Whats new in

Endocrinology
A H Sam, W. S. Dhillo and K. Meeran

Recent advances in endocrinology include the development of potential

new treatments as well as more convenient preparations of existing
therapies. In this article, we discuss the recent advances in endocrinology
which will be of interest to general physicians as well as specialists.
Keywords combined thyroxine and tri-iodothyronine; DHEA; eflornithine; growth hormone;
rimonabant; strontium; testosterone undecanoate

Weekly growth hormone

Long-term treatment with recombinant
growth hormone (GH) is indicated in children with growth failure secondary to GH
deficiency. Adult GH deficiency is also an
indication for GH replacement in individuals with a poor quality-of-life (QoL) score.
Currently, growth hormone is replaced with
daily subcutaneous injections. Daily GH
treatment has been shown to be effective
in the promotion of longitudinal growth in
children. In adults with GH deficiency, GH
replacement improves QoL scores and also
reduces central adiposity (Table 1).
However, receiving daily injections is
painful and inconvenient for patients. A
novel sustained-release GH preparation
(LB03002) comprises human GH in hyaluronate microspheres. A recent study of the

pharmacokinetics and pharmacodynamics

of LB03002 has shown that multiple
weekly doses of this new sustainedrelease GH appears safe and well tolerated.1 Comparable GH bioavailability and
sustained IGF-1 elevations support use of
this new once-weekly preparation, which
is more convenient for patients.

Treatment of acromegaly
First-line treatment for patients with
acromegaly is surgery. If biochemical cure
is not achieved, radiotherapy and somatostatin analogues are used. A significant
proportion of acromegalic patients will
continue to have high GH and IGF-1 levels,
despite maximal therapy. Pegvisomant is a
new drug which is genetically engineered

A H Sam BSc MRCP is an Academic Clinical Fellow at Imperial College London, London, UK, and
Specialist Registrar in Diabetes and Endocrinology. He qualified from the Royal Free Hospital,
University of London. Competing interests: none declared.
W S Dhillo MRCP PhD is a Clinical Senior Lecturer at Imperial College London and Consultant
Endocrinologist at Hammersmith Hospital, London, UK. He qualified from St Bartholomew's
Hospital, University of London and completed his postgraduate training in London. His main
clinical and research interests are in the field of neuroendocrine regulation of endocrine function
and appetite. Competing interests: none declared.
K Meeran MRCP MD is a Reader at Imperial College London and Consultant Endocrinologist at
Hammersmith Hospital, London, UK. He qualified from the Royal Free Hospital, University of
London and completed his postgraduate training in London. His main clinical and research
interests are in the field of neuroendocrine regulation of endocrine function and appetite.
Competing interests: none declared.

MEDICINE 35:2

125

to prevent dimerization and activation of

GH receptors.2 It has been shown to be
the most efficacious medical treatment in
normalizing IGF-1 (97% of patients). A
recent study has shown that treatment for
18 months with pegvisomant decreases
cardiac hypertrophy and enhances diastolic
and systolic cardiac function, and consequently partially, or completely, reverts
the cardiac insufficiency.3 Pegvisomant
will be a useful therapy in acromegalic
patients who do not achieve biochemical
remission, despite surgery, radiotherapy
and somatostatin analogue therapy.

Combination T4 and T3 therapy

The thyroid gland is the only source of
T4. However, only 20% of total T3 comes
from the thyroid gland and the remainder
is generated from peripheral conversion of
T4 to T3 in extraglandular tissues. Despite
adequate thyroxine replacement and normal serum thyroid-stimulating hormone
(TSH), some hypothyroid patients remain
symptomatic and may have impaired psychological wellbeing. This observation
has raised the question of the possible
benefit of combination T4 and T3 therapy
in hypothyroid patients.
This question has been evaluated in
several randomized trials. A recent metaanalysis of 11 published randomized studies has concluded that there is no benefit
of combined therapy.4 T4 monotherapy
should therefore remain the treatment of
choice for hypothyroidism.

2006 Elsevier Ltd. All rights reserved.

whats New in endocrinology

Treatment of hirsutism

Recent advances in endocrinology

New treatments
Pegvisomant
Eflornithine
Strontium
Rimonabant
Tolvaptan

Indications
Acromegaly
Hirsutism
Osteoporosis
Obesity
Hyponatraemia

New preparations
Weekly growth hormone
3-monthly testosterone

Growth hormone deficiency

Hypogonadism in males

Table 1

Thyroid hormones in pregnancy

Subclinical hypothyroidism precedes primary hypothyroidism and is defined, biochemically, as a raised plasma TSH with
normal plasma free thyroid hormone (fT4
and fT3) levels. Undetected subclinical
hypothyroidism in pregnant women
may have adverse effects on the neuropsychological development of the fetus.5
Screening for, and treatment of, subclincal hypothyroidism in pregnant women
has been advocated, and women should
be given replacement thyroxine therapy
to normalize their TSH levels.

Role of DHEA therapy in adrenal

insufficiency, hypopituitarism and aging
The primary source of androgen, in the
form of dehydroepiandrosterone (DHEA)
and DHEA-sulfate, in females is the adrenal cortex. In patients with primary adrenal insufficiency, DHEA production is
low. This results in androgen deficiency,
especially in female patients. The physiological role of these androgens in women
is not clear, and treatment with DHEA has
not been part of the replacement therapy
in patients with adrenal insufficiency.
However, treatment with DHEA in
women with primary adrenal insufficiency on adequate replacement with
glucocorticoids and mineralocorticoids
has been shown to improve well-being
and sexuality.6 The role of treatment with
DHEA in men with adrenal insufficiency
is not well-established.
DHEA levels are also low in secondary
adrenal insufficiency due to hypopituita
rism. A recent double-blind, placebocontrolled trial has studied the effect of
addition of DHEA to maintenance replacement, including GH, in hypopituitary

MEDICINE 35:2

adults.7 The study has shown that DHEA

replacement results in modest improvement in psychological wellbeing in female
and minor psychological improvement in
male hypopituitary patients.
As the population of elderly patients
increases, the prevention and delaying
of age-related disabilities have become
major focuses for research. One suggestion has been to replace the hormones,
such as DHEA and testosterone, which
decline with age. These are widely promoted as anti-aging supplements. A recent
placebo-controlled, double-blind study
has reported that neither DHEA nor lowdose testosterone replacement in elderly
people has physiologically relevant beneficial effects on body composition, physical performance, insulin sensitivity, or
quality of life.8

New parenteral testosterone preparation

Testosterone replacement for treatment
of hypogonadism in males is currently
available in the form of implants, or intramuscular, oral, transdermal and buccal
preparations. Conventional parenteral testosterone preparations have to be administered every 23 weeks and often result
in transient supraphysiological levels after
the injection and subphysiological levels prior to the next injection. Recently, a
new testosterone preparation, testosterone
undecanoate in castor oil, for intramuscular
injection (Nebido: Schering) has been intro
duced. It has been shown that testosterone
undecanoate injection in male hypogonadal patients at 12-week intervals is well
tolerated and results in testosterone levels
within normal ranges.9 Only four injections
of Nebido, instead of 12 or more injections
of the conventional testosterone enanthate
preparation, are required per year.
126

Hirsutism is a common clinical problem

and may be very distressing in female
patients. Current treatment of hirsutism
comprises combination of pharmacological treatment with anti-androgens and
hair removal by cosmetic procedures.
Eflornithine cream (Vaniqa: Shire Pharmaceuticals) is a new topical treatment for
facial hirsutism which has recently been
licensed. Eflornithine irreversibly inhibits
ornithine decarboxylase activity.10 This
enzyme catalyzes the rate-limiting step
in the production of polyamines, which
is required for cell division. Inhibition of
ornithine decarboxylase in the hair follicle reduces hair growth. Noticeable clinical results become apparent after about 8
weeks. However, once treatment with the
cream is stopped, hair returns to pretreatment levels after about 8 weeks. Acneiform reactions and mild transient skin
irritation may occur with this cream. Topical eflornithine has low systemic absorption. It is recommended that Eflornithine
is discontinued in the absence of improvement after 4 months.

Osteoporosis
Strontium ranelate is an orally active
drug which stimulates bone formation
and reduces bone resorption. The precise
cellular mechanism of action of strontium ranelate is not clear. The induction
of cellular differentiation11 and the activation of the calcium-sensing receptor12
have been proposed as contributing factors. Strontium ranelate has been shown
to increase vertebral bone mineral density.13 Treatment of postmenopausal osteo
porosis with strontium ranelate results in
early and sustained reductions in the risk
of vertebral fractures.14 In a large trial of
postmenopausal women with osteoporosis
randomly assigned to receive strontrium (2
g/day) or placebo, strontium ranelate significantly reduced the risk of all non-vertebral fractures.15 In addition, in a subgroup
of postmenopausal women with a high
fracture risk, hip fractures were reduced
over a 3-year period. Strontium ranelate
offers a safe and effective means of reducing osteoporosis-associated risk of fracture.
Strontium ranelate is licensed for treatment
of postmenopausal osteoporosis. It is a useful alternative treatment when bisphosphonates are contraindicated or not tolerated.

2006 Elsevier Ltd. All rights reserved.

whats New in endocrinology

Obesity
Users of cannabis are familiar with its
effects on increasing hunger. The physio
logical basis for this effect is that cannabis
binds to the cannabinoid-1 receptor in
the brain which results in an increased
food intake. The cannabinoid-1 receptor signalling pathway is now established
in the regulation of appetite, food intake
and body weight. Rimonabant (Acomplia:
Sanofi-Aventis) is a recently licensed drug
for obesity and is a selective cannabinoid1 receptor blocker with both central and
peripheral actions.
The RIO-Europe Study has shown
that rimonabant 20 mg, combined with
a hypocaloric diet over 12 months, promotes significant reduction of weight and
waist circumference, and improvement in
cardiovascular risk factors.16 Rimonabant
was generally well tolerated with mild
and transient side effects. Rimonabant
also significantly reduces body weight
and waist circumference and improves the
profile of several metabolic risk factors in
overweight patients with dyslipidaemia.17
A recent randomized, controlled study
has shown that rimonabant, in combination with diet and exercise, can produce
a clinically meaningful weight reduction
and improve HbA1c, and a number of
cardiovascular and metabolic risk factors,
in overweight or obese patients with type
2 diabetes inadequately controlled by
metformin or sulphonylureas.18
Glucagon-like peptide-1 (GLP-1) is
produced in L-cells of the small intestine.
GLP-1 stimulates insulin and inhibits glucagon secretion, slows gastric emptying,
and decreases appetite and food intake.
Exenatide, a GLP-1 receptor agonist administered subcutaneously, has been shown
to cause reductions in glucose (fasting and
postprandial), HbA1c, and body weight in
type 2 diabetes.19 The role of GLP-1 as a
treatment for weight loss in non-diabetic
patients is currently under investigation.

Hyponatraemia
The current management of hyponatraemia in euvolaemic and hypervolaemic
patients commonly involves water restriction, which is poorly tolerated. Tolvaptan
is an orally active vasopressin receptor
antagonist. It inhibits V2 receptors of the
distal nephron and promotes excretion of
electrolyte-free water. A recent study has

MEDICINE 35:2

examined the use of tolvaptan for 30 days

in an outpatient setting to correct and
maintain serum sodium concentrations
in a population with hyponatraemia from
various causes, such as chronic heart
failure, cirrhosis, and syndrome of inappropriate antidiuretic hormone (SIADH).
Tolvaptan was shown to be effective in
increasing serum sodium concentrations
at day 4 and day 30.20 Side effects associated with tolvaptan included dry mouth,
increased thirst and urination.

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2006 Elsevier Ltd. All rights reserved.