الغدة النخامية Pituitary gland
Anatomy
The pituitary gland was first called "hypophysis" by Thomas Soemmering in 1778. Hypophysis is a Greek term that describes how the pituitary appears to "grow beneath the brain." The pituitary gland carries the respectable sobriquet "master gland" because it produces hormones that regulate growth, development, and reproduction.
Despite its vital role, the pituitary gland is only the size of a pea. It is located in the middle cranial fossa within a recess of the sphenoid bone called the sella turcica
The pituitary gland has 2 parts: the anterior pituitary (adenohypophysis) which consists of hormone-producing epithelium.
and the posterior pituitary (neurohypophysis) which consists of nervous tissue branching out of the hypothalamus.
Blood supply:
-arterial: sup.&inf hypophyseal artery (from internal carotid artery)
-venous: hypothalamo-hypophyseal portal circulation. it consists of :
*1ry capillary plexus in hypothalamus
*Connected along pituitary stalk to a 2ndry plexus in anterior lobe.
Embryology
The pituitary develops in the third week of embryogenesis from interactions between the diencephalon part of the brain and the nasal cavity.
The brain cells secrete FGF-8, Wnt5a and BMP-4, and the nasal cavity BMP-2. Together, these cellular signals stimulate a group of cells from the nasal cavity to form Rathke's pouch, which becomes independent of the nasal cavity and develops into the anterior pituitary; this process includes the suppression of production of a protein called Sonic hedgehog by the cells of Rathke's pouch. The cells then differentiate further into the various hormone-producing cells of the pituitary. This requires particular transcription factors that induce the expression of particular genes. Some of these transcription factors have been found to be deficient in some forms of rare combined pituitary hormone deficiencies (CPHD) in childhood. These are HESX1, PROP1, POU1F1, LHX3, LHX4, TBX19, SOX2 and SOX3. Each transcription factor acts in particular groups of cells. Therefore, various genetic mutations are associated with specific hormone deficiencies. For instance, POU1F1 (also known as Pit-1) mutations cause specific deficiencies in growth hormone, prolactin and TSH. In addition to the pituitary, some of the transcription factors are also required for the development of other organs; some of these mutations are therefore also associated with specific birth defects.
Physiology
Hypothalamic-pituitary-end organ axis
Thyroid
Adrenal
Gonads
Growth Breast
Releasing hormone TRH CRH GnRH GHRH Dopamine (inhibitor)
Pituitary cells Thyrotrope
Corticotrope
Gonadotrope
Somatotrope
Lactotrope
Pituitary hormone TSH ACTH LH/FSH GH Prolactin
End organ Thyroid Adrenal Testes or ovaries Liver Breast gland
Product Thyroxine Cortisol Testosterone or estradiol IGF-1 Milk (no feedback)
Most of the hormones in the anterior pituitary are each part of an axis that is regulated by the hypothalamus. The hypothalamus secretes a number of releasing hormones, often according to a circadian rhythm, into blood vessels that supply the anterior pituitary; most of these are stimulatory (thyrotropin-releasing hormone, corticotropin-releasing hormone, gonadotropin-releasing hormone and growth hormone-releasing hormone), apart from dopamine, which suppresses prolactin production.[16] In response to the releasing hormone rate, the anterior pituitary produces its hormones (TSH, ACTH, LH, FSH, GH) that stimulate effector hormone glands in the body, although prolactin acts directly on the breast gland. Once the effector glands produce sufficient hormones (thyroxine, cortisol, estradiol or testosterone and IGF-1), both the hypothalamus and the pituitary cells sense their abundance and reduce their secretion of stimulating hormones.
The hormones of the posterior pituitary are produced in the hypothalamus and are carried by nerve endings to the posterior lobe; their feedback system is therefore located in the hypothalamus, but damage to the nerve endings would still lead to a deficiency in hormone release.
It is the decreased (hypo) secretion of hormones normally produced by the pituitary gland at the base of the brain. If there is decreased secretion of most pituitary hormones, the term panhypopituitarism is used.
Hypopituitarism in Childhood:
1-pituitary dwarfism
Causes: Deficiency of GH-RH
Deficiency of GH
End organ unresponsiveness
Clinical picture:
*proportionate dwarfism
*hypoglycemia
*hypogonadism may appear: hypopituitarism+hypogonadism =Infantilism
Investigations: GH level
Insulin stimulation test
Treament:*GH injection
*Thyroxin and gonadal hormones may be needed
2-Froehlich's syndrome:
Idiopathic mainly
Clinical picture:
obesity- hypogonadism-dwarfism –DI, polyphagia
3-laurence moon Biedl syndrome:
Similar to Froehlich's syndrome, plus polydactyl, skull deformities, Retinitis pigmentosa and mental retardation.
Hypopituitarism in adults:
1-isolated hormone deficiency:
* Decrease inTSH 2ndry hypothyroidism
* Decrease in ACTH (2ndry hypocorticism)
*Decrease in gonadotrophines: 2ndry hypogonadism
2- Panhypopituitarism "simmond's disease":
Causes
Causes of primary hypopituitarism (directly affecting pituitary gland):
1-pituitary tumors
pituitary adenomas compressing the normal tissue in the gland
2-inadequate blood supply to pituitary gland
Sheehan's syndrome:
During pregnancy, the pituitary gland enlarges due to hyperplasia and hypertrophy of the lactotroph cells, which produce prolactin. The hypophyseal vessels, which supply the pituitary, constrict in response to decreasing blood volume, and subsequent vasospasm occurs, causing necrosis of the pituitary gland. The degree of necrosis correlates with the severity of the hemorrhage.
As many as 30% of women experiencing postpartum hemorrhage with hemodynamic instability may develop some degree of hypopituitarism. These patients can develop adrenal insufficiency, hypothyroidism, amenorrhea, diabetes insipidus, and an inability to breastfeed.
Pituitary apoplexy
Pituitary apoplexy denotes the sudden destruction of the pituitary tissue resulting from infarction or hemorrhage into the pituitary.
o The most likely cause of the apoplexy is brain trauma; however, it can occur in patients with diabetes mellitus, pregnancy, sickle cell anemia, blood dyscrasias or anticoagulation, and increased intracranial pressure.
o Apoplexy usually spares the posterior pituitary and solely affects the anterior pituitary.
3-infections and/or inflammatory diseases
• infection of the gland itself, or it may be infiltrated by abnormal cells (histiocytosis) or excessive iron (hemochromatosis).
4-sarcoidosis - a rare inflammation of the lymph nodes and other tissues throughout the body
5-amyloidosis - a rare disease which causes the buildup of amyloid, a protein and starch, in tissues and organs
6-radiation therapy
7-surgical removal of pituitary tissue
8-autoimmune diseases
Causes of secondary hypopituitarism (affecting the hypothalamus):
1)tumors of the hypothalamus
2)inflammatory disease
3)physical
External physical causes for hypopituitarism include
traumatic brain injury
subarachnoid hemorrhage
neurosurgery
surgical damage to the pituitary and/or blood vessels or nerves leading to it
ionizing radiation (e.g. radiation therapy for a previous brain tumor
Epidemiology
There is only study that has measured the prevalence (total number of cases in a population) and incidence (annual number of new cases) of hypopituitarism.
This study was conducted in Northern Spain and used hospital records in a well-defined population. The study showed that 45.5 people out of 100,000 had been diagnosed with hypopituitarism, with 4.2 new cases per year. 61% were due to tumors of the pituitary gland, 9% due to other types of lesions, and 19% due to other causes; in 11% no cause could be identified.
Recent studies have shown that people with a previous traumatic brain injury, spontaneous subarachnoid hemorrhage (a type of stroke) or radiation therapy involving the head have a higher risk of hypopituitarism. After traumatic brain injury, as much as a quarter have persistent pituitary hormone deficiencies. Many of these people may have subtle or non-specific symptoms that are not linked to pituitary problems but attributed to their previous condition. It is therefore possible that many cases of hypopituitarism remain undiagnosed, and that the annual incidence would rise to 31 per 100,000 annually if people from these risk groups were to be tested.
Mortality/Morbidity
The systemic effects of pituitary hormone deficiencies vary depending on the extent of pituitary involvement. Given that the pituitary acts on numerous endocrine sites, the consequences of pituitary dysfunction range from subclinical disease to panhypopituitarism.
• Missed or delayed diagnosis could potentially lead to permanent disability or death.
• Female patients with hypopituitarism who are receiving controlled thyroid and steroid hormone substitution, but without growth hormone replacement, have more than a 2-fold increase in cardiovascular mortality compared with the general population.
• Cardiovascular disease is significantly higher among hypopituitary patients (incidence ratio, 3.7; 95% confidence interval, 1.2–11.3)
• Hypopituitary patients have lower high-density lipoprotein cholesterol (P = 0.002) and higher low-density/high-density lipoprotein ratio (P = 0.009).
Signs and symptoms
The hormones of the pituitary have different actions in the body, and the symptoms of hypopituitarism therefore depend on which hormone is deficient. In most of the cases, three or more hormones are deficient
• Adrenocorticotropic hormone deficiency
• Deficiency in corticotropin is characterized by a decrease in adrenal androgens and production of cortisol.
• Acute loss of adrenal function is a medical emergency and may lead to hypotension and death if not treated.
• Signs and symptoms of ACTH deficiency may be profound and potentially fatal and include myalgias, arthralgias, fatigue, headache, weight loss, anorexia, nausea, vomiting, abdominal pain, altered mentation or altered consciousness, dry wrinkled skin, decreased axillary and pubic hair, anemia of chronic disease, dilutional hyponatremia, hypoglycemia, hypotension, and shock.
• Symptoms are nearly identical to those of primary adrenal insufficiency but can be differentiated by lack of hyperpigmentation. Hyperpigmentation occurs in a long feedback loop in which a cortisol deficiency results in increased production of ACTH by the pituitary. The ACTH precursor coupled to melanocyte-stimulating hormone is not produced in those with pituitary disease, and therefore hyperpigmentation does not take place.
• Patients with secondary adrenal insufficiency usually are eukalemic. This differs from primary adrenal insufficiency, in which patients develop hyponatremia and hyperkalemia.
• Aldosterone secretion is not affected, as it does not depend on corticotropin but instead on the renin-angiotensin axis.
• Thyrotropin deficiency
• Secondary thyrotropin deficiency (ie, hypothyroidism) due to decreased TSH exhibits identical symptoms to primary thyroid disease, only typically less severe.
• Signs and symptoms of secondary hypothyroidism include fatigue, weakness, weight gain, thickened subcutaneous tissues, constipation, cold intolerance, altered mental status, impaired memory, and anemia.
• Physical examination may reveal bradycardia, delayed relaxation of the deep tendon reflexes, and periorbital edema.
• Gonadotropin deficiency
• Low FSH and LH levels increase risk of osteoporosis due to decreased bone density and result in hypogonadism in both men and women.
• In men, symptoms include decreased libido, varying degrees of erectile dysfunction, decreased ejaculate, muscle weakness, and fatigue.
• Men with long-standing hypogonadism have decreased hair growth, soft testes, and gynecomastia. Patients may be anemic due to decreased erythropoietin production, which causes a normochromic, normocytic anemia.
• Premenopausal women present with altered menstrual function, ranging from regular anovulatory periods to amenorrhea, hot flashes, decreased libido, breast atrophy, vaginal dryness, and dyspareunia.
• Pubic and axillary hair growth is usually normal unless a concomitant ACTH deficiency exists.
• Postmenopausal women usually present with headache or visual abnormalities due to other hormonal deficiencies or mass lesions.
• In children, FSH and LH deficiency can cause eunuchoidism and lack of sexual development.
• FSH and LH have an indirect effect on bone growth by causing closure of the epiphysis.
• Characteristics of eunuchoidism are due to delay in closure of the epiphysis, resulting in long extremities.
• Growth hormone deficiency
• In children, GH deficiency presents as growth retardation and delayed sexual maturation.
• Patients may present with fasting hypoglycemia due to loss of the gluconeogenic effect of GH, which counteracts the effect of insulin.
• In adults, GH deficiency presents as weakness, poor wound healing, wrinkling around the eyes and mouth ,decreased exercise tolerance, and decreased social functioning.
• Prolactin deficiency
• Tumor growth that decreases PRL production affects the process of lactation; these tumors become evident only in the postpartum state.
• PRL deficiency is very rare; any process that affects the hypothalamus and the pituitary stalk decreases the normal inhibitory effect of dopamine from the hypothalamus on the pituitary, causing a rebound increase in PRL.
D.D
(1) 1ry adrenal hypofunction"Addison's disease"
(2) 1ry hypothyroidism
(3) 1ry hypogonadism
(4) Anorexia nervosa
(5) Pernicious anemia
Diagnosis
The diagnosis of hypopituitarism is made on blood tests.
Two types of blood tests are used to confirm the presence of a hormone deficiency:
1- basal levels, where blood samples are taken–usually in the morning–without any form of stimulation
2- dynamic tests, where blood tests are taken after the injection of a stimulating substance.
Measurement of ACTH and growth hormone usually requires dynamic testing, whereas the other hormones (LH/FSH, prolactin, TSH) can typically be tested with basal levels.
Generally, the finding of a combination of a low pituitary hormone together with a low hormone from the effector gland is indicative of hypopituitarism.
Occasionally, the pituitary hormone may be normal but the effector gland hormone decreased; in this case, the pituitary is not responding appropriately, and the combination of findings is still suggestive of hypopituitarism.
Basal tests
*Levels of LH/FSH
In men, the combination of low LH and FSH in combination with a low testosterone confirms LH/FSH deficiency; a high testosterone would indicate a source elsewhere in the body (such as a testosterone-secreting tumor).
In women, the diagnosis of LH/FSH deficiency depends on whether the woman has been through the menopause. Before the menopause, abnormal menstrual periods together with low estradiol and LH/FSH levels confirm a pituitary problem; after the menopause (when LH/FSH levels are normally elevated and the ovaries produce less estradiol), inappropriately low LH/FSH alone is sufficient. Stimulation tests with GnRH are possible, but their use is not encouraged.
*TSH
basal measurements are usually sufficient, as well as measurements of thyroxine to ensure that the pituitary is not simply suppressing TSH production in response to hyperthyroidism (an overactive thyroid gland). A stimulation test with thyrotropin-releasing hormone (TRH) is not regarded as useful.
*Prolactin
can be measured by basal level, and is required for the interpretation of LH and FSH results in addition to the confirmation of hypopituitarism or diagnosis of a prolactin-secreting tumor.
Stimulation tests
1-Growth hormone:
Growth hormone deficiency is almost certain if all other pituitary tests are also abnormal, and insulin-like growth factor 1 (IGF-1) levels are decreased. If this is not the case, IGF-1 levels are poorly predictive of the presence of GH deficiency; stimulation testing with the insulin tolerance test is then required. This is performed by administering insulin to lower the blood sugar to a level below 2.2 mmol/l. Once this occurs, growth hormone levels are measured. If they are low despite the stimulatory effect of the low blood sugars, growth hormone deficiency is confirmed. The test is not without risks, especially in those prone to seizures or are known to have heart disease, and causes the unpleasant symptoms of hypoglycemia. Alternative tests (such as the growth hormone releasing hormone stimulation test) are less useful, although a stimulation test with arginine may be used for diagnosis, especially in situations where an insulin tolerance test is thought to be too dangerous. If GH deficiency is suspected, and all other pituitary hormones are normal, two different stimulation tests are needed for confirmation.
2-ACTH:
If morning cortisol levels are over 500 nmol/l, ACTH deficiency is unlikely, whereas a level less than 100 is indicative. Levels between 100-500 require a stimulation test. This, too, is done with the insulin tolerance test. A cortisol level above 500 after achieving a low blood sugar rules out ACTH deficiency, while lower levels confirm the diagnosis. A similar stimulation test using corticotropin-releasing hormone (CRH) is not sensitive enough for the purposes of the investigation. If the insulin tolerance test yields an abnormal result, a further test measuring the response of the adrenal glands to synthetic ACTH (the ACTH stimulation test) can be performed to confirm the diagnosis. Stimulation testing with metyrapone is an alternative. Some suggest that an ACTH stimulation test is sufficient as first-line investigation, and that an insulin torlerance test is only needed if the ACTH test is equivocal. The insulin tolerance test is discouraged in children. None of the tests for ACTH deficiency are perfect, and further tests after a period of time may be needed if initial results are not conclusive.
Further investigations
*magnetic resonance imaging (MRI)
scan of the pituitary is the first step in identifying an underlying cause. MRI may show various tumors and may assist in delineating other causes. Tumors smaller than 1 cm are referred to as microadenomas, and larger lesions are called macroadenomas.
*Computed tomography
Computed tomography with radiocontrast may be used if MRI is not available.
*Formal visual field testing by perimetry is recommended, as this would show evidence of optic nerve compression by a tumor.
Other tests that may assist in the diagnosis of Hypopituitarism (especially if no tumor is found on the MRI scan):
ferritin (elevated in hemochromatosis).
angiotensin converting enzyme (ACE) levels (often elevated in sarcoidosis).
human chorionic gonadotropin (often elevated in tumor of germ cell origin).
genetic testing may be performed, If a genetic cause is suspected.
Treatment
Treatment of hypopituitarism is threefold:
removing the underlying cause
treating the hormone deficiencies
addressing any other repercussions that arise from the hormone deficiencies.
Underlying cause:
Pituitary tumors
require treatment when they are causing specific symptoms, such as headaches, visual field defects or excessive hormone secretion. Transsphenoidal surgery (removal of the tumor by an operation through the nose and the sphenoidal sinuses) may, apart from addressing symptoms related to the tumor, also improve pituitary function, although the gland is sometimes damaged further as a result of the surgery.
When the tumor is removed by craniotomy (opening the skull), recovery is less likely–but sometimes this is the only suitable way to approach the tumor.
After surgery, it make take some time for hormone levels to change significantly. Retesting the pituitary hormone levels is therefore performed 2 to 3 months later.
Prolactinomas
may respond to dopamine agonist treatment–medication that mimics the action of dopamine on the lactrotrope cells, usually bromocriptine or cabergoline. This approach may improve pituitary hormone secretion in more than half the cases, and obviate the need for supplementary treatment.
Other specific underlying causes are treated as normally. For example, hemochromatosis is treated by venesection, the regular removal of a fixed amount of blood. Eventually, this decreases the iron levels in the body and improves the function of the organs in which iron has accumulated.
Hormone replacement
Most pituitary hormones can be replaced indirectly by administering the products of the effector glands:
1-Growth hormone
is available in synthetic form, but needs to be administered parenterally (by injection).
2-levothyroxine for hypothyroidism
3-testosterone for male hypogonadism and estradiol for female hypogonadism (usually with a progestagen to inhibit unwanted effects on the uterus).
4-hydrocortisone (cortisol) for adrenal insufficiency. Those requiring hydrocortisone are usually instructed to increase their dose in physically stressful events such as injury, hospitalization and dental work as these are times when the normal supplementary dose may be inadequate, putting the patient at risk of adrenal crisis.
Long-term follow up by specialists in endocrinology is generally needed for people with known hypopituitarism. Apart from ensuring the right treatment is being used and at the right doses, this also provides an opportunity to deal with new symptoms and to address complications of treatment.
Difficult situations arise in deficiencies of the hypothalamus-pituitary-gonadal axis in people (both men and women) who experience infertility; infertility in hypopituitarism may be treated with subcutaneous infusions of FSH, human chorionic gonadotropin–which mimics the action of LH–and occasionally GnRH.
Prognosis
Several studies have shown that hypopituitarism is associated with an increased risk of cardiovascular disease and some also an increased risk of death of about 50% to 150% the normal population. It has been difficult to establish which hormone deficiency is responsible for this risk, as almost all patients studied had growth hormone deficiency. The studies also do not answer the question as to whether the hypopituitarism itself causes the increased mortality, or whether some of the risk is to be attributed to the treatments, some of which (such as sex hormone supplementation) have a recognized adverse effect on cardiovascular risk.
The largest study to date followed over a thousand people for eight years; it showed an 87% increased risk of death compared to the normal population. Predictors of higher risk were: female sex, absence of treatment for sex hormone deficiency, younger age at the time of diagnosis, and a diagnosis of craniopharyngioma. Apart from cardiovascular disease, this study also showed an increased risk of death from lung disease.
Quality of life may be significantly reduced, even in those people on optimum medical therapy. Many report both physical and psychological problems. It is likely that the commonly used replacement therapies still do not completely mimic the natural hormone levels in the body. Health costs remain about double those of the normal population.
