Neuroendocrinology is the branch of biology (specifically of physiology) which studies the interaction between the nervous system and the endocrine system; i.e. how the brain regulates the hormonal activity in the body. The nervous and endocrine systems often act together in a process called neuroendocrine integration, to regulate the physiological processes of the human body. Neuroendocrinology arose from the recognition that the brain, especially the hypothalamus, controls secretion of pituitary gland hormones, and has subsequently expanded to investigate numerous interconnections of the endocrine and nervous systems.
Hypothalamic
interaction with the posterior and anterior pituitary glands. The
hypothalamus produces the hormones oxytocin and vasopressin in its
endocrine cells (left). These are released at nerve endings in the
posterior pituitary gland and then secreted into the systemic
circulation. The hypothalamus releases tropic hormones into the
hypophyseal portal system to the anterior pituitary (right). The
anterior pituitary then secretes trophic hormones into the circulation
which elicit different responses from various target tissues. These
responses then signal back to the hypothalamus and anterior pituitary to
either stop producing or continue to produce their precursor signals.
The hypothalamus
is commonly known as the relay center of the brain because of its role
in integrating inputs from all areas of the brain and producing a
specific response. In the neuroendocrine system, the hypothalamus
receives electrical signals from different parts of the brain and
translates those electrical signals into chemical signals in the form of
hormones or releasing factors. These chemicals are then transported to
the pituitary gland and from there to the systemic circulation.
The posterior pituitary is directly innervated by the hypothalamus; the hormones oxytocin and vasopressin
are synthesized by neuroendocrine cells in the hypothalamus and stored
at the nerve endings in the posterior pituitary. They are secreted
directly into systemic circulation by the hypothalamic neurons.
By contrast, the hormones of the anterior pituitary gland
(the adenohypophysis) are secreted from endocrine cells that, in
mammals, are not directly innervated, yet the secretion of these
hormones (adrenocorticotrophic hormone, luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone, prolactin, and growth hormone) remains under the control of the hypothalamus. The hypothalamus controls the anterior pituitary gland via releasing factors and release-inhibiting factors; these are substances released by hypothalamic neurons into blood vessels at the base of the brain, at the median eminence.
These vessels, the hypothalamo-hypophysial portal vessels, carry the
hypothalamic factors to the anterior pituitary, where they bind to
specific receptors on the surface of the hormone-producing cells.
For example, the secretion of growth hormone is controlled by two neuroendocrine systems: the growth hormone-releasing hormone (GHRH) neurons and the somatostatin neurons, which stimulate and inhibit GH secretion, respectively. The GHRH neurones are located in the arcuate nucleus of the hypothalamus, whereas the somatostatin cells involved in growth hormone regulation are in the periventricular nucleus. These two neuronal systems project axons to the median eminence, where they release their peptides
into portal blood vessels for transport to the anterior pituitary.
Growth hormone is secreted in pulses, which arise from alternating
episodes of GHRH release and somatostatin release, which may reflect
neuronal interactions between the GHRH and somatostatin cells, and
negative feedback from growth hormone.
Functions
The neuroendocrine systems control reproduction in all its aspects, from bonding to sexual behaviour. They control spermatogenesis and the ovarian cycle, parturition, lactation, and maternal behaviour. They control the body's response to stress and infection. They regulate the body's metabolism, influencing eating and drinking behaviour, and influence how energy intake is utilised, that is, how fat is metabolised. They influence and regulate mood, body fluid and electrolyte homeostasis, and blood pressure.
The neurons of the neuroendocrine system are large; they are mini factories
for producing secretory products; their nerve terminals are large and
organised in coherent terminal fields; their output can often be
measured easily in the blood; and what these neurons do and what stimuli
they respond to are readily open to hypothesis and experiment. Hence,
neuroendocrine neurons are good "model systems" for studying general
questions, like "how does a neuron regulate the synthesis, packaging,
and secretion of its product?" and "how is information encoded in
electrical activity?"
Roger Guillemin, a medical student of Faculté de Médecine of Lyon, and Andrew W. Schally of Tulane University
isolated these factors from the hypothalamus of sheep and pigs, and
then identified their structures. Guillemin and Schally were awarded the
Nobel Prize in Physiology and Medicine in 1977 for their contributions to understanding "the peptide hormone production of the brain".
Today,
neuroendocrinology embraces a wide range of topics that arose directly
or indirectly from the core concept of neuroendocrine neurons.
Neuroendocrine neurons control the gonads, whose steroids, in turn, influence the brain, as do corticosteroids secreted from the adrenal gland
under the influence of adrenocorticotrophic hormone. The study of these
feedbacks became the province of neuroendocrinologists. The peptides
secreted by hypothalamic neuroendocrine neurons into the blood proved to
be released also into the brain, and the central actions often appeared
to complement the peripheral actions. So understanding these central
actions also became the province of neuroendocrinologists, sometimes
even when these peptides cropped up in quite different parts of the
brain that appeared to serve functions unrelated to endocrine
regulation. Neuroendocrine neurons were discovered in the peripheral nervous system, regulating, for instance, digestion. The cells in the adrenal medulla that release adrenaline and noradrenaline
proved to have properties between endocrine cells and neurons, and
proved to be outstanding model systems for instance for the study of the
molecular mechanisms of exocytosis. And these, too, have become, by extension, neuroendocrine systems.
Neuroendocrine systems have been important to our understanding of many basic principles in neuroscience and physiology, for instance, our understanding of stimulus-secretion coupling. The origins and significance of patterning in neuroendocrine secretion are still dominant themes in neuroendocrinology today.
Neuroendocrinology is also used as an integral part of understanding and treating neurobiological brain disorders. One example is the augmentation of the treatment of mood symptoms with thyroid hormone. Another is the finding of a transthyretin (thyroxine transport) problem in the cerebrospinal fluid of some patients diagnosed with schizophrenia.
Experimental techniques
Since the original experiments by Geoffrey Harris
investigating the communication of the hypothalamus with the pituitary
gland, much has been learned about the mechanistic details of this
interaction. Various experimental techniques have been employed. Early
experiments relied heavily on the electrophysiology techniques used by Hodgkin and Huxley.
Recent approaches have incorporated various mathematical models to
understand previously identified mechanisms and predict systemic
response and adaptation under various circumstances.
Electrophysiology
Electrophysiology
experiments were used in the early days of neuroendocrinology to
identify the physiological happenings in the hypothalamus and the
posterior pituitary especially. In 1950, Geoffrey Harris and Barry Cross
outlined the oxytocin pathway by studying oxytocin release in response
to electrical stimulation.
In 1974, Walters and Hatton investigated the effect of water
dehydration by electrically stimulating the supraoptic nucleus—the
hypothalamic center responsible for the release of vasopressin.
Glenn Hatton dedicated his career to studying the physiology of the
Neurohypophyseal system, which involved studying the electrical
properties of hypothalamic neurons.
Doing so enabled investigation into the behavior of these neurons and
the resulting physiological effects. Studying the electrical activity of
neuroendocrine cells enabled the eventual distinction between central
nervous neurons, neuroendocrine neurons, and endocrine cells.
The
Hodgkin-Huxley model translates data about the current of a system at a
specific voltage into time-dependent data describing the membrane potential.
Experiments using this model typically rely on the same format and
assumptions, but vary the differential equations to answer their
particular questions. Much has been learned about vasopressin, GnRH,
somatotrophs, corticotrophs, and lactotrophic hormones by employing this
method.
The
integrate-and-fire model aims for mathematic simplicity in describing
biological systems. It describes on the threshold activity of a neuron.
By focusing only on this one aspect, the model successfully reduces the
complexity of a complicated system, however it ignores the actual
mechanisms of action and replaces them with functions-- rules governing
how the output of a system relates to its input. This model has been used to describe the hormones released to the posterior pituitary gland-- oxytocin and vasopressin.
The functional or mean fields model relies on the premise "simpler is better".
It strives to reduce the complexity of modelling multi-faceted systems
by using a single variable to describe an entire population of cells.
The alternative would be to use a different set of variables for each
population. When attempting to model a system where multiple populations
of cells interact, using several sets quickly becomes overcomplicated.
This model has been used to describe several systems, especially
involving the reproductive cycle (menstrual cycles, luteinizing hormone,
prolactin surges). Functional models also exist to represent cortisol secretion, and growth hormone secretion.
The exact cause of the disease is unclear; however, it is
believed to involve a combination of genetic and environmental factors. A person is more likely to be affected if they have a family member with the disease. If one twin is affected, a 30% chance exists that the other twin will also have the disease. The onset of disease may be triggered by physical or emotional stress, infection or giving birth. Those with other autoimmune diseases such as type 1 diabetes and rheumatoid arthritis are more likely to be affected. Smoking increases the risk of disease and may worsen eye problems. The disorder results from an antibody, called thyroid-stimulating immunoglobulin (TSI), that has a similar effect to thyroid stimulating hormone (TSH). These TSI antibodies cause the thyroid gland to produce excess thyroid hormones. The diagnosis may be suspected based on symptoms and confirmed with blood tests and radioiodine uptake. Typically, blood tests show a raised T3 and T4, low TSH, increased radioiodine uptake in all areas of the thyroid and TSI antibodies.
The three treatment options are radioiodine therapy, medications, and thyroid surgery. Radioiodine therapy involves taking iodine-131 by mouth, which is then concentrated in the thyroid and destroys it over weeks to months. The resulting hypothyroidism is treated with synthetic thyroid hormones. Medications such as beta blockers may control some of the symptoms, and antithyroid medications such as methimazole may temporarily help people while other treatments are having effect. Surgery to remove the thyroid is another option. Eye problems may require additional treatments.
Graves' disease will develop in about 0.5% of males and 3% of females. It occurs about 7.5 times more often in women than in men. Often, it starts between the ages of 40 and 60 but can begin at any age. It is the most common cause of hyperthyroidism in the United States (about 50 to 80% of cases). The condition is named after Irish surgeon Robert Graves, who described it in 1835. A number of prior descriptions also exist.
The exact cause is unclear; however, it is believed to involve a combination of genetic and environmental factors.
While a theoretical mechanism occurs by which exposure to severe
stressors and high levels of subsequent distress such as PTSD (Post
traumatic stress disorder) could increase the risk of autoimmune disease
and cause an aggravation of the autoimmune response that leads to
Graves' disease, more robust clinical data are needed for a firm
conclusion.
Genetics
A genetic predisposition for Graves' disease is seen, with some people more prone to develop TSH receptor activating antibodies due to a genetic cause. Human leukocyte antigen DR (especially DR3) appears to play a role. To date, no clear genetic defect has been found to point to a single-gene cause.
Since Graves' disease is an autoimmune disease which appears suddenly, often later in life, a viral or bacterial infection may trigger antibodies which cross-react with the human TSH receptor, a phenomenon known as antigenic mimicry.
The bacterium Yersinia enterocolitica bears structural similarity with the human thyrotropin receptor
and was hypothesized to contribute to the development of thyroid
autoimmunity arising for other reasons in genetically susceptible
individuals.
In the 1990s, it was suggested that Y. enterocolitica may be associated with Graves' disease.
More recently, the role for Y. enterocolitica has been disputed.
Thyroid-stimulating immunoglobulins recognize and bind to the thyrotropin receptor
(TSH receptor) which stimulates the secretion of thyroxine (T4) and
triiodothyronine (T3). Thyroxine receptors in the pituitary gland are
activated by the surplus hormone, suppressing additional release of TSH
in a negative feedback loop. The result is very high levels of
circulating thyroid hormones and a low TSH level.
Pathophysiology
Histopathological image of diffuse hyperplasia of the thyroid gland (clinically presenting as hyperthyroidism)
Graves' disease is an autoimmune disorder, in which the body produces antibodies that are specific to a self-protein: the receptor for thyroid-stimulating hormone. (Antibodies to thyroglobulin and to the thyroid hormones T3 and T4 may also be produced.)
These antibodies cause hyperthyroidism because they bind to the TSHr and chronically stimulate it. The TSHr is expressed on the thyroid follicular cells
of the thyroid gland (the cells that produce thyroid hormone), and the
result of chronic stimulation is an abnormally high production of T3 and
T4. This, in turn, causes the clinical symptoms of hyperthyroidism, and
the enlargement of the thyroid gland visible as goiter.
The infiltrative exophthalmos frequently encountered has been
explained by postulating that the thyroid gland and the extraocular
muscles share a common antigen which is recognized by the antibodies.
Antibodies binding to the extraocular muscles would cause swelling
behind the eyeball.
The "orange peel" skin has been explained by the infiltration of
antibodies under the skin, causing an inflammatory reaction and
subsequent fibrous plaques.
The three types of autoantibodies to the TSH receptor currently recognized are:
Thyroid stimulating immunoglobulins: these antibodies (mainly IgG) act as long-acting thyroid stimulants,
activating the cells through a slower and more drawn out process
compared to TSH, leading to an elevated production of thyroid hormone.
Thyroid growth immunoglobulins: these antibodies bind directly to the TSH receptor and have been implicated in the growth of thyroid follicles.
Thyrotrophin binding-inhibiting immunoglobulins: these antibodies inhibit the normal union of TSH with its receptor.
Some actually act as if TSH itself is binding to its receptor, thus inducing thyroid function.
Other types may not stimulate the thyroid gland, but preventTSI and TSH from binding to and stimulating the receptor.
Another effect of hyperthyroidism is bone loss from osteoporosis,
caused by an increased excretion of calcium and phosphorus in the urine
and stool. The effects can be minimized if the hyperthyroidism is
treated early. Thyrotoxicosis
can also augment calcium levels in the blood by as much as 25%. This
can cause stomach upset, excessive urination, and impaired kidney
function.
Diagnosis
Graves' disease may present clinically with one or more of these characteristic signs:
Exophthalmos (protuberance of one or both eyes), periorbital edema (25%)
Fatigue (70%), weight loss (60%) with increased appetite in young
people and poor appetite in the elderly, and other symptoms of
hyperthyroidism/thyrotoxicosis
Heat intolerance (55%)
Tremulousness (55%)
Palpitations (50%)
Two signs are truly 'diagnostic' of Graves' disease (i.e., not seen
in other hyperthyroid conditions): exophthalmos and nonpitting edema (pretibial myxedema).
Goiter is an enlarged thyroid gland and is of the diffuse type (i.e.,
spread throughout the gland). Diffuse goiter may be seen with other
causes of hyperthyroidism, although Graves' disease is the most common
cause of diffuse goiter. A large goiter will be visible to the naked
eye, but a small one (mild enlargement of the gland) may be detectable
only by physical examination. Occasionally, goiter is not clinically
detectable, but may be seen only with computed tomography or ultrasound examination of the thyroid.
Another sign of Graves' disease is hyperthyroidism; that is, overproduction of the thyroid hormones T3 and T4. Normal thyroid levels are also seen, and occasionally also hypothyroidism,
which may assist in causing goiter (though it is not the cause of the
Graves' disease). Hyperthyroidism in Graves' disease is confirmed, as
with any other cause of hyperthyroidism, by measuring elevated blood
levels of free (unbound) T3 and T4.
Other useful laboratory measurements in Graves' disease include
thyroid-stimulating hormone (TSH, usually undetectable in Graves'
disease due to negative feedback from the elevated T3 and T4), and protein-bound iodine (elevated). Serologically
detected thyroid-stimulating antibodies, radioactive iodine (RAI)
uptake, or thyroid ultrasound with Doppler all can independently confirm
a diagnosis of Graves' disease.
Biopsy to obtain histiological testing is not normally required, but may be obtained if thyroidectomy is performed.
The goiter in Graves' disease is often not nodular, but thyroid nodules are also common. Differentiating common forms of hyperthyroidism such as Graves' disease, single thyroid adenoma, and toxic multinodular goiter is important to determine proper treatment. The differentiation among these entities has advanced,
as imaging and biochemical tests have improved. Measuring TSH-receptor
antibodies with the h-TBII assay has been proven efficient and was the
most practical approach found in one study.
Thyroid-associated ophthalmopathy (TAO), or thyroid eye disease
(TED), is the most common extrathyroidal manifestation of Graves'
disease. It is a form of idiopathic lymphocytic orbital inflammation,
and although its pathogenesis is not completely understood, autoimmune
activation of orbital fibroblasts, which in TAO express the TSH receptor, is thought to play a central role.
Hypertrophy of the extraocular muscles, adipogenesis,
and deposition of nonsulfated glycoaminoglycans and hyaluronate, causes
expansion of the orbital fat and muscle compartments, which within the
confines of the bony orbit may lead to dysthyroid optic neuropathy, increased intraocular pressures, proptosis, venous congestion leading to chemosis and periorbital edema, and progressive remodeling of the orbital walls. Other distinctive features of TAO include lid retraction, restrictive myopathy, superior limbic keratoconjunctivitis, and exposure keratopathy.
Severity of eye disease may be classified by the mnemonic: "NO SPECS":
Class 0: No signs or symptoms
Class 1: Only signs (limited to upper lid retraction and stare, with or without lid lag)
Class 2: Soft tissue involvement (oedema of conjunctivae and lids, conjunctival injection, etc.)
Class 5: Corneal involvement (primarily due to lagophthalmos)
Class 6: Sight loss (due to optic nerve involvement)
Typically the natural history of TAO follows Rundle's curve, which
describes a rapid worsening during an initial phase, up to a peak of
maximum severity, and then improvement to a static plateau without,
however, resolving back to a normal condition.
Management
Treatment of Graves' disease includes antithyroid drugs that reduce the production of thyroid hormone, radioiodine (radioactive iodine I-131) and thyroidectomy
(surgical excision of the gland). As operating on a hyperthyroid
patient is dangerous, prior to thyroidectomy, preoperative treatment
with antithyroid drugs is given to render the patient euthyroid. Each of
these treatments has advantages and disadvantages, and no single
treatment approach is considered the best for everyone.
Treatment with antithyroid medications must be administered for
six months to two years to be effective. Even then, upon cessation of
the drugs, the hyperthyroid state may recur. The risk of recurrence is
about 40–50%, and lifelong treatment with antithyroid drugs carries some
side effects such as agranulocytosis and liver disease.
Side effects of the antithyroid medications include a potentially fatal
reduction in the level of white blood cells. Therapy with radioiodine
is the most common treatment in the United States, while antithyroid
drugs and/or thyroidectomy are used more often in Europe, Japan, and
most of the rest of the world.
β-Blockers (such as propranolol) may be used to inhibit the sympathetic nervous system symptoms of tachycardia
and nausea until antithyroid treatments start to take effect. Pure
β-blockers do not inhibit lid retraction in the eyes, which is mediated
by alpha adrenergic receptors.
Antithyroid drugs
The main antithyroid drugs are carbimazole (in the UK), methimazole (in the US), and propylthiouracil/PTU.
These drugs block the binding of iodine and coupling of iodotyrosines.
The most dangerous side effect is agranulocytosis (1/250, more in PTU).
Others include granulocytopenia (dose-dependent, which improves on cessation of the drug) and aplastic anemia.
Patients on these medications should see a doctor if they develop sore
throat or fever. The most common side effects are rash and peripheral neuritis. These drugs also cross the placenta and are secreted in breast milk. Lugol's iodine may be used to block hormone synthesis before surgery.
A randomized control trial
testing single-dose treatment for Graves' found methimazole achieved
euthyroid state more effectively after 12 weeks than did
propylthyouracil (77.1% on methimazole 15 mg vs 19.4% in the
propylthiouracil 150 mg groups).
No difference in outcome was shown for adding thyroxine to
antithyroid medication and continuing thyroxine versus placebo after
antithyroid medication withdrawal. However, two markers were found that
can help predict the risk of recurrence. These two markers are a
positive TSHrantibody (TSHR-Ab) and smoking. A positive TSHR-Ab at the end of antithyroid drug treatment increases the risk of recurrence to 90% (sensitivity 39%, specificity
98%), and a negative TSHR-Ab at the end of antithyroid drug treatment
is associated with a 78% chance of remaining in remission. Smoking was
shown to have an impact independent to a positive TSHR-Ab.
Radioiodine
Scan of affected thyroid before (top) and after (bottom) radioiodine therapy
Radioiodine (radioactive iodine-131) was developed in the early 1940s at the Mallinckrodt General Clinical Research Center.
This modality is suitable for most patients, although some prefer to
use it mainly for older patients. Indications for radioiodine are failed
medical therapy or surgery and where medical or surgical therapy are
contraindicated. Hypothyroidism may be a complication of this therapy,
but may be treated with thyroid hormones if it appears. The rationale
for radioactive iodine is that it accumulates in the thyroid and
irradiates the gland with its beta and gamma radiations, about 90% of
the total radiation being emitted by the beta (electron) particles. The
most common method of iodine-131 treatment is to administer a specified
amount in microcuries per gram of thyroid gland based on palpation or
radiodiagnostic imaging of the gland over 24 hours.
Patients who receive the therapy must be monitored regularly with
thyroid blood tests to ensure they are treated with thyroid hormone
before they become symptomatically hypothyroid.
Contraindications to RAI are pregnancy (absolute), ophthalmopathy (relative; it can aggravate thyroid eye disease), or solitary nodules.
Disadvantages of this treatment are a high incidence of
hypothyroidism (up to 80%) requiring eventual thyroid hormone
supplementation in the form of a daily pill(s). The radioiodine
treatment acts slowly (over months to years) to destroy the thyroid
gland, and Graves' disease–associated hyperthyroidism is not cured in
all persons by radioiodine, but has a relapse rate that depends on the
dose of radioiodine which is administered. In rare cases, radiation induced thyroiditis has been linked to this treatment.
This modality is suitable for young and pregnant people. Indications
for thyroidectomy can be separated into absolute indications or relative
indications. These indications aid in deciding which people would
benefit most from surgery. The absolute indications are a large goiter (especially when compressing the trachea), suspicious nodules or suspected cancer
(to pathologically examine the thyroid), and people with ophthalmopathy
and additionally if it is the person's preferred method of treatment or
if refusing to undergo radioactive iodine treatment. Pregnancy is
advised to be delayed for 6 months after radioactive iodine treatment.
Both bilateral subtotal thyroidectomy and the Hartley-Dunhill procedure (hemithyroidectomy on one side and partial lobectomy on other side) are possible.
Advantages are immediate cure and potential removal of carcinoma. Its risks are injury of the recurrent laryngeal nerve, hypoparathyroidism (due to removal of the parathyroid glands), hematoma
(which can be life-threatening if it compresses the trachea), relapse
following medical treatment, infections (less common), and scarring.
The increase in the risk of nerve injury can be due to the increased
vascularity of the thyroid parenchyma and the development of links
between the thyroid capsule and the surrounding tissues. Reportedly, a
1% incidence exists of permanent recurrent laryngeal nerve paralysis after complete thyroidectomy.
Removal of the gland enables complete biopsy to be performed to have
definite evidence of cancer anywhere in the thyroid. (Needle biopsies
are not so accurate at predicting a benign state of the thyroid). No
further treatment of the thyroid is required, unless cancer is detected.
Radioiodine uptake study may be done after surgery, to ensure all
remaining (potentially cancerous) thyroid cells (i.e., near the nerves
to the vocal cords) are destroyed. Besides this, the only remaining
treatment will be levothyroxine, or thyroid replacement pills to be taken for the rest of the patient's life.
A 2013 review article concludes that surgery appears to be the
most successful in the management of Graves' disease, with total
thyroidectomy being the preferred surgical option.
Eyes
Mild cases are treated with lubricant eye drops or nonsteroidal
anti-inflammatory drops. Severe cases threatening vision (corneal
exposure or optic nerve compression) are treated with steroids or
orbital decompression. In all cases, cessation of smoking is essential.
Double vision can be corrected with prism glasses and surgery (the
latter only when the process has been stable for a while).
Difficulty closing eyes can be treated with lubricant gel at night, or with tape on the eyes to enable full, deep sleep.
Orbital decompression can be performed to enable bulging eyes to
retreat back into the head. Bone is removed from the skull behind the
eyes, and space is made for the muscles and fatty tissue to fall back
into the skull.
Eyelid surgery can be performed on upper and/or lower eyelids to reverse the effects of Graves' disease
on the eyelids. Eyelid muscles can become tight with Graves' disease,
making it impossible to close the eyes all the way. Eyelid surgery
involves an incision along the natural crease of the eyelid, and a
scraping away of the muscle that holds the eyelid open. This makes the
muscle weaker, which allows the eyelid to extend over the eyeball more
effectively. Eyelid surgery helps reduce or eliminate dry eye symptoms.
For management of clinically active Graves' disease, orbitopathy
(clinical activity score >2) with at least mild to moderate severity,
intravenous glucocorticoids are the treatment of choice, usually
administered in the form of pulse intravenous methylprednisolone.
Studies have consistently shown that pulse intravenous
methylprednisolone is superior to oral glucocorticoids both in terms of
efficacy and decreased side effects for managing Graves' orbitopathy.
Prognosis
If left untreated, more serious complications could result, including birth defects in pregnancy, increased risk of a miscarriage, bone mineral loss
and, in extreme cases, death. Graves' disease is often accompanied by
an increase in heart rate, which may lead to further heart
complications, including loss of the normal heart rhythm (atrial
fibrillation), which may lead to stroke. If the eyes are proptotic
(bulging) enough that the lids do not close completely at night, dryness
will occur – with the risk of a secondary corneal infection, which
could lead to blindness. Pressure on the optic nerve behind the globe
can lead to visual field defects and vision loss, as well. Prolonged
untreated hyperthyroidism can lead to bone loss, which may resolve when
treated.
Graves' disease occurs in about 0.5% of people. Graves' disease data has shown that the lifetime risk for women is around 3% and 0.5% for men. It occurs about 7.5 times more often in women than in men[1] and often starts between the ages of 40 and 60. It is the most common cause of hyperthyroidism in the United States (about 50 to 80% of cases).
History
Graves' disease owes its name to the Irish doctor Robert James Graves, who described a case of goiter with exophthalmos in 1835. Medical eponyms are often styled nonpossessively; thus Graves' disease and Graves disease are variant stylings of the same term.
The German Karl Adolph von Basedow independently reported the same constellation of symptoms in 1840. As a result, on the European Continent, the terms Basedow syndrome, Basedow disease, or Morbus Basedow are more common than Graves' disease.
Graves' disease has also been called exophthalmic goiter.
Less commonly, it has been known as Parry disease, Begbie disease, Flajan disease, Flajani–Basedow syndrome, and Marsh disease. These names for the disease were derived from Caleb Hillier Parry, James Begbie, Giuseppe Flajani, and Henry Marsh. Early reports, not widely circulated, of cases of goiter with exophthalmos were published by the Italians Giuseppe Flajani and Antonio Giuseppe Testa, in 1802 and 1810, respectively. Prior to these, Caleb Hillier Parry, a notable provincial physician in England of the late 18th century (and a friend of Edward Miller-Gallus), described a case in 1786. This case was not published until 1825, which was still ten years ahead of Graves.
Ayaka,
Japanese singer, was diagnosed with Graves' disease in 2007. After
going public with her diagnosis in 2009, she took a two-year hiatus from
music to focus on treatment.
Susan Elizabeth Blow,
American educator and founder of the first publicly funded kindergarten
in the United States, was forced to retire and seek treatment for
Graves' disease in 1884.
George H. W. Bush, former U.S. president, developed new atrial fibrillation and was diagnosed in 1991 with hyperthyroidism due to the disease and treated with radioactive iodine. The president's wife, Barbara Bush, also developed the disease around the same time, which, in her case, produced severe infiltrative exophthalmos.
Gail Devers,
American sprinter: A doctor considered amputating her feet after she
developed blistering and swelling following radiation treatment for
Graves' disease, but she went on to recover and win Olympic medals.
The antennas contained in mobile phones, including smartphones, emit radiofrequency (RF) radiation (non-ionizing "radio waves" such as microwaves);
the parts of the head or body nearest to the antenna can absorb this
energy and convert it to heat. Since at least the 1990s, scientists have
researched whether the now-ubiquitous radiation associated with mobile
phone antennas or cell phone towers is affecting human health.
Mobile phone networks use various bands of RF radiation, some of which
overlap with the microwave range. Other digital wireless systems, such
as data communication networks, produce similar radiation.
In response to public concern, the World Health Organization established the International EMF (Electric and Magnetic Fields) Project
in 1996 to assess the scientific evidence of possible health effects of
EMF in the frequency range from 0 to 300 GHz. They have stated that
although extensive research has been conducted into possible health
effects of exposure to many parts of the frequency spectrum, all reviews
conducted so far have indicated that, as long as exposures are below
the limits recommended in the ICNIRP
(1998) EMF guidelines, which cover the full frequency range from
0–300 GHz, such exposures do not produce any known adverse health
effect. In 2011, International Agency for Research on Cancer (IARC), an agency of the World Health Organization, classified wireless radiation as Group 2B – possibly carcinogenic.
That means that there "could be some risk" of carcinogenicity, so
additional research into the long-term, heavy use of wireless devices
needs to be conducted.
The WHO states that "A large number of studies have been performed over
the last two decades to assess whether mobile phones pose a potential
health risk. To date, no adverse health effects have been established as
being caused by mobile phone use."
International guidelines on exposure levels to microwave
frequency EMFs such as ICNIRP limit the power levels of wireless
devices and it is uncommon for wireless devices to exceed the
guidelines. These guidelines only take into account thermal effects, as
non-thermal effects have not been conclusively demonstrated. The official stance of the British Health Protection Agency (HPA) is that "[T]here is no consistent evidence to date that Wi-Fi
and WLANs adversely affect the health of the general population", but
also that "... it is a sensible precautionary approach ... to keep the
situation under ongoing review ...". In a 2018 statement, the FDA
said that "the current safety limits are set to include a 50-fold
safety margin from observed effects of Radio-frequency energy exposure".
Exposure
Mobile phones
A mobile phone connects to the telephone network by radio waves exchanged with a local antenna and automated transceiver called a cellular base station (cell site or cell tower). The service area served by each provider is divided into small geographical areas called cells, and all the phones in a cell communicate with that cell's antenna. Both the phone and the tower have radio transmitters
which communicate with each other. Since in a cellular network the
same radio channels are reused every few cells, cellular networks use
low power transmitters to avoid radio waves from one cell spilling over
and interfering with a nearby cell using the same frequencies.
Mobile phones are limited to an effective isotropic radiated power
(EIRP) output of 3 watts, and the network continuously adjusts the
phone transmitter to the lowest power consistent with good signal
quality, reducing it to as low as one milliwatt when near the cell
tower. Tower channel transmitters usually have an EIRP power output of
around 50 watts. Even when it is not being used, unless it is turned
off, a mobile phone
periodically emits radio signals on its control channel, to keep contact
with its cell tower and for functions like handing off the phone to
another tower if the user crosses into another cell. When the user is
making a call, the phone transmits a signal on a second channel which
carries the user's voice. Existing 2G, 3G, and 4G networks use frequencies in the UHF or low microwave bands, 600 MHz to 3.5 GHz. Many household wireless devices such as WiFi networks, garage door openers, and baby monitors use other frequencies in this same frequency range.
Radio waves decrease rapidly in intensity by the inverse square
of distance as they spread out from a transmitting antenna. So the
phone transmitter, which is held close to the user's face when talking,
is a much greater source of human exposure than the tower transmitter,
which is typically at least hundreds of metres away from the user. A
user can reduce their exposure by using a headset and keeping the phone itself farther away from their body.
Next generation 5G cellular networks, which began deploying in 2019, use higher frequencies in or near the millimetre wave band, 24 to 52 GHz.
Millimetre waves are absorbed by atmospheric gases so 5G networks will
use smaller cells than previous cellular networks, about the size of a
city block. Instead of a cell tower, each cell will use an array of
multiple small antennas mounted on existing buildings and utility poles.
In general, millimetre waves penetrate less deeply into biological
tissue than microwaves, and are mainly absorbed within the first
centimetres of the body surface.
Cordless phones
The HPA also says that due to the mobile phone's adaptive power ability, a DECT
cordless phone's radiation could actually exceed the radiation of a
mobile phone. The HPA explains that while the DECT cordless phone's
radiation has an average output power of 10 mW, it is actually in the
form of 100 bursts per second of 250 mW, a strength comparable to some
mobile phones.
Wireless networking
Most wireless LAN
equipment is designed to work within predefined standards. Wireless
access points are also often close to people, but the drop off in power
over distance is fast, following the inverse-square law. However, wireless laptops are typically used close to people. WiFi had been anecdotally linked to electromagnetic hypersensitivity but research into electromagnetic hypersensitivity has found no systematic evidence supporting claims made by sufferers.
Users of wireless networking devices are typically exposed for
much longer periods than for mobile phones and the strength of wireless
devices is not significantly less. Whereas a Universal Mobile Telecommunications System (UMTS) phone can range from 21 dBm (125 mW) for Power Class 4 to 33 dBm (2W) for Power class 1, a wireless router can range from a typical 15 dBm (30 mW) strength to 27 dBm (500 mW) on the high end.
However, wireless routers are typically located significantly
farther away from users' heads than a phone the user is handling,
resulting in far less exposure overall. The Health Protection Agency
(HPA) says that if a person spends one year in a location with a WiFi
hot spot, they will receive the same dose of radio waves as if they had
made a 20-minute call on a mobile phone.
The HPA's position is that "... radio frequency (RF) exposures
from WiFi are likely to be lower than those from mobile phones." It also
saw "... no reason why schools and others should not use WiFi
equipment."
In October 2007, the HPA launched a new "systematic" study into the
effects of WiFi networks on behalf of the UK government, in order to
calm fears that had appeared in the media in a recent period up to that
time. Michael Clark of the HPA says published research on mobile phones and masts does not add up to an indictment of WiFi.
A
2010 review stated that "The balance of experimental evidence does not
support an effect of 'non-thermal' radio frequency fields" on the
permeability of the blood-brain barrier, but noted that research on low frequency effects and effects in humans was sparse.
A 2012 study of low-frequency radiation on humans found "no evidence
for acute effects of short-term mobile phone radiation on cerebral blood
flow".
There is no known way in which radiofrequency radiation (in contrast to ionizing radiation) affects DNA and causes cancer. In 2011 the IARC, a World Health Organization working group, classified mobile phone use as "possibly carcinogenic to humans".
The IARC summed up their conclusion with: "The human epidemiological
evidence was mixed. Several small early case–control studies were
considered to be largely uninformative. A large cohort study showed no
increase in risk of relevant tumours, but it lacked information on level
of mobile-phone use and there were several potential sources of
misclassification of exposure. The bulk of evidence came from reports of
the INTERPHONE study, a very large international, multicentre
case–control study and a separate large case–control study from Sweden
on gliomas and meningiomas of the brain and acoustic neuromas. While
affected by selection bias and information bias to varying degrees,
these studies showed an association between glioma and acoustic neuroma
and mobile-phone use; specifically in people with highest cumulative use
of mobile phones, in people who had used mobile phones on the same side
of the head as that on which their tumour developed, and in people
whose tumour was in the temporal lobe of the brain (the area of the
brain that is most exposed to RF radiation when a wireless phone is used
at the ear)". The CDC states that no scientific evidence definitively answers whether mobile phone use causes cancer.
In a 2018 statement, the US Food and Drug Administration
said that "the current safety limits are set to include a 50-fold
safety margin from observed effects of radiofrequency energy exposure".
On 1 November 2018, the US National Toxicology Program published the final version (after peer review
that was performed through March 2018) of its "eagerly anticipated"
study using rats and mice, conducted over some ten years. This report
concludes after the review with an updated statement that "there is
clear evidence that male rats exposed to high levels of radio frequency radiation
(RFR) like that used in 2G and 3G cell phones developed cancerous heart
tumors.... There was also some evidence of tumors in the brain and
adrenal gland of exposed male rats. For female rats, and male and female
mice, the evidence was equivocal as to whether cancers observed were
associated with exposure to RFR".
An analysis of preliminary results from the study argued that due to
such issues as the inconsistent appearances of "signals for harm" within
and across species and the increased chances of false positives due to
the multiplicity of tests, the positive results seen are more likely due
to random chance. The full results of the study were released for peer
review in February 2018.
A 2021 review concluded 5G radio frequencies in the range of 450
MHz to 6,000 MHz are probably carcinogenic for humans, particularly for gliomas and acoustic neuromas. Conclusions could not be drawn for higher frequencies due to insufficient adequate studies.
Fertility and reproduction
A decline in male sperm quality has been observed over several decades. Studies on the impact of mobile radiation on male fertility are conflicting, and the effects of the radio frequencyelectromagnetic radiation (RF-EMR) emitted by these devices on the reproductive systems are currently under active debate. A 2012 review concluded that "together, the results of these studies have shown that RF-EMR decreases sperm count and motility and increases oxidative stress".
A 2017 study of 153 men that attended an academic fertility clinic in
Boston, Massachusetts found that self-reported mobile phone use was not
related to semen quality, and that carrying a mobile phone in the pants
pocket was not related to semen quality.
A 2021 review concluded 5G radio frequencies in the range of 450
MHz to 6,000 MHz affect male fertility, possibly affect female
fertility, and may have adverse effects on the development of embryos,
foetuses and newborns. Conclusions could not be drawn for higher
frequencies due to insufficient adequate studies.
Some users of mobile phones and similar devices have reported feeling various non-specific symptoms
during and after use. Studies have failed to link any of these symptoms
to electromagnetic exposure. In addition, EHS is not a recognized
medical diagnosis.
Glucose metabolism
According to the National Cancer Institute,
two small studies exploring whether and how mobile phone radiation
affects brain glucose metabolism showed inconsistent results.
Effects on children
A report from the Australian Government's Radiation Protection and Nuclear Safety Agency (ARPANSA) in June 2017 noted that:
The 2010 WHO Research Agenda
identified a lack of sufficient evidence relating to children and this
is still the case. ... Given that no long-term prospective study has
looked at this issue to date this research need remains a high priority.
For cancer in particular only one completed case-control study involving
four European countries has investigated mobile phone use among
children or adolescents and risk of brain tumour; showing no association
between the two (Aydin et al. 2011). ... Given this paucity of
information regarding children using mobile phones and cancer ... more
epidemiological studies are needed.
Base stations
Cellular mobile and UHF antenna tower with multiple antennas
Experts consulted by France considered it was mandatory that the main
antenna axis should not to be directly in front of a living place at a
distance shorter than 100 metres. This recommendation was modified in 2003
to say that antennas located within a 100-metre radius of primary
schools or childcare facilities should be better integrated into the
city scape and was not included in a 2005 expert report. The Agence française de sécurité sanitaire environnementale as of 2009,
says that there is no demonstrated short-term effect of electromagnetic
fields on health, but that there are open questions for long-term
effects, and that it is easy to reduce exposure via technological
improvements. A 2020 study in Environmental Research
found that "Although direct causation of negative human health effects
from RFR from cellular phone base stations has not been finalized, there
is already enough medical and scientific evidence to warrant long-term
liability concerns for companies deploying cellular phone towers" and thus recommended voluntary setbacks from schools and hospitals.
Safety standards and licensing
To
protect the population living around base stations and users of mobile
handsets, governments and regulatory bodies adopt safety standards,
which translate to limits on exposure levels below a certain value.
There are many proposed national and international standards, but that
of the International Commission on Non-Ionizing Radiation Protection
(ICNIRP) is the most respected one, and has been adopted so far by more
than 80 countries. For radio stations, ICNIRP proposes two safety
levels: one for occupational exposure, another one for the general
population. Currently there are efforts underway to harmonize the
different standards in existence.
Radio base licensing procedures have been established in the
majority of urban spaces regulated either at municipal/county,
provincial/state or national level. Mobile telephone service providers
are, in many regions, required to obtain construction licenses, provide
certification of antenna emission levels and assure compliance to ICNIRP
standards and/or to other environmental legislation.
Many governmental bodies also require that competing
telecommunication companies try to achieve sharing of towers so as to
decrease environmental and cosmetic impact. This issue is an influential
factor of rejection of installation of new antennas and towers in
communities.
The safety standards in the US are set by the Federal Communications Commission
(FCC). The FCC has based its standards primarily on those standards
established by the National Council on Radiation Protection and
Measurements (NCRP) a Congressionally chartered scientific organization
located in the WDC area and the Institute of Electrical and Electronics Engineers (IEEE), specifically Subcommittee 4 of the "International Committee on Electromagnetic Safety".
Switzerland has set safety limits lower than the ICNIRP limits for certain "sensitive areas" (classrooms, for example).
In March 2020, for the first time since 1998, ICNIRP updated its
guidelines for exposures to frequencies over 6 GHz, including the
frequencies used for 5G that are over 6 GHz. The Commission added a
restriction on acceptable levels of exposure to the whole body, added a
restriction on acceptable levels for brief exposures to small regions of
the body, and reduced the maximum amount of exposure permitted over a
small region of the body.
Lawsuits
In the US, personal injurylawsuits have been filed by individuals against manufacturers (including Motorola,[48]NEC, Siemens, and Nokia) on the basis of allegations of causation of brain cancer and death. In US federal courts, expert testimony relating to science must be first evaluated by a judge, in a Daubert hearing, to be relevant and valid before it is admissible as evidence. In a 2002 case against Motorola,
the plaintiffs alleged that the use of wireless handheld telephones
could cause brain cancer and that the use of Motorola phones caused one
plaintiff's cancer. The judge ruled that no sufficiently reliable and
relevant scientific evidence in support of either general or specific
causation was proffered by the plaintiffs, accepted a motion to exclude
the testimony of the plaintiffs' experts, and denied a motion to exclude
the testimony of the defendants' experts.
Two separate cases in Italy, in 2009 and 2017, resulted in pensions being awarded to plaintiffs who had claimed their benignbrain tumors
were the result of prolonged mobile phone use in professional tasks,
for 5–6 hours a day, which they ruled different from non-professional
use.
In the UK Legal Action Against 5G sought a Judicial Review of the
government's plan to deploy 5G. If successful, the group was to be
represented by Michael Mansfield QC,
a prominent British barrister. This application was denied on the basis
that the government had demonstrated that 5G was as safe as 4G, and
that the applicants had brought their action too late.
According to the WHO, the "precautionary principle" is "a risk
management policy applied in circumstances with a high degree of
scientific uncertainty, reflecting the need to take action for a
potentially serious risk without awaiting the results of scientific
research." Other less stringent recommended approaches are prudent avoidance principle and as low as reasonably practicable.
Although all of these are problematic in application, due to the
widespread use and economic importance of wireless telecommunication
systems in modern civilization, there is an increased popularity of such
measures in the general public, though also evidence that such
approaches may increase concern.
They involve recommendations such as the minimization of usage, the
limitation of use by at-risk population (e.g., children), the adoption
of phones and microcells with as low as reasonably practicable levels of
radiation, the wider use of hands-free and earphone technologies such as Bluetooth
headsets, the adoption of maximal standards of exposure, RF field
intensity and distance of base stations antennas from human habitations,
and so forth.
Overall, public information remains a challenge as various health
consequences are evoked in the literature and by the media, putting
populations under chronic exposure to potentially worrying information.
Precautionary measures and health advisories
In May 2011, the World Health Organization's International Agency for Research on Cancer
announced it was classifying electromagnetic fields from mobile phones
and other sources as "possibly carcinogenic to humans" and advised the
public to adopt safety measures to reduce exposure, like use of
hands-free devices or texting.
Some national radiation advisory authorities, including those of Austria, France, Germany, and Sweden, have recommended measures to minimize exposure to their citizens. Examples of the recommendations are:
Use hands-free to decrease the radiation to the head.
Keep the mobile phone away from the body.
Do not use telephone in a car without an external antenna.
The use of "hands-free" was not recommended by the British Consumers' Association in a statement in November 2000, as they believed that exposure was increased. However, measurements for the (then) UK Department of Trade and Industry and others for the French Agence française de sécurité sanitaire environnementale [fr] showed substantial reductions. In 2005, Professor Lawrie Challis and others said clipping a ferrite bead onto hands-free kits stops the radio waves travelling up the wire and into the head.
Several nations have advised moderate use of mobile phones for children. A journal by Gandhi et al. in 2006 states that children receive higher levels of Specific Absorption Rate (SAR). When 5- and 10-year-olds are compared to adults, they receive about 153% higher SAR levels. Also, with the permittivity
of the brain decreasing as one gets older and the higher relative
volume of the exposed growing brain in children, radiation penetrates
far beyond the mid-brain.
The FDA is quoted as saying that it "...continues to believe that the
current safety limits for cellphone radiofrequency energy exposure
remain acceptable for protecting the public health."
During the COVID-19 pandemic, misinformation circulated claiming that 5G networks contribute to the spread of COVID-19.
Bogus products
Products have been advertised that claim to shield people from EM radiation from mobile phones; in the US the Federal Trade Commission
published a warning that "Scam artists follow the headlines to promote
products that play off the news – and prey on concerned people."
According to the FTC, "there is no scientific proof that
so-called shields significantly reduce exposure from electromagnetic
emissions. Products that block only the earpiece – or another small
portion of the phone – are totally ineffective because the entire phone
emits electromagnetic waves." Such shields "may interfere with the
phone's signal, cause it to draw even more power to communicate with the
base station, and possibly emit more radiation." The FTC has enforced false advertising claims against companies that sell such products.
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