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'Be the Match' event hopes to connect younger generation with the act of becoming a bone marrow donor - KETV Omaha

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Abstract

Hypopituitarism is a chronic endocrine illness that caused by varied etiologies. Clinical manifestations of hypopituitarism are variable, often insidious in onset and dependent on the degree and severity of hormone deficiency. However, it is associated with increased mortality and morbidity. Therefore, early diagnosis and prompt treatment is necessary. Hypopituitarism can be easily diagnosed by measuring basal pituitary and target hormone levels except growth hormone (GH) and adrenocorticotropic hormone (ACTH) deficiency. Dynamic stimulation tests are indicated in equivocal basal hormone levels and GH/ACTH deficiency. Knowledge of the use and limitations of these stimulation tests is mandatory for proper interpretation. It is necessary for physicians to inform their patients that they may require lifetime treatment. Hormone replacement therapy should be individualized according to the specific needs of each patient, taking into account possible interactions. Long-term endocrinological follow-up of hypopituitary patients is important to monitor hormonal replacement regimes and avoid under- or overtreatment.

Keywords: Hypopituitarism, Adrenocorticotropic hormone deficiency, Thyrotropin deficiency, Gonadotropin deficiency, Growth hormone deficiency, Anti-diuretic hormone deficiency

Hypopituitarism is defined as the total or partial loss of anterior and posterior pituitary gland function that is caused by pituitary or hypothalamic disorders [1]. The incidence rate (12 to 42 new patients per million per year) and the prevalence rate (300 to 455 patients per million) seems to underestimate the actual incidence of this disorder given that as many as 30% to 70% of patients with brain injury exhibit symptoms of diminished hormone secretion from their pituitary gland [2]. Additionally, factors such as the cause of hypopituitarism, age of onset, and the speed and degree of loss of hormone secretion may affect the clinical manifestations of hypopituitarism. For example, although a partial hormone deficiency that progresses slowly may go undetected for years, the sudden and complete loss of hormone secretion results in an emergency situation that requires immediate medical attention [2]. The treatment of hypopituitarism typically involves a replacement of the deficient hormone but care must be taken because several studies have reported an increased incidence of cardiovascular disorders and number of deaths among these patients [3]. Additionally, a significant proportion of patients who have been treated for a hormone deficiency suffer from more or less vague discomforts and a reduced quality of life [4]. The present review will describe the general aspects of hypopituitarism focusing on the limitations of the stimulation test and hormone replacement treatment.

A variety of diseases may cause hypopituitarism and, accordingly, this disorder can be divided into two types depending on its cause [1]. Primary hypopituitarism is caused by disorders of the pituitary gland itself and may be due to the loss, damage, or dysfunction of pituitary hormone-secreting cells. On the other hand, secondary hypopituitarism is the result of diseases of the hypothalamus or pituitary stalk interrupting the nerve or vascular connections to the pituitary gland, thereby reducing the secretion of the pituitary hormones (). Reductions in hormone secretion in the posterior pituitary gland may largely be due to failures in hormone synthesis or secretion from the hypothalamus while decreased hormone secretion in the anterior pituitary gland may be due to deficiencies in the activity of one or more of the neurohormones secreted from the hypothalamus [1].

Causes of Hypopituitarism

The most common causes of primary hypopituitarism are pituitary adenoma and complications from surgery or radiation therapy for the treatment of pituitary adenoma [5]. In these situations, the diameter of the pituitary adenoma is 1 cm or larger and, the onset of hypopituitarism is usually slow unless the patient suffers from a pituitary apoplexy whose symptoms occur within several hours or a few days [5]. Several putative mechanisms of hormone deficiency include the application of direct pressure onto or damage to the normal tissues surrounding the tumor, mechanical compression of the portal veins by the pituitary stalk, raised intrasellar pressure, and focal necrosis due to the prolonged portal vein interruption [5]. Furthermore, inflammatory hypophysitis (including various types of autoimmune hypophysitis), which has an unknown etiology and presents with symptoms that are difficult to differentiate from those associated with a tumor, is another possible cause of hypopituitarism [5]. Although this cause is rare, it is known to exhibit clinical features such as the isolated or combined lack of adrenocorticotropic hormone (ACTH), thyroid stimulating hormone (TSH), gonadotropin, and/or growth hormone (GH) [5].

Radiation exposure for the treatment of malignant conditions in the head and neck area may also cause hypopituitarism [6]. Additionally, a variety of hormone deficiencies may occur when treating a pituitary tumor with radiotherapy and the onset of these conditions depends on the total amount of radiation, whether fractioning was done, and the time elapsed after radiation [5]. The frequency of the manifestation of a hormone deficiency is greater than 50% at 10 years after the radiation exposure. Most patients, like patients with pituitary adenomas, present with a typical course starting with GH deficiency, gonadotropin deficiency, ACTH deficiency, progressing to TSH deficiency (or TSH deficiency followed by ACTH deficiency) [7]. Additionally, although further study is warranted, it is generally accepted that the incidence of hypopituitarism is lower following gamma knife radiosurgery than after conventional radiotherapy techniques [5].

The occurrence of hypopituitarism following surgery to remove a pituitary tumor varies from 10% to 25% and may have to do with the size of the tumor, the degree of invasion, the quantity of remaining normal tissues, and the degree of technical competency of the neurosurgeon [5]. In rare cases, hypopituitarism has been observed when a cytomegalovirus infection occurs in patients with the AIDS virus [8]. Sheehan's syndrome, which is hypopituitarism caused by the postpartum hemorrhage of the pituitary gland, frequently occurred in the past but it is rarely seen today [5]. Tuberculosis meningitis and hemorrhagic fever with renal syndrome, which were occasionally observed in the past but are virtually nonexistent today [1]. In still rarer cases, solitary or complicated pituitary hormone deficiency syndromes may occur due to genetic causes and typically affect children () [5].

Genetic Causes of Hypopituitarism

Damage to the pituitary stalk often occurs after the head and/or neck injury accompanying a fracture of the bones surrounding the sella turcica [5]. Additionally, tumors near the sella turcica may press against the stalk and damage it. The stalk is often accidentally severed during surgery on a sellar or parasellar mass [1]. Central nervous system disorders involving the hypothalamus, such as craniopharyngioma and germ cell tumor, may also cause hypopituitarism by impeding the secretion of releasing hormone from hypothalamus [1]. Depending on the anatomical location of the lesion, patients may manifest symptoms consistent with a single hormone deficiency, panhypopituitarism, or a posterior pituitary failure (diabetes insipidus) [1]. Recently, the prevalence of idiopathic hypopituitarism has increased but it is thought that these cases are likely due to a severed stalk resulting from traumatic brain injury (TBI) or hypothalamic damage [1]. Similarly, the incidence of hypopituitarism after a TBI seems to be more frequent than previously thought as the prevalence rate ranges from 30% to 70% based on the patients' charateristics and the types of diagnostic tests [2]. The most common problem associated with hypopituitarism is a GH deficiency. Following TBI, the early diagnosis of a hormone deficiency has an important impact on their degree of recovery from TBI [2]. Additionally, it has been demonstrated that hormone replacement therapy improves rehabilitation outcome and the quality of life of a patient [9]. Whereas approximately half of the patients who exhibit hypopituitarism within 6 months of a TBI recover normal pituitary function within 1 year, some patients with normal hormone levels after a TBI develop new hormone deficiency after 12 months [2]. Early posttraumatic panhypopituitarism generally persists [2]. Thus, it is recommended to re-evaluate anterior pituitary function and quality of life after approximately 6 to 12 months of an injury [2]. However, it is controversial regarding the most appropriate early evaluation time after this type of injury.

It is also important to closely monitor patients after a subarachnoid hemorrhage because the symptoms of a pituitary hormone deficiency may become evident [2]. Generally, the loss of pituitary function due to secondary hypopituitarism (dysfunction in the hypothalamus or pituitary stalk) is less serious than primary hypopituitarism but diabetes insipidus is more frequent in secondary hypopituitarism [1].

Health problems such as metabolism disorders, systemic diseases, and stress can all be related to selective pituitary hormone deficiencies. The influence of stress seems to manifest via inflammatory cytokines such as interleukin 1 (IL-1) and IL-6, which have severely suppressive effects on thyroid releasing hormone (TRH) and gonadotropin releasing hormone (GnRH) levels while at the same time stimulating the secretion of corticotropin releasing hormone (CRH). This is one possible explanation for euthyroid sick syndrome or hypothalamic amenorrhea because when the original stress is eliminated, these suppressive effects are also ameliorated. In contrast, inflammatory or invasive diseases that destroy the hypothalamus may explain the infrequent recovery of neuroendocrine function in patients suffering from these disorders even after the underlying disease is treated [1].

In rare cases, genetic conditions such as Kallmann syndrome or neurohypophyseal diabetes insipidus may contribute to reduced pituitary function. Kallmann syndrome manifests from a wide array of genetic mutations, including the KAL1 gene [10]. In these patients, there is a loss of GnRH neurons in the hypothalamus which leads to GnRH deficiencies and hypogonadotropic hypogonadism (the lack of secondary sex characteristics) in conjunction with olfactory loss (anosmia or hyposmia) that is due to olfactory bulb loss or hypoplasia [10]. There is also a condition known as neurohypophyseal (familial) diabetes insipidus that is triggered by mutations of the neurophysin II part of the vasopressin-neurophysin precursor genes [11]. Due to these mutations, the precursor genes do not divide into vasopressin and neurophysin II which, in turn, causes an excessive accumulation of the precursor substance within the cells that leads to the eventual death of the hypothalamic neurons (apoptosis) in which these genes are expressed. Depending on the genetic disorders or degree of the mutation, the symptoms manifest immediately after the birth or during childhood [11].

The underlying pathology, speed of onset and the severity of hypopituitarism have a significant impact on the clinical features [5]. In particular, if hypopituitarism is caused by a space-occupying lesion (tumor), then mass effects such as headache, visual impairment, and rarely, personality changes and hypothalamic syndrome may appear [5]. The clinical expression of severe panhypopituitarism, which typically occurs immediately after hypopituitary patients discontinue hormone replacement or following the pituitary apoplexy or hypophysectomy, may be evident within several hours (diabetes insipidus) or a few days (adrenal insufficiency) [4]. However, most patients exhibit a slow and progressive loss of pituitary function with a relatively mild and vague or nonspecific clinical symptoms. In fact, in many cases, these patients are not diagnosed with hypopituitarism for a prolonged time [3].

GH-secreting cells (somatotrophs) are particularly vulnerable to pressure, which is why GH deficiency occurs first and most frequently among all pituitary hormones, followed by deficiencies of gonadotropin (luteinizing hormone [LH] and follicle stimulating hormone [FSH]), TSH and ACTH (or ACTH and TSH), and prolactin [12]. The most common hormones that show selective deficiencies are GH and gonadotropins. Children tend to suffer from GH deficiency while adults often complain of symptoms from gonadotropin deficiency [3]. The clinical symptoms stemming from a lack of ACTH, TSH, and/or gonadotropins vary somewhat but are similar to those associated with target gland hormone deficiency; the major symptoms are listed in [4].

Clinical Symptoms and Signs of Hypopituitarism

If ACTH deficiency is partial, then the patient may experience a relatively normal and event-free life, but patients with severe ACTH deficiency suffer from a variety of vague and nonspecific complaints [13]. ACTH deficiency (secondary adrenal insufficiency) is different from a primary adrenal insufficiency (Addison's disease) in that the true onset of an Addisonian crisis (adrenal crisis) is very rare because aldosterone secretion is partially independent of the pituitary gland [13]. Although it is possible that aldosterone secretion may be diminished in the case of hypopituitarism due to ACTH deficiency, the residual secretion of aldosterone, which is controlled by the renin/angiotensin system, is sufficient for the maintenance of normal plasma volume and blood pressure except acute stress [13]. No hyperpigmentation has been observed in other cases of ACTH deficiencies [13]. Because ACTH stimulates the secretion of adrenal androgen, the lack of adrenal androgen due to ACTH deficiency may contribute to the loss of sexual desire in females and it may become the primary cause for the loss of pubic and axillary hair [13]. In contrast, the loss of adrenal androgen is not as important for males due to the abundant testosterone that is secreted from the testicles [13].

TSH deficiency produces symptoms that are similar to those associated with primary hypothyroidism except that its clinical symptoms are not as severe [14]. Although the underlying mechanism has yet to be ascertained, the cases of family with isolated TSH deficiency have been reported [15].

In both males and females, complete FSH/LH deficiency is tantamount to the loss of the target organs function (gonads) but the clinical expression varies depending on whether it occurs prior to or after puberty [6]. Partial FSH/LH deficiency due to hypothalamic lesions may often be associated with the loss of sexual desire, oligomenorrhea, and anovulation, In most cases, both LH and FSH are diminished at the same time, but cases in which just one of these hormones is deficient have been reported [6].

GH deficiency results in growth disorders; the degree of decreased GH secretion and the extent of the growth delay may be severe when they are associated with organic illnesses of the pituitary gland [16]. On the other hand, when there is no organic illness (idiopathic GH deficiency), the deficiency in GH secretion and the accompanying growth delay vary widely such that the height of the affected children may be the same as shorter unaffected children of the same age [16]. In the case of idiopathic severe GH deficiency, they presented fasting hypoglycemia, and it is of the utmost importance to perform a detailed assessment of the family history and to conduct complementary hormone measurements. On the other hand, a GH deficiency in adults is difficult to clinically diagnose because it is usually nonspecific. The typical symptoms include fatigue, general weakness, reduced vitality and physical strength, and diminished mental agility. Additionally, moderate obesity with evident visceral deposition may occur and hyperlipidemia, reduced levels of high density lipoprotein cholesterol, osteopenia, and reduced myocardial contractility are typically observed [16]. The increase in cardiovascular risks may be related to an increased frequency of metabolic syndrome and a higher incidence of death among these patients [16].

Prolactin deficiency cause only one clinical symptom, which is the inability to produce milk after childbirth [6]. A lack of prolactin is more closely associated with difficulty synthesizing milk than with producing milk and is not clinically important in countries where artificial lactation is readily available [6]. However, because prolactin is regulated by dopamine, which acts as a neuroendocrine inhibitor in the hypothalamus, hyperprolactinemia accompanied by other pituitary hormone deficiencies is more frequent and problematic and may result in hypogonadism [6].

Of the two posterior pituitary hormones, oxytocin and vasopressin (anti-diuretic hormone [ADH] or arginine vasopressin [ADH]), only vasopressin deficiency leads to the clinical presentation. The major symptoms include polydipsia, polyuria, and nocturia. The onset of the disorder may be acute or chronic depending on the underlying diseases [6]. Because patients with partial diabetes insipidus may not show severe symptoms, this disorder may not be immediately diagnosed. Moreover, the symptoms associated with diabetes insipidus may improve when accompanied by an anterior pituitary hormone deficiency, in particular ACTH deficiency or severe TSH deficiency. This may be because there is an enhanced secretion of ADH due to a cortisol deficiency or because ADH functionality of the renal tubule is strengthened [6]. Accordingly, the symptoms of diabetes insipidus reappear after cortisol or thyroxine replacement.

The diagnosis of hypopituitarism is made by measuring basal hormone levels in the morning fasting status or performing stimulation tests if necessary. Six anterior pituitary hormones (GH, prolactin, LH, FSH, TSH, and ACTH) as well as target hormones can be measured via sensitive and reliable immunoassay techniques. Other pituitary hormones except GH and ACTH deficiency can be diagnosed with basal hormone measurement. Hence, combined pituitary function tests (i.e., the cocktail test) is rarely used [17].

Measurement of basal hormone levels is sufficient for the differentiation of hypopituitarism from primary target organ hormone deficiency. For example, the lack of an increase in pituitary hormone levels in conjunction with reduced target organ hormone levels is typically observed in case of a hypothalamic or pituitary gland disease [4]. Conversely there is an increase in pituitary hormone levels when there is target organ hormone deficiency. Thus, the differentiation of a target organ deficiency from a hypothalamic or pituitary gland disease is relatively simple but a stimulation test may also be necessary to determine the origin of the disease, albeit rarely. The expected values and responses of the pituitary gland and target organ hormones under basal and stimulated states are provided in . In several cases, it is necessary to distinguish between a pituitary disease (primary hypopituitarism) and a hypothalamic disease (secondary hypopituitarism), but this is not easily accomplished. In these situations, it is helpful to diagnose hypothalamic diseases based on the expression of clinical manifestations, such as diabetes insipidus or hypopituitarism accompanying hyperprolactinemia, neuro-ophthalmological symptom, such as visual impairments, neuropsychiatric symptoms [5]. For purposes of differentiation, a stimulation test using hypothalamus releasing hormones can be performed. However, sellar magnetic resonance imaging (MRI) can distinguish pituitary diseases from hypothalamic diseases, and treatment is not different. Thus, differentiation pituitary diseases from hypothalamic diseases may not be necessary.

Diagnostic Evaluation of Hypopituitarism

Pituitary ACTH deficiency is difficult to diagnose using basal ACTH or cortisol measurements. Because cortisol levels are normally at their peak in the morning due to diurnal rhythm, it is advisable to measure these concentrations at approximately 8:00 AM to 9:00 AM [4]. If the cortisol level is very low (<3 to 4 g/dL) or very high (>15 to 16 g/dL) then a stimulation test is not needed. Because this value is not absolute, a stimulation test is only necessary when a definite diagnosis is required and, in this case, ACTH deficiency can be diagnosed by measuring ACTH and/or cortisol levels via the administration of metyrapone, ACTH, or CRH, or with an insulin-induced hypoglycemia test (insulin tolerance test) [4]. The insulin tolerance test has long been considered to be the gold standard test for this diagnosis but it may cause severe hypoglycemia [4]. However, it can be safely administered under the close supervision of a physician to effectively determine the level of GH secretion as well as the presence of an ACTH deficiency. In a clinical context, the rapid ACTH stimulation test, which measures cortisol levels after the administration of ACTH, is preferred if the risk of hypoglycemia is evident in a patient (normal level, >18 to 20 g/dL) [4]. An insulin tolerance test is conducted when it is necessary to determine GH levels.

It is widely accepted that maximum serum cortisol levels can be observed after the administration of doses of ACTH much lower than the usual dose of 250 g that is given in the rapid ACTH test [18]. This implies that the sensitivity of the test can be improved by reducing the amount of ACTH that is administered. Indeed, several studies have reported that the low-dose 1 g ACTH stimulation test is more sensitive than the usual 250 g ACTH dose that is generally used in the rapid ACTH test for diagnosing adrenal gland hypofunction (central or secondary adrenal insufficiency) due to ACTH deficiency [18]. However, the low-dose ACTH stimulation test has not yet replaced the standard 250 g stimulation test in clinical contexts because other studies have reported that the low-dose diagnostic test is not as precise as the conventional high-dose test and that there are technical problems associated with diluting a 250 g solution into a 1 g solution [19]. A recent study conducted by the present author indicated that the low-dose 1 g ACTH stimulation test is not superior to the standard high-dose 250 g test [20]; as a result, this author continues to utilize the conventional high-dose ACTH stimulation test. Furthermore, the findings of this study demonstrated that the normal range of the cortisol response during the ACTH stimulation test exceeded 18 g/dL for patients with hypopituitarism and 20 g/dL for all others. This is likely because other pituitary hormone deficiencies typically accompany ACTH deficiencies, which would make the cortisol response of these patients lower than that of healthy individuals [20].

It is possible to diagnose a TSH deficiency using only a thyroid function test. Despite the presence of reduced free thyroid hormones, TSH concentrations that are at or below the normal range (with often a slight increase in its concentration) imply that there is a problem in the pituitary gland or the hypothalamus [4]. TSH deficiency can be easily distinguished from primary hypothyroidism in cases where the TSH level increases inordinately [5]. Although the TRH stimulation test is not administered clinically [21], it is possible to easily distinguish pituitary lesions from hypothalamic lesions because hypothalamic diseases result in an increased but delayed TSH response [21].

In many cases, it is possible to diagnose gonadotropin deficiency using a basal hormone test and an evaluation of clinical symptoms. This is particularly true for postmenopausal females because it is always possible to diagnose this population based on the lack of an increase in gonadotropin concentrations [2,4]. For males, this diagnosis can be made based on normal or reduced serum LH and FSH concentrations despite reduced serum testosterone levels [4]. For females, it is possible to make this diagnose based on reduced levels of estradiol and normal or reduced levels of LH and FSH in conjunction with oligomenorrhea or amenorrhea. Moreover, it is also necessary to distinguish gonadotropin deficiencies that are due to hyperprolactinemia, which frequently occurs in male and female hypopituitary patients [4], and to determine whether reduced serum testosterone levels in males are due to decreased levels of sex-hormone binding globulin. In a clinical context, the GnRH stimulation test is often performed to diagnose gonadotropin deficiency and may be helpful for identifying problems in the pituitary gland and hypothalamus [10]. However, it takes several days of stimulation for the gonadotrophs that were not stimulated by GnRH due to a hypothalamic disease to detect the gonadotropin secretion response. This makes it difficult to determine the primary cause of a gonadotropin deficiency with only a single GnRH injection.

When diagnosing GH deficiency in adult patients, the basal GH concentration is not considered to be valuable but measures of insulin-like growth factor 1 (IGF-1) may be of some use, although they are not sufficient themselves [4]. Thus, a stimulation test is necessary for a definitive diagnosis. Additionally, the use of previous test results and other data is warranted, including past medical records detailing GH deficiencies, organic pituitary gland diseases, and other pituitary hormone deficiencies during childhood (during which it is sufficient to use a single stimulation test) [4,5]. Although controversy remains regarding which GH stimulation test is the most appropriate for the purpose, the most widely used and reliable measure is the insulin tolerance test in which GH levels lower than 3 g/L are considered to indicate a severe deficiency, GH levels between 3.0 and 4.9 g/L indicate a partial deficiency, and GH levels higher than 5.0 g/L are considered normal [4]. For patients in whom hypoglycemia is contraindicated, it is possible to administer a variety of stimulation tests and, in this case, the diagnostic criteria of GH deficiency according to the type of stimulation tests and standard GH assay [4].

The diagnosis of posterior pituitary hormone deficiency can be easily made through a review of clinical symptoms/signs and a water deprivation test [5]. Additionally, the recently available plasma ADH concentration measurement technique can distinguish central diabetes insipidus from nephrogenic diabetes insipidus although it cannot differentiate central diabetes insipidus from compulsive water drinking or psychogenic polydipsia [5]. Given the limited availability of reliable laboratories that are capable of testing blood ADH levels and the longer time that it takes to perform and analyze these levels compared to the performance of the water deprivation test, the blood ADH test is conducted only when absolutely necessary [5].

It is advisable to re-evaluate pituitary gland functionality 2 to 3 months after an operation because, although most hypopituitarism symptoms are irreversible, a patient may recover some of level of function [4]. When a pituitary hormone deficiency occurs following a TBI, it is also necessary to re-evaluate function after some time has elapsed. In addition, of the patients with prolactinoma that are treated with a dopamine agonist, two-thirds recover pituitary gland function [22], which indicates that sporadic re-evaluations of pituitary gland function can prevent unnecessary replacement therapy. Similarly, children who exhibit an idiopathic single GH deficiency or severe GH deficiencies due to radiotherapy require re-evaluation of their GH function when they reach maturity [4].

The pre- and postoperative incidence rates of hypopituitarism are similar because some hormone function can be recovered following the removal of a pituitary tumor [5] whereas deficiencies in other pituitary hormones may develop after surgery. Except in cases such as transient diabetes insipidus after surgery or hypopituitarism after TBI, most hypopituitarism symptoms are irreversible [4]. This is why it is necessary for physicians to inform their patients that they may require lifetime treatment unless there are special circumstances, such as the discontinuation of estrogen replacement after menopause [3]. Accordingly, the primary goals of treatment should be centered around the recuperation of the physiological health of the patient in terms of growth, reproduction, metabolism, and body composition [2,4,5].

Although replacement with hypothalamic or pituitary hormones are physiologic (at least theoretically), we administrate target organ hormone due to the high cost and inconvenience of repeated injections. Exception is GH or ADH replacement and the recovery of reproductive abilities [3]. In clinical situations, prolactin and oxytocin deficiency are generally not treated [4]. Although the basic principles underlying the replacement of deficient hormones remain very clear and simple, it is not possible to replace hormones to physiological levels using current treatment technologies and there are limitations to monitor the treatment response [3,4]. There is no doubt that hypopituitarism is associated with an increased incidence of cardiovascular death but the mechanisms linking these disorders remain unclear [3]. However, possible contributing factors include GH deficiencies that are left untreated, replacement of other target hormones in non-physiological ways, and the specific underlying disease. For example, if hypopituitarism develops in a patient with acromegaly, Cushing's disease, or craniopharyngioma then the underlying disease may increase the mortality [3]. Similarly, the method of tumor treatment will matter because surgery, pharmacotherapy, or i.e., radiotherapy may increase the incidence of death [3]. Given that there is a variety of causes underlying hypopituitarism as well as varying degrees of hormone deficiencies and types of deficient hormones, it is important to individualize hormone replacement therapy to the specific needs of a particular patient.

ACTH deficiency can be treated with either hydrocortisone or prednisolone, which is a synthetic corticosteroid drug [3]. In patients with hypopituitarism whose aldosterone levels are approximately normal, there is no need to replace mineralocorticoids [3]. However, in most cases of hypopituitarism, ACTH deficiency is only partial which makes it difficult to determine whether the patient needs lifetime therapy or treatment only under conditions of stress [3]. If blood cortisol levels exceed 10 g/dL during a stimulation test in conjunction with the absence of specific deficiency symptoms, then there is likely to be a partial deficiency and, thus, it would be advisable for the physician to either monitor the patient but not administer medicine or to observe the progress of the patient after administration of 10 mg of hydrocortisone or 2.5 mg of prednisolone [3]. If there is little difference in clinical response before and after the administration, the treatment can be discontinued. If clinical improvement is seen in patients after the administration, it must be decided whether the treatment can proceed using the same dose or if it should be slightly increased to 12.5 to 15.0 mg of hydrocortisone or to 3.75 mg of prednisolone. The choice of hydrocortisone or prednisolone is at the physician's preference but the use of hydrocortisone, which is more physiologic glucocorticoid, is recommended because prednisolone has been associated with more side effects following long-term use despite the longer and stronger efficacy [3].

The dose of the drug may be steadily increased but it is advisable that administration of hydrocortisone be performed only once or twice a day with daily dose of 10 to 15 mg. Although the most commonly used treatment regimens include two times per day, some doctors advocate the use of three administration. It may also be possible to treat patients with a partial deficiency using 5 to 10 mg of hydrocortisone once a day [3]. When using prednisolone, it is desirable to take 2.5 to 3.75 mg once a day on an empty stomach [3]; the present author prefers to use once a day prednisolone with administration of 2.5 and 3.75 mg on alternate days. In terms of the appropriate dosage, there are no biochemical markers to aid in the determination of proper glucocorticoid levels and, as a result, it is recommended that the minimum dose needed to improve patients' symptoms [3]. When using hydrocortisone, the measurement of cortisol concentrations in the blood or urine does not aid in determining proper dosage. The recommended doses for hydrocortisone (20 mg a day) and prednisolone (5 mg) are clearly excessive for the average Korean patient. Although there is a new slow-acting formulation of hydrocortisone and a special hydrocortisone drug has been designed to take into account the diurnal differences that parallel normal cortisol secretion [3]. It is too early to tell if these drugs are appropriate for clinical purposes.

Under stressful conditions, a patient must be treated with the same methods as those used to treat patients with primary adrenal insufficiency; i.e., increase the dose by 2- to 3-fold for mild stress and administer an intravenous (IV) injection of hydrocortisone (150 to 200 mg) a day for severe stress. Moreover, it is necessary to increase glucocorticoid doses by 1.5- to 2-fold when used in tandem with liver enzyme inducers such as phenytoin, barbiturate, rifampin, and carbamazepine, and to reduce the glucocorticoid dose when liver enzyme inhibitors such as ketoconazole, itoconazole, cyclosporine, and tacrolimus are being used [3]. If the liver or renal function of a patient is not at an ideal level, the dose should not be adjusted [3].

For pregnant women, it is advisable to prescribe hydrocortisone rather than prednisolone because the latter can pass through the placental barrier [4]. During the first trimester of pregnancy, there is no need to increase the dose of glucocorticoid but an increase of approximately 50% (2.5 to 10.0 mg) is needed during the third trimester due to increased levels of corticosteroid binding globulin [4]. At the time of delivery, a large amount of hydrocortisone needs to be injected intravenously [4]. In contrast to pregnant females, females that are receiving estrogen therapy do not require an adjustment in glucocorticoid doses [4]. Although several studies have indicated that replacement with dehydroepiandrosterone (DHEA), which is the adrenal androgen that is typically deficient in women, improves sexual desire [23], it is not yet recognized as a standard replacement treatment. In these situations, the patient must be trained regarding the onset of acute adrenal insufficiency (adrenal crisis), which requires an increase in dose, and must always carry a hydrocortisone injection as well as a card indicating his/her status as an adrenal insufficient patient. Additionally, the patient should learn how to self-inject hydrocortisone.

TSH deficiency is treated with L-thyroxine (T4) [4]. Because the biological activities of currently available drugs are quite similar to T4, there is no need to change doses when shifting from one drug to another [4]. It is advisable to initiate drug treatment with 25 to 50 g per day and then steadily increase the dose to 75 to 125 g per day (0.6 g/kgbody weight/day) and to administer the drug on an empty stomach [4]. Since the TSH concentration has dropped below normal levels, it is more appropriate to evaluate the treatment response using clinical symptoms and measures of plasma free T4 concentrations [3,4]. These levels should be measured prior to administration and then maintained within the mid-range of normal concentrations.

Triiodothyronine should not be used to treat hypopituitarism except under special circumstances. In patients with clear indications of adrenal insufficiency, glucocorticoids should be administered prior to or in conjunction with T4 to prevent adrenal crisis [3]. When used in combination with liver enzyme inducers such as phenytoin, barbiturate, rifampin, and carbamazepine, the dose of T4 should be increased by 30% to 50%, especially when treating females in early pregnancy and patients receiving estrogen [3,4]. On the other hand, the T4 dose should be reduced by approximately 20% when it is given to patients receiving testosterone or to those who are elderly [3,4]. Additionally, although there is no need to adjust the dose when a patient exhibits reduced liver or renal function, it must be increased in the case of nephrotic syndrome [3,4].

For patients with hypogonadotropic hypogonadism, it is important to consider both gonad steroid replacement treatment and fertility. Androgen replacement for men can be accomplished using testosterone; for example, the treatment preferred by the present author includes intramuscular injections of testosterone enanthate or cypionate (200 mg per injection) every 3 to 4 weeks and oral pills of testosterone undecanoate (80 to 120 mg twice a day) with or immediately after a meal. Korean patients require smaller doses of testosterone than Western patients but have few problems taking the medication orally. In addition to shots and tablets, a transdermal gel can be applied to the skin of the patient, a patch can be applied on the patient's testicles or other sites, and pellets can be implanted in a muscle once every 6 months [3,4]. Although these drugs are expensive, the biological activity of testosterone is excellent. Recently, a novel testosterone undecanoate injection that is administered intramuscularly once every 3 months was introduced and shown to effectively maintain appropriate concentrations of testosterone in the blood [4]. However, the drug chosen for treatment depends on the patient based on factors such as efficacy, side effects, convenience, and cost.

The primary goal of gonadotropin treatment in males is to completely recover characteristics such as beard growth, physical strength, sexual desire, and sexual functionality. For patients who have yet to undergo puberty, the initial dose must be small and then it can be gradually increased depending upon the clinical response and presence of side effects until a maximum dose is reached. In addition to the clinical response, measures of serum testosterone concentrations are helpful for determining the appropriate dose when intramuscular delivery methods are used and it is advisable to maintain blood testosterone concentrations at 400 to 700 g/dL in the middle of an injection procedure [2]. For elderly patients or patients with obstructive sleep apnea syndrome, it is desirable to adjust the testosterone dose downward. Side effects of testosterone were erythrocytosis, acne, prostate hyperplasia, prostate cancer, and/or reduced spermatogenesis [4]. In the initial stages of testosterone treatment, it is important to perform hematocrit and reduce the dose if the result is over 50% and discontinue treatment if the result is over 55%. For patients over 40 years of age, a prostate cancer test is also necessary and a digital rectal exam and blood prostate-specific antigen (PSA) test should be conducted 3 to 6 months after treatment and once per year thereafter. If the results of the PSA test are over 3 ng/mL immediately after treatment, show an increase of 1.4 ng/mL at 1 year after treatment, or exhibit a PSA growth rate of more than 0.4 ng/mL per year for more than 2 years and there are unusual findings from the digital rectal exam or prostate ultrasonic test, the patient must visit a urologist [24].

When a male patient wishes to father a child, various infertility treatments can be used depending on the type of disease. In the case of hypothalamic hypogonadotropic hypogonadism, sporadic GnRH treatment using an infusion pump (2 g via subcutaneous injection every 2 hours) will restore masculinity and improve sperm count. However, this technique is used only infrequently due to the inconvenience of continuously carrying a bulky infusion pump. Similar to the case of hypopituitary hypogonadotropic hypogonadism, treatment with gonadotropin is used in this situation [2]. Like gonadotropin, human chorionic gonadotropin (hCG) and human menopausal gonadotropin (hMG; which is a drug extracted from the urine of menopausal women, generic name: menotropin) are available commercially as are recombinant LH (rLH) and FSH (rFSH) [2]. Gonadotropin typically needs to be injected intramuscularly 2 to 3 times per week, although subcutaneous injection is also available, and its use requires regular sperm analysis to determine the efficacy of the treatment [2]. Approximately 60% of males whose sperm counts have recovered to normal levels exhibit a restoration of their reproductive abilities [2]. If a patient suffers from hypogonadotropic hypogonadism prior to puberty, his testicles will be smaller than normal and the possibility of maintaining full reproductive abilities is very low, even following treatment [2]. Thus, prepubescent patients are advised to undergo gonadotropin treatment even though it is considerably more expensive and inconvenient than other methods.

For females with hypopituitarism, the administration of ethinyl estradiol (2 to 4 mg a day), which is a conjugated estrogen (0.625 to 1.25 mg a day) combined with progesterone, or the use of oral contraceptives can fully restore regular menstruation prior to menopause [2]. However, if the patient did not fully physically develop during puberty, then it is necessary to increase the estrogen dose during the initial stages of treatment and administer daily administration without drug holiday. For females with an intact uterus, administration of medroxyprogesterone (10 mg), which is a type of progesterone, 12 to 14 days per month in conjunction with estrogen treatment is recommended [2]. Transdermal estrogen patches may also be used as a complementary measure and, although it is an expensive regimen, it is efficacious for maintaining biological activity. Treatment must be continued at least until menopause to prevent osteoporosis and to maintain the antiatherosclerotic lipoprotein effects and, after menopause, the dose of estrogen should be progressively reduced until treatment is discontinued. Moreover, the patient should take annual mammography and breast ultrasound and gynecologic exam if unexpected vaginal bleeding or the patient wants to get pregnant [2].

Similar to males, the restoration of reproductive ability may be accomplished via the administration of hCG and hMG (or rLH and rFSH) as these hormone therapies are known to improve the possibilities of ovulation and conception. Due to recent advancements in dosage determination and supervising techniques, the incidence rates of ovarian hyperstimulation and multiple pregnancies have substantially declined, although these risks are still present. With respect to the possibility of these risks, the pulsatile injection of GnRH rather than gonadotropin treatment is considered to be much safer in hypothalamic hypogonadism. Additionally, the GnRH-based treatment is more effective and has fewer side effects but, in real clinical situations, the gonadotropin treatment is preferred due to the inconvenience of carrying the injection pump and other disadvantages [2].

For patients with hyperprolactinemia, which in most cases represents only a slight increase unless it is prolactinoma, the administration of a small amount of a dopamine agonist (bromocriptine or cabergoline) will return prolactin levels to normal [4]. If prolactinoma is present, then treatment with an adequate dose of a dopamine agonist is conducted for an extended period so that the prolactin levels can be reduced to within a normal range. If gonadotropin deficiency continues despite treatment, then the appropriate (male/female) hormone replacement treatment can be initiated.

In the past, GH replacement treatment is generally only utilized in children with growth disorder due to GH deficiency. However, the recent development of recombinant human GH has made it possible to use GH to treat adults with hypopituitarism or reduced GH secretion (e.g., due to obesity, old age, burn injury, and catabolic disease) [5]. This treatment technique was used in Europe earlier than in the United States and showed positive results including the post-treatment normalization of body composition (reduced body fat and increased muscle mass), improvements in muscular strength and physical vitality, increased bone density, reduced cardiovascular risks (particularly improved dyslipidemia), enhanced cardiac function, and improved mental health [5]. The recommended initial dose of GH is 0.5 units a day but the dose steadily increases after a few weeks. According to the experience of the present author, the maintenance dosage for Korean patients is 1 to 2 units per day with smaller amounts for older people. The best way to gauge the dosage over an extended period of time is to determine the optimal amount (lowest dose) at which the body composition of the patient can be maintained at a normal level. During short treatment periods, it is advisable to maintain IGF-1 levels within the mid-ranges according to the gender and age of the patient [5].

Males respond to GH treatment better than females, which implies that females will require a greater number of doses than males. This is likely because the efficacy of GH in the liver is interfered with by orally-administered estrogen which, in turn, inhibits the production of IGF-1. In contrast, testosterone tends to enhance IGF-1 levels [4]. The administration of GH also seems to influence the metabolism rates of hydrocortisone and T4 such that the doses of these drugs need to be adjusted upward [2]. If cortisone, which is not used in Korea, is utilized instead of hydrocortisone, then problems may occur but there will not be a need to adjust the dose of hydrocortisone, at least in the experience of the present author. GH treatment is never recommended for patients with malignant tumors, increased intracranial pressure, or proliferative diabetic retinopathy or for pregnant females [5]. A majority of the short-term side effects associated with GH treatment stem from overdoses or retained fluids due to normal GH mechanisms while side effects such as arthralgia, dilated cardiomyopathy, and diabetes mellitus have been reported with the long-term use of GH [5]. However, most of these side effects disappear once the dose is reduced. The effects of GH emerge after a few months of treatment and patients with more severe deficiencies exhibit the most improvement. In terms of body composition, a full recovery of muscular strength and physical ability may take several years [4].

After 20 years of using GH treatment for hypopituitarism patients, there is still no evidence demonstrating that this regimen may increase the incidence of cancer or cause the recurrence of a tumor [5]. Nonetheless, patients undergoing GH treatment warrant careful observation to identify the development of additional risk factors. Additionally, future studies are required to determine whether GH treatment may reverse the high mortality (or shortening of life expectancy) due to cardiovascular events. Because GH requires daily subcutaneous injections and its efficacy is not evident over extended periods of time, patients tend to discontinue treatment or receive the treatment only infrequently. Recently, a once-a-week self-administered subcutaneous injection of GH was developed and is currently undergoing clinical study. Once this treatment modality is made available in Korea, it is expected that the compliance rate for GH treatment will improve substantially.

Diabetes insipidus that results from ADH deficiency can be easily treated with a novel synthetic analogue of vasopressin known as desmopressin (1-desamino-8-D-arginine vasopressin [DDAVP]) which specifically interacts with ADH V2 receptors in the kidney [3]. DDAVP can be administered orally at doses of 0.1 to 0.2 mg 2 to 3 times a day, nasally at doses of 10 g/0.1 mL 2 to 3 times per day, or intravenously at 1 to 2 g twice a day. Beginning with oral doses at 0.05 mg one a day (before bedtime) or 0.05 mg twice a day, it is possible to gradually increase the dose or adjust the intervals between doses depending on the amount of urine. As a result, it is necessary to perform regular tests to assess electrolyte levels, particularly serum sodium levels. This drug is considered to be safe even during pregnancy but the dose should be increased during the second trimester based on the amount of urine and the degree of thirst [3]. When it is not feasible to orally administer DDAVP, for example, following surgery, it is necessary to utilize IV techniques when there is a rapid increase in urine volume by closely monitoring the amount of urine and serum sodium levels in the urine [3]. In the postoperative period, it is better to administer the drug when necessary rather than regular administration. It is advisable to regularly resume oral drug if the patient can take the drug orally. If there is an abrupt decrease in the amount of urine in conditions such as dehydration due to diarrhea, vomiting, or severe perspiration, DDAVP can be administered as needed. Drugs such as glucocorticoids, T4, alcohol, lithium, and demeclocycline decrease DDAVP efficacy. On the other hand, drugs like chlorpropamide, carbamazepine, and nonsteroidal anti-inflammatory medications can enhance DDAVP actions. In this case, the patient may suffer from either hypernatremia or hyponatremia and, thus, close supervision is warranted. If diabetes insipidus is accompanied by hypopituitarism, particularly in conjunction with an adrenal insufficiency or severe T4 deficiency, symptoms such as polyuria, polydipsia, and nocturia improve due to increased ADH secretion and action. As a result, this may lead medical staff to believe that the patient's symptoms are improving but once the patient complements his/her deficient hormone levels, the symptoms associated with diabetes insipidus will return. However, diabetes insipidus may improve over time especially if it is due to only a partial deficiency. Currently, it is better to discontinue drug administration intermittently and resume the treatment regimen only if urine volume increases [3].

More:
Diagnosis and Treatment of Hypopituitarism - PMC - National Center for ...

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People often turn to genetic testing to investigate possible health conditions that run in families or even explore their own family history and heritage.

With advancements in technology, genetic testing is becoming more precise and more affordable than before. This opens it up to a wider range of people seeking answers to questions about their health and family.

This article will describe the clinical and research purposes of genetic testing, the health conditions it may help detect, and what you may want to consider when talking with your healthcare team about this type of testing.

Genetic testing is a broad term used to describe a medical test that identifies changes in a DNA sequence or chromosomal structure.

Genetic testing can also measure results of gene changes, like an RNA analysis of a genes expression. It may analyze and measure the specific makeup of a certain gene, in order to help better identify the particular genetic makeup that might be shared with others or signal a possible health concern.

There are many uses for genetic testing. It can help people plan for the future by telling them the likelihood of developing a specific health condition.

It can also be used to help diagnose rare genetic conditions or to get information for better precision medicine when tailoring treatment options for an individual.

People may opt to have genetic testing done during pregnancy to rule out specific hereditary conditions, such as Down syndrome or potential problems with the unborn childs number of sex chromosomes.

According to the National Institutes of Health, genetic tests are available for many different genetic conditions.

Genetic testing can also be used to broadly trace ones ancestry and ethnicity or to provide information about biological parents and close relatives.

Clinical genetic testing aims to find out about any likelihood of an inherited genetic condition in a particular person and/or their family. These results are added to the medical record, and they can help inform people about the best course of treatment or prevention.

Research genetic testing, on the other hand, occurs when genetic testing is done on a person who volunteers for a clinical trial. The testing is done as part of a research study.

The outcomes of research-based genetic testing arent available to the participants or their doctors. The outcomes are also not added to anyones medical record, because theyre simply to help inform the research study.

People wont personally benefit from this type of genetic testing, and it cant be used to make individual diagnoses. But it does contribute to research.

Genetic testing isnt required during pregnancy. But many people opt for it to rule out any life threatening conditions to the fetus or other chromosomal conditions, such as Down syndrome, trisomy 18 (Edwards syndrome), or trisomy 13 (Patau syndrome).

There are certain factors that may increase someones likelihood to opt for genetic testing, including:

Advanced maternal age increases the likelihood that the fetus may have chromosomal irregularities, and having genetic testing on the fetus can rule those out.

Genetic testing is available for the following types of cancer:

Getting genetic testing for cancer can help you predict your risk of developing a certain type of cancer, but it doesnt predict that you will or wont develop any type of cancer.

It may, however, find out if you have genes that may pass an increased cancer risk onto your children (the BRCA gene for breast cancer, for example).

About 13% of women will develop breast cancer at some point in their lives, according to the American Cancer Society (ACS). By contrast, up to 72% who inherit the BRCA1 variant and as many as 69% of people who inherit the BRCA2 variant will develop breast cancer during their lifetime, according to a 2017 study.

Even someone who has a high likelihood of developing breast cancer if they have the BRCA1 or BRCA2 variant may never develop the disease. Also, someone who doesnt have these gene mutations may go on to develop breast cancer in their lifetime.

Having access to that information may help you make informed decisions about healthcare procedures and genetic testing to detect possible cancers.

Genetic testing cant detect or help diagnose all conditions, such as autism. However, genetic testing can be used to help predict or assess ones risk for many health issues, including conditions that newborns should be screened for. These conditions may include:

The following conditions can be genetically tested in utero:

While theres no genetic test for diabetes, children who have a sibling with type 1 diabetes may opt for an antibodies test that measures the antibody response to insulin, the islet cells in the pancreas, or to an enzyme called glutamic acid decarboxylase (GAD).

High levels indicate that a child has a higher likelihood of developing type 1 diabetes, but it doesnt guarantee that theyll develop type 1 diabetes.

Talk with your doctor if youre interested in getting genetic testing either for you or your children. If youre pregnant, you may want to opt for genetic testing for your baby, especially if any of the previously mentioned conditions run in your family.

Genetic testing can either be done at home with a saliva sample or in a laboratory, with a small blood sample.

In pregnant people, genetic testing is usually done via amniotic fluid through amniocentesis, or the placenta, through chorionic villus sampling (CVS).

Testing can also be done directly on the embryo during in vitro fertilization (IVF). Results can take a few weeks after samples are drawn.

You should consider genetic testing if theres a particular condition that runs in the family and you might be concerned about it materializing in your life.

Additionally, you may consider genetic testing if you want to learn what the risk is for a future pregnancy or to see if youre a carrier of a genetic condition (or if your child is a carrier or has a genetic condition themselves).

It can guide treatment and prevention planning for you and your family, especially when it comes to cancer.

People who are at higher risk for having a child with a genetic condition may opt for genetic testing. This includes:

People may also opt for genetic testing for simple peace of mind if their risk tolerance is low. Talk with your doctor or a genetic counselor if you want more information or if you feel that genetic testing is appropriate for you or your children.

Genetic testing is used for both research and clinical reasons, and it can be used to help trace family lineage as well as possible health conditions, including cancer.

While genetic testing isnt required during pregnancy, some people who are pregnant may consider it to evaluate the possible risk of health conditions that can be passed on to a child.

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Genetic Testing: What You Should Know - Healthline

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What are DNA, genes and chromosomes?

Your body is made up of millions of tiny cells. Different types of cells form the different structures of the body, including skin, muscles, nerves and also organs such as the liver and kidneys.

This image was derived from Eukaryote DNA.svg, via Wikimedia Commons

In the centre (nucleus) of most cells in your body, the DNA molecule is packaged into thread-like structures called chromosomes. You have 46 chromosomes arranged in 23 pairs. These include one pair of sex chromosomes (either XX for females and XY for males). The other chromosomes that do not determine whether we are male or female are called autosomes. There are 22 pairs of autosomes (numbered 1 to 22). One chromosome from each pair comes from your mother and one from your father.

A gene is the basic unit of your genetic material. It is made up of a sequence (or piece) of DNA and sits at a particular place on a chromosome. So, a gene is a small section of a chromosome. Each gene controls a particular feature or has a particular function in your body. For example, dictating your eye colour or hair colour, making all the various proteins in your body, etc. Each gene is part of a pair. One gene from each pair is inherited from your mother, the other from your father. Each chromosome carries hundreds of genes. Humans have between 20,000 and 25,000 genes altogether. The total of all your genes is called your genome.

DNA stands for deoxyribonucleic acid. DNA forms your genetic material. Genes, which are made up of DNA, act as instructions to make proteins. In humans, genes vary in size from just a very small amount of DNA to very large amounts of DNA.

Proteins are large, complicated molecules that play many important roles in your body. They do most of the work in cells and are required for the structure, function and regulation of your body's tissues and organs.

As our cells are multiplying all the time, our genetic information needs to stay the same. Normally, there are excellent mechanisms in place to make sure each cell gets the exact same copy of DNA, the material that makes up our genes. However, sometimes the copying mechanism makes mistakes or other problems can occur with your genetic material. Problems and abnormalities in genes can lead to genetic diseases.

Genetic testing is a type of medical test that identifies changes in chromosomes, genes or proteins. Gene tests look for abnormalities in DNA taken from a person's blood, body fluids or tissues. The tests can look for large mistakes such as a gene that has a section missing or added. Other tests look for small changes within the DNA. Other mistakes that can be found include genes that are too active, genes that are turned off, or those that are lost entirely.

Genetic tests examine a person's DNA in a variety of ways. They are all designed to identify differences between the gene being tested and what would be considered to be a normal version of the same gene.

There are different types of genetic testing which include:

These look at single genes or short lengths of DNA taken from a person's blood or other body fluids (for example, saliva) to identify large changes, such as:

An example of a genetic disorder that is tested in this way is cystic fibrosis.

However, there are limitations to genetic testing, as it is only useful if it is known that a specific genetic mutation causes a certain condition. A mutation or error in copying the DNA results in a permanent change to the DNA which can result in a number of diseases. For example, a specific gene mutation is known to cause Huntington's disease. It is therefore possible to test a blood sample for the presence or absence of this gene mutation. For many conditions - for example, diabetes - there may be any one of hundreds or even thousands of different possible mutations in a particular gene. This means genetic testing for those conditions is virtually impossible.

These look at the features of a person's chromosomes, including their structure, number and arrangement. Parts of a chromosme can be missing, be extra or even be moved to a different part on another chromosome.

There are different ways in which chromosome tests can be undertaken. These include:

Biochemical tests look at the amounts or activities of key proteins. As genes contain the DNA code for making proteins, abnormal amounts or activities of proteins can signal genes that are not working normally. These types of tests are often used for newborn baby screening. For example, biochemical screening can detect infants who have a condition affecting one of the many essential chemical reactions in the body (metabolic condition) such as phenylketonuria.

Genetic test results can confirm or rule out a suspected genetic condition or help determine a person's chance of developing or passing on a genetic disorder. More than 2,000 genetic tests are currently in use, and more are being developed all the time.

Genetic testing is performed in different ways including:

Newborn screening is done just after birth to identify genetic disorders that can be treated early in life. For example, every baby in the UK is tested for cystic fibrosis as part of the heel prick test.

Diagnostic testing is used to identify or rule out a specific genetic disorder if a baby or person has symptoms to suggest a certain genetic disorder (for example, Down's syndrome).

Carrier testing is used to identify people who carry one copy of a gene mutation (a genetic change) that, when present in two copies, causes a genetic disorder (for example, sickle cell disease). This type of test can be useful to provide information about a couple's risk of having a child with a genetic disorder.

Before birth (prenatal) testing is used to detect changes in an unborn baby's genes. This type of testing is offered during pregnancy if there is an increased risk that the baby will have a genetic or chromosomal disorder. It cannot identify all possible inherited disorders and birth defects, however.

Pre-implantation genetic testing is available for couples who are at risk of having a child with a specific genetic or chromosome disorder, eg cystic fibrosis, sickle cell disease or Huntington's disease.

Egg cells are removed from the woman's ovaries and then fertilised with sperm cells outside the body. This is called in-vitro fertilisation (or IVF). The eggs are fertilised with sperm cells to form embryos. The fertilised embryos develop for three days and then one or two cells are removed from each embryo.

The genetic material (DNA and chromosomes) from the cells are tested for the known disorder in the family history. One or two of the unaffected embryos are then transferred into the mother's womb (uterus). If the pregnancy is successful, the baby will not be affected by the disorder it was tested for.

Predictive testing is used to detect genetic mutations associated with disorders that appear after birth, often later in life. These tests can be helpful to people who have a family member with a genetic disorder but who have no features of the disorder themselves at the time of testing (for example, breast cancer associated with the BRCA1 gene). Predictive testing can identify mutations that increase a person's risk of developing disorders with a genetic basis, such as certain types of cancer.

Testing can also determine whether a person will develop a genetic disorder, such as haemochromatosis, before any signs or symptoms appear. People in families at high risk for a genetic disease have to live with uncertainty about their future and their children's future.

A genetic test result showing a known gene mutation responsible for a certain disease as not being present in a person can provide a sense of relief. However a positive result may have a devastating effect on a person's life, especially if there is no known treatment.

However for some disorders a positive result may help you to consider options to prevent the disorder. For example, women with BRAC1 are at increased risk of breast cancer and may decide to have surgery to remove their breasts (mastectomy) or to take a medicine called tamoxifen to reduce the risk. See the separate leaflet on Breast Cancer for more information.

Therefore before having predictive testing it is essential for a specialist to carefully discuss with you your risks of being affected by the disorder, how the disorder would affect you and the benefits and risks of having a genetic test for the disorder. See the section on genetic counselling below.

Forensic testing uses DNA sequences to identify a person for legal purposes. Unlike the tests described above, forensic testing is not used to detect gene mutations associated with disease. This type of testing can also be used to work out the paternity of a child. Forensic testing can also be used for identifying human remains when identification is not possible by other means - for example, after a natural disaster such as a fire or tsunami.

Genetic testing usually involves taking a sample of blood or tissue. In adults and children this usually involves taking a blood sample from a vein. Some genetic tests can be done from samples of saliva or from taking a sample (swab) from the inside of your mouth.

In pregnancy, a sample may be taken from the baby by amniocentesis or chorionic villus sampling. In amniocentesis a sample of the liquid (amniotic fluid) that surrounds a baby is taken. It is done by putting a needle though the tummy (abdomen) into the womb (uterus). In chorionic villus testing a sample of part of the placenta is taken. This is either done by inserting a needle into the abdomen like in amniocentesis or by putting a thin tube into the neck of the womb (cervix). Both tests involve a very small risk that you may have a miscarriage as a result of having the test. If you are offered these tests, doctors will discuss the risks involved to help you to make a choice about whether to have the test or not.

In recent years the Harmony test has become available. This can be used during pregnancy and is done using a sample of the mother's blood, so there is no risk of miscarriage as there is with amniocentesis or chorionic villus sampling.

In newborns, routine screening for genetic disorder such as phenylketonuria happens as part of a baby's heel prick test when they around 5 days old.

After the sample has been taken it is sent to the laboratory for testing.

It may take anywhere from weeks to months for the results of all the tests to come back. This depends on the type of genetic test you've had. Your doctor should advise you how long the results will be.

A variety of genetic tests can be bought individually, many now over the Internet, which usually involve scaping the inside of your cheek to obtain some cells for testing. These are not recommended by doctors. Many test for genetic disorders for which there is no treatment, so they can heighten anxieties if you test positive for one of these disorders. They may also test for diseases that you may never actually develop in the future if you do not have other risk factors. For example, testing positive for the BRAC1 gene does not mean that you will definitely develop breast cancer in the future.

Before you undergo any of these tests, it may be worth asking yourself if you are prepared to make changes in your lifestyle, based on the test results. If you are not willing to take actions like stopping smoking or exercising more, such tests may not be of much benefit to you.

Many of these tests are also unreliable and can lead to very misleading results. If you would like to be tested for a genetic disorder then you should talk to your doctor about this in more detail.

The information obtained from genetic testing can have a profound impact on your life so you may be referred to a genetic counsellor Genetic counselling is available to anyone undergoing, or thinking of undergoing, any form of genetic testing. Genetic counselling is not a psychological therapy. It aims to provide you with all the information you need to make a decision about whether you should have a genetic test.

Genetic counselling may include information about:

The information is given in a way that will allow you to make your own decision. Only you can decide what is right for you. The counselling is essential to make sure you have all the important information you need to make the decision.

As they consider the options available to them, people are influenced by:

Post-test counselling is also available to help you deal with the results of the test.

More:
Genetic Testing: How It Works, Types, and Diagnosis | Patient

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From Wikipedia, the free encyclopedia

Dietary supplement company

The Biomedical Research & Longevity Society, formerly the Life Extension Foundation (LEF), is a company founded in 1980 to extend the healthy human lifespan by discovering methods to control aging and eradicate disease. Along with the Life Extension Buyer's Club, which sells vitamins and supplements, the Life Extension Foundation (LEF) was headquartered in Fort Lauderdale, Florida. It also has a call center location in Las Vegas, Nevada. The company changed its name in 2018 to Biomedical Research & Longevity Society.[1]

Along with the Life Extension Buyer's Club, the Life Extension Foundation (LEF) was headquartered in Fort Lauderdale, Florida. The Life Extension Foundation (LEF) was primarily funded by the sale of nutritional supplements to members of an affiliated entity, the Life Extension Buyer's Club.[citation needed] The Life Extension Buyer's Club was incorporated in Nevada, and has a separate EIN employer number than the Life Extension Foundation. Its name was changed to the Biomedical Research & Longevity Society in 2018.[1]

In 1981 LEF recommended DHEA, in 1983 it recommended low-dose aspirin, and also in 1983 was the first organization in the United States to recommend coenzyme Q10 (CoQ10). In 1992 it introduced melatonin into its product line.

The Biomedical Research & Longevity Society, which was originally named Life Extension Foundation (LEF), was founded by Saul Kent and William Faloon in 1980.[2][3]

In 1987, the FDA raided the Life Extension Foundation's warehouse, and charged Kent and Faloon with 27 counts, including distributing unapproved drugs. 11 years later, all, by then, 56 FDA charges were dismissed by a federal judge. In 1994, Kent and Faloon opened the FDA Holocaust Museum to highlight millions of deaths they felt were caused by the FDA withholding or delaying approval of life-saving drugs and treatments.[4]

In a 2009 tax filing, the company declared assets of over $25 million and netted more than $3 million on revenue of more than $18 million that year.[5]

In May 2013, the Internal Revenue Service revoked the Life Extension Foundations tax-exempt status, retroactive to 2006.[6] Forbes reported that "The IRS' problem with the Foundation is [...] an entirely worldly one: it asserts the membership organization's operations seem to be too entwined with the for-profit Life Extension Buyers Club."[5] On August 7, 2013, LEF filed a Complaint for Declaratory Judgment in U.S. District Court for the District of Columbia challenging the IRS' allegations.[7]

In 2018, foundation's tax-exempt status was reinstated retroactive to the date it was revoked, May 2013.[8][9] The Life Extension Foundation also changed its name the same year, becoming the Biomedical Research and Longevity Society, Inc., or BRLS.[1]

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Biomedical Research & Longevity Society - Wikipedia

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Conscious Consumption : Sustainable Shopping Through Clothing Life Extension and BEAUTYCYCLE with Nordstrom  Marketscreener.com

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Conscious Consumption : Sustainable Shopping Through Clothing Life Extension and BEAUTYCYCLE with Nordstrom - Marketscreener.com

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Lean Gene Reviews (USA) Does This Weight Loss Supplement Work? LeanGene Ingredients, Price, Where to Buy?  Outlook India

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Lean Gene Reviews (USA) Does This Weight Loss Supplement Work? LeanGene Ingredients, Price, Where to Buy? - Outlook India

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Cell And Gene Therapy Market Anticipated To Witness High Growth In The Near Future | GlaxoSmithKline,  EIN News

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Cell And Gene Therapy Market Anticipated To Witness High Growth In The Near Future | GlaxoSmithKline, - EIN News

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Genetic testing can give several possible results: positive, negative, true negative, uninformative negative, variant of uncertain significance, or benign (harmless) variant.

Positive result. A positive test result means that the laboratory found a genetic variant that is associated with an inherited cancer susceptibility syndrome. A positive result may:

Also, people who have a positive test result that indicates that they have an increased risk of developing cancer in the future may be able to take steps to lower their risk of developing cancer or to find cancer earlier, including:

Negative result. A negative test result means that the laboratory did not find the specific variant that the test was designed to detect. This result is most useful when a specific disease-causing variant is known to be present in a family. In such a case, a negative result can show that the tested family member has not inherited the variant that is present in their family and that this person therefore does not have the inherited cancer susceptibility syndrome tested for. Such a test result is called a true negative. A true negative result does not mean that there is no cancer risk, but rather that the risk is probably the same as the cancer risk in the general population.

When a person has a strong family history of cancer but the family has not been found to have a known variant associated with a hereditary cancer syndrome, a negative test result is classified as an uninformative negative (that is, it typically does not provide useful information).

In the case of a negative test result, it is important that the persons doctors and genetic counselors ensure that that person is receiving appropriate cancer screening based on that persons personal and family history and any other risk factors they may have. Even when the genetic testing is negative, some individuals may still benefit from increased cancer surveillance.

Variant of uncertain significance. If genetic testing shows a change that has not been previously associated with cancer, the persons test result may report a variant of uncertain significance, or VUS. This result may be interpreted as uncertain, which is to say that the information does not help to clarify their risk and is typically not considered in making health care decisions.

Some gene variants may be reclassified as researchers learn more about variants linked to cancer. Most often, variants that were initially classified as variants of uncertain significance are reclassified as being benign (not clinically important), but sometimes a VUS may eventually be found to be associated with increased risks for cancer. Therefore, it is important for the person who is tested to keep in touch with the provider who performed thegenetic testing to ensure that they receiveupdates if any new information on thevariant is learned.

Benign variant. If the test reveals a genetic change that is common in the general population among people without cancer, the change is called a benign variant. Everyone has commonly occurring benign variants that are not associated with any increased risk of disease.

Genetic test results are based on the best scientific information available at the time of the testing. While unfortunately no testing can be 100% error free, most genetic testing is quite accurate. However, it is very important to have thegenetic testing orderedby a provider knowledgeable in cancer genetics who can choose a reputable testing lab to ensure the most accurate test results possible.

Excerpt from:
Genetic Testing Fact Sheet - NCI - National Cancer Institute

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When it comes to health and disease and, of course, many other aspects of life one thing is certain: genes matter. A single gene mutation can cause some conditions, such as sickle cell anemia and cystic fibrosis. More often, multiple genes are involved in disease development, and they act in concert with nongenetic factors, such as diet or exercise, to affect disease risk.

Several companies offer you the opportunity to look at your genes. But how might that help you from a health standpoint? And how do such tests differ from the genetic testing a doctor may recommend?

Consider the example of familial hypercholesterolemia (FH), a condition in which multiple variants of several different genes lead to markedly high cholesterol. This greatly increases the risk of heart attack, stroke, and other health problems. FH affects about one in 300 adults, which means it isnt rare. Among adults who have the most common genetic variants that cause it, heart attack or sudden cardiac death may occur in middle age. Children who have a double dose of a gene variant linked to this condition may die of cardiovascular disease before age 20. Earlier treatments intended to reduce the risk of complications, such as cholesterol-lowering drugs, are available if a child or adult is known to have a mutation linked to FH.

In recent years, theres been a dramatic increase in genetic testing. It was nearly unheard of only a few decades ago. Now, you or someone you know has likely had genetic testing within the last year or two.

And while healthcare providers can now order far more genetic tests for their patients than in the past, you dont need a doctors order to request this. 23andMe, Ancestry.com, and a number of other testing companies are ready and willing to check your genes for variants associated with certain health conditions, as well as your family ancestry. In fact, spending on direct-to-consumer genetic testing is predicted to reach $2.5 billion within the next few years.

For some people, the answer is clearly yes. When performed accurately, genetic tests can uncover a disease or a tendency to develop certain conditions, and it can lead to close relatives getting tested as well. Preventive measures or treatment can be lifesaving. Here are four examples (though there are many more).

In these cases, knowing you might develop a condition or are a carrier can help direct medical care, and may inform life decisions or encourage you or other family members to consider genetic counseling.

But the answer can also be no. Results of genetic testing may provide information you already know, may be unhelpful, or may even be misleading. For example, testing could reveal that you have a genetic mutation that rarely causes any health problems. Learning that you have this mutation may not help you though it might alarm you. Or, learning youre at increased risk for developing Alzheimers disease late in life may be more upsetting than useful, as there are currently no reliably effective preventive treatments.

Genetic testing may have more than one kind of cost. A genetic test ordered by your doctor for a specific medical reason may be covered by your health insurance, but its unlikely that an over-the-counter test will be. And, as one company states on its website, "knowing about genetic risks could affect your ability to get some kinds of insurance."

A 2021 study published in the medical journal JAMA Cardiology demonstrates how direct-to-consumer testing may be misleading.

The researchers looked at genetic testing for familial hypercholesteremia. They compared the results from a comprehensive panel of genetic testing ordered by doctors (which included more than 2,000 gene variants) with results from the more limited genetic testing (24 variants) provided by 23andMe.

Among more than 4,500 people tested for a medical reason, such as evaluating an unexpectedly high cholesterol level, the more limited testing would have missed important genetic variants for

This suggests that a large number of people would be falsely reassured by the results of their genetic tests for FH if they relied on the type of screening offered by a popular over-the-counter product. And results may be particularly unreliable among persons of color.

Its true that you cant pick your genes. But thanks to an ever-expanding menu of options, you can pick your tests. In many cases, its best to review your decision to have genetic testing with your doctor before having it done. You may choose to see a genetic counselor about the ramifications of testing before you jump in and let your doctor do the testing, rather than ordering it yourself. Or, you may decide the best plan is no testing at all.

Follow me on Twitter @RobShmerling

More:
Tempted to have genetic testing? First ask why - Harvard Health

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TAYSHA GENE THERAPIES, INC. Management's Discussion and Analysis of Financial Condition and Results of Operations. (form 10-K)  Marketscreener.com

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Predictive Oncology Announces Collaboration with Integra Therapeutics to Advance Gene Therapy  Marketscreener.com

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Gene Therapy Market Size (USD 46.5 billion by 2030) Poised for Explosive Growth to Meet Rising Healthcare  EIN News

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Gene Therapy Market Size (USD 46.5 billion by 2030) Poised for Explosive Growth to Meet Rising Healthcare - EIN News

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The biggest shock was not having a uterus the film about intersex beauty queen Sharon-Rose Khumalo  The Guardian

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The biggest shock was not having a uterus the film about intersex beauty queen Sharon-Rose Khumalo - The Guardian

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CRISPR is the basis of a revolutionary gene editing system. One day, it could make it possible to do everything from resurrect extinct species to develop cures for chronic disease.

Its built on a natural adaptation found in the DNA of bacteria and single-celled organisms.

CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats.

Theyre really just bits of genetic code with a specific, recognizable format. They contain a sequence that shows up over and over again, though its often reversed each time.

Thats what makes it "Palindromic: palindromes are words that can be read the same backwards as forwards. Palindromes are common in DNA. Some serve as backups for damage to our genetic code, while others are common in cancer mutations.

With CRISPR, a group of enzymes recognize certain repeats, and break the DNA there to insert important information in the middle. These insertions are called spacers, and they contain the genetic code of different viruses that have invaded in the past.

Such previous invasions served a very important evolutionary purpose: immunizing against foreign threats.

Researchers first discovered CRISPR in E. Coli in the 1980s. When E. coli survives viral attacks, it incorporates some of the virus DNA into its own genetic code.

E. Coli isnt unique in using this strategy. Between the 1980s and 2000, scientists found that lots of bacteria and single-celled organisms incorporate viral DNA this way.

Cells use these sequences as templates for transcribing complementary strands of RNA.

When viruses matching the template sequence enter the cell, the complementary RNA binds to them, and directs a series of CRISPR-associated enzymes, or Cas enzymes, to attackcutting invader DNA at the binding site. That neutralizes the viral threat.

The CRISPR-Cas system is incredibly effective. Its also easy to manipulate, letting us alter a cells genetic code however we want.

In 2012, French microbiologist Emmanuelle Charpentier and American biochemist Jennifer Doudna discovered that Cas enzymesspecifically Cas9can be reprogrammed to cut nearly any part of the genome, using RNA sequences made in a lab. Those guide RNA molecules tell Cas9 where to cut DNA in a cell.

For their discovery, Charpentier and Doudna won the Nobel Prize in Chemistry in 2020.

And the use of CRISPR has taken off in science since their breakthrough.

But scientists are still far from realizing CRISPRs potential.

Cas9 is great at suppressing or knocking out unwanted genes. But for most medical purposes, its not enough to cut unwanted DNA out. Scientists need to control how the DNA repairs itself.

Left to their own devices, cells tend to repair broken DNA using a method that introduces lots of random errors. Researchers can provide cells with templates to guide the repair process, but theyre still working on making that more reliable.

Researchers have found lots of applications for CRISPR in animals, like making disease-resistant chickens and pigs, and mosquitos that cant bite or lay eggs. But theyve got many projects underway, like making disease-resistant cropsincluding wine grapes. More ambitiously, theyre working to genetically alter pigs so their organs could be transplanted into humans. And bring extinct species such as the passenger pigeon back to life, by tweaking the genomes of similar birds.

When it comes to the human genome, though, scientists have been more hesitant. Editing our own DNA could easily end up causing more problems than it solves.

While Cas9 reliably cuts DNA where we want it to, recent experiments have shown it can also affect genes far off-target. And even if we could get it to work reliably, many experts have flagged ethical concerns about using the technology for eugenics and designer babies. If parents can one day pay scientists to edit their babies DNA, making them stronger and smarter, CRISPR could make the world even more unequal and prejudiced.

In 2018, Chinese researcher HEH JEE'-an-qway claimed hed used CRISPR to make HIV-resistant children. Whether or not he succeeded, his work violated Chinas National Health Commission rules, and he was sentenced to three years in prison.

Using CRISPR on babies is widely illegal. But there are some cases where using CRISPR on humans may be worth the risk.

In 2020, American researchers began the first clinical trials injecting CRISPR directly into living humans, aiming to repair a genetic mutation that causes blindness.

Many researchers hope CRISPR-based therapies could eventually cure hereditary diseases; theyve already seen promising results in various animal studies. Though given the risks of editing the human genome, were still a ways off from widespread use of CRISPR in medicine.

CRISPR has given science a tool to reliably tinker with the code of life. But the question remains: can we do so safely and ethically, while avoiding the unintended consequences of such power?

Read more from the original source:
What Is CRISPR, and Why Is It So Important? - Scientific American

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Texas panel advances bill that would hinder transgender kids access to puberty blockers & hormone therapies  25 News KXXV and KRHD

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Texas panel advances bill that would hinder transgender kids access to puberty blockers & hormone therapies - 25 News KXXV and KRHD

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Lentiviral Vectors Market to surge ahead at a CAGR of 11.4% to reach a Revenue of US$ 411.2 Million by the end  EIN News

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Global Gene Editing Partnering Deal Terms and Agreements Analysis Report 2023 & Directory of 400+ Deals Signed  EIN News

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Global Gene Editing Partnering Deal Terms and Agreements Analysis Report 2023 & Directory of 400+ Deals Signed - EIN News

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What causes hormonal imbalance and how to avoid it?  GMA News Online

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What causes hormonal imbalance and how to avoid it? - GMA News Online

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Gene Therapy Market Size (USD 46.5 Bn by 2030): A Growing Industry and Its Impact on Healthcare Systems  EIN News

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Gene Therapy Market Size (USD 46.5 Bn by 2030): A Growing Industry and Its Impact on Healthcare Systems - EIN News

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Global CRISPR Technology Market Is Projected To Grow At A 22% Rate Through The Forecast Period  EIN News

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It took me 2 years to get diagnosed as menopausal because I'm in my 30s. And I'm nonbinary, so doctors were ev  Business Insider India

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It took me 2 years to get diagnosed as menopausal because I'm in my 30s. And I'm nonbinary, so doctors were ev - Business Insider India

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What happens when you stop taking Ozempic? Doctors explain long-term effects of weight loss, diabetes drug  The Hill

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What happens when you stop taking Ozempic? Doctors explain long-term effects of weight loss, diabetes drug - The Hill

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Cell Therapy Market is estimated to be US$ 19.6 billion by 2030 with a CAGR of 13.1% during the forecast  EIN News

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Cell Therapy Market is estimated to be US$ 19.6 billion by 2030 with a CAGR of 13.1% during the forecast - EIN News

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Father of young Staten Islander with rare disease is in urgent need of bone marrow transplant. Heres how you  SILive.com

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Father of young Staten Islander with rare disease is in urgent need of bone marrow transplant. Heres how you - SILive.com

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