Hypopituitarism is the decreased ("hypo") secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain. If there is decreased secretion of one specific pituitary hormone, the condition is known as selective hypopituitarism. If there is decreased secretion of most or all pituitary hormones, the term panhypopituitarism ("pan" meaning "all") is used. The signs and symptoms of hypopituitarism vary, depending on which hormones are undersecreted and on the underlying cause of the abnormality. The diagnosis of hypopituitarism is made by blood tests, but often specific scans and other investigations are needed to find the underlying cause, such as tumors of the pituitary, and the ideal treatment.
Introduction
Hypopituitarism
Hypopituitarism | Introduction
A decreased ("hypo") secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain. It is the decreased secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain It  is the decreased ("hypo") secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain. It is the decreased ("hypo") secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain.
hypothalamic amenorrhea will result in the increased secretion of thyroid stimulating hormone (tsh)
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what is hypopituitarism?
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Most hormones controlled by the secretions of the pituitary can be replaced by tablets or injections. Hypopituitarism is a rare disease, but may be significantly underdiagnosed in people with previous traumatic brain injury. The first description of the condition was made in 1914 by the German physician Dr Morris Simmonds.
Hypopituitarism | Introduction
Occasionally, the pituitary hormone may be normal but the effector gland hormone decreased; in this case, the pituitary is not responding appropriately to effector hormone changes, and the combination of findings is still suggestive of hypopituitarism.
Hypopituitarism | Diagnosis
Hypopituitarism is the decreased ("hypo") secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain. If there is decreased secretion of one specific pituitary hormone, the condition is known as selective hypopituitarism. If there is decreased secretion of most or all pituitary hormones, the term panhypopituitarism ("pan" meaning "all") is used. The signs and symptoms of hypopituitarism vary, depending on which hormones are undersecreted and on the underlying cause of the abnormality. The diagnosis of hypopituitarism is made by blood tests, but often specific scans and other investigations are needed to find the underlying cause, such as tumors of the pituitary, and the ideal treatment.
Hypopituitarism | Introduction
Treatment of hypopituitarism is threefold: removing the underlying cause, treating the hormone deficiencies, and addressing any other repercussions that arise from the hormone deficiencies.
Hypopituitarism | Treatment
Stimulation tests with GnRH are possible, but their use is not encouraged. For TSH, basal measurements are usually sufficient, as well as measurements of thyroxine to ensure that the pituitary is not simply suppressing TSH production in response to hyperthyroidism (an overactive thyroid gland). A stimulation test with thyrotropin-releasing hormone (TRH) is not regarded as useful. Prolactin can be measured by basal level, and is required for the interpretation of LH and FSH results in addition to the confirmation of hypopituitarism or diagnosis of a prolactin-secreting tumor.
Hypopituitarism | Basal tests
The hypothalamus and pituitary gland are tightly integrated. Damage to the hypothalamus will impact the responsiveness and normal functioning of the pituitary. Hypothalamic disease may cause insufficient or inhibited signalling to the pituitary leading to deficiencies of one or more of the following hormones: thyroid-stimulating hormone, adrenocorticotropic hormone, beta-endorphin, luteinizing hormone, follicle-stimulating hormone, and melanocyte–stimulating hormones. Treatment for hypopituitarism involves hormone replacement therapy.
Hypothalamic disease | Hypopituitarism
Children experience growth retardation and short stature.
Hypopituitarism | Anterior pituitary
If the TSH level is normal or low and serum free T levels are low, this is suggestive of central hypothyroidism (not enough TSH or TRH secretion by the pituitary gland or hypothalamus). There may be other features of hypopituitarism, such as menstrual cycle abnormalities and adrenal insufficiency. There might also be symptoms of a pituitary mass such as headaches and vision changes. Central hypothyroidism should be investigated further to determine the underlying cause.
Hypothyroidism | Central
If a genetic cause is suspected, genetic testing may be performed.
Hypopituitarism | Further investigations
Health costs remain about double those of the normal population.
Hypopituitarism | Prognosis
Production of TSH and TRH is decreased by thyroxine by a negative feedback process. Not enough TRH, which is uncommon, can lead to not enough TSH and thereby to not enough thyroid hormone production.
Hypothyroidism | Pathophysiology
Long-term follow up by specialists in endocrinology is generally needed for people with known hypopituitarism. Apart from ensuring the right treatment is being used and at the right doses, this also provides an opportunity to deal with new symptoms and to address complications of treatment. Difficult situations arise in deficiencies of the hypothalamus-pituitary-gonadal axis in people (both men and women) who experience infertility; infertility in hypopituitarism may be treated with subcutaneous infusions of FSH, human chorionic gonadotropin–which mimics the action of LH–and occasionally GnRH.
Hypopituitarism | Hormone replacement
If the hypopituitarism is caused by the blood loss associated with childbirth, the disorder is referred to as Sheehan syndrome.
Anterior pituitary | Decreased activity
The pituitary was known to the ancients, such as Galen, and various theories were proposed about its role in the body, but major clues as to the actual function of the gland were not advanced until the late 19th century, when acromegaly due to pituitary tumors was described. The first known report of hypopituitarism was made by the German physician and pathologist Dr Morris Simmonds. He described the condition on autopsy in a 46-year-old woman who had suffered severe puerperal fever eleven years earlier, and subsequently suffered amenorrhea, weakness, signs of rapid aging and anemia. The pituitary gland was very small and there were few remnants of both the anterior and the posterior pituitary.
Hypopituitarism | History
The thyroid gland is an auxiliary organ to the hypothalamus-pituitary system. Thyrotropin-releasing hormone (TRH) produced by the hypothalamus signals to the pituitary to release thyroid-stimulating hormone (TSH), which then stimulates the thyroid to secrete T and T thyroid hormones. Secondary hypothyroidism occurs when TSH secretion from the pituitary is impaired, whereas tertiary hypothyroidism is the deficiency or inhibition of TRH. Thyroid hormones are responsible for metabolic activity. Insufficient production of the thyroid hormones result in suppressed metabolic activity and weight gain. Hypothalamic disease may therefore have implications for obesity.
Hypothalamic disease | Tertiary hypothyroidism
These mutations also lead to varying degrees of hypopituitarism.
Development of the endocrine system | Parathyroid glands
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.
Hypopituitarism | Epidemiology
The diagnosis of hypopituitarism is made on blood tests. Two types of blood tests are used to confirm the presence of a hormone deficiency: basal levels, where blood samples are taken–usually in the morning–without any form of stimulation, and dynamic tests, where blood tests are taken after the injection of a stimulating substance. Measurement of ACTH and growth hormone usually requires dynamic testing, whereas the other hormones (LH/FSH, prolactin, TSH) can typically be tested with basal levels. There is no adequate direct test for ADH levels, but ADH deficiency can be confirmed indirectly; oxytocin levels are not routinely measured. Generally, the finding of a combination of a low pituitary hormone together with a low hormone from the effector gland is indicative of hypopituitarism.
Hypopituitarism | Diagnosis
These potential conditions include hyperprolactinemia, POI, and polycystic ovary syndrome.
Hypoestrogenism | Functional hypothalamic amenorrhea
Several hormone deficiencies associated with hypopituitarism may lead to secondary diseases. For instance, growth hormone deficiency is associated with obesity, raised cholesterol and the metabolic syndrome, and estradiol deficiency may lead to osteoporosis. While effective treatment of the underlying hormone deficiencies may improve these risks, it is often necessary to treat them directly.
Hypopituitarism | Complications
In response to the releasing hormone rate, the anterior pituitary produces its hormones (TSH, ACTH, LH, FSH, GH) which in turn stimulate effector hormone glands in the body, while prolactin (PRL) acts directly on the breast gland. Once the effector glands produce sufficient hormones (thyroxine, cortisol, estradiol or testosterone and IGF-1), both the hypothalamus and the pituitary cells sense their abundance and reduce their secretion of stimulating hormones. The hormones of the posterior pituitary are produced in the hypothalamus and are carried by nerve endings to the posterior lobe; their feedback system is therefore located in the hypothalamus, but damage to the nerve endings would still lead to a deficiency in hormone release.
Hypopituitarism | Pathophysiology
Deficiency of all anterior pituitary hormones is more common than individual hormone deficiency. Deficiency of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), together referred to as the gonadotropins, leads to different symptoms in men and women. Women experience oligo- or amenorrhea (infrequent/light or absent menstrual periods respectively) and infertility. Men lose facial, scrotal and trunk hair, as well as suffering decreased muscle mass and anemia. Both sexes may experience a decrease in libido and loss of sexual function, and have an increased risk of osteoporosis (bone fragility). Lack of LH/FSH in children is associated with delayed puberty. Growth hormone (GH) deficiency leads to a decrease in muscle mass, central obesity (increase in body fat around the waist) and impaired attention and memory.
Hypopituitarism | Anterior pituitary
Granulomas in the pituitary gland, which produces numerous hormones, is rare but leads to any of the symptoms of hypopituitarism: amenorrhoea (cessation of the menstrual cycle), diabetes insipidus (dehydration due to inability to concentrate the urine), hypothyroidism (decreased activity of the thyroid) or hypocortisolism (deficiency of cortisol).
Neurosarcoidosis | Endocrine
Overexpression of deiodinase can thus lead to consumptive hypothyroidism. The thyroid gland is the only source of thyroid hormone in the body; the process requires iodine and the amino acid tyrosine. Iodine in the bloodstream is taken up by the gland and incorporated into thyroglobulin molecules. The process is controlled by the thyroid-stimulating hormone (TSH, thyrotropin), which is secreted by the pituitary. Not enough iodine, or not enough TSH, can result in decreased production of thyroid hormones. The hypothalamic–pituitary–thyroid axis plays a key role in maintaining thyroid hormone levels within normal limits. Production of TSH by the anterior pituitary gland is stimulated in turn by thyrotropin-releasing hormone (TRH), released from the hypothalamus.
Hypothyroidism | Pathophysiology
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.
Hypopituitarism | Prognosis
This allowed the direct measurement of the hormones of the pituitary, which as a result of their low concentrations in blood had previously been hard to measure. Stimulation tests were developed in the 1960s, and in 1973 the triple bolus test was introduced, a test that combined stimulation testing with insulin, GnRH and TRH. Imaging of the pituitary, and therefore identification of tumors and other structural causes, improved radically with the introduction of computed tomography in the late 1970s and magnetic resonance imaging in the 1980s.
Hypopituitarism | History
The eponym "Simmonds' syndrome" is used infrequently for acquired hypopituitarism, especially when cachexia (general ill health and malnutrition) predominates. Most of the classic causes of hypopituitarism were described in the 20th century; the early 21st century saw the recognition of how common hypopituitarism could be in previous head injury victims. Until the 1950s, the diagnosis of pituitary disease remained based on clinical features and visual field examination, sometimes aided by pneumoencephalography and X-ray tomography. Nevertheless, the field of pituitary surgery developed during this time. The major breakthrough in diagnosis came with the discovery of radioimmunoassay by Rosalyn Yalow and Solomon Berson in the late 1950s.
Hypopituitarism | History
There is no direct way of increasing thyroid hormone secretion by the thyroid gland.
Hypothyroidism | Hormone replacement
However, the rest of the tissues will instead selectively display the defective gene, resulting in haploinsufficiency of the GNAS1 product in most tissues, and giving the phenotype of pseudohypoparathyroidism type 1a. As a result, there is also a normal response of urinary cAMP to PTH, and normal serum PTH.
Pseudopseudohypoparathyroidism | Pathophysiology
Each transcription factor acts in particular groups of cells. Therefore, various genetic mutations are associated with specific hormone deficiencies. For instance, "POU1F1" (also known as Pit-1) mutations cause specific deficiencies in growth hormone, prolactin and TSH. In addition to the pituitary, some of the transcription factors are also required for the development of other organs; some of these mutations are therefore also associated with specific birth defects. Most of the hormones in the anterior pituitary are each part of an "axis" that is regulated by the hypothalamus. The hypothalamus secretes a number of releasing hormones, often according to a circadian rhythm, into blood vessels that supply the anterior pituitary; most of these are stimulatory (thyrotropin-releasing hormone, corticotropin-releasing hormone, gonadotropin-releasing hormone and growth hormone-releasing hormone), apart from dopamine, which suppresses prolactin production.
Hypopituitarism | Pathophysiology
An increase in the serum TSH level following TRH administration means that the cause of the hypothyroidism is in the hypothalamus (tertiary hypothyroidism), i.e. the hypothalamus is not producing TRH. Therefore, when TRH is given exogenously, TSH levels increase.If the increase in serum TSH level following TRH administration is absent or very slight, then the cause of the hypothyroidism is in the anterior pituitary gland, i.e. the pituitary is not secreting TSH. Therefore, even when TRH is given exogenously, TSH levels do not rise as the pituitary is diseased.
TRH stimulation test | Process and interpretation
The hormones of the pituitary have different actions in the body, and the symptoms of hypopituitarism therefore depend on which hormone is deficient. The symptoms may be subtle and are often initially attributed to other causes. In most of the cases, three or more hormones are deficient. The most common problem is insufficiency of follicle-stimulating hormone (FSH) and/or luteinizing hormone (LH) leading to sex hormone abnormalities. Growth hormone deficiency is more common in people with an underlying tumor than those with other causes. Sometimes, there are additional symptoms that arise from the underlying cause; for instance, if the hypopituitarism is due to a growth hormone-producing tumor, there may be symptoms of acromegaly (enlargement of the hands and feet, coarse facial features), and if the tumor extends to the optic nerve or optic chiasm, there may be visual field defects.
Hypopituitarism | Signs and symptoms
The word "hypothyroidism" is from Greek "hypo-" meaning reduced, "thyreos" for shield, and "eidos" for form.
Hypothyroidism | Introduction
Hypophysitis refers to an inflammation of the pituitary gland. Hypophysitis is rare and not fully understood.
Hypophysitis | Introduction
Because many of the symptoms overlap with those of organic hypothalamic, pituitary, or gonadal disease and therefore must be ruled out, FHA is a diagnosis of exclusion; "functional" is used to indicate a behavioral cause, in which no anatomical or organic disease is identified, and is reversible with correction of the underlying cause. Diagnostic workup includes a detailed history and physical, laboratory studies, such as a pregnancy test, and serum levels of FSH and LH, prolactin, and thyroid-stimulating hormone (TSH), and imaging. Additional tests may be indicated in order to distinguish FHA from organic hypothalamic or pituitary disorders. Patients present with a broad range of symptoms related to severe hypoestrogenism (including cardiovascular and skeletal irregularities) as well as hypercortisolemia, low serum insulin levels, low serum insulin-like growth factor 1 (IGF-1), and low total triiodothyronine (T3).
Functional hypothalamic amenorrhea | Introduction
Lower strength estimates, abnormal bone microarchitectures, and deficient volumetric bone density has been found in young adult amenorrheic athletes.
Functional hypothalamic amenorrhea | Diagnosis
Deiodination is controlled by numerous hormones and nerval signals including TSH, vasopressin and catecholamines. Both peripheral thyroid hormones (iodothyronines) inhibit thyrotropin secretion from the pituitary (negative feedback). Consequently, equilibrium concentrations for all hormones are attained.
Hypothalamic–pituitary–thyroid axis | Physiology
While GnRH receptors in the hypothalamus do not contain receptors for leptin, a positive correlation has been shown to exist between leptin receptor mRNA and the kisspeptin-expressing cells which are known to stimulate GnRH release.
Functional hypothalamic amenorrhea | Neuroendocrine
Hypopituitarism commonly develops after radiation therapy for sellar and parasellar neoplasms, extrasellar brain tumours, head and neck tumours, and following whole body irradiation for systemic malignancies. Radiation-induced hypopituitarism mainly affects growth hormone and gonadal hormones. In contrast, adrenocorticotrophic hormone (ACTH) and thyroid stimulating hormone (TSH) deficiencies are the least common among people with radiation-induced hypopituitarism. Changes in prolactin-secretion is usually mild, and vasopressin deficiency appears to be very rare as a consequence of radiation.
Radiation therapy | Effects on pituitary system
Together, these cellular signals stimulate a group of cells from the oral cavity to form Rathke's pouch, which becomes independent of the nasal cavity and develops into the anterior pituitary; this process includes the suppression of production of a protein called Sonic hedgehog by the cells of Rathke's pouch. The cells then differentiate further into the various hormone-producing cells of the pituitary. This requires particular transcription factors that induce the expression of particular genes. Some of these transcription factors have been found to be deficient in some forms of rare combined pituitary hormone deficiencies (CPHD) in childhood. These are "HESX1", "PROP1", "POU1F1", "LHX3", "LHX4", "TBX19", "SOX2" and "SOX3".
Hypopituitarism | Pathophysiology
Unless the pituitary damage is being caused by a tumor that overproduces a particular hormone, it is the lack of pituitary hormones that leads to the symptoms described above, and an excess of a particular hormone would indicate the presence of a tumor. The exception to this rule is prolactin: if a tumor compresses the pituitary stalk, a decreased blood supply means that the lactotrope cells, which produce prolactin, are not receiving dopamine and therefore produce excess prolactin. Hence, mild elevations in prolactin are attributed to stalk compression. Very high prolactin levels, though, point more strongly towards a prolactinoma (prolactin-secreting tumor).
Hypopituitarism | Pathophysiology
Hypopituitarism is characterized by a decreased secretion of hormones released by the anterior pituitary. For example, hypo-secretion of GH prior to puberty can be a cause of dwarfism. In addition, secondary adrenal insufficiency can be caused by hypo-secretion of ACTH which, in turn, does not signal the adrenal cortex to produce a sufficient amount of cortisol. This is a life-threatening condition. Hypopituitarism could be caused by the destruction or removal of the anterior pituitary tissue through traumatic brain injury, tumor, tuberculosis, or syphilis, among other causes. This disorder used to be referred to as Simmonds' disease but now according to the Diseases Database it is called Sheehan syndrome.
Anterior pituitary | Decreased activity
Hyperpituitarism is a condition due to the primary hypersecretion of pituitary hormones; it typically results from a pituitary adenoma. In children with hyperpituitarism, disruption of growth regulation is rare, either because of hormone hypersecretion or because of manifestations caused by local compression of the adenoma.
Hyperpituitarism | Introduction
Specifically, this underlies why the hypothalamus is necessarily sensitive to internal and external stimuli in its regulation of menstruation. Complete synchrony or the HPO axis is required for ovulation and reproduction in order to ensure pulsatile release of GnRH. Without this pulsatile release, the reduced levels of gonadotropins LH and FSH are insufficient to maintain full folliculogenesis and ovulatory ovarian function, resulting in profound hypoestrogenism. Additionally, external stress factors activate the HPA axis; increased corticotropin-releasing hormone (CRH) secretion results in increased secretion of ACTH from the pituitary gland, and thus increased secretion of cortisol from the adrenal glands. CRH, a regulator of the HPA and HPO axis, can be stimulated for release by the central nervous system in states of physical or mental stress that accompany the lifestyle factors contributing to amenorrhea.
Functional hypothalamic amenorrhea | Hormonal
Relative energy expenditure (REE) is also closely linked to T, as is evidenced by a correlation between macronutrient intake, REE, and thyroid hormone levels. It has been found that AN patients who regain weight can restore T and REE independent of changes in FFM. Other hormonal changes in FHA include increased levels of nighttime serum growth hormone (GH), decreased levels of 24 hour prolactin, low serum insulin and IGF-1, and increased insulin sensitivity. GH has been found to be higher systemically in AN and exercise-induced FHA, with women who have the lowest FFM and body mass index BMI displaying the highest levels of circulating GH The result is peripheral resistance to GH, and this underlies the reduction in hepatic IGF-1 synthesis observed in many of these patients.
Functional hypothalamic amenorrhea | Hormonal
Hypoprolactinemia is a medical condition characterized by a deficiency in the serum levels of the hypothalamic-pituitary hormone prolactin.
Hypoprolactinemia | Introduction
The use of the term hypogonadotropic relates to the fact that the hypogonadism found in HH is caused by a disruption in the production of the gonadotropin hormones normally released by the anterior pituitary gland known as luteinising hormone (LH) and follicle stimulating hormone (FSH). Failure in GnRH activity can otherwise be due to the absence of the GnRH releasing neurons inside the hypothalamus. HH can occur as an isolated condition with just the LH and FSH production being affected or it can occur in combined pituitary deficiency conditions. In the first 10 weeks of normal embryonic development, the GnRH releasing neurons migrate from their original source in the nasal region and end up inside the hypothalamus.
Kallmann syndrome | Pathophysiology
FHA results from a functional reduction or disruption in GnRH release due to chronic negative energy balance, metabolism, body composition, and stress; such risk factors become relevant in cases of emotional stress, excessive exercise, and nutrient starvation. Metabolic cues, including an increase in body weight, are influential in the initiation of pulsatile GnRH release from the hypothalamus during puberty; this event allows for the pituitary to begin producing and releasing pulses of LH. Full folliculogenesis cannot occur if the initial GnRH drive is disrupted, and this can be caused by reduced leptin from loss of body fat due to nutritional deprivation, excessive exercise in which the calories burned are more than those consumed, and states of hypercortisolism due to stress-inducing attitudinal or environmental pressures.
Functional hypothalamic amenorrhea | Hormonal
If one of these tests shows a deficiency of hormones produced by the pituitary, magnetic resonance imaging (MRI) scan of the pituitary is the first step in identifying an underlying cause. MRI may show various tumors and may assist in delineating other causes. Tumors smaller than 1 cm are referred to as "microadenomas", and larger lesions are called "macroadenomas". Computed tomography with radiocontrast may be used if MRI is not available. Formal visual field testing by perimetry is recommended, as this would show evidence of optic nerve compression by a tumor. Other tests that may assist in the diagnosis of hypopituitarism, especially if no tumor is found on the MRI scan, are ferritin (elevated in hemochromatosis), angiotensin converting enzyme (ACE) levels (often elevated in sarcoidosis), and human chorionic gonadotropin (often elevated in tumor of germ cell origin).
Hypopituitarism | Further investigations
In this population, where success in sport is highly emphasized, decreasing training intensity is typically not an option. Parents and legal guardians should be made aware of the long-term risk factors for osteoporosis and infertility which underlie this condition when deciding on a treatment plan. A multi-disciplinary team approach in management that includes a medical doctor, dietitian, and a psychiatrist or psychologist to provide psychological support is recommended. If menstruation does not resume spontaneously following lifestyle changes, the patient should be monitored for thyroid function, HPO axis function, and concentrations of ACTH, cortisol, and prolactin every 4–5 months.
Functional hypothalamic amenorrhea | Management
Conversely, acromegaly and gigantism are conditions of GH and IGF-1 excess usually due to a pituitary tumor, and are characterized by overgrowth and tall stature.
Hypothalamic–pituitary–somatotropic axis | Introduction
Functional hypothalamic amenorrhea (FHA) is a form of amenorrhea and chronic anovulation and is one of the most common types of secondary amenorrhea. It is classified as hypogonadotropic hypogonadism. It was previously known as "juvenile hypothalamosis syndrome," prior to the discovery that sexually mature females are equally affected. FHA has multiple risk factors, with links to stress-related, weight-related, and exercise-related factors. FHA is caused by stress-induced suppression of the hypothalamic-pituitary-ovarian (HPO) axis, which results in inhibition of gonadotropin-releasing hormone (GnRH) secretion, and gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Severe and potentially prolonged hypoestrogenism is perhaps the most dangerous hormonal pathology associated with the disease, because consequences of this disturbance can influence bone health, cardiovascular health, mental health, and metabolic functioning in both the short and long-term.
Functional hypothalamic amenorrhea | Introduction
A GnRH stimulation or challenge test should be used to identify FHA as the cause hypogonadotropic hypogonadism in women presenting with symptoms, as hypothalamic dysfunction due to delayed-onset puberty or other pituitary disease will not respond to exogenous GnRH. Hypothalamic disorders are differentiated when GnRH administration results in abnormal increases of gonadotropins. Combined pituitary and hypothalamic impairment is differentiated when there is a decreased or absent response to GnRH secretion; as a result, it impossible to determine if the observed low levels of FSH/LH are due to hypothalamic or pituitary dysfunction, and pulsatile GnRH administration with cyclomate is required to diagnose this distinction (pulsatile LH-RH challenge).
Functional hypothalamic amenorrhea | Diagnosis
Sheehan's syndrome, also known as postpartum pituitary gland necrosis, is hypopituitarism (decreased functioning of the pituitary gland), caused by ischemic necrosis due to blood loss and hypovolemic shock during and after childbirth.
Sheehan's syndrome | Introduction
The pituitary gland is located at the base of the brain, and intimately connected with the hypothalamus. It consists of two lobes: the posterior pituitary, which consists of nervous tissue branching out of the hypothalamus, and the anterior pituitary, which consists of hormone-producing epithelium. The posterior pituitary secretes antidiuretic hormone, which regulates osmolarity of the blood, and oxytocin, which causes contractions of the uterus in childbirth and participates in breastfeeding. The pituitary develops in the third week of embryogenesis from interactions between the diencephalon part of the brain and the nasal cavity. The brain cells secrete FGF-8, Wnt5a and BMP-4, and the oral cavity BMP-2.
Hypopituitarism | Pathophysiology
FHA may present with weight loss, bradycardia, mottled, cool extremities, and/or yellowing of the skin.
Functional hypothalamic amenorrhea | History and physical exam
Levels of LH/FSH may be suppressed by a raised prolactin level, and are therefore not interpretable unless prolactin is low or normal. In men, the combination of low LH and FSH in combination with a low testosterone confirms LH/FSH deficiency; a high testosterone would indicate a source elsewhere in the body (such as a testosterone-secreting tumor). In women, the diagnosis of LH/FSH deficiency depends on whether the woman has been through the menopause. Before the menopause, abnormal menstrual periods together with low estradiol and LH/FSH levels confirm a pituitary problem; after the menopause (when LH/FSH levels are normally elevated and the ovaries produce less estradiol), inappropriately low LH/FSH alone is sufficient.
Hypopituitarism | Basal tests
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.
Hypopituitarism | Epidemiology
See Genetics of GnRH deficiency conditions
Isolated hypogonadotropic hypogonadism | Genetics
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.
Hypopituitarism | Prognosis
Hypothalamic disease therefore affects the functioning of the pituitary and the target organs controlled by the pituitary, including the adrenal glands, ovaries and testes, and the thyroid gland. Numerous dysfunctions manifest as a result of hypothalamic disease. Damage to the hypothalamus may cause disruptions in body temperature regulation, growth, weight, sodium and water balance, milk production, emotions, and sleep cycles. Hypopituitarism, neurogenic diabetes insipidus, tertiary hypothyroidism, and developmental disorders are examples of precipitating conditions caused by hypothalamic disease.
Hypothalamic disease | Introduction
Antidiuretic hormone (ADH) deficiency leads to the syndrome of "diabetes insipidus" (unrelated to diabetes mellitus): inability to concentrate the urine, leading to polyuria (production of large amounts of clear urine) that is low in solutes, dehydration and—in compensation—extreme thirst and constant need to drink (polydipsia), as well as hypernatremia (high sodium levels in the blood). ADH deficiency may be masked if there is ACTH deficiency, with symptoms only appearing when cortisol has been replaced. Oxytocin (OXT) deficiency generally causes few symptoms, as it is only required at the time of childbirth and breastfeeding.
Hypopituitarism | Posterior pituitary
Thus, reproductive function can be altered through psychological or physiological stress through the HPA axis due to the modulatory effects that this pathway has on the HPO axis: its activation, which can occur in states of low energy availability (LEA) as an adaptive response to physical, nutritional, or extreme emotional stress, causes the release of CRH; In turn, this leads to the inhibition of GnRH pulsatility directly at the level of the hypothalamus and therefore precludes multilevel inhibition of the HPO axis. The hypothalamic-pituitary-thyroid axis is also altered in FHA; TSH levels are low-to-normal and there is an increase in reverse triiodothyronine and low level of triiodothyronine.
Functional hypothalamic amenorrhea | Hormonal
Also, the pattern of secretion of growth hormone is sexually dimorphic; this is why in many species, adult males are visibly distinguishable from females.
Hypothalamus | Sexual dimorphism
In a transsphenoidal hypophysectomy, the pituitary gland or section of the pituitary gland is removed through the sphenoid sinus and out through the nose.
Hypophysectomy | Transsphenoidal hypophysectomy
Treatment is primarily managing the primary cause of the FHA with behavioral modifications. While hormonal-based therapies are potential treatment to restore menses, weight gain and behavioral modifications can have an even more potent impact on reversing neuroendocrine abnormalities, preventing further bone loss, and re-establishing menses, making this the recommended line of treatment. If this fails to work, secondary treatment is aimed at treating the effects of hypoestrogenism, hypercortisolism, and hypothyroidism.
Functional hypothalamic amenorrhea | Introduction
Lifelong hormone replacement therapy for the hormones that are missing. This may involve treatment with glucocorticoids. After hormone profiling, treatment with cortisol, ACTH, thyroid hormones, gonadotropins, and prolactin as seen in cases of hypopituitarism may occur.
Sheehan's syndrome | Treatment
As a result, ACTH is released from the pituitary along with other pro-opiomelanocortin-related peptides such as beta-endorphin and b-lipotropic hormone. It is possible that increased levels of ghrelin in amenorrheic populations sensitizes the adrenal cortex to ACTH and is thereby associated with both hypothalamic CRH release and the frequency of cortisol bursts. Glucocorticosteroids are generally associated with inhibition of GnRH, adding strength to the stress-induced hypothesis of amenorrhea in some patients. By stimulating beta-endorphin, a hypothalamic and pituitary endogenous peptide, CRH can indirectly alter LH function by acting upstream on GnRH. A combination of this factor, along with the direct inhibition of GnRH caused by elevated CRH, may suggest a relationship between the incidence of stress- and exercise-related FHA and opioidergic activity.
Functional hypothalamic amenorrhea | Hormonal
Dysfunction of the hypothalamus results in loss of regulation over behavior and function of the pituitary gland (master gland). Hypopituitarism is present in 75% to 80% of patients with ONH. The anterior pituitary gland contributes to growth, metabolism, and sexual development. The most common pituitary endocrinopathies are growth hormone (GH) deficiency (70%), hypothyroidism (43%), adrenal insufficiency (27%), and diabetes insipidus (5%). Absence of GH may often be indicated by short stature, although this is not always the case. Other indicators of GH deficiency may include hypoglycemic events (including seizures), prolonged jaundice, micropenis in boys, and delayed dentition. Testing for GH may involve blood tests (IGF-1 and IGFBP-3), growth hormone stimulation test, or bone age x-ray of the hand or wrist (or body for children younger than 2 years).
Optic nerve hypoplasia | Hypothalamic dysfunction
Studies indicate that the loss of endogenous estrogens through hypothalamic suppression may worsen an already-existing hyperglycemia, further antagonizing estrogen-mediated NO release and compounding the risk for vascular dysfunction in patients with both FHA and diabetes mellitus.
Functional hypothalamic amenorrhea | Cardiovascular
Symptoms caused by hormone excess and associated mass effects include:
Hyperpituitarism | Symptoms and signs
In turn, the hypothalamus controls the release of hormones from the anterior pituitary by secreting a class of hypothalamic neurohormones called releasing and release-inhibiting hormones—which are released to the hypothalamo-hypophyseal portal system and act on the anterior pituitary.
Tropic hormone | Hypothalamus
The hypothalamus contains neurons that react strongly to steroids and glucocorticoids – (the steroid hormones of the adrenal gland, released in response to ACTH). It also contains specialized glucose-sensitive neurons (in the arcuate nucleus and ventromedial hypothalamus), which are important for appetite. The preoptic area contains thermosensitive neurons; these are important for TRH secretion.
Hypothalamus | Steroids
Hyponatremia, an unusually low level of sodium in the blood that may cause confusion and seizures, is found in 40% of cases. This may be caused by low cortisol levels or by inappropriate release of antidiuretic hormone (ADH) from the posterior pituitary. Several other hormonal deficiencies may develop in the subacute phase. 50% have a deficiency in thyroid-stimulating hormone (TSH), leading to hyposecretion of thyroid hormone by the thyroid gland and characteristic symptoms such as fatigue, weight gain, and cold intolerance. 75% develop a deficiency to gonadotropins (LH and FSH), which control the reproductive hormone glands. This leads to a disrupted menstrual cycle, infertility, and decreased libido.
Pituitary apoplexy | Endocrine dysfunction
Together with Rudolf Fahlbusch she described a form of tertiary hypothyroidism in pituitary stalk transection syndrome (Pickardt-Fahlbusch syndrome) Since 2001 she has been an emeritus professor.
Renate Pickardt | Biography
It is possible that heterozygosity at these loci are not sufficient to cause IHH, but decrease the threshold for HPO inhibition due to environmental factors such as weight loss, stress, and excessive exercise. Functionally speaking, carrying these mutations could confer a selective advantage in a famine conditions, and it is not uncommon for the alleles to be inherited from an asymptomatic parents in both heterozygous and homozygous recessive manifestations of IHH.
Functional hypothalamic amenorrhea | Genetic Predisposition
In the case of prolactin and leptin, there is evidence of active uptake at the choroid plexus from the blood into the cerebrospinal fluid (CSF). Some pituitary hormones have a negative feedback influence upon hypothalamic secretion; for example, growth hormone feeds back on the hypothalamus, but how it enters the brain is not clear. There is also evidence for central actions of prolactin. Findings have suggested that thyroid hormone (T4) is taken up by the hypothalamic glial cells in the infundibular nucleus/ median eminence, and that it is here converted into T3 by the type 2 deiodinase (D2). Subsequent to this, T3 is transported into the thyrotropin-releasing hormone (TRH)-producing neurons in the paraventricular nucleus.
Hypothalamus | Blood-borne stimuli
Functional hypothalamic amenorrhea (FHA) is diagnosed based on findings of amenorrhea lasting three months or more, low serum hormone of gonadotropins and estradiol. Since common causes of FHA include exercising too much, eating too little, or being under too much stress, diagnosis of FHA includes accessing for any changes in exercise, weight, and stress. In addition, evaluation of amenorrhea includes a history and physical examination, biochemical testing, imaging, and measuring estrogen level. Examination of menstrual problems and clinical tests to measure hormones such as serum prolactin, thyroid-stimulating hormone, and follicle-stimulating hormone (FSH) can help rule out other potential causes of amenorrhea.
Hypoestrogenism | Functional hypothalamic amenorrhea
Loss of function of LH receptors can cause male pseudohermaphroditism. In females mutations would have analogous effects. Hormone replacement can be used to initiate puberty and continue if the gene mutation occurs in the gene coding for the hormone. Chromosomal mutations tend to affect the androgen production rather than the HPG axis.
Hypothalamic–pituitary–gonadal axis | Gene mutations
A pituitary disease is a disorder primarily affecting the pituitary gland. The main disorders involving the pituitary gland are: Overproduction or underproduction of a pituitary hormone will affect the respective end-organ. For example, insufficient production (hyposecretion) of thyroid stimulating hormone (TSH) in the pituitary gland will cause hypothyroidism, while overproduction (hypersecretion) of TSH will cause hyperthyroidism. Thyroidisms caused by the pituitary gland are less common though, accounting for less than 10% of all hypothyroidism cases and much less than 1% of hyperthyroidism cases.
Pituitary disease | Introduction
The hypothalamic–pituitary–thyroid axis (HPT axis for short, a.k.a. thyroid homeostasis or thyrotropic feedback control) is part of the neuroendocrine system responsible for the regulation of metabolism and also responds to stress. As its name suggests, it depends upon the hypothalamus, the pituitary gland, and the thyroid gland. The hypothalamus senses low circulating levels of thyroid hormone (Triiodothyronine (T3) and Thyroxine (T4)) and responds by releasing thyrotropin-releasing hormone (TRH). The TRH stimulates the anterior pituitary to produce thyroid-stimulating hormone (TSH). The TSH, in turn, stimulates the thyroid to produce thyroid hormone until levels in the blood return to normal. Thyroid hormone exerts negative feedback control over the hypothalamus as well as anterior pituitary, thus controlling the release of both TRH from hypothalamus and TSH from anterior pituitary gland.
Hypothalamic–pituitary–thyroid axis | Introduction
In addition, physicians should also inquire about eating and reproductive disorders within the family. In patients presenting with structural abnormalities that may preclude regular menses, it is still necessary to take emotional history and lifestyle into account before establishing a diagnosis. These patients may still demonstrate patterns of excessive exercise or restrictive eating, proving the important role of behavioral etiology in FHA diagnosis. A full physical exam, external gynecological and bimanual exam can be performed to assess for organic causes of amenorrhea. Symptoms of hypoestrogenism, whose severity will positively correlate with the duration of hypoestrogenism, will be present in FHA patients; these can can include lack of cervical mucus, pale areola and nipples, thinned, reddened vaginal and vestibular epithelium, and uterine hyperplasia, though FHA is not typically associated with hot flashes.
Functional hypothalamic amenorrhea | History and physical exam
In adult women, FHA can lead to atrophic changes, such as lack of cervical mucus, thinning of vaginal epithelium, and uterine muscle atrophy (hypoplasia), which can lead to painful intercourse (dyspareunia).
Functional hypothalamic amenorrhea | Reproductive
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Hypochondrogenesis | External links
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.
Hyperpituitarism | Cause
According to the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists, menstrual status should be considered a “vital sign” for all routine clinical visits because of the known effects of hypoestrogenism on bone and tissue health.
Functional hypothalamic amenorrhea | Presentation
It is easy to see from these interplays why anorexics with decreased leptin and athletes who consume less calories than they expend are likely to present with FHA as a mechanism to preserve energy for processes critical to survival.
Functional hypothalamic amenorrhea | Risk factors
In amenorrheic athletes who have a near-normal weight, menses may be restored during periods of deceased training. The fact that nutritional restoration is insufficient for restoring menses in some women highlights the influence that psychological issues, including mood disorders and obsessive patterns of behavior such as hyper-exercise and/or restrictive eating behavior, impart on the etiology of FHA. The disease can present in a variety of ways in both adolescents and adult women. Patients may present with subclinical menstrual dysfunction, ovulatory amenorrhea, amenorrhea, or have a history of combination of these disturbances. In most cases, there is a gradual loss of ovulation and menses demonstrated as the diseases manifests, followed by the eventual cessation of menstrual cycles altogether.
Functional hypothalamic amenorrhea | Presentation
Thyrotropes (also called thyrotrophs) are endocrine cells in the anterior pituitary which produce thyroid stimulating hormone (TSH) in response to thyrotropin releasing hormone (TRH). Thyrotropes consist around 5% of the anterior pituitary lobe cells. Thyrotropes appear basophilic in histological preparations.
Thyrotropic cell | Introduction
In this particular form of hypoparathyroidism, the parathyroid glands are underdeveloped and therefore do not produce enough parathyroid hormone. This is caused by a mutation on the x chromosome in the region of Xq26-27.
X-linked recessive hypoparathyroidism | Pathophysiology
A poorly functioning pituitary gland may also cause a lack of thyroid hormone, leading to central hypothyroidism. Thyroid hormone is critical for growth and brain development, especially during the first few weeks to months of life. Children with untreated hypothyroidism are at high risk of mental retardation; thus, early detection is crucial. Central hypothyroidism can be diagnosed by a low or normal thyroid-stimulating hormone (TSH) in the presence of a low level of free T4. Free T-4 should be checked annually for at least four years.
Optic nerve hypoplasia | Hypothalamic dysfunction
The risk of FHA due to weight-related factors increases across a series of four behaviors: 1) aesthetic dieting; 2) dieting due to obsessive ideals about diet and/or weight; 3) suppression of appetite, whether by drugs or self; 4) eating disorder, generally anorexia nervosa. Patients affected by eating disorders have overactive hypothalamic-pituitary systems, causing increased cortisol release and elevated β-endorphin concentrations. Hyperactivation of the hypothalamic-pituitary system appears to be manifested through increased secretion of CRH and beta-endorphin by the central nervous system, both of which can alter GnRH pulsatility. LH secretion may return to prepubertal levels, which is likely due to decreased GnRH secretion.
Functional hypothalamic amenorrhea | Weight-related
The genes implicated included the following: FGFR1, which is involved in the specification, fate, migration, and survival of GnRH-secreting neurons, PROKR2 and KAL1, which enable the migration of GnRH-secreting neurons, and GNRHR, which encodes the pituitary receptor activated by GnRH1. Mutations in PROKR2 or FGFR1 may cause mechanistic dysfunction of GnRH pathways by either decreasing the number of GnRH-secreting cells that are able to migrate to the hypothalamus in development, inhibiting maturation of these cells during maturity, or disrupting GnRH secretion in adulthood. FHA patients harboring these mutations have been shown to be able to resume regular menses, further reinforcing that while genetic defects may predispose one to the condition, environmental factors play a pivotal role in disease manifestation.
Functional hypothalamic amenorrhea | Genetic Predisposition
Laboratory testing of thyroid stimulating hormone levels in the blood is considered the best initial test for hypothyroidism; a second TSH level is often obtained several weeks later for confirmation. Levels may be abnormal in the context of other illnesses, and TSH testing in hospitalized people is discouraged unless thyroid dysfunction is strongly suspected. An elevated TSH level indicates that the thyroid gland is not producing enough thyroid hormone, and free T4 levels are then often obtained. Measuring T is discouraged by the AACE in the assessment for hypothyroidism. There are a number of symptom rating scales for hypothyroidism; they provide a degree of objectivity but have limited use for diagnosis.
Hypothyroidism | Diagnosis
Hypothalamic–pituitary hormones are hormones that are produced by the hypothalamus and pituitary gland. Although the organs in which they are produced are relatively small, the effects of these hormones cascade throughout the body. They can be classified as a hypothalamic–pituitary axis (HP axis) of which the adrenal (), gonadal (), thyroid (), somatotropic (), and prolactin () axes are branches. It is possible for the function of these hormones to be altered by physical activity.. In posterior pituitary we have hormones that control absorption of water and oxytocin.
Hypothalamic–pituitary hormone | Introduction
It was characterized in 1952 by Fuller Albright as "pseudo-pseudohypoparathyroidism" (with hyphen).
Pseudopseudohypoparathyroidism | History
Hypothyroidism is a disease that may have severe, adverse effects on the brain development in a fetus. These problems are often caused by a "passing-down" from the mother or from an external neurotoxin causing impaired cognitive ability and, in extreme cases, mental retardation. Hypothyroidism is usually caused by an iodine deficiency that results in the under production of thyroid hormones or an underdeveloped thyroid gland with similar effects. Thyroid hormone release is regulated by a stimulating hormone called thyrotropin (TSH) in a normal functioning person. In abnormal cases when there are lowered levels of thyroid hormone, TSH levels increase to compensate, thus doctors and medical researchers can measure TSH levels to predict hypothyroidism.
Prenatal memory | Hypothyroidism
Thymic hypoplasia is a condition where the thymus is underdeveloped or involuted. Calcium levels can be used to distinguish between the following two conditions associated with thymic hypoplasia:
Thymic hypoplasia | Introduction
Hypergonadotropic hypogonadism (HH), also known as primary or peripheral/gonadal hypogonadism, is a condition which is characterized by hypogonadism due to an impaired response of the gonads to the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and in turn a lack of sex steroid production and elevated gonadotropin levels (as an attempt of compensation by the body). HH may present as either "congenital" or "acquired", but the majority of cases are of the former nature.
Hypergonadotropic hypogonadism | Introduction
Hypophysectomy is the surgical removal of the hypophysis (pituitary gland). It is most commonly performed to treat tumors, especially craniopharyngioma tumors. Sometimes it is used to treat Cushing's syndrome due to pituitary adenoma or Simmond's disease It is also applied in neurosciences (in experiments with lab animals) to understand the functioning of hypophysis. There are various ways a hypophysectomy can be carried out. These methods include transsphenoidal hypophysectomy, open craniotomy, and stereotactic radiosurgery. Medications that are given as hormone replacement therapy following a complete hypophysectomy (removal of the pituitary gland) are often glucocorticoids. Secondary Addison's and hyperlipidemia can occur. Thyroid hormone is useful in controlling cholesterol metabolism that has been affected by pituitary deletion.
Hypophysectomy | Introduction