inhibiting hormone (PIH) aka dopamineb. Lactotrophs are stimulated by prolactin releasing hormone (PRH)3. Thyrotrophs are stimulated by TRH to synthesize/ release thyroid stimulating hormone (TSH)a. Not all cells are under the influence of a releasing hormone and an inhibiting hormone have to find a way to turn this off  thyroid hormones feed back to inhibit by negative feedback4. Corticoitrophs are stimulated by CRH to synthesize/release adrenocorticotrophic hormone (ACTH)a. Inhibited by negative feedback5. Gonadotrophs are stimulated by GnRH to synthesize/ release 2 hormonesa. Luteinizing hormone (LH)b. Follicle stimulating hormone (FSH)Growth hormone (GH) = Somatotropin- Growth hormone is a 191 amino acid polypeptide hormone released by the somatotrophs in the anterior pituitary-Growth hormone release declines with ageo Children release 1,600 ug- 1,800 ug/day release more as a childo Adults release 400 ug/day- Growth hormone is not released into fetal blood; therefore you can’t often tell if there is a defect early on. The effects of GH are seen after birth takes awhile before the physician can see any defectso Always have to adjust for parental heightso Gene for tallness is dominant so that it is still possible to have a short child with two tall parents, which could be heterozygous and have short alleles- Release more growth hormone when you sleep- Plasma half-life is 20 min-50 minFactors that affect Growth hormone release- Factors that increase growth hormone levelso Increased GHRH secretion from the hypothalamus can stimulate the Somatotrophs to release more GHo Sleep- 70% of daily GH secretion occurs during the 3rd and 4th stages of sleep Sleep divided into 4 stages Release more in deep sleep (3rd stage) Light also effects release release less when you sleep during the dayo Stress- emotional, physical, exercise, trauma, surgeryo Metabolic factors Hyperaminoacidemia (high levels of amino acids)- Amino acids in the blood are used for protein synthesis Hypoglycemia- low levels of blood glucose- Hormone works to bring glucose back into the bloodo Anorexia nervosa and starvation- results in hypoglycemia- can act as a stimuluso Dopamine (PIH) agonistso Chronic liver failure results in low levels of IGF which removes negative feedback mechanism that inhibits GH releaseIn normal conditions, GH stimulates the hypothalamic cells to synthesize/release insulin like growth factors (IGF1 and IGF2) aka SomatomedinsHigh levels of IGF will inhibit GH release via negative feedback mechanism- Factors that decrease growth hormone levelso Increased somatostatin (GHIH) secretiono Hyperglycemia- high levels of glucoseo Hyperlipidemia- high levels of fatty acidso Obesity- due to persistent hyperglycemia and hyperlipidemiao Severe emotional depressiono Dopamine antagonistsParadoxically, dopamine agonists SUPPRESS growth hormone levels in acromegalyBiological Actions of Growth Hormone- Growth hormone binds to growth hormone receptors that recruit Tyrosine Kinase (JAK/MAPK/STAT signal transduction pathway)o Need to dimerize receptor--- binds to two receptorso JAK will phosphorylate other downstream proteins including STAT and MAPK- Biological actions may be direct and indirect- Direct biological actions of GHo GH stimulates lipolysis; GH is a lipolytic hormone Break down fatty acids and feed into the energy pathwayso GH inhibits cellular uptake of glucose resulting in increased blood glucose levels= GH is aninsulin antagonist GH is a diabetogenic hormone- GH increases blood glucose levels by preventing cellular uptake of glucose Neurons, liver, and skeletal muscles are some of the major users of glucose and are all insulin dependent- they must be able to pick up glucoseo GH stimulates the production of IGFs (Insulin-like Growth factors) by hepatocytes- Indirect biological actions of GHo GH stimulates the production of IGF-1 and IGF-2 which then stimulate postnatal longitudinal bone growth (IGFs stimulate proliferation of cartilage epiphyseal plates) and growth of the organso Growth hormone (via IGF) synergizes with sex steroid hormones to cause adolescent growth spurt An increase in GH increase in IGR increase linear bone growth by the IGFs stimulating growth of the epiphyseal plates and ossification of the long bone abutting the epiphyseal plates Lengthen shaft diaphysis which will lengthen the bone and increase height Add hylein cartilage to epiphyseal plates (top and bottom)--- the same amount will be turned into bone tissue—shifting top superior and bottom inferior (plate shifting) When GH is released after the plates close due to high levels of the sec steroid hormones, you see widening of bones that would otherwise growth tallo Stimulates cellular uptake of amino acids and protein synthesiso Hence, the growth-promoting effects of GH are indirect (via IGF actions)Abnormal GrowthAbnormal growth is not always due to growth hormone dysfunction  there are many other causes!- Some causes of short stature:o Hypothalamic dysfunction- hyposecretion of GHRHo Pituitary dysfunction- GH deficiency in childhood results in dwarfismo GH receptor insensitivity- Laron’s dwarfismo Hypothyroidismo Vitamin D deficiency (rickets)o Chronic renal diseaseo IGF (Somatomedin) deficiency/resistance- pygimieso Chromosomal abnormalities such as Down syndrome, Turner’s syndromeo Pseudohypoparathyroidismo Chronic renal diseaseso Progeria- rare genetic disease with aging symptomsThere are a lot of causes of abnormal growth rather than just growth hormoneProgeria- Progeria, or Hutchinson-Gilford Progeria