Clinical Pharmacology and Therapeutics

ANTERIOR PITUITARY HARMONES AND RELATED DRUGS 317
with symptoms caused by the release of pharmacologically
active substances from gastro-enteropancreatic tumours, including
patients with carcinoid syndrome, insulinoma, VIPoma or
glucagonoma. It reduces symptoms of flushing, diarrhoea or
skin rash, but does not reduce the size of the tumour. It is more
effective than bromocriptine (now mainly used in Parkinson’s
disease, see Chapter 21) in lowering somatotropin levels in
patients with acromegaly, but it is not generally an acceptable
alternative to surgery, and must be administered parenterally
(usually subcutaneously three times daily). It is also effective in
patients with TSH-secreting basophil tumours of the adenohypophysis
causing thyrotoxicosis (an extremely rare cause of
hyperthyroidism). It reduces portal pressure in portal hypertension,
and is effective in the acute therapy of bleeding
oesophageal varices. It is also used to reduce ileostomy diarrhoea
and the diarrhoea associated with cryptosporidiosis in
AIDS patients. Gastro-intestinal side effects are minimized if
octreotide is given between meals. A long-acting microsphere
octreotide formulation in poly (alkyl cyanoacrylate) nanocapsules
is administered intramuscularly once a month.
Adverse effects
These include:
• gastro-intestinal upset, including anorexia, nausea,
vomiting, abdominal pain, diarrhoea and steatorrhoea;
• impaired glucose tolerance, by reducing insulin secretion;
• increased incidence of gallstones and/or biliary sludge
after only a few months of treatment, especially at higher
doses. Ultrasound evaluation of the gall bladder is
recommended before starting therapy and if biliary
symptoms occur during therapy.
Key points
Growth hormone (GH, somatropin)
• Somatropin (recombinant GH) is used to treat short
stature due to:
– GH deficiency;
– Turner’s syndrome;
– Prader–Willi syndrome;
– chronic renal impairment;
– children who were born small for gestational age.
• Somatropin is also used for adults with severe
symptomatic GH deficiency.
• GH secretion is controlled physiologically by:
– somatorelin (stimulates GH secretion);
– somatostatin (inhibits GH secretion).
• Somatostatin is secreted by D cells in the islets of
Langerhans, as well as centrally, and inhibits the
secretion of many gut hormones in addition to GH.
• Octreotide is a somatostatin analogue used:
– in acromegalics with persistent raised GH despite
surgery/radiotherapy;
– in functional neuroendocrine tumours (e.g.
carcinoid, VIPomas, glucagonomas);
– to reduce portal pressure in variceal bleeding
(unlicensed indication).
• Pegvisomant is a specific GH receptor antagonist: it is used
for acromegaly when conventional treatment has failed.
GONADOTROPHINS
The human pituitary gland secretes follicle-stimulating hormone
(FSH) and luteinizing hormone (LH). FSH is a glycoprotein
which in females controls development of the primary
ovarian follicle, stimulates granulosa cell proliferation and
increases oestrogen production, while in males it increases
spermatogenesis. LH is also a glycoprotein. It induces ovulation,
stimulates thecal oestrogen production and initiates and
maintains the corpus luteum in females. In males, LH stimulates
androgen synthesis by Leydig cells, and thus has a role in
the maturation of spermatocytes and the development of secondary
sex characteristics.
Human menopausal urinary gonadotrophin (HMG), human
chorionic gonadotrophin (HCG) and synthetic LH and recombinant
FSH (follitropin alfa and beta) are all commercially available.
They are used to induce ovulation in anovulatory women
with secondary ovarian failure in whom treatment with
clomifene (see Chapter 41) has failed. Treatment must be supervised
by specialists experienced in the use of gonadotrophins
and be carefully monitored with repeated pelvic ultrasound
scans to avoid ovarian hyperstimulation and multiple pregnancies.
Gonadotrophins are also effective in the treatment of
oligospermia due to secondary testicular failure. They are, of
course, ineffective in primary gonadal failure.
GONADORELIN ANALOGUES
Gonadorelin (gonadotrophin-releasing hormone, GnRH) is the
FSH/LH-releasing factor produced in the hypothalamus. It may
be used in a single intravenous dose to assess anterior pituitary
reserve. Analogues of GnRH (Table 42.1) such as goserelin,
buserelin and leuprorelin are also used to treat endometriosis,
female infertility (see Chapter 41), prostate cancer and
advanced breast cancer (see Chapter 48). Buserelin is given
intranasally, and goserelin is usually given by subcutaneous
injection/implant into the anterior abdominal. In benign conditions
use should be limited to a maximum of six months because
reduced oestrogen levels lead to reduced bone density, in addition
to menopausal-type symptoms (see below). For indications
such as endometriosis, it is possible to combine a GnRH analogue
with low-dose oestrogen replacement to avoid this.
Mechanism of action
GnRH analogues initially stimulate the release of FSH/LH,
but then downregulate this response (usually after two weeks)
Table 42.1: GnRH analogues
Drug
Goserelin
Leuprorelin
Buserelin
Use and additional comments
Used to treat endometriosis, prostate
cancer and advanced breast cancer
Used to treat endometriosis and
prostate cancer
Used to treat endometriosis. Prostate
cancer. Induction of ovulation prior
to IVF