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Several studies have shown that hypopituitarism is associated with an increased risk of cardiovascular disease and some also an increased risk of death of about 50% to 150% the normal population. It has been difficult to establish which hormone deficiency is responsible for this risk, as almost all patients studied had growth hormone deficiency. The studies also do not answer the question as to whether the hypopituitarism itself causes the increased mortality, or whether some of the risk is to be attributed to the treatments, some of which (such as sex hormone supplementation) have a recognized adverse effect on cardiovascular risk.
The largest study to date followed over a thousand people for eight years; it showed an 87% increased risk of death compared to the normal population. Predictors of higher risk were: female sex, absence of treatment for sex hormone deficiency, younger age at the time of diagnosis, and a diagnosis of craniopharyngioma. Apart from cardiovascular disease, this study also showed an increased risk of death from lung disease.
Quality of life may be significantly reduced, even in those people on optimum medical therapy. Many report both physical and psychological problems. It is likely that the commonly used replacement therapies do not completely mimic the natural hormone levels in the body. Health costs remain about double those of the normal population.
Hypopituitarism is usually permanent. It requires lifelong treatment with one or more medicines.
Thyroid hormone resistance syndrome is rare, incidence is variously quoted as 1 in 50,000 or 1 in 40,000 live births. More than 1000 individuals have been identified with thyroid hormone resistance, of which 85% had thyroid hormone beta receptor mutation.
There is only one study that has measured the prevalence (total number of cases in a population) and incidence (annual number of new cases) of hypopituitarism. This study was conducted in Northern Spain and used hospital records in a well-defined population. The study showed that 45.5 people out of 100,000 had been diagnosed with hypopituitarism, with 4.2 new cases per year. 61% were due to tumors of the pituitary gland, 9% due to other types of lesions, and 19% due to other causes; in 11% no cause could be identified.
Recent studies have shown that people with a previous traumatic brain injury, spontaneous subarachnoid hemorrhage (a type of stroke) or radiation therapy involving the head have a higher risk of hypopituitarism. After traumatic brain injury, as much as a quarter have persistent pituitary hormone deficiencies. Many of these people may have subtle or non-specific symptoms that are not linked to pituitary problems but attributed to their previous condition. It is therefore possible that many cases of hypopituitarism remain undiagnosed, and that the annual incidence would rise to 31 per 100,000 annually if people from these risk groups were to be tested.
Autopsy studies indicate that 6-25% of the U. S. population have small pituitary tumors. Forty percent of these pituitary tumors produce prolactin, but most are not considered clinically significant. Clinically significant pituitary tumors affect the health of approximately 14 out of 100,000 people. In non-selective surgical series, this tumor accounts for approximately 25-30% of all pituitary adenomas. Some growth hormone (GH)–producing tumors also co-secrete prolactin. Microprolactinomas are much more common than macroprolactinomas.
In a study of 1,034 symptomatic adults, Sheehan syndrome was found to be the sixth most frequent etiology of growth hormone deficiency, being responsible for 3.1% of cases (versus 53.9% due to a pituitary tumor).
The incidence of idiopathic GHD in infants is about 1 in every 3800 live births, and rates in older children are rising as more children survive childhood cancers which are treated with radiotherapy, although exact rates are hard to obtain.
The incidence of genuine adult-onset GHD, normally due to pituitary tumours, is estimated at 10 per million.
All causes in this category are genetic, and generally very rare. These include mutations to the "SF1" transcription factor, congenital adrenal hypoplasia due to "DAX-1" gene mutations and mutations to the ACTH receptor gene (or related genes, such as in the Triple A or Allgrove syndrome). "DAX-1" mutations may cluster in a syndrome with glycerol kinase deficiency with a number of other symptoms when "DAX-1" is deleted together with a number of other genes.
Outcomes are typically good when treated. Most can expect to live relatively normal lives. Someone with the disease should be observant of symptoms of an "Addison's crisis" while the body is strained, as in rigorous exercise or being sick, the latter often needing emergency treatment with intravenous injections to treat the crisis.
Individuals with Addison's disease have more than a doubled mortality rate. Furthermore, individuals with Addison's disease and diabetes mellitus have an almost 4 time increase in mortality compared to individuals with only diabetes.
Iatrogenic Cushing's syndrome (caused by treatment with corticosteroids) is the most common form of Cushing's syndrome. Cushing's disease is rare; a Danish study found an incidence of less than one case per million people per year. However, asymptomatic microadenomas (less than 10 mm in size) of the pituitary are found in about one in six individuals.
People with Cushing's syndrome have increased morbidity and mortality as compared to the general population. The most common cause of mortality in Cushing's syndrome is cardiovascular events. People with Cushing's syndrome have nearly 4 times increased cardiovascular mortality as compared to the general population.
Neonatal thyroid screening programs from all over the world have revealed that congenital hypothyroidism (CH) occurs with an incidence of 1:3000 to 1:4000. The differences in CH-incidence are more likely due to iodine deficiency thyroid disorders or to the type of screening method than to ethnic affiliation. CH is caused by an absent or defective thyroid gland classified into agenesis (22-42%), ectopy (35-42%) and gland in place defects (24-36%). It is also found to be of increased association with female sex and gestational age >40 weeks.
The frequency rate of Addison's disease in the human population is sometimes estimated at roughly one in 100,000. Some put the number closer to 40–144 cases per million population (1/25,000–1/7,000). Addison's can affect persons of any age, sex, or ethnicity, but it typically presents in adults between 30 and 50 years of age. Research has shown no significant predispositions based on ethnicity.
Certain medications can have the unintended side effect of affecting thyroid function. While some medications can lead to significant hypothyroidism or hyperthyroidism and those at risk will need to be carefully monitored, some medications may affect thyroid hormone lab tests without causing any symptoms or clinical changes, and may not require treatment. The following medications have been linked to various forms of thyroid disease:
- Amiodarone (more commonly can lead to hypothyroidism, but can be associated with some types of hyperthyroidism)
- Lithium salts (hypothyroidism)
- Some types of interferon and IL-2 (thyroiditis)
- Glucocorticoids, dopamine agonists, and somatostatin analogs (block TSH, which can lead to hypothyroidism)
The cause of pituitary tumors remains unknown. It has been shown that stress can significantly raise prolactin levels, which should make stress a diagnostic differential, though it usually is not considered such. Most pituitary tumors are sporadic — they are not genetically passed from parents to offspring.
The majority of moderately raised prolactin levels (up to 5000 mIU/L) are not due to microprolactinomas but other causes. The effects of some prescription drugs are the most common. Other causes are other pituitary tumours and normal pregnancy and breastfeeding. This is discussed more under hyperprolactinaemia.
The xenoestrogenic chemical Bisphenol-A has been shown to lead to hyperprolactinaemia and growth of prolactin-producing pituitary cells. The increasing and prolonged exposure of Bisphenol-A from childhood on, may contribute to the growth of a Prolactinoma.
Autoimmune adrenalitis is the most common cause of Addison's disease in the industrialised world. Autoimmune destruction of the adrenal cortex is caused by an immune reaction against the enzyme 21-hydroxylase (a phenomenon first described in 1992). This may be isolated or in the context of autoimmune polyendocrine syndrome (APS type 1 or 2), in which other hormone-producing organs, such as the thyroid and pancreas, may also be affected.
Adrenal destruction is also a feature of adrenoleukodystrophy (ALD), and when the adrenal glands are involved in metastasis (seeding of cancer cells from elsewhere in the body, especially lung), hemorrhage (e.g. in Waterhouse-Friderichsen syndrome or antiphospholipid syndrome), particular infections (tuberculosis, histoplasmosis, coccidioidomycosis), or the deposition of abnormal protein in amyloidosis.
Hyperthyroidism is a state in which the body is producing too much thyroid hormone. The main hyperthyroid conditions are:
- Graves' disease
- Toxic thyroid nodule
- Thyroid storm
- Toxic nodular struma (Plummer's disease)
- Hashitoxicosis: "transient" hyperthyroidism that can occur in Hashimoto's thyroiditis
Normal thyroid hormone function requires normal thyroid hormone transport across cell membrane, appropriate deiodination, thyroid hormone nuclear receptor, thyroid hormone response elements, co-activators, co-repressors, and normal histone acetylation. Any abnormalities in this chain can result in thyroid hormone resistance.
The most common cause of the syndrome are mutations of the β (beta) form ("THRB" gene) of the thyroid hormone receptor, of which over 100 different mutations have been documented.
Mutations in "MCT8" and "SECISBP2" have also been associated with this condition.
Cases of Cushing's disease are rare, and little epidemiological data is available on the disease. An 18-year study conducted on the population of Vizcaya, Spain reported a 0.004% prevalence of Cushing's disease. The average incidence of newly diagnosed cases was 2.4 cases per million inhabitants per year. The disease is often diagnosed 3–6 years after the onset of illness.
Several studies have shown that Cushing's disease is more prevalent in women than men at a ratio of 3-6:1, respectively. Moreover, most women affected were between the ages of 50 and 60 years.
The prevalence of hypertension, and abnormalities in glucose metabolism are major predictors of mortality and morbidity in untreated cases of the disease. The mortality rate of Cushing's disease was reported to be 10-11%, with the majority of deaths due to vascular disease Women aged 45–70 years have a significantly higher mortality rate than men.
Moreover, the disease shows a progressive increase with time. Reasons for the trend are unknown, but better diagnostic tools, and a higher incidence rate are two possible explanations.
Pseudoacromegaly is a condition with the usual acromegaloid features, but without an increase in growth hormone and IGF-1. It is frequently associated with insulin resistance. Cases have been reported due to minoxidil at an unusually high dose. It can also be caused by a selective postreceptor defect of insulin signalling, leading to the impairment of metabolic, but preservation of mitogenic, signalling.
Most children born with congenital hypothyroidism and correctly treated with thyroxine grow and develop normally in all respects. Even most of those with athyreosis and undetectable T levels at birth develop with normal intelligence, although as a population academic performance tends to be below that of siblings and mild learning problems occur in some.
Congenital hypothyroidism is the most common preventable cause of intellectual disability. Few treatments in the practice of medicine provide as large a benefit for as small an effort.
The developmental quotient (DQ, as per Gesell Developmental Schedules) of children with hypothyroidism at age 24 months that have received treatment within the first 3 weeks of birth is summarised below:
Growth hormone-releasing hormone (GHRH) is another releasing factor secreted by the hypothalamus. GHRH stimulates the pituitary gland to secrete growth hormone (GH), which has various effects on body growth and sexual development. Insufficient GH production may cause poor somatic growth, precocious puberty or gonadotropin deficiency, failure to initiate or complete puberty, and is often associated with rapid weight gain, low T, and low levels of sex hormones.
Most XY children are so undervirilized that they are raised as girls. The testes are uniformly nonfunctional and undescended; they are removed when the diagnosis is made due to the risk of cancer development in these tissues.
The most common cause of Cushing's syndrome is the taking of glucocorticoids prescribed by a health care practitioner to treat other diseases (called iatrogenic Cushing's syndrome). This can be an effect of corticosteroid treatment of a variety of disorders such as asthma and rheumatoid arthritis, or in immunosuppression after an organ transplant. Administration of synthetic ACTH is also possible, but ACTH is less often prescribed due to cost and lesser utility. Although rare, Cushing's syndrome can also be due to the use of medroxyprogesterone acetate. In this form of Cushing's, the adrenal glands atrophy due to lack of stimulation by ACTH, since glucocorticoids downregulate production of ACTH. Cushing's syndrome in childhood usually results from use of glucocorticoid medication.
Endogenous Cushing's syndrome results from some derangement of the body's own system of secreting cortisol. Normally, ACTH is released from the pituitary gland when necessary to stimulate the release of cortisol from the adrenal glands.
- In pituitary Cushing's, a benign pituitary adenoma secretes ACTH. This is also known as Cushing's disease and is responsible for 70% of endogenous Cushing's syndrome.
- In adrenal Cushing's, excess cortisol is produced by adrenal gland tumors, hyperplastic adrenal glands, or adrenal glands with nodular adrenal hyperplasia.
- Tumors outside the normal pituitary-adrenal system can produce ACTH (occasionally with CRH) that affects the adrenal glands. This etiology is called ectopic or paraneoplastic Cushing's disease and is seen in diseases such as small cell lung cancer.
- Finally, rare cases of CRH-secreting tumors (without ACTH secretion) have been reported, which stimulates pituitary ACTH production.
The cause of hyperpituitarism in most cases is due to pituitary adenomas. They usually come from the anterior lobe, are functional and secrete the hormone, GH and prolactin.
Radiation therapy has been used both as a primary treatment and combined with surgery or drugs. It is usually reserved for patients who have tumor remaining after surgery. These patients often also receive medication to lower GH levels. Radiation therapy is given in divided doses over four to six weeks. This treatment lowers GH levels by about 50 percent over 2 to 5 years. Patients monitored for more than 5 years show significant further improvement. Radiation therapy causes a gradual loss of production of other pituitary hormones with time. Loss of vision and brain injury, which have been reported, are very rare complications of radiation treatments.
Worldwide about one billion people are estimated to be iodine deficient; however, it is unknown how often this results in hypothyroidism. In large population-based studies in Western countries with sufficient dietary iodine, 0.3–0.4% of the population have overt hypothyroidism. A larger proportion, 4.3–8.5%, have subclinical hypothyroidism. Of people with subclinical hypothyroidism, 80% have a TSH level below the 10 mIU/l mark regarded as the threshold for treatment. Children with subclinical hypothyroidism often return to normal thyroid function, and a small proportion develops overt hypothyroidism (as predicted by evolving antibody and TSH levels, the presence of celiac disease, and the presence of a goiter).
Women are more likely to develop hypothyroidism than men. In population-based studies, women were seven times more likely than men to have TSH levels above 10 mU/l. 2–4% of people with subclinical hypothyroidism will progress to overt hypothyroidism each year. The risk is higher in those with antibodies against thyroid peroxidase. Subclinical hypothyroidism is estimated to affect approximately 2% of children; in adults, subclinical hypothyroidism is more common in the elderly, and in Caucasians. There is a much higher rate of thyroid disorders, the most common of which is hypothyroidism, in individuals with Down syndrome and Turner syndrome.
Very severe hypothyroidism and myxedema coma are rare, with it estimated to occur in 0.22 per million people a year. The majority of cases occur in women over 60 years of age, although it may happen in all age groups.
Most hypothyroidism is primary in nature. Central/secondary hypothyroidism affects 1:20,000 to 1:80,000 of the population, or about one out of every thousand people with hypothyroidism.