The Hypothalamic-Pituitary AxisHigher brain centers, aka the central nervous system stimulate the hypothalamus, where set points are stored. The Hypothalamus secretes tropic hormones to communicate with pituitary, which then secretes hormones to individual endocrine glands. Tropic hormones cause release of another hormone.Humoral control also affects hormone release. “Something” in the blood that is not a tropic hormone causes hormone secretion. - parathyroid hormone/calcitonin release by low/high calcium- insulin/glucagon release by high/low blood sugarHormone release may also be regulated by circadian rhythms (light/dark cycles), Established by the pineal gland, located just next to the optic chasm. A stress is considered as any change from homeostasis. Hypothalamic Hormone GPCR Anterior PituitaryThyrotropin-releasing hormone (TRH)GqReleases thyrotropin (TSH) and prolactinCorticotropin-releasing hormone(CRH)GsReleases corticotropin (ACTH)Gonadotropin-releasing hormone (GnRH)GqReleases LH and FSH (gonadotropins)Growth Hormone releasing hormone (GHRH)GsReleases growth hormoneGrowth Hormone Inhibiting Hormone (GHIH, somatostatin)GiInhibits release of growth hormoneProlactin-stimulating hormone (PRF/PRH)not wellknownReleases prolactinProlactin-inhibiting hormone (PIH, dopamine)GiInhibits release of prolactin The pituitary gland hangs from the hypothalamus and has two functional lobes. The posterior pituitary is nervous tissue, and secretes oxyctocin and AHD. The anterior pituitary is glandular tissue and secretes TSH, ACTH, FSH, LH, GH, Prolactin and Endorphins. Hypothalamus- synthesizes neurohormones, released in pulsatile fashion- contains groups of functionally distinct cells called nuclei - Oxytocin and ADH are synthesized as preprohormones, then transported to posterior pituitary and storedGnRH deficiency- GnRH can be suppressed by stress, drugs, alcohol- Early in life, leads to delayed onset of puberty- Later in life leads to infertility, more pronounced in women, amenorrhea, anovulation which can lead to ovarian failure due to insufficient estrogen. The posterior pituitary releases oxytocin and antidiuretic hormone (ADH). Both are nonapeptides (9 amino acids) with similar structures that differ only by two amino acids. Oxytocin - Synthesized as preprooxyphysin- Stimulates:o Uterine contractions in laboro Milk ejection into breast ductso Smooth muscle contraction of vas deferens- May also act to facilitate sperm transport in uterus in non-pregnancy state- Also associated with love, pairbonding (trust) and maternal behavior- Hyposecretion:o leads to low milk production and difficult laboro linked to autism, as lack of social interaction. Nasal spray of oxyctocin has been shown to improve social behavior of children with autism- Hypo- and hypersecretion associated with autoimmune diseasesVassopressin (ADH)- Osmolarity is more important to maintain than blood pressure because electrolyte concentration affects nervous system function- Promotes water reabsorption by kidneys, acts on V2 receptors by Gs- Causes vasoconstriction, acts on V1a recptors by Gq using calcium as second messenger- Decreases osmolarity & increases BP- Secretion is stimulated by:o Increase in osmolarity from normal (285 mosm/kg)o Large decrease in blood volumeo Decrease in blood pressureVasopressin has also been linked to love and monogamy. Moles that have fewer V1a receptors (leads to vasoconstriction) were more promiscuous. This is because they live on the mountain, where water is plentiful and can mate whenever they want, have plenty of babies that will survive. Moles who live on the prairie have more V1a receptor because they do not always get a lot of water, have to be more conservative and protect their babies. Hypersecretion leads to serum hypervolemia, hypo-osmolarity, and with vasoconstriction, hypertension. Hyposecretion – leads to central diabetes insipidus, polyuria, inability toconcentrate urine, bedwetting (normally, more ADH is released at night so you don’t pee yourself).Molecular Effects of ADH on the KidneyHigh osmolarity/low blood pressureADH secretionGs increases cAMPActivates protein kinaseAquaporin 2 is produced and inserted into the apical membraneWater can cross apical membrane from kidney collecting duct into principle cells lining the ductWater crosses baslateral membrane (exits cell on other side) by aquaporin 3Water is reabsorbed by plasma in peritubular capillaryDecreases osmolarity/ increases BPThe anterior pituitary releases six hormones. Two affect non-endocrine targets: growth hormone and prolactin. The other four are tropic hormones: thyroid-stimulating hormone, adrenocorticotropic hormone, Leutinizing hormone, follicle stimulating hormone.Growth Hormone- Pulsatile release, greatest during sleep- Increases blood glucose:o Inhibits glycogen synthesiso Inhibits insulin receptor productiono Inhibits glucose uptake by muscle o Stimulates liver gluconeogenesiso Hypersecretion may cause DM- Indirect Effects:o Increases cell division and tissue growth. Stimulates synthesis of IGF-I (insulin-like growth factor I), which increases clonal expansion of chondrocytes in growing end-plates of long boneso Increases amino acid uptake & protein synthesiso Increases fatty acid release from adipose tissue and utilization by muscleso Increases fibroblast differentiation to chondrocytes to form cartilage then form bone- Secretion increases by:o Hypoglycemiao Pubertyo Estrogen, > testosterone- Secretion decreases by:o Hyperglycemiao Circulating fatty acids- Laron syndrome is an insensitivity to growth hormone due to a mutation of the receptor. - Children with hypoglycemia can be treated with GH because GH deficiency causes increased sensitivity to insulin. - Hyposecretiono In childhood: dwarfismo In adulthood: decreased muscle mass, low bone density- Hypersecretion:o In childhood: gigantismo In adulthood: acromegalyGrowth Hormone Receptor PathwayGrowth hormone binds receptorReceptor dimerizesSelf-phosphorylation of janus tyrosine kinase (JAK)*Phosphorylation and dimerization of STAT kinasesDimer translocation into the nucleusActivation of transcription factorsIncreased gene expression Growth, proliferation and differentiation*self-phosphorylation of JAK also leads to:- SHC kinase activation- MAPK cascade- IRS-PI3 kinase pathways All of which cause metabolic changes that eventually contribute to growth, proliferation, and differentiation. SHP tyrosine phosphorylase