MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY MOLECULAR ASPECTS OF GIANTISM, ACROMEGALY AND PITUITARY DWARFISM

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ACROMEGALY

Dwarf mice

GH-SECRETING PITUITARY TUMOURS ~ 40% of human GH-producing tumours contain high level of cyclic AMP. Adenylate cyclase is constitutively active. Gs was cloned from such tumours and showed single aa substitutions (Landis): Arg201Ser, Cys or His; Glu227Arg or Leu. Somatic mutations - DNA from non-pituitary tissue not affected. Mutant G proteins have low GTPase activity Arg201 is ribosylated by cholera toxin; Glu227 is in GTP/GDP binding site) Defines the gsp oncogene

GH secretion

Gs AND ADENYLATE CYCLASE ACTIVATION Gas bg From Stryer

OTHER CAUSES OF ACROMEGALY 1. Inappropriate secretion of GHRH by somatotrophs (giving autocrine stimulation) [rare?]. 2. Activating GHRH mutations [rare] 3. Loss of function mutations in regulatory subunit of PKA [rare] 4. Defects in alternative pathway for GH regulation (Ghrelin) [?] 5. Ectopic GHRH secretion by tumours of other tissues (esp. pancreas and lung) - less rare (but acromegaly may not be main problem)

TREATMENT OF ACROMEGALY Surgery and/or irradiation Octreotide (somatostatin analogue) Dopamine agonists (e.g.bromocryptine) GH antagonist - pegvisomant

A GH-RECEPTOR ANTAGONIST From Drake et al (2001)

The GH-IGF-Somatic axis

PATTERNS OF HUMAN GH SECRETION IGHD Type 1B GH Neurosecretory dysfunction Normal GH concentration (ng/ml) Time

HEREDITARY GH DEFICIENCY Type IA Autosomal recessive. Severe GH deficiency; may develop antibodies to GH used for treatment Type IB Autosomal recessive. Some residual GH present. Type II Autosomal dominant. GH mutation? Type III X-linked

A FAMILY OF PATIENTS SHOWING IGHD Type IA From Phillips et al (1981)

DELETIONS OF THE hGH GENE CLUSTER

IGHD TYPE 1B Low levels of GH retained, so GH treatment usually effective Various causes, including: Inactivating GHRH mutations (including lit) mouse Defective GH, grossly altered so not detectable in RIA

INACTIVATING MUTATIONS OF THE GHRH RECEPTOR UNDERLY SOME CASES OF IGHD IB From Frohman & Kineman (2002)

IGHD Type II. Often due to production of a mutant GH lacking Exon 3. Why is this dominant? Shortened GH is not active, but seems to interfere with processing of normal GH in somatotroph

MPHD Often due to transcription factor mutations that affect development of several different pituitary cell types and expression of several different hormones. E.g dwarf (dw)mouse - mutant Pit 1 transcription factor - Trp  Cys mutation. Production of GH, PRL and TSH all affected.

BIOINACTIVE GH GH levels usually apparently normal, but patients respond to exogenous GH. Dwarfism due to production of inactive GH. Mutations identified include: Asp112  Gly Arg77  Cys (dominant negative)

LARON DWARFISM Very stunted growth, but GH levels normal or above normal. No response to GH treatment. Fibroblasts respond to IGF-I but not GH; no GH binding. Due to deletions of GH receptor gene, point mutations (e.g. Phe96  Ser), frame shift mutations, chain termination mutations. Mutations can have varying effects on binding, production of GH binding protein etc.

GH RECEPTOR MUTATIONS From Johnston et al (1998)

GROWTH AND IGF-1 LEVELS IN PYGMIES

IDIOPATHIC SHORT STATURE Cases of short stature with no obvious cause. May reflect: 1. Impared secretion (GH neurosecretory dysfunction) 2. Bioinactive 3. GH insensity (but not Laron)- GH receptor defects with minor effects 4. None of the above. Note that short stature may be unrelated to GH defects - e.g. Achondroplasia - point mutation of FGF receptor 3 (expressed in cartilage). Heterozygotes dwarfed; homozygote lethal. But aetiology different from dwarfism due to GH deficiency

GH AND AGEING GH secretion in humans decreases with age. Suggestions that reversing this may overcome some effects of ageing Pros include: increased muscle mass (but not necessarily strength) decreased body fat increased “well-being” Cons include: increased risk of diabetes? joint problems increased cancer risk?