Aberrant receptor expression in thyroid tissue: A role in the pathogenesis of multinodular goiter?
A pilot study

Aberrant receptor expression in thyroid tissue: A role in the pathogenesis of
multinodular goiter? A pilot study

Background
Toxic Multinodular Goiter (TMNG): Two key factors in the development of TMNG
are hyperplasia * i.e. nodule and goiter - and hyperfunction * i.e. thyroid
autonomy. Although TMNG is associated with iodine deficiency, this factor alone
can not explain sufficiently the pathogenesis of TMNG, since TMNG also occurs
in individuals from iodine sufficient areas. So the underlying mechanism of
both hyperplasia and hyperfunction is not yet completely understood.
ACTH-independent macronodular adrenal hyperplasia (AIMAH): Recent research has
shown that the enhanced cortisol production in patients with AIMAH, despite a
suppressed ACTH, is regulated by hormones other than ACTH, via the aberrant
expression of several G-protein coupled hormone receptors mimicking the
cellular events that in normal circumstances are triggered by ACTH receptors.
AIMAH and TMNG: similarities: Two important similarities can be noted in the
abovementioned diseases: 1) Hyperfunction: overproduction of cortisol and
thyroid hormone, respectively and 2) Hyperplasia: gradual development of
macronodular hyperplasia, overpassing the midline * i.e. bilateral hyperplasia
in the adrenal glands and multinodular goiter in the whole thyroid gland.

Objective
The main goal of this investigation is to evaluate the thyroid hormone response
in patients with TMNG and control subjects in response to various
pharmacological and physiological stimuli, administered according to the
dynamic exposure test as described by Lacroix.

Design
After an overnight fast, patients will visit the research unit on three
separate days, between each day a one-week interval, in order to prevent
uncertainty about the agent causing the peak in FT4 and T3. We will evaluate
the thyroid response to three different stimuli that we think are most likely
involved in the pathogenesis of TMNG. Starting 30 minutes after administration
of each stimulatory agent * GnRH, metoclopramide and a mixed meal - blood will
be drawn every 30 minutes for determination of the thyroid hormone response *
i.e. T4, T3, TSH and FT4 * in 10 drug naive patients with toxic multinodular
goiter en in 5 age and sex matched healthy controls.
On each testing day, blood is sampled at baseline and once every 30 minutes,
starting 30 minutes after administration of the stimulatory agent/ mixed meal
until 5 hours thereafter. The following thyroid hormones will be measured: FT4,
T3, total T4 and TSH, using routine immunoassay: T4 and T3 with in-house RIA,
FT4 and TSH by a commercial (Delfia, PerkinElmer) method.

no intervention

Burden for the participants
The risk for participants is judged to be minor. Participation mainly requires
an investment of time, undergoing insertion of an intravenous catheter for
blood sampling and administration of a single dose of 10 mg metoclopramide and
a single dose of 100 mcg gonadorelin. We do not expect any side effects from a
single gift of these agents. Side effects of metoclopramide are dose-related
and include drowsiness, diarrhea and extrapiramidal symptoms, like rigidity of
the muscles and tremor. These extrapiramidal symptoms dissappear spontaneously
after discontinuing the metoclopramide. For gonadorelin, short-term nausea,
headache and abdominal pain have been described as side effects.