1. Drugs and the Treatment of Pituitary Disease Joe Collier

2. Aims The session will describe: –how drugs can modify pituitary function, –how drugs can be used to treat patients with abnormal circulating blood levels of: prolactin, growth hormone, testosterone, oestrogen and vasopressin. –Key pharmacodynamic and pharmacokinetic properties of the drugs will be reviewed, as will the main unwanted effects

3. At the end of the session you should be able to describe –how drugs are used to treat patients with abnormal circulating blood levels of: prolactin, growth hormone, testosterone, oestrogen and vasopressin. –the actions of dopamine agonists (bromocriptine), growth hormone and its analogue (somatropin) gonadorelin analogues (goserelin), somatostatin analogues (octreotide), oestrogen receptor antagonists (clomiphene) and carbamazepine and the vasopressin analogues desmopressin, explaining, where possible, the pharmacokinetics of these drugs. –briefly their interactions and unwanted effects and the principles of their use.

4. Effects of circulating prolactin Prolactin is a 198 amino acid single chain polypeptide released from the anterior pituitary. –normal (physiological) properties: initiation and maintenance of lactation (effects on breast tissue balanced by oestrogen) –pathophysiological effects (as in hyperprolactinaemia): infertility (amenorrhoea, anovulatory cycles or sperm motility problems, reduced semen volume) lack of libido galactorrhoea gynaecomastia

5. Control of Prolactin Release Primarily through an inhibitory (braking) system whereby dopamine released by the hypothalamus inhibits prolactin release from the anterior pituitary. There is also probably a prolactin releasing factor released by the hypothalamus which promotes prolactin release from the anterior pituitary.

6. Causes of hyperprolactinaemia Anything that reduces dopamine inhibition: –(hypothalamic disease) –(stalk section) –inhibitors of dopamine production or release: methyl dopa reserpine inhibitors of dopamine receptors –antipsychotics (haloperidol, chlorpromazine etc) –metoclopramide –(pituitary tumour)

7. Reducing Prolactin Levels  Stop dopamine antagonist  Give dopamine agonist such as bromocriptine (used for inhibiting lactation in women not wishing to breast feed). Unwanted effects are dose- dependent eg nausea, vomiting, hypotension, stroke, confusion, dyskinetic movements.  Give stilboestrol to potentiate the negative oestrogen effect (post partum). The drug must be started straight after birth. The risks include increased thromboembolism and uterine bleeding.

8. Pituitary Growth hormone (GH) 191 amino acid single chain polypeptide; synthetic derivative known as somatropin. Control. GH release is regulated by hypothalamic:  Growth Hormone-Releasing Factor (GHRF; synthetic derivative known as sermorelin)  Growth Hormone-Release-Inhibiting Factor (GHRIF or somatostatin; synthetic derivative known as octreotide)  Dopamine which inhibits release

9. Treating GH Deficiency This uses somatropin, produced by recombinant DNA technology, with the same amino acid sequence as naturally occurring GH, is given by subcutaneous or im injection. Uses:  Children; somatropin is given to those with pituitary insufficiency and reduced growth  In adults; somatropin is given to those with Turner syndrome and (sometimes) those with GH- deficiency syndromes (lassitude, muscle weakness, heart failure, diminished bone density). The place of GH in adult deficiency syndromes is not yet established.

10. Drug treatment of excess growth hormone secretion Bromocriptine (orally up to four times daily, which acts as a dopamine receptor stimulant and so inhibits GH release. Doses higher than used in suppression of lactation and unwanted effects more pronounced; tolerance to these develops with repeated exposure.

11. Drug treatment of excess growth hormone secretion Octreotide. This is a synthetic somatostatin given by im or subcutaneous injection three times daily (reserved for those in whom surgery or bromocriptine are unsuccessful or inappropriate). A new depot formulation of octreotide for im injection (Sandostatin LAR) needs to be given only monthly.

12. Treatment of low levels of testosterone  Secondary to hypothalamic disease  GnRH (gonadorelin) subcutaneuosly in pulsed doses  Secondary to pituitary disease  Human chorionic gonadotrophin (this has LH activity).  Primary testicular failure testosterone:  oral capsules (twice daily, unpredictable),  im injections (every three weeks),  subdermal implants (every 4-6 months)  skin patches (predicatable, once daily).

13. Treatment to lower testosterone Give synthetic GnRH (gonadorelin) such as goserelin as a subcutaneous injection once monthly. This initially stimulates LH release from the pituitary, then after 2- 3weeks, inhibits LH release due to receptor desensitisation. NB The initial LH release gives a testosterone burst (flare) which might need to be blocked by a testosterone receptor antagonist such as flutamide.

14. Oestrogen Physiological control. Oestrogen is synthesised in the ovary in response to follicular stimulating hormone (FSH) and luteinising hormone(LH) released from the anterior pituitary. These are synthesised in response to hypothalamic Gonadotrophin- Releasing Hormone (GnRH; gonadorelin). Circulating oestrogen levels inhibit gonadorelin release.

15. Oestrogen  Raising the levels of LH and FSH so stimulating ovulation  Give a central oestrogen receptor blocker such as the stilboestrol analogue clomiphene (taken orally for 5 days). Lowering the levels of oestrogens (as for example in endometriosis or breast cancer). Give a synthetic gonadorelin such as goserelin.

16. Vasopressin (anti diuretic hormone ADH) A nonapeptide synthesised in the hypothalamus and subsequently secreted from the posterior pituitary in response to increased blood osmotic pressure. Pharmacological properties of vasopressin: –increases permeability of the collecting ducts to water so causing water retention (reabsorption). –vasoconstriction (arteries, arterioles & venules). –increases gut motility. Note that its effects on vessels and tubule are about equal.

17. Diabetes insipidus treatment Desmopressin (desamino-8-D-arginine vasopressin - ADH activity:vasoconstrictor activity 3000:1) Desmopressin is destroyed in the gut and has a half-life of 75min. Give as nasal instillation, spray or subcutaneous injection 2-3 times daily. Additional approaches: Chlorpropamide (increases renal sensitivity to ADH), carbamazepine (potentiates release of ADH from pituitary) bendrofluazide (paradoxically effects renal tubules to cause water retention).