Clinical Pharmacology and Therapeutics

318 THE PITUITARY HORMONES AND RELATED DRUGS
and thereby reduce pituitary stimulation of male or female
gonads, effectively leading to medical orchidectomy/ovariectomy
(a state of hypopituitary hypogonadism).
Adverse effects
Menopausal symptoms are common in addition to decreased
trabecular bone density, and local symptoms caused by irritation
of the nasal mucosa with buserelin.
Pharmacokinetics
Gonadorelin analogues are peptides and are given parenterally.
Goserelin may be given as intravenous pulses to
mimic the physiological release of GnRH. Depot preparations
are available to suppress FSH/LH release (see above). GnRH
analogues are cleared by a combination of hepatic metabolism
and renal excretion.
Key points
Gonadotrophins and GnRH analogues
• FSH and LH are secreted in pulses and stimulate
gonadal steroid synthesis.
• GnRH analogues initially stimulate, but then
downregulate the release of FSH and LH.
• GnRH analogues (e.g. goserelin, buserelin) are used in
the treatment of :
– endometriosis;
– female infertility;
– prostate cancer;
– advanced breast cancer.
• Side-effects of GnRH analogues include:
– menopausal symptoms;
– reduced bone density (by reducing oestrogen secretion).
relation to the treatment of diabetes insipidus. Demeclocycline
is an antagonist of ADH and has been used in patients with
hyponatraemia caused by the syndrome of inappropriate ADH
secretion (SIADH). More specific antagonists of ADH are in
development. The use of oxytocin for induction of labour is
described in Chapter 41.
Key points
Physiology of the pituitary
Anterior pituitary
secretes:
• growth hormone (GH);
• follicle-stimulating hormone (FSH);
• luteinizing hormone (LH);
• adrenocorticotrophic hormone (ACTH);
• prolactin;
• thyroid-stimulating hormone (TSH).
is controlled by:
• hypothalamic hormones (stimulatory/inhibitory);
• feedback inhibition.
Posterior pituitary
Related octapeptides, synthesized in the hypothalamus
and released by neurosecretion:
1. Vasopressin (ADH):
– increases blood pressure;
– causes renal water retention.
2. Oxytocin:
– stimulates uterine contractions;
– used in obstretrics (for induction of labour).
Case history
ADRENOCORTICOTROPHIC HORMONE
Adrenocorticotrophic hormone (ACTH, corticotropin) is no
longer commercially available in the UK. A synthetic analogue
of ACTH, containing only the first 24 amino acids, is available as
tetracosactide. This possesses full biological activity, the remaining
15 amino acids of ACTH being species specific and associated
with antigenic activity. The t 1/2 of tetracosactide (15 minutes)
is slightly longer than that of ACTH, but otherwise its properties
are identical. Tetracosactide is used as a diagnostic test in the
evaluation of patients in whom Addison’s disease (adrenal insufficiency)
is suspected. A single intravenous or intramuscular dose
is administered, followed by venous blood sampling for plasma
cortisol determination. There is a small risk of anaphylaxis.
POSTERIOR PITUITARY HORMONES
Vasopressin (antidiuretic hormone, ADH) and oxytocin are
related octapeptide hormones synthesized in the supra-optic
and paraventricular hypothalamic nuclei and transported
along nerve fibres to the posterior lobe of the pituitary gland
for storage and subsequent release (neurosecretion). Vasopressin
and desmopressin (DDAVP) are discussed in Chapter 36, in
A 64-year-old man was investigated for worsening chronic
back pain and was found to have osteosclerotic bony metastases
from prostate carcinoma. Analgesia with adequate
doses of NSAIDs successfully controlled his bone pain, and
he was started on GnRH analogue therapy with goserelin
given subcutaneously, 3.6 mg per month. After one week
his pain was worse, especially at night, without evidence of
spinal compression.
Question
What is the likely cause of the deterioration in his symptoms
and how would you treat him?
Answer
The most likely cause of his symptoms worsening in the first
week of GnRH analogue therapy is the ‘tumour flare reaction’.
GnRH analogues increase secretion of FSH/LH for one
to two weeks, causing an initial increase in testosterone.
They subsequently produce downregulation, leading to
decreased secretion of FSH/LH and hence decreased testosterone
levels. In patients with metastatic prostate cancer it
is essential to initiate GnRH analogue therapy only after
several weeks of treatment with an androgen receptor
antagonist such as cyproterone acetate, flutamide or bicalutamide.
The use of anti-androgens prevents the ‘tumour
flare’. Thus this patient should be given adequate analgesia
and an androgen receptor antagonist (e.g. oral flutamide)
started at once. Goserelin can then be restarted in
several weeks time.