Lithuanian University of Health Sciences
Value Of Dynamic Tests in Diagnostics and Follow Up of Hypopituitarism
Author: Hussein Al-Faloji
Supervisor: Prof.dr. Birutė žilaitienė
Abstracts ...4 Summary ...5 Acknowledgements ...6 Conflict Of interest ...7 Abbreviations List ...8 Key Terms: ...9 Introduction ... 10 Body glands ... 11 Pituitary gland ... 13
Regulation Hypothalamic-pituitary and pituitary tumor disease ... 15
AIMS AND OBJECTIVES OF THE THESIS ... 21
Literature review ... 22
3.1 Hypothalamus ... 22
3.2 hypopituitarism ... 23
3.3 Growth Hormone Deficiency (GH) ... 23
3.4 Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) deficiency ... 23
3.5. Thyroid Stimulating Hormone Deficiency (TSH) ... 24
3.6 Adrenocorticotropic Hormone Deficiency (ACTH) ... 24
3.7 Antidiuretic Hormone Deficiency (ADH) ... 24
3.8.1Causes of pituitary deficiency ... 26
3.8.2 Symptoms of pituitary deficiency ... 27
3.8.3 Hormone changes in pituitary deficiency: ... 27
SYSTEMATIC REVIEW ... 30
Patients with AGHD and evaluation of pituitary function in patients after GHD ... 30
Methodology ... 34
AGHD diagnostic test: ... 37
Analyzing the effect of age, BMI, and sex on the test: ... 37
Analysis of macimorelin vs ITT performance over a range of GH cut points: ... 38
Result ... 39
The effect of age, BMI, and sex on the test: ... 39
Macimorelin vs ITT performance over a range of GH cut points: ... 40
Abstracts
Hypopituitarism as a various and wide range of hormone deficiency is studied and discussed using any combination of hypopituitarism, growth hormone deficiency, dynamic tests, PCTH, gonadotropin deficiency, ACTH, TSH deficiency.
Hypopituitarism resulting in different symptoms and clinical features in different body systems
Summary
Author: Hussein Al-faloji
Supervisor: prof.dr.Birutė Žilaitienė
Title of thesis: Value of dynamic tests in diagnostics and follow up of hypopituitarism: a
systematic review
Aim: The aim of this study is to evaluate the dynamic tests in the diagnosis and follow-up of adult
patients between the ages of 20 and 25 with acquired hypopituitarism and GHD.
Objectives: 1. To determine the diagnostic tests for hypopituitarism in adults 2. To compare diagnostic
tests for hypopituitarism and detect advantages and disadvantages among tests 3. To review the recommendation of treatment and follow-up plans for adults with diagnosed hypopituitarism.
Method of studies:
The systematic review will report according to the recommendation of the Preferred Reporting Items for Systematic Reviews and Meta-examinations (PRISMA) statement (1).We include original
controlled studies but also some guidelines and important recommendations of management published in any language with a sample size >10 patients evaluating adult patients with hypopituitarism (treated or not with GH replacement therapy). Several databases will comprehensively searcher from each database’s earliest origin through August 2015, using controlled vocabulary and text words. The research gap is about six years. The main reason is that through this, sufficient information can be obtained easily.
Conclusion of study:
Acknowledgements
Conflict Of interest
Abbreviations List
• Adult growth hormone deficiency (AGHD) • Traumatic brain injury (TBI)
• Growth hormone deficiency (Gh) • Luteinizing hormone (Lh)
• Follicle-stimulating hormone deficiency (FSH) • Thyroid stimulating hormone deficiency (TSH) • Adrenocorticotropic hormone deficiency (ACTH) • Antidiuretic hormone deficiency (ADH)
• Body mass index (BMI)
• Insulin tolerance test (ITT)
Key Terms:
• Hypopituitarism• AGHD (adult growth hormone deficiency) • Macimorelin
Introduction
Hypopituitarism is a rare and severe disorder that can present with a deficiency of any of the anterior pituitary hormones. The prevalence of hypopituitarism is approximately 45.5 cases per 100 000 people and therefore it is a rare disease.
Hypopituitarism may be isolated/selective; deficiency specific to a single hormone, multiple/partial; deficiency involving more than one hormone, or complete/panhypopituitarism; deficiency of all pituitary hormones.
The clinical expression depends on hormonal deficiencies, it can affect number of functions and systems, such as linear growth disorders, affect the blood pressure, or reproduction function (2).
In children the growth hormone deficiency (GHD) mostly affects linear growth and results in retardation. On the other hand, growth hormone deficiency (GHD) in adults impacts the body composition (lean and fat body mass distribution). That also leads to an increasing risk of cardiovascular diseases and a decrease in the mineral bone density along with the glucose tolerance. The studies revealed that the majority of hypopituitarism mortality was due to adult growth hormone deficiency (AGHD). In addition to the increased mortality, AGHD deficiency also increases the risk of obesity, diabetes, cerebrovascular and cardiovascular diseases.
The AGHD treatment using growth hormone and replacement therapy can result in various clinical
The protocol of the study is improved through the boards of institutional reviews for each individual. High risk groups for AGHD participants are also compared and analyzed along with the matched control
groups.
The AGHD probability is estimated by looking at the GH peak level; adjusted to age, sex and BMI. The sensitivity and the specificity for the given tests (shown in the result section) is determined by the cut points and the percentage of the groups by negative, positive and overall agreement of the GH cut points. The GH peak level after the administration of ghrelin is significantly reduced in adults in comparison to younger patients. (Garcia et al, 2021).
Body glands
The body's endocrine glands secrete hormones that affect almost every cell, organ, and function in the body. The endocrine system is very useful in regulating mental state, growth, tissue function, and metabolism, as well as sexual functions and reproductive processes in the body(1).
In general, the endocrine system is responsible for the body's processes that take place, such as cell growth. Faster processes such as breathing and body movement are controlled by the nervous system. But although the nervous system and the endocrine system are completely separate devices, they usually work together to improve bodily functions(2).
Although there are different types of hormones circulating in the bloodstream, each only affects a cell that is genetically programmed to receive and respond to its messages. Hormone levels can be affected by factors such as stress, infections and diseases, and changes in the balance of fluids and minerals in the blood(1).
A gland is a collection of cells that produce and secrete chemicals. The gland selects and excretes substances from the blood, performs processes on them, and releases chemicals for use at one point in the body. Some types of glands release their secretions in certain areas(2).
The main glands that make up the endocrine system of the human body are the hypothalamus, pituitary, thyroid, parathyroid, adrenal, pineal gland and genitals, which include the ovaries and testes. The
pancreas is also involved in the digestive system, but because it produces and secretes digestive enzymes, it is part of this hormone-secreting system. Although the endocrine glands are the body's main producers of hormones, some non-endocrine organs — such as the brain, heart, lungs, kidneys, thymus gland, skin, and placenta — also produce and secrete hormones(3).
The hypothalamus, a collection of visceral cells located in the lower part of the brain center, is the main interface between the endocrine system and the nervous system. Nerve cells in the hypothalamus control the pituitary gland by producing chemicals that either intensify or stop the production and secretion of hormones(4).
While the pituitary gland is not much bigger than a pea (about 0.8 cm), it is an important part of the endocrine system. This organ is sometimes called the "main gland" because it produces hormones that control other endocrine glands(5).
Hypothalamus sends signals about temperature, light exposure or emotions to pituitary gland so in this way it effects the pituitary gland secretions and hormones production (6).
The pituitary gland is divided into two parts: the anterior part and the posterior part. The anterior part regulates the activity of the growth, thyroid, adrenal, and genital glands. Among the hormones that this gland secretes, the following can be mentioned: growth hormone, which stimulates the growth of bones and other tissues in the body and is involved in the body's use of nutrients and minerals. The prolactin hormone, which activates milk production in lactating women.
Thyrotropin (TSH) stimulates the thyroid gland to produce thyroid hormone. Corticotrophin(ACTH) stimulates the adrenal glands to produce certain hormones. The pituitary gland also secretes endorphins.
The posterior pituitary gland secretes anti-urinary hormones that help maintain the body's water balance by acting on the kidneys and urinating. Another hormone secreted by this section is oxytocin, which causes uterine contractions during pregnancy (8).
Thyroid hormones also play an important role in bone growth and brain and nervous system development in children. The production and release of thyroid hormones is controlled by thyrotropin, which in turn is secreted by the pituitary gland (9).
Four small glands attached to the thyroid gland, which together act and called parathyroid. These glands secrete parathyroid hormone and with the help of calcitonin, which is produced in the thyroid, it regulates the level of calcium in the blood. The body has two triangular adrenal glands, each of which is located on one of the kidneys. The adrenal glands have two parts, each of which produces a series of hormones and has different functions (10).
The outer part, the adrenal cortex, produces hormones called corticosteroids that regulate the body's salt and water balance, the body's response to stress, metabolism, the immune system, and sexual growth and function. The internal part produces catecholamines such as epinephrine.
Epinephrine, also called adrenaline, raises blood pressure and heart rate in the face of stress. A pineal gland which is located in the middle of the brain secretes melatonin, a hormone that regulates the sleep-wake cycle (11).
In menthe gonads are located in the scrotum. The male glands, or testes, produce hormones called androgens, the most important of which is testosterone. These hormones regulate body changes caused by sexual growth, such as enlargement of the penis and the appearance of other masculine features such as thickening of the voice, growth of facial and pubic hair, and increased muscle growth and strength. Testosterone is also involved in the production of sperm by the testicles (12).
The female glands, the ovaries, are located in the pelvis. These glands produce eggs and produce female hormones such as estrogen and progesterone. Estrogen is involved in the development of female sexual characteristics such as breast growth and the accumulation of body fat in the thighs and buttocks. Both estrogen and progesterone are involved in pregnancy and menstruation. The pancreas (in addition to the others) produces two important hormones, insulin and glucagon. These hormones work together to maintain glucose or blood sugar balance and maintain the body's fuel and energy stores(13).
The pituitary gland is a small endocrine gland which is located in sella turcica of sphenoid bone. It is attached to the base of the brain by a thin stem. The pituitary gland is often called the master gland because it controls several other hormonal glands in the body, including the thyroid and adrenals, ovaries and testicles (14).
It secretes hormones from both the anterior (anterior) and posterior (posterior) parts of the gland. Hormones can transmit signals from one cell to another and so pituitary gland If the pituitary gland is releasing or producing inadequately called this Hypopituitarism (15).
The pituitary gland responds to complex central and peripheral signals by two mechanisms. First, trophic hormone secretion is subtly controlled to regulate homeostasis. Second, evolutionary or acquired pituitary signals may elicit plastic pituitary growth responses that include hypoplasia, hyperplasia, or adenoma formation (16).
These clinically obvious plastic changes of the pituitary mass indicate physiological or pathological responses to signals outside the urine or inside the pituitary gland. Pituitary proliferative changes are usually associated with dysfunction of hormone secretion, leading to hormone deficiency or excess syndromes (2).
Mutations in early evolutionary genes such as Rpx, Lhx3, Lhx4, Pitx2 affect the adjacent midline structures pleiotropically, as a result, pituitary hypoplasia and pituitary hormone deficiency, while mutations in genes that determine the age of certain pituitary glands, including Prop1, Pit1, and Tpit, are involved in pituitary hormone deficiency with hypoplasia (17).
Pit1, and Tpit are involved in pituitary hormone deficiency with hypoplasia. Excess pituitary hormone secretion is usually associated with benign monoclonal adenomas always caused by a specific cell type And although pituitary chromosome instability is a primary feature of pituitary development further development of pituitary carcinomas not often seen yet can cause reversible changes in cells such as hyperplasia . The hypothalamic-anterior pituitary unit integrates central and peripheral excitatory and inhibitory signals for the synthesis and secretion of hormones by five highly differentiated cell types: somatotrophs, gonadotrophs, lactotrophs, thyroidotrophs, and corticotrophs(18).
Each of these cells expresses unique G-pair protein receptors (GPCRs) that are specific for
(including luteinizing hormone [LH] And follicle-stimulating hormone (FSH]), lactation (including prolactin [PRL]), metabolism (including thyroid stimulating hormone [TSH]), and stress responses (including adrenocorticotropic hormone [ACTH])(19, 20).
Using dual labeling with both BrdU and anterior pituitary hormone-specific markers, it is evident that even after differentiation, pituitary cells continue to mitosis, which may be amplified under certain conditions in adults (such as pregnancy). About 30% of mouse pituitary cells arise from the "self-mitosis" of already aggregated cells, while others are produced by the aggregation of indifferent hetero cells, or possibly pituitary stem cells. Thus, proliferative and apoptotic changes are observed in the pituitary gland during the first year of rodent life, and are more likely to occur in the human pituitary gland (20).
Tumors may arise from any of these cells, and their secretory products depend on the stem cell. Functional classification of pituitary tumors is facilitated by immunocytochemistry or in situ mRNA detection of cell gene products, as well as by measuring circulating concentrations of trophic and target hormones (14).
Excessive ACTH results in Cushing's syndrome, with features of hypercortisolism; Excess GH leads to acral overgrowth and metabolic dysfunction associated with acromegaly; And too much PRL leads to Oglandal insufficiency, secondary infertility, and galactorrhea (7).
High TSH leads to hyperthyroidism and goiter, and excessive gonadotropins (or subunits) lead to gonadal dysfunction. Mixed tumors of GH co-secreting with PRL, TSH, or ACTH may also arise from single cells. In contrast, gonadotropin induced tumors do not secrete their gene products efficiently, and are usually clinically silent (21).
Regulation Hypothalamic-pituitary and pituitary tumor disease
Hormone secretion from pituitary tumors, although excessive and with unique phenotypic features, but it often maintains intact trophic control. For example, dopaminergic agents adequately suppress PRL secretion by prolactinomas, and dexamethasone may suppress ACTH secretion in patients with Cushing's pituitary disease(22).
invasive growth may occur, their general failure is attractive for continued true malignancy with
malignant meta cranial metastases. These adenomas grow slowly, and up to 25% of unselected autopsy specimens are detected(23).
Although the natural history of pituitary microadenoma growth is difficult to study due to the inherent access of pituitary tissue, it is clear that microadenomas do not always progress to macroadenomas. In addition, macroadenomas are stable or exhibit very slow growth, and in fact spontaneous oncogenic mutations commonly encountered in non-endocrine neoplasms (e.g., Ross and p53) are generally absent in pituitary adenomas, with However, impaired expression of paracrine growth factor inside the pituitary gland and function have been widely documented (24).
Human pituitary tissue is challenging due to a number of limitations, including the lack of anatomical access to the pituitary gland, the lack of functional human cells in culture, the paleness of loyal animal models, and the unique distinctive tumor behaviors. Mouse models are much different to humans; however, its’ study does provide significant information for humans regarding the course of the disease. Animal studies have largely followed two approaches to pituitary proliferative changes. First, disruption of known tumor suppressor genes tested in terragenic animal models revealed unexpected pituitary hyperplasia and tumor phenotypes (25).
Second, transgenic animals were used to test genes known for pituitary regulatory function (e.g., GH-releasing hormone [GHRH], nerve growth factor [NGF], and cytokines). This helps us have a better understanding of pituitary cell cycle proteins (19).
Pituitary hypoplasia: regulation of pituitary development transcription factor. Hormone-specific anterior pituitary cells are embryonically derived from a proliferative precursor, resulting from the coordinated temporal and anatomical control of the homeodomain suppressor and the expression of activating transcription factor (26).
Rpx is critical to the development of the Ratke sac, and Rpx mutations are rare in individuals with septic optic dysplasia (midbrain abnormalities, optic nerve hypoplasia, and pituitary dysplasia). A T-box factor, Tbx19 / Tpit, has been reported to interact with PitX1 in corticotropes and loss of T-pit function in patients with isolated ACTH deficiency (26).
indicate growth retardation, hypothyroidism, and infertility. Inadequate timing of pituitary transcription factor expression may also lead to evolutionary consequences (27).
Stable pituitary moraine teragia Prop-1 expresses results in Morin gonadotropin delay, persistent
Rathke cleft cyst, pituitary enlargement, and depleted pituitary abnormalities. Pituitary hyperplasia. The pituitary gland responds to induced signals as well as their output by regulating both trophic hormone secretion and mitotic and apoptotic growth changes. Pituitary hyperplasia is characterized by increased proliferation of a single cell type, which may be focal, nodular, or diffuse (27).
There is an absolute increase in the number of specific cells, with pituitary enlargement visible on MRI. Pituitary hyperplasia may increase from a medium cell type to a large glandular extension with drastically altered tissue architecture and range rheology (28).
The pathological diagnosis of hyperplasia is difficult and is best made by showing the intact structures of the acinar using a mesh spot. In particular, corticotropic hyperplasia may be associated with hyaline croc alterations, and thyroid hyperplasia, with periodic Schiff-positive periodic lysosomes. Pituitary hyperplasia is usually secondary, meaning its caused by external signals. The height of a normal pituitary gland, as measured by MRI, is up to 9 mm in healthy individuals, while adolescent females tend to have a larger pituitary gland (29).
It is clear that hormonal and clinical evaluations are required for all images of an enlarged pituitary gland, as "primary" pituitary enlargement is rare, especially in men. Always, the enlarged pituitary gland discovered by chance on MRI can be attributed to a pituitary adenoma (28).
Interestingly, in postmenopausal women, the pituitary gland is usually small, despite increased gonadotropin production (FSH and LH) due to loss of ovarian function (29).
Since the main observations of absent or at least true mitotic activity in hyperplastic pituitary glands, the origin of hyperplastic cells has been discussed. Although most of these organisms have their origins in expanded clones from a stem cell., But several lines of evidence support the concept of "reversible DNA transfer" in which cells are absorbed by heterologous cell types.
Early in evolution, GH-secreting cells have different transmitting capacity to gonadotrophs (30). The reversible phenotype of GH and PRL gene expression has long been reported in experimental rat pituitary tumor cells, and reflects a common precursor of acidophilic stem cells for both PRL and GH cells. There are several rodent models of pituitary hyperplasia, including pregnancy and the
administration of antithyroid drugs; It exhibits the plastic exchange of PRL and GH, as well as TSH- and GH secreted cell populations. During pregnancy, lactotrophic cells are absorbed by GH-secreting cells, and the hyperplastic cell population may be bi-hormonal and secrete both hormones. Similarly, patients with hypothyroidism show thyroid hyperplasia by absorbing GH-secreting cells, leading to TSH and GH-cell hyperplasia (30).
It is unclear whether these dual-hormonal, hypertrophic cells arise as a result of transmitting the differences of currently committed cells, or whether the more primitive stem cells expand earlier. Several lines of evidence support the concept of a hypothalamic role for pituitary tumorigenesis. True pituitary adenomas often retain the capacity to respond to trophic hypothalamic stimuli. In addition, pituitary adenomas, especially prolactinomas, may resolve spontaneously, indicating dental pituitary cell growth plasticity (31).
Finally, the clear manifestations of pituitary tumor shrinkage in patients receiving somatostatin
analogues for acromegaly or dopaminergic therapy for prolactinomas support the hypothesis that some altered pituitary cells retain hypothalamic control measurements with the capacity to reverse adenoma growth (32).
estrogen-responsive genes, with a stronger estrogen response due to ERα than ERβ. High doses of estrogen induce rat lactotrophic hyperplasia and adenoma formation (33),
and prenatal morin exposure to diethylstilbestrol significantly increases prolactinoma development in female offspring. Women's prolactinoma readiness and increase in size during pregnancy may be attributed to high estradiol levels, especially as prolactinomas overexpress estrogen receptors (29).
In addition to the effects of cellular trophies, estrogen induces the prolactin promoter, and activates the pituitary tumor-transforming gene (PTTG), FGF-β, FGF-β receptors, and the
pregnancy and the administration of antithyroid drugs; It exhibits the plastic exchange of PRL and GH, as well as TSH- and GH secreted cell populations. During pregnancy, lactotrophic cells are absorbed by GH-secreting cells, and the hyperplastic cell population may be bi-hormonal and secrete both
hormones. Similarly, patients with hypothyroidism show thyroid hyperplasia by absorbing GH-secreting cells, leading to TSH and GH-cell hyperplasia (30).
It is unclear whether these dual-hormonal, hypertrophic cells arise as a result of transmitting the differences of currently committed cells, or whether the more primitive stem cells expand earlier. Several lines of evidence support the concept of a hypothalamic role for pituitary tumorigenesis. True pituitary adenomas often retain the capacity to respond to trophic hypothalamic stimuli. In addition, pituitary adenomas, especially prolactinomas, may resolve spontaneously, indicating dental pituitary cell growth plasticity (31).
Finally, the clear manifestations of pituitary tumor shrinkage in patients receiving somatostatin
analogues for acromegaly or dopaminergic therapy for prolactinomas support the hypothesis that some altered pituitary cells retain hypothalamic control measurements with the capacity to reverse adenoma growth (32).
and prenatal morin exposure to diethylstilbestrol significantly increases prolactinoma development in female offspring. Women's prolactinoma readiness and increase in size during pregnancy may be attributed to high estradiol levels, especially as prolactinomas overexpress estrogen receptors (29). In addition to the effects of cellular trophies, estrogen induces the prolactin promoter, and activates the pituitary tumor-transforming gene (PTTG), FGF-β, FGF-β receptors, and the expression of TGF-β and α, all of which are involved in pituitary tumors. Alternately spliced ERα mRNAs Iso formed by the altered response to estrogens and antiestrogens, suggest a mechanism for
carcinogens (33).
ER transcripts have been detected in almost all prolactinomas by deleting exons 2 and 5, which act as excitatory or ligand-independent isoforms. In contrast, deletions encoding the predominantly negative ERα isoforms lacking DNA binding or transactivation functions are less common in prolactinomas, respectively (30).
PTTG is expressed in the pituitary gland of female mice in an estrous cycle-dependent fashion, suggesting the involvement of PTTG in pituicyte proliferation after proptosis. Pituitary expression of PTTG in rats is induced early by estrogen and before estrogen-induced pituitary hyperplasia and adenoma formation (34).
Antiestrogens reduce the pituitary expression of PTTG while blocking the cellular effects of estrogen, and these factors also inhibit the proliferation of tumor pituitary cells in vitro and in vivo (35).
Although animal models depict estrogen-induced pituitary hyperplasia as pre-adenoma formation, only rare cases of prolactinoma formation have been reported in patients receiving high doses of estrogen. A transgender patient exposed to excess estrogen (35)
AIMS AND OBJECTIVES OF THE THESIS
Aim:
The aim of this study was to evaluate the dynamic tests in the diagnosis and follow-up of patients with this complication.
Objective:
1. To determine the diagnostic tests for hypopituitarism in adults
2. To compare diagnostic tests for hypopituitarism and detect advantages and disadvantages among tests
Literature review
3.1 Hypothalamus
The hypothalamus, which controls the pituitary by transmitting information, is found immediately above the pituitary. It acts as a communication center for the pituitary gland, sending signals to the pituitary gland in the form of hormones that circulate through the bloodstream and the nerves below the pituitary gland (37).
These signals, in turn, control the production and release of more hormones from the pituitary gland, which signals to other glands and organs in the body. The hypothalamus affects the functions of temperature regulation, food intake, thirst and water intake, sleep-wake patterns, emotional behavior, and memory(38).
The most common pituitary problem occurs when a benign tumor (used to describe a 'growth') develops, also called an adenoma. Pituitary tumors are not 'brain tumors'. The term benign is used by doctors to describe swelling that is not cancerous. Some pituitary tumors can exist for years without causing symptoms, and some will never produce symptoms(38).
Most pituitary tumors occur in people that don't have a family history of pituitary problems and therefore the condition is typically not passed down to offspring. Only occasionally inherited tumor - for example, in a condition known as multiple endocrine neoplasia. It is a tumor that does not produce any hormones(32).
It can cause headaches and vision problems or it can put pressure on the pituitary gland, causing it to stop producing the required amount of one or more pituitary hormones. This effect can also occur following treatment for a given tumor, such as surgery or radiation therapy.
3.2 hypopituitarism
The pituitary gland is a pea size gland located at the base of the human brain Hypopituitarism may be isolated/selective; deficiency specific to a single hormone, multiple/partial; deficiency involving more than one hormone, or complete/panhypopituitarism; deficiency of all pituitary hormones. The
prevalence of hypopituitarism is approximately 45.5 cases per 100 000 people which is therefore classified as a rare endocrine disease. It is part of the body's endocrine system, which is made up of all the glands that produce and regulate hormones. Despite its small size, the pituitary gland produces and releases a number of hormones that act on almost every part of the body (25).
Besides the classification regarding hormone involvement, hypopituitarism can also be classified into two types according to the anatomical location of the underlying pathology. 1- Primary
hypopituitarism caused by pathology of the pituitary itself, as opposed to 2- Secondary
Hypopituitarism as a sequela to hypothalamic disease and dysregulation of hypothalamic hormones. Hypopituitarism is when there is a short supply (deficiency) of one or more pituitary hormones. These hormonal deficiencies can affect any number of normal functions of the body, such as growth, blood pressure, or reproduction. Symptoms are usually different, depending on which hormone or hormones are missing. The signs and symptoms of hypopituitarism usually develop gradually and get worse over time. Sometimes they are subtle and can be ignored for months or even years. But for some people, the signs and symptoms develop suddenly (39).
The signs and symptoms of hypopituitarism vary depending on which pituitary hormones are affected and to what extent. In people with more than one pituitary hormone deficiency, the second deficiency may increase or, in some cases, mask the symptoms of the first deficiency (20).
3.3 Growth Hormone Deficiency (GH)
In children, GH deficiency can cause growth retardation and short stature. Most adults with GH deficiency have no symptoms, but for some adults it can cause (7):
Fatigue • Muscle weakness • Changes in body fat composition • Lethargy • Lower self estee 3.4 Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) deficiency
drive, infertility or fatigue. In children and adolescents, delayed puberty is usually the only symptom (40, 41).
3.5. Thyroid Stimulating Hormone Deficiency (TSH)
This hormone controls the level of the thyroid. Low TSH production can lead to hypothyroidism. This causes symptoms such as(42): • Fatigue •Weight Gain •dry skin • Constipation • Sensitivity to cold or difficulty staying warm
3.6 Adrenocorticotropic Hormone Deficiency (ACTH)
This hormone helps the adrenal hormones to properly function, and aids the body’s response to stress. Symptoms of ACTH deficiency include (43): Severe fatigue Low blood pressure, which can lead to fainting Frequent and prolonged infections Nausea, vomiting or abdominal pain Confusion.
3.7 Antidiuretic Hormone Deficiency (ADH)
This hormone, also called vasopressin, helps the body balance its fluid levels. An ADH deficiency can cause a disorder called insomnia, which can cause (44): Excessive urination, severe thirst, Electrolyte imbalance.
3.8 Prolactin
Diagram of the pituitary gland, the hormones it releases, and its target organs (20)
Hormones released by the pituitary gland include (20, 45, 46):
• Adrenocortical hormone (ACTH): This hormone helps maintain blood pressure and blood sugar by stimulating the adrenal glands to release cortisol.
• Growth Hormone (GH): Regulates the growth and development of the body.
• Thyroid Stimulating Hormone (TSH): This hormone controls the thyroid gland for the release of thyroid hormone, which affects metabolism.
• Antidiuretic hormone (ADH): which regulates water absorption and excretion by the kidneys. • Follicle-stimulating hormone (FSH): Controls reproductive function in both men and women. • Luteinizing hormone (LH): Controls reproductive function. Oxytocin: Responsible for uterine
Sign and symptoms Corresponding Pituitary hormone deficiency
General sign such as:
depression cold intolerance insomnia weight loss TSH,GH,LH-FSH TSH TSH,LH-FSH,GH ACTH
Dermatoogical signs such as:
pale and dry skin, loss of body hair
ACTH,LH-FSH ACTH,TSH,LH-FSH
Cardiovascular signs and symptoms: hypertension bradycardia hyperlipidemia hypoglycemia premature atherosclerosis TSH,GH TSH TSH,GH ACTH TSH,GH Respiratory signs: dyspnea ACTH,TSH Gasterointestinal symptoms: Anorexia Diarrhea constipation ACTH ACTH TSH Reproductive symptoms: Oligo/amenorrhea Erectile dysfunction Infertility Viginal dryness ACTH,TSH,LH-FSH,GH LH-FSH LH-FSH LH-FSH
3.8.1Causes of pituitary deficiency
Some of the common causes of hypopituitarism include (32, 47): Congenital:
• Maternal hyperglycemia
• Congenital infections ie. Syphilis and toxoplasmosis • Ectopic neurohypophysis
• Hypothalamic hamartoma and polydactyly • Midline defect cleft lip
Prenatal Neonatal causes:
• -Birth trauma asphyxia (pituitary stalk junction) • -Neonatal sepsis • -Hemochromatosis Acquired: • Head injury • Brain surgery • Stroke
• Infection of the brain and surrounding tissue i.e meningitis • Tuberculosis
• Aneurysms which lead to bleeding Tumors which effect the pituitary:
• Adenomas
• Craniopharyngiomas • Meningiomas
• Optic nerve gliomas
• Breast, lung, melanoma and renal cell carcinoma
• Diseases which lead to ischemic necrosis of the pituitary • Sheehan’s syndrome
• Diabetes mellitus
3.8.2 Symptoms of pituitary deficiency
Clinical features of pituitary deficiency Because the release of the pituitary gland affects some of the major hormones, different symptoms may occur. Clinical features depend on the organs and the number of hormones that are affected by pituitary deficiency. Symptoms can also change. Sometimes there are no symptoms and sometimes there are acute symptoms. Acute symptoms usually start suddenly and can lead to coma.
3.8.3 Hormone changes in pituitary deficiency:
• Malaise • Dizziness • Anorexia • Weight Loss • Gastrointestinal disturbances • Hyponatremia
• Low blood pressure • Anemia
• Stunting and delayed puberty may also be seen in children • Pale complexion
Growth Hormone (GH) Deficiency
Adults:
▪ Often asymptomatic
▪ Possibility of – fatigue, abdominal obesity and loss of muscle mass Children:
▪ Constitutional growth delay
Prolactin Deficiency
▪ Inability to lactate postpartum
▪ Sheehan syndrome’s first manifestation
Thyroid Stimulating Hormone Deficiency (TSH)
▪ Secondary hypopituitarism
▪ Apathy and cold intolerance opposite of hypothyroidism symptoms
Gonadotropin Deficiency
Men:
▪ Loss of libido ▪ Erectile dysfunction ▪ Infertility
▪ Atrophy of testes ▪ Gynecomastia Female: ▪ Oligomenorrhea ▪ Loss of libido ▪ Dyspareunia
▪ Loss of secondary sex characteristics (estrogen deficiency)
SYSTEMATIC REVIEW
Patients with AGHD and evaluation of pituitary function in patients after GHD
In the last few decades, high prevalence (about 60%) of pituitary deficiency can be seen extremely high due to TBI. On the other hand, the researchers and doctors highlighted huge variations in the reported prevalence rats. It can be seen that there are several factors that are putting huge impact on the prevalence of hypopituitarism after TBI. Moreover, it also effects the time interval present between TBI and
endocrine assessment. The next important factor is related to the type and severity of the trauma and also its other methods. All of these methods are sued for diagnosing hypopituitarism. According to this, there are some reviews that have shown some TBI related hypopituitarism. Furthermore, it is also showing that hypopituitarism is considered as the main complication for TBI disease. Moreover, it is also contributing morbidity and also provide poor recovery of the brain parts just after the injury. Secondly, all of these reviews are not contributing in the variability of the different diagnostic strategies and other definitions of pituitary insufficiency. For this purpose, different research had hypothesized that methodologies are contributing differently after disease. It shows that the main aim of this research is to provide systematic review of the second chapter. Moreover, after this, also critically compared and analyse the main
difference between the hypopituitarism and TBI on the pituitary function according to the pituitary axis. According to these facts, it can be noted that the prevalence rates of pituitary insufficiency may vary considerably and also connected with some important difference in endocrine and other analytic methods for accessing results. All of these results are mainly used for diagnosing hypopituitarism. Due to this, the study is showing different endocrine test, analytical methods and also cut off values. On the other hand, it also shows some confounding factors that were not included in it while accessing pituitary axes. Due to this, there is comprehensive increase in the importance of GH axis and it will also show decrease in concentration with the increase of BMI. Due to this factor, there will be overestimation of the
Hypopituitarism is a chronic endocrine disorder that can be caused by a number of factors. Hypopituitarism has a wide range of clinical manifestations, which are often intriguing at first and depend on the degree and seriousness of synthetic need. Nonetheless, it is associated with a high rate of mortality and a sense of impending doom. As a result, it's crucial to get a checkup and treatment as soon as possible. In addition to enhancement compound (GH) and adrenocorticotropic synthetic (ACTH) insufficiency, hypopituitarism may be effectively investigated by evaluating basal pituitary and target substance levels. In dark basal substance levels and GH/ACTH deficiency, dynamic generation tests are visible. For accurate interpretation, information on the use and limitations of these actuation tests is needed. It's important for doctors to remind their patients that they can need care for the rest of their lives (Corenblum, 2020).
Synthetic replacement care should be tailored to each individual's particular needs, taking into account planned associations. Endocrinological follow-up of hypopituitary patients over a long period of time is essential to screen hormone replacement frameworks and prevent under- or overtreatment.
Hypopituitarism is described as the complete or partial loss of front and back pituitary organ function caused by pituitary or hypothalamic dysfunction. Given that as many as 30 percent to 70 percent of patients with frontal cortex injury display signs of decreased compound emanation from their pituitary organ, the incidence and prevalence rate tend to be unconcerned about the true event of this problem. Furthermore, the clinical presentation of hypopituitarism may be influenced by factors such as the cause of hypopituitarism, the time of onset, and the speed and severity of compound release deficiency.
For example, although a slow-moving fragmentary substance inadequacy can go unnoticed for a long time, a sudden and complete insufficiency of compound release creates an emergency situation that necessitates fast clinical thinking. The treatment for hypopituitarism usually entails replacing the missing synthetic, but caution should be exercised in light of the fact that a few studies have nitty gritty a prolonged event of cardiovascular problems and the number of deaths among these patients. Furthermore, a significant number of patients who have been treated for a compound deficiency suffer from the negative effects of muddled bothers and decreased person fulfillment. The present study will concentrate on the limitations of the induction test and compound replacement therapy, as well as the general components of hypopituitarism (Khardori, 2019).
vein impedance. Another potential justification for hypopituitarism is red hot hypophysitis, which has a mysterious etiology and poses with symptoms that are difficult to distinguish from those associated with a tumor. Though this description is extraordinary, clinical features such as a disengaged or combined
shortfall of adrenocorticotropic drug, thyroid-fortifying substance, gonadotropin, and advancement synthetic are referred to.
Hypopituitarism may also be caused by exposure to radiation for the treatment of painful conditions in the head and neck region. Furthermore, when radiotherapy is used to treat a pituitary tumor, an arrangement of material needs can occur, and the onset of these conditions is dependent on the total amount of radiation given, whether fractioning was used, and the amount of time that passed after the radiation. At ten years after the radiation transparency, the repeat of the sign of a material insufficiency is more noticeable than half. Most patients, like those with pituitary adenomas, have a typical path that begins with GH deficiency, progresses to gonadotropin insufficiency, ACTH requirement, and finally TSH insufficiency. Similarly, though further research is recommended, it is widely acknowledged that the risk of hypopituitarism is lower after gamma sharp edge radiosurgery than after traditional radiotherapy techniques (Yolanda, 2018).
Hypopituitarism can occur anywhere from 10% to 25% of the time after a pituitary tumor is removed. This may be due to the size of the tumor, the degree of attack, the amount of remaining common tissues, or the neurosurgeon's level of specific competency. When cytomegalovirus tainting occurs in patients with AIDS infection, hypopituitarism has been observed in exceptional cases. Sheehan's disease,
hypopituitarism caused by the pituitary organ's post-pregnancy channel, has occurred on a regular basis in the past, but it is only seen now on occasion. Tuberculosis meningitis and hemorrhagic fever with renal disease, which were sometimes seen in the past but are now almost non-existent. Specific or obfuscated pituitary compound need conditions may occur as a result of inherited causes in rare cases, and they typically affect teenagers.
following a TBI seems to be faster than previously thought, with the transcendence rate ranging from 30% to 70% depending on the patients' characteristics and specific tests (Ibrahim, 2020).
The most common problem associated with hypopituitarism is GH deficiency. Following a TBI, the early detection of a compound inadequacy has a significant impact on the degree of recovery. Furthermore, synthetic replacement therapy has been shown to increase reclamation outcomes as well as a patient's individual fulfillment. Despite the fact that approximately half of patients who experience hypopituitarism within a half year of a TBI return to their usual pituitary limit within a year, a few patients who have normal compound levels after a TBI develop new synthetic deficiency after a year. Panhypopituitarism that develops early after a traumatic event usually progresses. As a result, it is suggested that the front pituitary limit and person fulfillment be reassessed after around 6 to a period of an actual problem. Regardless, determining the most appropriate early assessment period after such an injury is difficult.
It is also critical to thoroughly screen patients after a subarachnoid release, since the effects of a pituitary drug need can become obvious. While diabetes insipidus is more persistent in discretionary hypopituitarism, the inadequacy of pituitary limit due to helper hypopituitarism is less certifiable than fundamental hypopituitarism. Ailments like absorption problems, central contaminations, and tension, for example, may all be linked to particular pituitary synthetic deficiencies. Provocative cytokines such as interleukin and, which have truly suppressive effects on thyroid conveying compound (TRH) and gonadotropin-conveying substance (GnRH) levels while also speeding up the release of corticotropin-conveying synthetic, appear to be the mechanism by which pressing factor works (CRH). This is one possible reason for euthyroid insufficiency or hypothalamic amenorrhea, since when the primary suppressive factor is eliminated, these suppressive effects are often reduced. Surprisingly, provocative or prominent infections that destroy the operational hub may explain the unusual recovery of neuroendocrine limit in patients who have these problems even after the secret illness has been treated (Pekic, 2017).
Genetic disorders such as Kallmann's issue or neurohypophyseal diabetes insipidus may contribute to a lower pituitary limit in exceptional cases. Kallmann's disease manifests a wide range of inherited changes, including KAL1 consistency. GnRH deficiencies and hypogonadotropic hypogonadism are associated with the olfactory setback that is a direct consequence of olfactory bulb mishap or hypoplasia in these patients due to an inadequacy of GnRH neurons in the operational center. Changes in the neurophysin II piece of the vasopressin-neurophysin forerunner characteristics may also cause a disorder called
neurohypophyseal diabetes insipidus.
changes and hypothalamic problems. The clinical manifestation of exaggerated panhypopituitarism, which often occurs after hypopituitary patients finish synthetic replacement or have a pituitary circulatory problem or undergo hypophysectomy, can be seen within a few hours to two or three days. In either case, the majority of patients experience a gradual and reformist loss of pituitary limit, with clinical symptoms that are typically fragile, dim, or obscure. When in question, these patients aren't resolved to live with hypopituitarism for a longer period of time (Pekic, Expanding the cause of hypopituitarism, 2017).
Since GH-emanating cells are especially vulnerable to strain, GH deficiency is the first and most common pituitary synthetic requirement, followed by gonadotropin deficiency (luteinizing compound [LH] and follicle-empowering substance [FSH], TSH, and ACTH (or ACTH and TSH), and prolactin deficiency. GH and gonadotropins are two of the most well-known synthetic compounds that exhibit unique insufficiencies. Children will suffer the negative effects of GH deficiency in general, while adults will often experience symptoms of gonadotropin deficiency. Medical symptoms of a lack of ACTH, TSH, or possibly gonadotropins vary, but they are similar to those associated with target organ drug deficiency.
If ACTH deficiency is mild, the patient can live a relatively ordinary and event-free life; however, patients with severe ACTH deficiency suffer the negative consequences of a series of hazy and uncertain battles. ACTH deficiency (discretionary adrenal insufficiency) is distinct from basic adrenal insufficiency (Addison's disease) in that the observable onset of an Addisonian crisis (adrenal crisis) is exceptional given that aldosterone release is only partially liberated from the pituitary organ. Despite the fact that aldosterone secretion may be reduced as a result of hypopituitarism due to ACTH deficiency, the excessive release of aldosterone, which is compelled by the
renin/angiotensin structure, is sufficient for the support of common plasma volume and heartbeat in the absence of a severe pressing factor. In multiple occurrences of ACTH deficiency, no hyperpigmentation has been observed. Due to the fact that ACTH stimulates the release of adrenal androgen, a lack of adrenal androgen in response to ACTH deficiency can contribute to female sexual inadequacy and may be the primary cause of pubic and axillary hair loss. Surprisingly, given the abundance of testosterone released from the balls, the lack of adrenal androgen isn't as important for people (Kim, 2015).
Inclusion Criteria
The inclusion criteria were the following: 1- observational studies and randomized controlled trials, 2- studies done on adult humans, 3- studies concerning hypopituitarism, growth hormone deficiency, dynamic tests of hypopituitarism, adrenocorticotropic hormone (ACTH) deficiency, thyroid stimulating hormone (TSH) deficiency. 4- studies published in the past 6 years (2015-2021), 5- full-text format accessible through the Lithuanian University of Health Sciences’ Databases’ function and 6- text is in English.
Exclusion Criteria
The exclusion criteria were the following: 1- other study designs, 2- studies published earlier than 2015, 3- full-text format inaccessible and 4- text is not in English.
Our systematic review will report according to the recommendation of the Preferred Reporting Items for Systematic Reviews and Meta-examinations (PRISMA) statement(1). We include original controlled studies published in any language with a sample size >10 patients evaluating adults patients with
AGHD diagnostic test:
Participants and procedure:
Momentarily, examinations were performed utilizing information from 140 members matured 18–66 years with BMI <37 kg/m2 and shifting levels of probability for AGHD. Members were delegated having high (Gathering A), moderate (Gathering B), or low (Gathering C) probability for AGHD and were contrasted and coordinated with solid controls (Gathering D). Members were considered to have a high probability of AGHD (Gathering A) in the event that they had a primary hypothalamic or pituitary sore and low serum IGF-I levels in addition to ≥3 other pituitary chemical insufficiencies, or youth beginning GHD with underlying sores and low serum IGF-I levels. Members were considered to have a low probability of AGHD (Gathering C) in the event that they had 1 danger factor for AGHD (for example history of removed horrendous mind injury, just 1 other pituitary chemical insufficiency, or adolescence beginning confined GHD). Members were considered to have a middle of the road probability of AGHD (Gathering B) on the off chance that they didn't meet the standards for Gatherings An or C. Coordinating with
members in Gathering A with members in Gathering D depended on age, sex, BMI, and estrogen status (Garcia, 2021).
Members were randomized to go through either the macimorelin GHST (Aeterna Zentaris, Frankfurt, Germany) trailed by the ITT or the ITT followed by the macimorelin GHST. The ITT was performed with standard human insulin got from drug store stock. Serum GH fixations were estimated utilizing a
ultrasensitive approved ImmunoChem luminescence test (IDS-iSYS human GH) that is normalized to the World Wellbeing Association recombinant GH alignment standard (98/574) and conforms to suggestions for examine normalization. GHSTs were performed 7–28 days separated under abstained conditions. Test outcomes were considered 'positive' for GHD if the pinnacle GH esteem was not exactly a cut point set up deduced; tests were considered 'negative' for GHD if the pinnacle GH esteem was more prominent than or equivalent to this cut point. In the essential investigation, the GH cut points decided deduced were 2.8 ng/mL for the macimorelin test and 5.1 ng/mL for the ITT.
Analyzing the effect of age, BMI, and sex on the test:
The likelihood of AGHD was assessed utilizing four calculated models, with top GH level as the
informative variable, fitted to the information: unadjusted, age-changed, BMI-changed, and sex-changed. Each model thought about all subjects as autonomous perceptions, not representing coordinating (Garcia, 2021).
The region under the bend (AUC) of the assessed collector working trademark (ROC) bend (scope of 0–1, where 1 is great) was estimated after organization of the macimorelin GHST. ROC AUC results from each changed model were contrasted and results from the unadjusted model. Assessed affectability and
explicitness were determined for each model utilizing macimorelin cut point upsides of 2.8 and 5.1 ng/mL. Assessed affectability and particularity from the model adapted to BMI were determined at the base, mean, middle, and greatest BMI upsides of study members.
Analysis of macimorelin vs ITT performance over a range of GH cut points:
The rate understanding (negative, positive, and generally) between tests was resolved utilizing GH cut point upsides of 2.8, 4.0, 5.1, and 6.5 ng/mL for both the macimorelin GHST and the insulin tolerance test (ITT) in members from all investigation gatherings (A, B, C, and D). The cut point of 2.8 ng/mL was chosen dependent on a past post hoc investigation. The cut point of 5.1 ng/mL was assessed on the grounds that it is an approved and broadly referred to cut point for the ITT. The cut point of 4.0 ng/mL was chosen since it is the rough midpoint somewhere in the range of 2.8 and 5.1 ng/mL. The cut point of 6.5 ng/mL was assessed in light of the fact that it is the most minimal cut point that compared to an expected affectability of 100% for the ITT. The rate arrangement between tests was determined as the level of members with a similar discovering (positive, negative, or in general (for example both positive and negative)) utilizing a predefined macimorelin cut point and a predetermined ITT cut point. Two-sided 95% CIs of the rate arrangement between tests were determined dependent on the Clopper–Pearson strategy.
The assessed explicitness and affectability of the two tests were resolved at all cut points. Particularity was determined as the level of members in Gathering D (sound controls) with a negative discovering utilizing the predefined GH cut point. Affectability was determined as the level of members in Gathering A (high probability of AGHD) with a positive discovering utilizing the predetermined GH cut point (Garcia, 2021).
Result
The effect of age, BMI, and sex on the test:
By and large, the examination included 41 members with a high probability of AGHD (Gathering A) and 29 solid controls (Gathering D). Segment qualities were similar between members in Gathering A and Gathering D. Generally speaking, the mean (SD) age was 41.7 (13.9) a long time, and the periods of all members went from 18 to 66 years. The mean (SD) BMI was 27.1 (4.0) kg/m2 (territory, 20.4–36.6 kg/m2). 39 of 70 (55.7%) members were male. True to form, mean (SD); range top GH focus was considerably lower in Gathering A (0.91 (1.9); 0.1–8.6 ng/mL) than in Gathering D (16.2 (7.4); 2.2–34.6 ng/mL).
Execution of the macimorelin test was not genuinely influenced by age, BMI, or sex. The ROC AUC (95% CI) for the unadjusted model was 0.9924 (0.9807–1) contrasted and 0.9924 (0.9807–1) for the age-changed model (P = 1), 0.9916 (0.9786–1) for the BMI-age-changed model (P = 0.6861), and 0.9950 (0.9861– 1) for the sex-changed model (P = 0.4207).
Utilizing the macimorelin cut point of 2.8 ng/mL, assessed affectability was 88% and explicitness was 97% for the unadjusted model. These qualities continued as before while adapting to age and for mean or middle BMI. Adapting to most extreme BMI (36.6 kg/m2) brought about affectability of 76% and
Macimorelin vs ITT performance over a range of GH cut points:
This investigation remembered members for the changed goal to-treat populace (n = 140; all randomized members with evaluable information from both the macimorelin GHST and the ITT). Members
incorporated those with a high (Gathering A; n = 38), halfway (Gathering B; n = 37), or low (Gathering C; n = 40) probability for AGHD and solid coordinated with controls (Gathering D; n = 25). Utilizing an ITT cut point of 5.1 ng/mL, 74 members were named GH-inadequate and 66 were named GH-adequate. Choosing the equivalent cut point values for macimorelin and the ITT yielded high sure, negative, and generally arrangement rates. At a GH cut point worth of 2.8 ng/mL for the two tests, positive
understanding was 87.1% (95% CI, 76.2–94.3%), negative arrangement was 93.6% (95% CI, 85.7– 97.9%), and in general arrangement was 90.7% (95% CI, 84.6–95.0%). At a GH cut point worth of 5.1 ng/mL for the two tests, positive arrangement was 82.4% (95% CI, 71.8–90.3%), negative understanding was 92.4% (95% CI, 83.2–97.5%), and generally speaking understanding was 87.1% (95% CI, 80.4– 92.2%).
Accepting that all members in Gathering A (n = 38) were AGHD cases and that all members in Gathering D (n = 25) were solid controls, the macimorelin GHST and the ITT had indistinguishable assessed
specificities of 96% at GH cut point upsides of 2.8, 4.0, or 5.1 ng/mL. At the GH cut point of 5.1 ng/mL, the assessed affectability was 92% with the macimorelin GHST and 97% with the ITT. Expanding the GH cut point to 6.5 ng/mL expanded the affectability of the macimorelin test to 97% and the ITT to 100%. In any case, these expansions in affectability were to the detriment of diminished particularity (92 and 88%, individually, for the macimorelin test and the ITT at 6.5 ng/mL). Affectability and explicitness esteems fluctuated marginally when determined utilizing the relapse models [2].
According to the studies conducted on the studies of hypopituitary during the years 2015 to 2021, the summary of the results are included into the table.
M. J. Hannon (2015) (33 )
41 Both anterior and posterior hypopituitarism are very uncommon following SAH and are
not predicted by acute clinical, hemodynamic or endocrinological parameters. Routine neuroendocrine screening is not justified in SAH patients. Martín Cuesta
et al. (2015)(9)
113 Symptoms of hypogonadism are sufficiently predictive of hypopituitarism to justify
screening for hypopituitarism after moderate/severe TBI. Nonspecific symptoms of hypopituitarism are no more
predictive than unselected screening. Sofia Llahana
(2019)(21 )
Growth hormone (GH) deficiency is very common in adults with hypopituitarism and requires replacement with daily subcutaneous
injections. A provocative stimulation test is required to establish the diagnosis of GH deficiency in adults with the insulin tolerance
test being regarded as the “gold standard”. Akimi Soga et al
(2020)(7)
76 Compared with group M, group L patients were significantly older and more gonadotropin and ACTH deficient. A
lower
peak GH release during a GHRP-2 test was associated with a higher number of anterior pituitary hormone deficiencies across all 76 patients. Postoperatively. Preoperative peak GH concentrations assessed during a GHRP-
2 test reflected the severity of hypopituitarism and the recovery of
Erik Kronvall (2015)(51 )
60 Application of dynamic endocrine tests revealed a high frequency of long-term hypothalamic-pituitary dysfunction after aneurysmal SAH. The role of pituitary dysfunction in the
recovery after SAH merits further evaluation. Asta Dogg
Jonasdottir et al (2018)(52)
27 There is a considerable risk of HP after TBI and reason to study pituitary function further in
patients with SAH. We believe that neuroendocrine evaluation is important in these
patients. Since recovery commonly occurs 12 months after the event, evaluation should be
performed after that time if not clinically indicated earlier Natasha (2015)
(34)
22 The results are showing that about 198 survivors who are struggling with structural
TBI able to sustain in the early childhood. Moreover, there are some struggling with this
problem after 6.5 years after injury. From them, there are about 64 of the injuries were
considered as inflicted and about 134 were considered as accidental. There are about two
participants that have developed precocious puberty. It shows that permanent hypopituitarism is rare just after accidental and
Maria Fleseriu (2016) (35)
33 One of the main facts is that one group meetings. Email, and some several conference calls are creating problems. It shows that some members of Endocrine Society, committees
and the American association for clinical chemistry is showing proper results. It can be seen that through evidence-based approach the
guideline address is extremely important for dealing with clinical issues during the evaluation of hypopituitarism in children and adults. This report is discussing some specific therapeutic decisions that will help to decrease
the value of co-morbidities. Akimi Soga
(2016)(53)
21 It can be seen that a lower peak GH value can easily affect the patient during the GHRP-2
test. On the other hand, NFPA is also connected with such higher number of anterior
pituitary hormone deficiencies. Furthermore, some peak preoperative G values during GHRP-2 test is also reflecting the recovery
operation. Junko
Matsuyama (2019)(54)
34 According to results, it can be seen that the serum IGF-1 SD is scoring a sensitive measure
of the integrated GH levels present in such patients struggling with hypopituitarism. On the other hand, it is also related to the clinical
and also biochemical markers of the disease activity. Furthermore, it is also considered as
Guillem Cuatrecasas (2017)(24)
34 It can be noted that Functional defects present in growth hormone secretion and its efficacy is
considered as important treatment for the disease hypopituitarism. For this purpose, there
are about 120 patients were enrolled in a multicenter and study is conducted for 18
months. Another thing is that they were randomly assigned to take medication for about 0.006 mg of GH. Due to this, Placebo arm was also moved towards GH treatment for
six months. It shows that some standard treatment hypopituitarism include re-uptake inhibitors, and amitriphty. At the end of the results there are about 11 tender point received
by group A with 53% and group B with 33% . But for group A the results are positive
compared with the group B. Marco Losa
(2020) (38)
23 The results are showing that there are about 283 patients are struggling with AGHD due to
NFPA and also craniopharyngioma between the years 1995 and 2018. For this purpose,
rhGH treatment is considered as important dose and injected in about 123 patients. On the
other hand, other 160 were served as control. The results are showing that there is no association is present between the rhGH replacement and also increased risk of tumor
Discussion
Hypopituitarism is defined as one or more pituitary hormone deficits due to a lesion and lack of hormones in the hypothalamic–pituitary region. By far, the most common cause of hypopituitarism associated with a seller mass is a pituitary adenoma. A high index of suspicion is required for
diagnosing hypopituitarism in several other conditions such as other masses in the sellar and parasellar region, brain damage caused by radiation and by traumatic brain injury, vascular injury, inflammatory disorders (lymphocytic hypophysitis, sarcoidosis), infectious diseases and genetic mutations.
Hypopituitarism can be due to brain injury or a congenital disorder or acquired like caused by
radiations these changes can be reversible (could recover by treatment after many years) or irreversible damages.recently has been reported many patients whom hypopituitarism is diagnosed in late stages of disease.in this review we look at database available about patients who were diagnosed in earlier stages. In Jonasdottir from 27 diagnosed hypopituitarism 15 TBI and 12 who has SAH. In these patients'
diagnoses was bases on ITT and GHRH-arginine test to evaluate their pituitary function. The hormones such as gonadotropin showed the most deficiency in the 3-month investigation and growth hormone showed the same results but in 12 months, both hormones showed an increase concentration of most hormones was reported after 12-month.
In Kronvall et al(51), pituitary hormones were investigated in the range of 6 to 12 month and the from 12 to 24 months after SAH. After in 24-month hormone investigation was done as a follow up a dynamic test for evaluation of ACTH and GH using ITT or stimulation of hormone performed. The final report revealed diagnosed hypopituitarism after 6-12 month was about 34 percent and about 41 percent for 12-24 month. The dynamic test ITT can diagnose more of hypoadrenalism and GH deficiency compared to stimulating-provocation tests.
missed.. The ITT also has the advantage of testing the corticotrophic axis(10). However, when ITT is contraindicated in patients (i.e patients with a history of cardiovascular disease or seizure disorders), GH releasing hormone (GHRH)-Arginine test is a valid alternative where it provides equivalent specificity and sensitivity to ITT (10). Another alternative would be a glucagon stimulation test (GST) (16).
In Cuesta et al study which 2 sets of patients were studied one that patients with no symptoms were screened and in other patients with hypopituitarism were selected. Inn this study different pituitary hormones were compared. Their results showed Patients referred with menstrual dysfunction had more GH (50% vs 11%, P = 0·001), ACTH (60% vs 14%, P < 0·0001), GT (90% vs 16%, P < 0·0001) deficiency and any pituitary hormone deficit (80% vs 33%, P = 0·003) than G1. Men with symptoms of hypogonadism had more GH (33% vs 11%, P = 0·003), GT (58% vs 16%, P < 0·0001) and TSH (16% vs 1%, P = 0·03)
deficiency than G1(8). Patients with nonspecific symptoms weren't more likely to have hypopituitarism than patients who are screened consecutively.
A low IGF-1, in the absence of poorly controlled diabetes, liver disease, and oral estrogen therapy, is useful in identifying patients who may potentially be GH deficient and require further diagnostic investigations
(16).
Patients with suspected GH deficiency should undergo pituitary provocative (dynamic) testing to diagnose adult GH deficiency. There are several diagnostic tests available, where the insulin tolerance test (ITT) is the first choice for adults and considered the gold standard. The diagnostic criterion for adult GH deficiency (AGHD) is a GH cutoff level between 3 and 5 μg/L in response to insulin-induced hypoglycemia (glucose <2.2 mmol/L), although this may differ from country to country depending on national guidelines or local assays used for biochemistry analysis (16, 46). Hannan et al(32) in their study, 100 patients from the time of presentation with acute SAH arrived.
testing. Although 14 of 100 had acute glucocorticoid deficiency immediately following SAH, only two of 41 had long‐term adrenocorticotrophic hormone (ACTH) deficiency and four of 41 had growth hormone (GH) deficiency. None were hypothyroid or gonadotrophin deficient. None had chronic CDI or hyponatremia. There was no association between acute glucocorticoid deficiency, acute CDI or acute hyponatremia and long‐ term pituitary dysfunction.
Brain injuries can damage the pituitary gland and reduce growth hormone (14, 53). it has been hypothesized that because pituitary omatotropic cells are located in the lateral wings of the gland, where perfusion and oxygen supply depend on the hypothalamus–pituitary portal vessels, the arterial blood supply is particularly vulnerable to shearing injury after brain trauma (15).
Consensus guidelines agreed that on the basis of the published data, severe growth hormone
deficiency occurs in 15–20% of patients after moderate or severe TBI. As growth hormone and ACTH deficiency require dynamic testing for (31) accurate diagnosis, the demands of screening are
considerable prompting the publication of specific criteria for dynamic testing for post-TBI hypopituitarism.
In Cuesta et al study they reported that screening on the basis of nonspecific symptoms of hypopituitarismis no better than systematic screening, in identifying pituitary hormone deficiency following moderate or severe TBI (8).
In some studies, the study of libido as well as erection in men can predict patients' pituitary problems. In a study (36) it was stated that in men post-TBI, depression is the most sensitive predictor of sexual dysfunction, which explains why some patients with referred on the basis of poor libido had normal pituitary– gonadal axes.
In the Akimi et al (7) study They divided patients into two groups. Then they saw Compared with group M, group L patients were significantly older and more gonadotropin and ACTH deficient. A lower peak GH release during a GHRP-2 test was associated with a higher number of anterior pituitary hormone deficiencies across all 76 patients. Postoperatively, seven in group M and no patient in group L were assessed as having no longer severe AGHD, respectively.
Preoperative peak GH concentrations assessed during a GHRP-2 test reflected the severity of
