1 / 166

Pituitary Function and Pathology

Pituitary Function and Pathology. Dr Duncan Fowler The Ipswich Hospital. Overview. Anatomy Physiology Assessment of pituitary function: static and dynamic tests Clinical scenario’s: Cushing’s Disease Acromegaly Prolactinoma Apoplexy. Learning Objectives.

Download Presentation

Pituitary Function and Pathology

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.


Presentation Transcript

  1. Pituitary Function and Pathology Dr Duncan Fowler The Ipswich Hospital

  2. Overview • Anatomy • Physiology • Assessment of pituitary function: static and dynamic tests • Clinical scenario’s: • Cushing’s Disease • Acromegaly • Prolactinoma • Apoplexy

  3. Learning Objectives • Describe pituitary anatomy and endocrine physiology • Describe methods for assessing pituitary function using static and dynamic testing • Describe the new standard for the measurement of growth hormone & its effects on clinical criteria • Be are of the importance of screening for macroprolactin

  4. Hypothalamo-pituitary anatomy • Hypothalamus is the part of the diencephalon associated with visceral, autonomic, endocrine affective and emotional behaviour • Ventral portion forms the infundibulum • Posterior to this is the median eminence – the final point of convergence of pathways from the CNS on the endocrine system and is vascularised by the primary capillaries of the hypothalamo-hypophyseal portal vessels

  5. Sella turcica

  6. Terminology • Adenohypophysis = anterior pituitary controlled by releasing and inhibiting factors released from nerves in the median eminence into the hypophyseal portal vessels which carry them to the pituitary • Neurohypophysis = posterior pituitary. It is an extension of the CNS. Its function is controlled by direct neural connection to the hypothalamus

  7. Presentation • Hormonal hypersecretion e.g. Acromegaly • Hormonal deficiency e.g amenorrhoea • Local pressure effects: headaches, visual field loss – bitemporal hemianopia – bump into things

  8. Identical  chain but specific  chain – non covalently associated • Luteinising hormone (LH) • Follicular stimulating hormone (FSH) • Thyroid stimulating hormone (TSH) • (human chorionic gonadotrophin – hCG) Potential for cross reaction e.g. hyperemesis

  9. Control of anterior pituitary function

  10. Stimulators of TSH • Pulsatile release (~9 x/24 hours) – amplitude at night • Secretion stimulated by thyrotrophin releasing hormone (TRH) released into the hypohyseal portal vessels in the median eminence • (TRH also stimulates prolactin release and in some circumstances growth hormone)

  11. Inhibitors of TSH • Thyroid hormones directly inhibit TSH (and to a lesser extent TRH) release • This can prevent the action of TRH which is basis for TRH test • Dopamine and somatostatin inhibit release ?physiologically important but useful clinically for TSHomas

  12. Stimulators of LH/FSH • Pulsatile secretion • Stimulated by pulsatile secretion of gonadotrophin secreting hormone (GnRH) into the hypophyseal portal vessels • GnRH release is complex and very susceptible to stress and changes to nutrition and energy homeostasis e.g. hypothalamic hypogonadotrophic hypogonadism seen in weight loss or extreme exercise

  13. Inhibitors of LH/FSH • Oestradiol and progesterone inhibit LH release directly and via GnRH but in the follicular phase oestradiol becomes stimulatory inducing a surge of LH and ovulation (positive feedback) • Inhibin from the ovary inhibits FSH release • In the late follicular phase inhibin and oestradiol inhibit FSH release • In men equally complex but more static

  14. Stimulators of ACTH • ACTH is a single chain peptide cleaved from POMC along with MSH and  endorphin (hence pigmentation in Addison’s) • Secreted in pulsatile fashion in response to corticotrophin releasing hormone (CRH) – determines set point around which cortisol feedback works • Circadian rhythm with superimposed effects of stress

  15. Inhibitors of ACTH • Feedback from cortisol mainly directly on pituitary but also on CRH release • Other adrenal androgens whose secretions are enhanced by ACTH do not have a feedback effect e.g. in congenital adrenal hyperplasia • Feedback can be imitated by synthetic glucocorticoids e.g. Dexamethasone (used in suppression testing – tumorous corticotrophs less susceptible to feedback)

  16. Stimulators of GH release • Growth hormone releasing hormone (GHRH) stimulates synthesis/release of GH in pulsatile fashion – mostly at night • Ghrelin may have a role in secretion • GH exerts its effects directly and via IGF-1 production by the liver • Hypoglycaemia stimulates GH release (basis of ITT for GH deficiency) • Amino acids stimulate GH release (arginine can be used if ITT contraindicated)

  17. Inhibitors of GH release • Somatostatin inhibits GH release • Feedback from GH and IGF-1 inhibit GH release at pituitary and hypothalamic level • Free fatty acids inhibit GH release • Glucose inhibits GHRH and GH release (basis of GH suppression test for acromegaly)

  18. Stimulators of prolactin release • Released in pulsatile fashion especially at night • No direct stimulatory factor • Prolactin release is under tonic inhibitory control • Oestrogens cause hyperplasia of lactotrophs (hence care with COC with prolactinomas) & enhance prolactin release • TRH causes release of prolactin as well as TSH but this is not physiological

  19. Inhibitors of prolactin release • Dopamine tonically inhibits release • Impeding the hypophyseal portal circulation causes enhanced prolactin release in contrast to other pituitary hormones. Prolactin can rise to 2000 mU/l due to this ‘stalk effect’ • Dopamine antagonist drugs e.g. metoclopramide, tricyclic antidepressants can stimulate prolactin release

  20. Static Pituitary Tests

  21. Prolactin • TFT’s • LH/FSH and testosterone/oestradiol – but timing important • IGF-1 (for GH) • Cortisol – random samples not usually helpful –usually done 9am • Serum and urine osmolality (plus additional tests to investigate SIADH)

  22. Prolactin • If in doubt measure basal prolactin on 3 occasions

  23. Macroprolactin • Non-bioactive prolactin: monomer of prolactin and IgG molecule with prolonged clearance rate • Accounts for 10-30% of hyperprolactinaemia • Some but not all assay systems claim to detect macroprolactin but there are doubts • Treat sera with polyethylene glycol to precipitate out immunoglobulins then re assay for prolactin • Screening recommended for all hyperprolactinaemic sera (Clin Endo 71,466)

  24. Clinical relevance • Macroprolactin is not biologically active – people with it have normal gonadal function • If someone with gonadal dysfunction due to another cause is found to have “hyperprolactinaemia” due to macroprolactin: • inappropriate dopamine agonist treatment • imaging of the pituitary undertaken revealing incidentalomas (found in up to 10%) and unnecessary investigation and treatment

  25. Prevalence of macroprolactinaemiaClin Endo 71;702 (2009) • 1330 hospital workers in Japan screened for hepatitis B • 49 of 1330 (3.7%) had macroprolactin • 15 (30.6%) of these 49 had hyperprolactinaemia – all had normal monomeric prolactin on PEG precipitation • 29 of 1281 (2.26%) without macroprolactin had (true) hyperprolactinaemia

  26. Of the 44 hyperprolactinaemias, 15 had macroprolactinaemia (34%) • Nobody had macroprolactinaemia and raised free prolactin • All sera with macroprolactin showed complexes of prolactin and IgG – most had anti PRL Abs, with others showing a variety of prolactin complexes

  27. Total PRL-free PRL/total PRL x 100 : if >57% = macroprolactinaemia

  28. IgG bound 100% Anti PRL Abs 76% Glycosylated PRL 20% (?relevant)

  29. Of the 12 sera without antiPRL Abs Covalent disulfide bonds may be involved Suggests non covalent binding of IgG to prolactin and/or other proteins or aggregation of PRL

  30. TFT’s - Lack of elevation of TSH in the presence of low T4 • Indicates pituitary or hypothalamic cause of hypothyroidism – or sick euthyroid syndrome • Same pattern can occur in 1st few months of treatment of thyrotoxicosis: T4 and T3 can be reduced below normal by carbimazole yet TSH remains suppressed

  31. Sick euthyroid syndrome • Any severe non thyroidal illness can cause • fT4 low • fT3 is low or undetectable – reduced more than T4 • TSH is usually normal but may be low • Reverse T3 is normal or elevated • Preferential production of rT3, reduced binding globulins and circulating thyroid homone binding inhibitors • Clinical judgement but more common than 2º hypothyroidism

  32. TFT’s - Elevated fT4 and fT3 with failure of suppression of TSH Discordant T4 and T3 • Interfering antibodies – no clinical signs • Amiodarone • Familial dysalbuminaemic hyperthyroxinaemia

  33. TFT’s - Elevated fT4 and fT3 with failure of suppression of TSH Other • Intermittent T4 therapy • Resistance to thyroid hormone* • TSH secreting tumour* • Acute psychiatric illness

  34. TSHoma vs hormone resistance

  35. Gonadotophins • In menstruating females tests not usually needed • Day 21 progesterone gives information on ovulation • High prolactin can suppress gonadotrophin secretion • In males if 9am testosterone is normal then gonadotrophin secretion is adequate

  36. Growth hormone • Random tests not helpful due to pulsatile secretion • Need dynamic testing or IGF-1

  37. GH assays • Evolved from polyclonal RIA’s to 2 site monoclonal antibody non-isotopic assays with enhanced sensitivity • Accurately quantify previously undetectable values • Do we need age and gender dependent reference ranges ?

  38. Growth Hormone Units – a mess! • Previous standard not pure & contained a number of isoforms: 22kD, 20kD and dimers/oligomers • UKNEQAS showed between method variation increasing from 1994 to 1998 from 17 to 30% - most negatively biased assay reported values ½ that of most positively biased • In past: UK used mU/l and US mcg/l • Various conversion factors between 2 and 3 used • No simple conversion factor suitable

  39. New standard • EU legislation means all lab results must be traceable to a defined material (98/79/EC) • Since 2001 new international standard in use (IS98/574): 22kD GH of >95% purity • Now we should use mcg/l of IS98/574 • We should not use mIU/l but assigned conversion factor is 3.0 IU/mg • Criteria need to be looked at again

  40. 9am cortisol • ‘normal’ cortisol concentration does not exclude dysfunction • >500 nmol/l makes deficiency unlikely (unless v sick) • <100 nmol/l likely to be abnormal. Coincident ACTH can help • Need further testing • Salivary cortisol may become more important

  41. Posterior Pituitary • Paired serum and urine osmolality on rising • Normal serum osmolality 280-295 mosmol/kg and concentrated urine (ratio >2:1) excludes DI • In DI serum osmolality is raised and urine ratio is <2.0 (but still may be more than serum in mild cases) • Most need water deprivation test

More Related