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The Anterior Pituitary and its Hormones
The Anterior Pituitary and its Hormones Christopher Phelps USFCOM, Tampa, USA ã 2007 Elsevier Inc. All rights reserved.
Although the pituitary gland was recognized by Galen and the early Greek Physicians, it was regarded as a vestigial organ with no apparent function until the end of the nineteenth century. Acromegaly was the first pituitary-related disorder identified. First described in 1886, acromegaly results from a pituitary tumor and is characterized by a general overgrowth. In 1901, Frohlich described a case of pituitary tumor without acromegaly, but associated with obesity and hypogonadism. He attributed these functional changes to the destruction of the gland by the tumor. In 1908, Harvey Cushing contrasted the hyperpituitarism of acromegaly with the hypopituitarism resulting from partial destruction of the gland by tumor or surgical excision. Some of the earliest cases of severe hypopituitarism were described by Simmonds between 1914–1918. In this series, Simmonds attributed the associated atrophy of gonads, thyroid, and adrenal glands found at autopsy to infarction of the anterior portion of the pituitary. From these early observations, there followed physiological and clinical studies that led to the modern concept of the anterior pituitary gland as the master endocrine organ controlling the activities of the gonads, thyroid, and adrenal glands, as well as influencing body size and location.
Pituitary Gland Anatomy The human pituitary gland is divided into two parts, the anterior pituitary, or adenohypophysis, and the posterior pituitary, or neurohypophysis (Fig 1). The posterior portion of the gland is derived embryologically from the floor of the brain (neuroectoderm). The anterior pituitary consists of three parts: (1) pars anterior (pars distalis, anterior lobe) (2) pars tuberalis (3) pars intermedia (intermediate lobe) The pars anterior is the largest part of the anterior pituitary and, from a functional perspective, the most important part of the adenohypophysis in most animals. In humans, the pars intermedia is a poorly developed rudimentary structure with no apparent endocrine significance. Located between the anterior and posterior lobes, it consists of a few cystic cavities filled with a colloid-like material and lined by cuboidal epithelium. The pars tuberalis is the upward extension of the pars anterior, encircling the pituitary stalk like a cuff of cells that are extensions of those that comprise the pars anterior. The pars tuberalis does not play a major endocrine role.
Anterior Pituitary Blood Supply and Innervation Blood supply.The anterior pituitary receives its blood supply from the superior hypophysial artery, a branch of the internal carotid artery. There are two superior hypophysial arteries, one from each internal carotid artery. Branches from each superior hypophysial artery penetrate the funnel-shaped floor of the hypothalamus, called the infundibulum, which constitutes the upper end of the pituitary stalk. There, the branches of the superior hypophysial artery terminate in a primary capillary network with little windows (fenestra) 1
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Fig 1 Diagrams representing sagittal sections of a mammalian pituitary gland showing the divisions, components, and parts. In many mammals, the anterior lobe of the pituitary is entirely composed of pars anterior tissue. In humans, the pars intermedia (intermediate lobe of the pituitary) is a thin remnant of the embryological anlagen (Rathke’s pouch) that abuts the pars nervosa (posterior lobe of pituitary) and forms a series of small cystic cavities that represent the lumen of Rathke’s pouch.
in their cell linings (endothelia) that allow for the rapid passage of hypothalamic-releasing hormones from the brain to arterial blood within the capillary beds that is then collected into portal veins transporting blood to the anterior pituitary. Once the blood reaches the anterior pituitary, it disperses within a secondary capillary (fenestrated) bed within the gland. This rather indirect route, the hypothalamo-hypophysial venous portal system, for arterial blood to reach the anterior pituitary is the major source of oxygenated blood to the anterior lobe Harris (1955). It also ensures that the blood contains relatively high concentrations of the different releasing hormones produced in brain to regulate the release of the different anterior pituitary hormones. Innervation.Sympathetic nerve fibers pass from surrounding perivascular plexuses to the anterior pituitary where they are destined mainly for the pars tuberalis. The pars distalis receives very few, if any, nerve fibers Harris (1955). There is no sound evidence that the sympathetic innervation of the anterior pituitary gland plays any part in regulating the secretory activity of the anterior lobe Harris (1955). Parasympathetic nerve fibers are reported to branch from the Vidian ganglion situated at the junction of the greater superficial and great deep petrosal nerve in the rat. While the nerves course to the capsule of the gland, there is no evidence that the parasympathetic innervation of the anterior pituitary gland plays any part in regulating its activity Harris (1955).
Adenohypophysial Cells Outside the Adenohypophysis Adenohypophysial cells are found outside the adenohypophysis in the pharyngeal hypophysis and the posterior lobe. The cells of the pharyngeal hypophysis are largely undifferentiated, nonstaining (‘‘chromophobe’’) cells embedded within the sphenoid bone at the base of the skull. These cells receive no portal blood containing releasing hormones from the hypothalamus.
The Anterior Pituitary and its Hormones
The adenohypophysial cells embedded in the posterior pituitary lobe are basophilic and are representative of a cell invasion of the neural tissue of the posterior lobe. In humans, this invasion occurs after puberty in approximately 50% of the population and is not associated with any abnormality or disease.
Anterior Pituitary Cytology and Relationship of Cell Type to Hormone Production There are six cell types known in the human adenohypophysis, with each producing more than one hormone. There are three main pathways for anterior pituitary cell differentiation. Pathway 1 produces the complex family of cells that mature into somatotrophs (growth hormone), mammosomatotrophs (growth hormone and prolactin), lactotrophs (prolactin), or thyrotrophs (thyroid stimulating hormone or thyrotropin). Pathway 2 produces the corticotrophs (adrenocorticotropic hormone, [ACTH]) or corticotropic-producing corticotrophs), while Pathway 3 produces the gonadotrophs (follicle stimulating hormone [FSH] and luteinizing hormone [LH]) Asa et al (2001).
Pathway 1 (somatotrophs, mammotrophs, lactotrophs, thyrotrophs)
Somatotrophs Growth hormone-producing cells constitute about half of the total number of cells in the human adenohypophysis. Relative to other cell types found in the anterior pituitary, these are of mid-range size and they reside chiefly in the lateral wings of the anterior lobe. Under the light microscope they appear ovoid. Their cytoplasmic granules stain with acid dyes (eosinophilic) and show strong immunocytochemical reactivity for growth hormone. Examination by electron microscopy reveals that the majority of somatotrophs have a spherical nucleus, well-developed rough endoplasmic reticulum (RER) situated in the periphery of the cell, and a prominent Golgi apparatus. Many of these cells are densely populated with large numbers of spherical secretory granules with a uniform density. The secretory granules measure approximately 250–500 nm, with the majority measuring 350–450 nm. There is also relatively unstained cytoplasm without granules in each cell. The number, ultrastructure, and immunoreactivity of somatotrophs are remarkably unchanged throughout the life. In some instances of functional reduction in growth hormone (GH) secretion, there is an associated reduction in the number of somatotrophs in the anterior pituitary (see the section further down on Abnormalities).
Mammosomatotrophs These cells are a subset of GH-producing cells that also manufacture prolactin (PRL). This type of cell is considered ‘‘transitional’’ in that it is capable of, or has the potential for, alternating between somatotroph and lactotroph secretory functions. Evidence for this alternating function is obtained by double-antibody staining (GH and PRL), which identifies their bi-hormonal characteristics. This approach is most productive using the electron microscope and immunogold technique. Under the light microscope, these relatively large acidophilic (acid dye-loving) cells are difficult to identify. Using the
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electron microscope for ultrastructural study, these cells resemble densely granulated somatotrophs, although the secretory granules are unusually large and variable in shape with a nonhomogeneous texture. When examined using EM, secretory granule extrusions along the lateral cell membrane, commonly referred to as ‘‘misplaced exocytosis’’, are visible. This is also a characteristic feature of PRL-secreting cells.
Lactotrophs Lactotrophs are the PRL-producing cells (also called mammotrophs) that constitute 10–30% of the total cell population in the anterior pituitary. These cells are located throughout the adenohypophysis, with slightly greater concentrations in the posterior and lateral portions of the anterior pituitary. Lactotrophs usually demonstrate a strong PRL immunoreactivity that is localized chiefly in the Golgi region, although occasional PRLreactive cells may exhibit diffuse staining throughout the cytoplasm. Under the electron microscope, the lactotrophs exhibit ovoid, densely granulated secretory granules, with well-developed RER and a prominent Golgi complex. The secretory granules are numerous, spherical, or ovoid and in the range of 400–700 nm. There are also a few, smaller (200–350 nm) secretory granules. Finally, there is the ultrastructural hallmark of PRLsecreting cells, the ‘‘misplaced’’ exocytosis-extrusion of secretory granules at the lateral cell boundaries. The number of PRL-secreting cells increases dramatically during pregnancy and lactation, with some of the gestationally related increase in numbers due to recruitment of the bi-hormonal somatomammotrophs.
Thyrotrophs Thyrotrophs, which are thyroid stimulating hormones (TSH), or thyrotropin-producing cells, constitute approximately 5% of the adenohypophysial cells. They are most readily identified using specific antibodies to TSH-beta and the immunoperoxidase technique. Electron microscopic examination reveals an elongated, angular profile with slightly dilated RER profiles and numerous Golgi vesicles. The secretory granules are small (100–300 nm), mostly spherical, with variable electron opacity. When these cells are sparsely populated with secretory granules, they are often positioned near the plasmalemma. Thyrotrophs undergo hypertrophy and increase in number in certain forms of hypothyroidism or after prolonged treatment with goitrogens. The thyrotrophs associated with removal of the thyroid gland (‘‘thyroidectomy’’ cells) contain immunoreactive TSH and reveal an extensively developed, dilated RER, as well as a prominent Golgi apparatus. However, the ‘‘thyroidectomy’’ cell usually has a reduced number of secretory granules in the cytoplasm. While these ‘‘thyroidectomy’’ cells regress after treatment with thyroid hormone, the fine structure of this suppressed thyrotroph has not been adequately studied.
Pathway 2 (corticotrophs)
Corticotrophs Corticotrophsproduce adrenocorticotropic hormone (ACTH) and constitute approximately 20% of the total number of adenohypophysial cells. Specific identification of corticotrophs is most readily accomplished with antibodies ACTH 1–39, although
The Anterior Pituitary and its Hormones
antibodies to beta-lipotropin, another derivative of the pro-opiomelanocortin (POMC) molecule, also work well, as do some antibodies to the endorphins. When viewed under the EM, corticotrophs, like thyrotrophs, are elongated and angular, with round, and sometimes irregular, nuclei. The cells have a well-developed RER with a prominent Golgi complex that may contain immature secretory granules. The cytoplasm contains a relatively large number of either spherical or slightly indented secretory granules with variable electron densities. The secretory granules measure 250–400 nm in diameter. The cytoplasm is also characterized by bundles of cytokeratins and the occurrence of large lysosomal bodies. In cases of adrenal insufficiency, pituitary corticotrophs become enlarged and contain very few secretory granules, whereas with high levels of adrenal hormones (endogenous or exogenous), the characteristic abnormality seen is ‘‘Crooke’s hyalinization’’. This is characterized by the accumulation of faintly eosinophilic, glassy homogeneous substance in the cytoplasm around the cell nucleus, displacing the secretory granules to the periphery of the cell. Crooke’s hyaline material, which contains no immunoreactive ACTH, is composed of keratin filaments that immuno-react with antibodies to low-molecular-weight cytokeratins.
Pathway 3 (gonadotrophs)
Gonadotrophs Gonadotrophs produce follicle stimulating hormone (FSH) and luteinizing hormone (LH). Although early studies suggested two distinct types of gonadotrophs in rat and bat, with one producing FSH and the other LH, it appears that with human tissue, one type of gonadotroph secretes both FSH and L H. The total number of gonadotrophs in the human anterior pituitary constitutes about 15% of the total number of adenohypophyseal cells. These gonadotrophs contain cytoplasmic granules that are immunoreactive for the beta subunits of FSH and LH, in addition to the subunit common to both. Using the electron microscope, the gonadotrophs are oval, small to mid-sized cells relative to surrounding cell types producing other (nongonadotropic) hormones. The gonadotroph nucleus is spherical or ovoid, with the cytoplasm containing a well-developed RER that has highly dilated cisternae containing fine granular substance. The RER cisternae may occupy up to 15% of the cytoplasmic area in a particular cell. The Golgi complex is large and ring-shaped, with immature secretory granules observed within the latter. Mature secretory granules are usually 250–300 nm, although larger ones (400–450 nm) are also seen with some regularity. Gonadotrophs enlarge and become vacuolated when the gonads are removed and sex steroid production is curtailed. Electron microscopic examination of these ‘‘castration cells’’ reveals that a large portion (more than 50%) of this cellular enlargement is due to dilation of the RER and the Golgi complex. When visible secretory granules are present in these castration cells, they are displaced to the periphery as a result of the organelle dilation. Normal gonadotrophs are often found adjacent to lactotrophs (PRL-secreting cells), suggesting a potential paracrine relationship between these two cell types. In addition to the six cell types associated with hormone production, there are additional cell types found in the adenohypophysis of humans and some lower animals Asa et al (2001). Follicular cells are epithelioid-like in that they present a free surface and junctional specializations, but lack a defined basement membrane. These follicular cells are joined together to form acinus (‘‘grape’’) structures that may resemble a hollow ball or true follicular sphere. The function of these cells, which usually lack secretory granules, is
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unclear Horvath et al (1974). Folliculostellate cells, which are also known as stellate cells, are believed to have both a supportive role and a paracrine function. With respect to the latter, there is some experimental evidence for paracrine release of cytokines that modulate hormone production locally in the pituitary Baes et al (1987). Immunoreactive S100 and glial fibrillary acidic protein (GFAP) have been identified in human folliculostellate cells Hofler et al (1984), Girod et al (1985).
Abnormalities Affecting The Structure of the Anterior Pituitary Several abnormalities affect the structure of the anterior pituitary and, in some cases, may be associated with alterations in hormone secretion Asa et al (2001). Vascular Lesions: Hemorrhages in the anterior lobe, while uncommon, are sometimes found in association with head injuries or with rapidly growing tumors. The latter may alter pressure within the pituitary causing vascular compression, redistribution of blood circulation, or frank hypoxia and cell death. Infarcts due to interruption of the blood supply to the anterior lobe are often found at autopsy (1–6% of unselected cases). Small infarcts generally are clinically irrelevant and are only recognized by histological examination. Infarcts of the anterior lobe are more often detected in patients with diabetes mellitus, head injury, cerebrovascular accidents, or increased intracranial pressure. More frequent occurrences of adenohypophyseal infarcts are found in patients maintained on mechanical ventilators.
Hyperplasias Somatotrophs: GH-secreting hyperplasia is associated with hypersecretion of GHReleasing Hormone (GHRH) that may be produced by various endocrine neoplasms. Hypersecretion of GH associated with somatotroph hyperplasia is usually associated with acromegaly or gigantism. Lactotrophs: PRL-secreting hyperplasia may accompany neoplastic or non-neoplastic anterior pituitary lesions, such as corticotroph adenomas, thyrotroph hyperplasia, or any suprasellar (above the pituitary) mass enlargement that may impinge on the pituitary stalk. The effects of pressure on the stalk may interrupt the inhibitory action of hypothalamic dopamine on the release of PRL. Thyrotrophs: TSH-secreting hyperplasia is common in patients with untreated hypothyroidism and is sometimes associated with measurable anterior pituitary enlargement. Treatment with thyroid hormone causes regression of this type of anterior pituitary enlargement. Corticotrophs: The proliferation of corticotrophs may be dispersed and, therefore, not lead to changes in tissue architecture. There is also a nodular form of corticotroph hyperplasia that can lead to changes in tissue architecture. Massive nodular corticotroph hyperplasia may occur in cases of ectopic production of corticotropin-releasing hormone (CRH). Inflammatory Lesions:Inflammatory lesions may cause massive destruction of the anterior pituitary gland. Infectious diseases, such as tuberculosis and syphilis, as well as opportunistic infections in those with acquired immunodeficiency, are capable of causing destructive inflammatory lesions in the adenohypophysis. An autoimmune mechanism has been postulated as the cause of lymphatic hypophysitis, a chronic inflammatory disorder that occurs most often in women. Pituitary Neoplasms: Neoplasms account for approximately 10% of all intracranial tumors. They can be primary or secondary, benign or malignant, hormone producing, or functionally inactive.
The Anterior Pituitary and its Hormones
Anterior Pituitary Hormones
Growth Hormone (GH) While several different forms of growth hormone are present in the anterior pituitary, some of the reported forms are artifacts of analytical procedures. Approximately 75% of pituitary GH is a nonglycosylated single chain 191 amino acid, 22-kd protein with two intramolecular disulfide bonds. Approximately 5–10% of pituitary GH is a 20-kd form produced by alternate splicing of the second coding exon that deletes the codons for amino acids 32–46 from the RNA Cooke et al (1988), DeNoto et al (1981). Remaining percentages occur as monomeric, dimeric, tri-, tetra-, and pentameric forms, as well as complexed 22-kd and 20-kd forms. GH is released in a pulsatile pattern that is regulated by two hypothalamic regulatory hormones, GHRH and somatostatin. GHRH controls GH synthesis, whereas somatostatin determines the timing and amplitude of GH pulses, but has no effect on GH synthesis. The actions of GH are manifold. GH increases linear growth, amino acid uptake, protein synthesis, fatty acid release (from adipose tissue), insulin resistance, and blood glucose. Moreover, GH reduces glucose uptake into muscle.
Prolactin (PRL) Human PRL consists of 199 amino acids and has three intramolecular disulfide bonds, one more than human G H. Only 16% of PRL amino acids are homologous with those of G H. PRL circulates in blood predominantly in a monomeric form (‘‘little prolactin’’, 22-kd), but also exists in dimeric (‘‘big prolactin’’, 48–56-kd) and polymeric (>100-kd) forms. Glycosylated PRL also exists. The biologic significance of these different forms is unclear, although the larger ones may have reduced receptor-binding affinity and biologic activity. As with all anterior pituitary hormones, PRL is secreted in an episodic manner. Its secretion is inhibited by dopamine (DA) and enhanced by various prolactin-releasing factors. Unique among the anterior pituitary hormones, it is under tonic hypothalamic inhibition by way of DA produced by tuberoinfundibular neurons. PRL acts through prolactin receptors located throughout the body, including the breast, liver, ovary, testis, and prostate. In humans, these receptors are also stimulated by GH, which displays an affinity equal to PR L. The main site of PRL action is in the mammary gland where it initiates and maintains lactation. Its actions at nonbreast locations are poorly understood. It also acts in the hypothalamus to regulate DA turnover and to influence gonadotropin secretion.
Thyrotropin (TSH) The three anterior pituitary glycoprotein hormones are TSH, FSH, and L H. Each consists of two noncovalently linked subunits, alpha and beta. Although the alpha subunit is common to all three, the beta subunit is unique for each and confers biologic specificity. The subunits are synthesized as separate peptides from distinct mRNAs. Microheterogeneity of the carbohydrate constituents of the individual hormones cause differences in receptor affinity, biologic potency, and metabolic clearance Thorner et al (1998). The
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alpha subunits are approximately 20–22kd and have 92 amino acid residues in humans. There are two N-linked carbohydrate groups. The TSH beta subunit is approximately 18kd, consists of 110 amino acids, and contains one N-linked complex carbohydrate. The mRNAs that encode alpha and beta thyrotropin subunits are regulated by thyroid hormones, with the degree of suppression of TSH beta by thyroid hormone being greater than suppression of the alpha subunit. Thyrotropin Releasing Hormone (TRH) from the hypothalamus increases TSH alpha and beta mRNA levels within 30 minutes, with the levels declining thereafter. The extent of stimulation by TRH for both alpha and beta is equal. Secretion of TSH is regulated by both hypothalamic hormones and circulating thyroid hormones. The principal regulator of TSH is feedback by thyroid hormones Thorner et al (1998). TSH regulates both the synthesis and secretion of thyroid hormones by increasing the size and vascularity of the gland. This results in an increase in iodide transport, thyroglobulin synthesis, iodotyrosine, iodothyronine formation, thyroglobulin proteolysis, and T4 and T3 release (thyroxine and triiodothyronine).
Gonadotropins (LH and FSH) The beta subunits of both LH and FSH are composed of 115 amino acids and have two carbohydrate side chairs. The structure of the beta subunit of LH is similar to that of human chorionic gonadotropin (hCG), except that the hCG subunit has an additional 32 amino acids and additional carbohydrate residues on the COOH end. A terminal sialic acid is frequently present on the carbohydrate side chairs of the beta subunit of hCG and FS H. Thorner et al (1998). Secretion from the gonadotrope is regulated by integration of the luteinizing hormone-releasing hormone (LHRH) (also known as GnRH) from the hypothalamus and feedback effects of gonadal steroid and peptides (e.g., inhibin). LHRH (GnRH) interacts with a gonadotrope membrane receptor to regulate both LH and FSH release and synthesis and is necessary for gonadotrope function. Both gonadal steroids and inhibin are ineffective alone in regulating release. There is uncertainty regarding the mechanism of LHRH (GnRH) action. LH regulates gonadal steroid production by Leydig cells of the testis and by the ovarian follicles. The preovulatory surge of LH in women produces rupture and luteinization of the follicle. FSH stimulates gametogenesis and Sertoli cells, which have an important role in spermatogenesis. FSH is also critical for development of ovarian follicles.
Corticotropin (ACTH) Corticotropin is a 39 amino acid peptide synthesized as part of a large, 241-amino acid precursor molecule, pro-opiomelanocortin (POMC). POMC undergoes extensive posttranslational processing, including glycosylation, enzymatic cleavage, phosphorylation, NH2-terminal acetylation, and COOH-terminal amination of certain cleared peptides. This processing is species and tissue specific. In the human anterior pituitary, POMC is cleaved at dibasic amino acids into beta-lipotropin, corticotropin, joining peptide, and NH2-terminal peptide. The first 18 amino acids have full biologic activity and the first 24 amino acids are identical across species. Secretion of ACTH is stimulated by corticotropin-releasing hormone (CRH) produced in hypothalamic neurons and released into the primary capillary network located in the infundibulum, which is situated in the floor of the hypothalamus. When ACTH is
The Anterior Pituitary and its Hormones
secreted in bursts that cause similar sharp peaks in plasma cortisol released by the adrenal. CRH rapidly releases ACTH and related peptides and increases POMC gene transcription and POMC synthesis. The pulsatile release of ACTH increases in frequency after 3–5 hr of sleep in humans, are maximal prior to waking and for about one hour after waking. Corticotropin (ACTH) is also under circadian control that is regulated by several factors. In normal individuals, ACTH levels decline during the morning, reaching a nadir in the evening. The rhythm is established after the first year of life and the timing of the peak level of ACTH is shifted to 3 hr earlier in the elderly. The circadian rhythm is otherwise quite resilient and is unaffected by short-term sleep deprivation, continuous feeding, prolonged bed rest, or even working on a night shift, provided a normal sleep pattern is preserved on weekends. The rhythm can be disrupted by a major time shift, as may occur after traveling across several time zones. Psychological and physical stress activates the hypothalamic-pituitary-adrenal (HPA) axis, resulting in the increased secretion of both ACTH and adrenal cortisol. Ordinarily, glucocorticoids, like cortisol, inhibit ACTH secretion at multiple sites within the corticotrope pituitary cell, including inhibition of the corticotropin response to CRH and inhibition of ACTH synthesis by blockade of the POMC gene transcription and POMC synthesis. Glucocorticoids also inhibit arginine vasopressin (AVP) secreted by hypothalamic, which, by itself, is a weak secretogogue of ACTH Thorner et al (1998). Corticotropin (ACTH) stimulates cortisol synthesis and secretion. Acute effects of ACTH on the adrenal include an increase on adrenal blood flow and stimulation of the initial rate-limiting step of cholesterol conversion to pregnenolone. There is also an acute effect of ACTH on increasing the supply of cholesterol esters and more prolonged effects of corticotropin on the maintenance and growth of the adrenal through an increase in the synthesis of proteins, including the enzymes involved in steroid biosynthesis.
Treatment of Hypopituitarism Endocrine replacement therapy should be designed to mimic the normal hormonal milieu as much as is possible. The goal is to improve symptoms while avoiding overtreatments. Growth Hormone Deficiency: Current practice in most clinics is to offer GH therapy only in severely GH-deficient adult patients who present with symptoms of fatigue, reduced vitality, or who have significant osteopenia or osteoporosis. Until 1989, the sole indication for GH therapy was in children with GH deficiency. The availability of recombinant DNA-derived GH has gradually changed the approach to GH therapy to include adults. The majority of modern regimens recommend a low starting dose (0.27 mg/day subcutaneously) followed by an increase every 4–6 weeks based on clinical response until a steady replacement dose is reached. Only those patients showing a definite improvement should continue treatment Lissett and Shalet (2001). Gonadotropin Deficiency: In adult patients not desiring fertility, the most appropriate form of replacement therapy is sex steroid therapy. In the hypogonadotropic hypogonadal patient, fertility can be achieved with gonadotropin therapy provided primary gonadal dysfunction does not coexist. In the male, excellent success rates can usually be achieved. The choices range from gonadotropin replacement to gonadotropin-releasing hormone (GnRH). In the case of the former, initial LH-like activity is provided by human chorionic gonadotropin (HCG) administered subcutaneously (SC) or intramuscularly (IM) (dosage range between 1000 and 2000 IU) 2–3 times per week, continued for 6 months. Sperm counts usually show improvements during the months 3–6 of the therapy. If adequate spermatogenesis is not achieved, then FSH in the form of human menopausal gonadotropin (HMG), or a more purified preparation of FSH, is added to the treatment. The dose of FSH is increased if adequate spermatogenesis is not achieved in 6 months of
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combined (FSH plus HCG) treatment. The alternate therapy for idiopathic hypogonadotropic hypogonadism and in Kallmann’s syndrome is pulsatile GnRH therapy (GnRH administered SC via a catheter attached to a minipump). Use of the latter therapy implies that there is a hypothalamic defect with essentially normal pituitary gonadotrophs Lissett and Shalet (2001). In women with hypogonadotropic hypogonadism, pregnancy rates of 83% after pulsatile GnRH or gonadotropins therapy are reported. These are better pregnancy rates than those that are achieved in women having ovulation induced for other pathologic conditions. As for males (see above), the range of choices lie between GnRH therapy and gonadotropin therapy, but in women with enough residual gonadotroph function, pulsatile GnRH therapy is more likely than hMG to result in ovulation of a single follicle, thereby reducing the chances of hyperstimulation and multiple gestation Lissett and Shalet (2001). ACTH Deficiency: This is the most life-threatening feature of hypopituitarism. In addition to other causes of pituitary failure, functional ACTH deficiency may occur after discontinuation of exogenous glucocorticoids or ACTH, even when these hormones have been administered for only a few weeks. Isolated deficiencies of ACTH are very rare, and tests for ACTH deficiency, as is the case for testing of the hypothalamo-pituitary-adrenal (HPA) axis in general, are not infallible. Nonetheless, the replacement hormone of choice for ACTH deficiency, once it is established, is hydrocortisone (10 mg morning, 5 mg noon, 5 mg evening, to 10 mg), total daily dose being 20 mg to start. Monitoring of therapy usually involves the use of an 8-hour hydrocortisone day curve or a modified three-point day curve, with the goal being to normalize cortisol levels. Monitoring of this therapy permits detection of minor degrees of over- or under replacement, which are unlikely to be clinically obvious Lissett and Shalet (2001). Thyroid Stimulating Hormone (TSH) Deficiency: Hypothyroidism secondary to low or absent pituitary TSH secretion is treated the same way as hypothyroidism attributable to primary thyroid gland failure to secrete thyroid hormones, with thyroxine (T4) replacement therapy. The normal beginning dose of T4 in a young patient without evidence of cardiac disease is 100 mg/day. In elderly patients, or in a patient with evidence of ischemic heart disease, T4 therapy should be started at lower (25–50 mg/day) doses. The objective is to restore serum free T4 to its normal range. In a patient with suspected hypopituitarism involving multiple hormones, T4 therapy should be delayed until ACTH deficiency has been excluded or treated, as there is a risk of worsening the features of cortisol deficiency Lissett and Shalet (2001). Prolactin (PRL) Deficiency: When PRL deficiency occurs, it is normally one component of a combined pituitary hormone deficiency, although there have been a few cases in women of PRL deficiency without evidence of other pituitary defects. No cases of isolated PRL deficiency in men have been reported. Prolactin Hypersecretion: Hypersecretion of PRL is among the most common of pituitary disorders. The causes are manifold: (1) physiologic (sleep, stress, pregnancy nursing, orgasm); (2) pharmacologic (dopamine receptor blockers—phenothiazines, butyrophenones, thioxanthenes, tiaprides, dopamine synthesis inhibitors, catecholamine depletors, opioids, Histamine (H2) antagonists, imipramines, serotonin reuptake inhibitors, calcium antagonists, estrogens); (3) Pathologic (lesions of the hypothalamus or pituitary stalk), pituitary lesions, primary hypothyroidism, polycystic ovary syndrome, neurogenic, chronic renal failure, and liver cirrhosis. Medications that elevate PRL secretion by antagonizing dopamine (DA) action or by elevating serotonin or endorphin bioactivity (commonly used antiemetics, antidepressants, and narcotics) are manifold: reserpine and methyldopa increase PRL secretion due to DA depletion; DA receptor antagonists such as haloperidol and phenylthiazines increase PRL secretion; serotonin reuptake inhibitors such as fluoxetine elevate serum
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PR L. It is uncommon for any of these medications to cause clinical signs of hyperprolactemia because the levels of PRL seldom reach more than 30 to 50 ng/ml with these drugs. There may be subtle hormonal effects after long-term treatments with these drugs Horseman (2001). Summary:The anterior pituitary regulates most endocrine glands in the body. This is accomplished by integrating signals from the brain and the feedback effects of peripheral hormones produced by the target endocrine glands, such as the thyroid or adrenal. The anterior pituitary synthesizes six major tropic hormones that, in turn, stimulate the target endocrine organs to produce their hormonal products that are then released into the peripheral circulation. With the possible exception of prolactin, anterior pituitary hormones are under feedback regulation through the integration of target organ hormones and signals from the brain (releasing hormones). Thus, signals from the brain and the periphery interact to regulate anterior pituitary hormone secretion and maintain a normal endocrine state. If a target organ fails, reduction in the negative feedback leads to an augmented secretion of the tropic brain (hypothalamic) hormone, resulting in the enhancement of pituitary tropic hormone secretions. All anterior pituitary hormones are secreted in a pulsatile fashion. The concept of a link between the hypothalamus and the anterior pituitary was first suggested, and later demonstrated, by Geoffrey Harris. The existence of a tiny series of blood capillary vessels in a hypothalamo-hypophyseal portal vascular arrangement, leading from the base of the hypothalamus to the anterior pituitary, was demonstrated by Harris in an elegant series of studies Harris (1955). This neurovascular arrangement constitutes the substrate for brain regulation of the cells producing tropic hormones for secretion by the anterior pituitary.
Other Information – Web Sites Site is a good structural and functional review of pituitary gland: http://www.emc. maricopa.edu/faculty/f
Journal Citations Baes, M., Allaerts, W., Denef, C., 1987. Evidence for functional communication between folliculo-stellate cells and hormone-secreting cells in perifused anterior pituitary aggregates. Endocrinology, 120, 685–691. Cooke, N.E., Ray, J., Watson, M. A. et al., 1988. Human growth hormone gene and the highly homologous growth hormone variant gene display different splicing patterns. J. Clin. Invest., 82, 270–275. DeNoto, F.M., Moore, D.D., Goodman, H.M., 1981. Human growth hormone DNA sequence and mRNA structure: possible alternative splicing. Nucleic Acids Res., 9, 3719–3730. Girod, C., Trouillas, J., Dubois, M.P., 1985. Immunocytochemical localization of S-100 protein in stellate cells (follicle-stellate cells) of the anterior lobe of the normal human pituitary. Cell Tiss. Res., 241, 505–511. Hofler, H., Walter, G.F., Denk, H., 1984. Immunohistochemistry of folliculo-stellate cells in normal human adenohypophyses and in pituitary adenomas. Acta Neuropathol. (Berl), 65, 35–40. Horvath, E., Kovacs, K., Penze, G., Ezrin, C., 1974. Origin, possible function and fate of ‘‘;follicular cells’’ in the anterior lobe of the human pituitary. Am. J. Pathol., 27, 199–212.
Book Citations Asa, S.L., Horvath, E., Kovacs, K.T., 2001. Functional Pituitary Anatomy and Histology. DeGroot, L.J., Jameson, J.L. (Ed.), Endocrinology, Edition 4, pp. 167–182, W. B. Saunders, Philadelphia, PA. Harris, G.W., 1955. Bayliss, L.E., Feldberg, W., Hodgkin, A.L. (Ed.), Neural Control of the Pituitary Gland, Monographs of the Physiological Society, Edition 3, pp. 1–298, Edward Arnold Publishers, London.
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The Anterior Pituitary and its Hormones Thorner, M.O., Vance, M.L., Laws, E.R., Horvath, E., Kovacs, K., 1998. The Anterior Pituitary. Wilson, J.D., Foster, D.W., Kronenberg, H.M., Larsen, P.R. (Ed.), Williams Textbook of Endocrinology, Edition 9, pp. 249–340, W. B. Saunders, Philadelphia, PA. Lissett, C.A., Shalet, S.M., 2001. Hypopituitarism. DeGroot, L.J., Jameson, J.L. (Ed.), Endocrinology, Edition 4, pp. 289–299, W. B. Saunders, Philadelphia, PA. Horseman, N.O., 2001. Prolactin. DeGroot, L.J., Jameson, J.L. (Ed.), Endocrinology, Edition 4, pp. 209–220, W. B. Saunders, Philadelphia, PA.
Although the pituitary gland was recognized by Galen and the early Greek Physicians, it was regarded as a vestigial organ with no apparent function until the end of the nineteenth century. Acromegaly was the first pituitary-related disorder identified. First described in 1886, acromegaly results from a pituitary tumor and is characterized by a general overgrowth. In 1901, Frohlich described a case of pituitary tumor without acromegaly, but associated with obesity and hypogonadism. He attributed these functional changes to the destruction of the gland by the tumor. In 1908, Harvey Cushing contrasted the hyperpituitarism of acromegaly with the hypopituitarism resulting from partial destruction of the gland by tumor or surgical excision. Some of the earliest cases of severe hypopituitarism were described by Simmonds between 1914–1918. In this series, Simmonds attributed the associated atrophy of gonads, thyroid, and adrenal glands found at autopsy to infarction of the anterior portion of the pituitary. From these early observations, there followed physiological and clinical studies that led to the modern concept of the anterior pituitary gland as the master endocrine organ controlling the activities of the gonads, thyroid, and adrenal glands, as well as influencing body size and location.
Pituitary Gland Anatomy The human pituitary gland is divided into two parts, the anterior pituitary, or adenohypophysis, and the posterior pituitary, or neurohypophysis (Fig 1). The posterior portion of the gland is derived embryologically from the floor of the brain (neuroectoderm). The anterior pituitary consists of three parts: (1) pars anterior (pars distalis, anterior lobe) (2) pars tuberalis (3) pars intermedia (intermediate lobe) The pars anterior is the largest part of the anterior pituitary and, from a functional perspective, the most important part of the adenohypophysis in most animals. In humans, the pars intermedia is a poorly developed rudimentary structure with no apparent endocrine significance. Located between the anterior and posterior lobes, it consists of a few cystic cavities filled with a colloid-like material and lined by cuboidal epithelium. The pars tuberalis is the upward extension of the pars anterior, encircling the pituitary stalk like a cuff of cells that are extensions of those that comprise the pars anterior. The pars tuberalis does not play a major endocrine role.
Anterior Pituitary Blood Supply and Innervation Blood supply.The anterior pituitary receives its blood supply from the superior hypophysial artery, a branch of the internal carotid artery. There are two superior hypophysial arteries, one from each internal carotid artery. Branches from each superior hypophysial artery penetrate the funnel-shaped floor of the hypothalamus, called the infundibulum, which constitutes the upper end of the pituitary stalk. There, the branches of the superior hypophysial artery terminate in a primary capillary network with little windows (fenestra) 1
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Fig 1 Diagrams representing sagittal sections of a mammalian pituitary gland showing the divisions, components, and parts. In many mammals, the anterior lobe of the pituitary is entirely composed of pars anterior tissue. In humans, the pars intermedia (intermediate lobe of the pituitary) is a thin remnant of the embryological anlagen (Rathke’s pouch) that abuts the pars nervosa (posterior lobe of pituitary) and forms a series of small cystic cavities that represent the lumen of Rathke’s pouch.
in their cell linings (endothelia) that allow for the rapid passage of hypothalamic-releasing hormones from the brain to arterial blood within the capillary beds that is then collected into portal veins transporting blood to the anterior pituitary. Once the blood reaches the anterior pituitary, it disperses within a secondary capillary (fenestrated) bed within the gland. This rather indirect route, the hypothalamo-hypophysial venous portal system, for arterial blood to reach the anterior pituitary is the major source of oxygenated blood to the anterior lobe Harris (1955). It also ensures that the blood contains relatively high concentrations of the different releasing hormones produced in brain to regulate the release of the different anterior pituitary hormones. Innervation.Sympathetic nerve fibers pass from surrounding perivascular plexuses to the anterior pituitary where they are destined mainly for the pars tuberalis. The pars distalis receives very few, if any, nerve fibers Harris (1955). There is no sound evidence that the sympathetic innervation of the anterior pituitary gland plays any part in regulating the secretory activity of the anterior lobe Harris (1955). Parasympathetic nerve fibers are reported to branch from the Vidian ganglion situated at the junction of the greater superficial and great deep petrosal nerve in the rat. While the nerves course to the capsule of the gland, there is no evidence that the parasympathetic innervation of the anterior pituitary gland plays any part in regulating its activity Harris (1955).
Adenohypophysial Cells Outside the Adenohypophysis Adenohypophysial cells are found outside the adenohypophysis in the pharyngeal hypophysis and the posterior lobe. The cells of the pharyngeal hypophysis are largely undifferentiated, nonstaining (‘‘chromophobe’’) cells embedded within the sphenoid bone at the base of the skull. These cells receive no portal blood containing releasing hormones from the hypothalamus.
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The adenohypophysial cells embedded in the posterior pituitary lobe are basophilic and are representative of a cell invasion of the neural tissue of the posterior lobe. In humans, this invasion occurs after puberty in approximately 50% of the population and is not associated with any abnormality or disease.
Anterior Pituitary Cytology and Relationship of Cell Type to Hormone Production There are six cell types known in the human adenohypophysis, with each producing more than one hormone. There are three main pathways for anterior pituitary cell differentiation. Pathway 1 produces the complex family of cells that mature into somatotrophs (growth hormone), mammosomatotrophs (growth hormone and prolactin), lactotrophs (prolactin), or thyrotrophs (thyroid stimulating hormone or thyrotropin). Pathway 2 produces the corticotrophs (adrenocorticotropic hormone, [ACTH]) or corticotropic-producing corticotrophs), while Pathway 3 produces the gonadotrophs (follicle stimulating hormone [FSH] and luteinizing hormone [LH]) Asa et al (2001).
Pathway 1 (somatotrophs, mammotrophs, lactotrophs, thyrotrophs)
Somatotrophs Growth hormone-producing cells constitute about half of the total number of cells in the human adenohypophysis. Relative to other cell types found in the anterior pituitary, these are of mid-range size and they reside chiefly in the lateral wings of the anterior lobe. Under the light microscope they appear ovoid. Their cytoplasmic granules stain with acid dyes (eosinophilic) and show strong immunocytochemical reactivity for growth hormone. Examination by electron microscopy reveals that the majority of somatotrophs have a spherical nucleus, well-developed rough endoplasmic reticulum (RER) situated in the periphery of the cell, and a prominent Golgi apparatus. Many of these cells are densely populated with large numbers of spherical secretory granules with a uniform density. The secretory granules measure approximately 250–500 nm, with the majority measuring 350–450 nm. There is also relatively unstained cytoplasm without granules in each cell. The number, ultrastructure, and immunoreactivity of somatotrophs are remarkably unchanged throughout the life. In some instances of functional reduction in growth hormone (GH) secretion, there is an associated reduction in the number of somatotrophs in the anterior pituitary (see the section further down on Abnormalities).
Mammosomatotrophs These cells are a subset of GH-producing cells that also manufacture prolactin (PRL). This type of cell is considered ‘‘transitional’’ in that it is capable of, or has the potential for, alternating between somatotroph and lactotroph secretory functions. Evidence for this alternating function is obtained by double-antibody staining (GH and PRL), which identifies their bi-hormonal characteristics. This approach is most productive using the electron microscope and immunogold technique. Under the light microscope, these relatively large acidophilic (acid dye-loving) cells are difficult to identify. Using the
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electron microscope for ultrastructural study, these cells resemble densely granulated somatotrophs, although the secretory granules are unusually large and variable in shape with a nonhomogeneous texture. When examined using EM, secretory granule extrusions along the lateral cell membrane, commonly referred to as ‘‘misplaced exocytosis’’, are visible. This is also a characteristic feature of PRL-secreting cells.
Lactotrophs Lactotrophs are the PRL-producing cells (also called mammotrophs) that constitute 10–30% of the total cell population in the anterior pituitary. These cells are located throughout the adenohypophysis, with slightly greater concentrations in the posterior and lateral portions of the anterior pituitary. Lactotrophs usually demonstrate a strong PRL immunoreactivity that is localized chiefly in the Golgi region, although occasional PRLreactive cells may exhibit diffuse staining throughout the cytoplasm. Under the electron microscope, the lactotrophs exhibit ovoid, densely granulated secretory granules, with well-developed RER and a prominent Golgi complex. The secretory granules are numerous, spherical, or ovoid and in the range of 400–700 nm. There are also a few, smaller (200–350 nm) secretory granules. Finally, there is the ultrastructural hallmark of PRLsecreting cells, the ‘‘misplaced’’ exocytosis-extrusion of secretory granules at the lateral cell boundaries. The number of PRL-secreting cells increases dramatically during pregnancy and lactation, with some of the gestationally related increase in numbers due to recruitment of the bi-hormonal somatomammotrophs.
Thyrotrophs Thyrotrophs, which are thyroid stimulating hormones (TSH), or thyrotropin-producing cells, constitute approximately 5% of the adenohypophysial cells. They are most readily identified using specific antibodies to TSH-beta and the immunoperoxidase technique. Electron microscopic examination reveals an elongated, angular profile with slightly dilated RER profiles and numerous Golgi vesicles. The secretory granules are small (100–300 nm), mostly spherical, with variable electron opacity. When these cells are sparsely populated with secretory granules, they are often positioned near the plasmalemma. Thyrotrophs undergo hypertrophy and increase in number in certain forms of hypothyroidism or after prolonged treatment with goitrogens. The thyrotrophs associated with removal of the thyroid gland (‘‘thyroidectomy’’ cells) contain immunoreactive TSH and reveal an extensively developed, dilated RER, as well as a prominent Golgi apparatus. However, the ‘‘thyroidectomy’’ cell usually has a reduced number of secretory granules in the cytoplasm. While these ‘‘thyroidectomy’’ cells regress after treatment with thyroid hormone, the fine structure of this suppressed thyrotroph has not been adequately studied.
Pathway 2 (corticotrophs)
Corticotrophs Corticotrophsproduce adrenocorticotropic hormone (ACTH) and constitute approximately 20% of the total number of adenohypophysial cells. Specific identification of corticotrophs is most readily accomplished with antibodies ACTH 1–39, although
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antibodies to beta-lipotropin, another derivative of the pro-opiomelanocortin (POMC) molecule, also work well, as do some antibodies to the endorphins. When viewed under the EM, corticotrophs, like thyrotrophs, are elongated and angular, with round, and sometimes irregular, nuclei. The cells have a well-developed RER with a prominent Golgi complex that may contain immature secretory granules. The cytoplasm contains a relatively large number of either spherical or slightly indented secretory granules with variable electron densities. The secretory granules measure 250–400 nm in diameter. The cytoplasm is also characterized by bundles of cytokeratins and the occurrence of large lysosomal bodies. In cases of adrenal insufficiency, pituitary corticotrophs become enlarged and contain very few secretory granules, whereas with high levels of adrenal hormones (endogenous or exogenous), the characteristic abnormality seen is ‘‘Crooke’s hyalinization’’. This is characterized by the accumulation of faintly eosinophilic, glassy homogeneous substance in the cytoplasm around the cell nucleus, displacing the secretory granules to the periphery of the cell. Crooke’s hyaline material, which contains no immunoreactive ACTH, is composed of keratin filaments that immuno-react with antibodies to low-molecular-weight cytokeratins.
Pathway 3 (gonadotrophs)
Gonadotrophs Gonadotrophs produce follicle stimulating hormone (FSH) and luteinizing hormone (LH). Although early studies suggested two distinct types of gonadotrophs in rat and bat, with one producing FSH and the other LH, it appears that with human tissue, one type of gonadotroph secretes both FSH and L H. The total number of gonadotrophs in the human anterior pituitary constitutes about 15% of the total number of adenohypophyseal cells. These gonadotrophs contain cytoplasmic granules that are immunoreactive for the beta subunits of FSH and LH, in addition to the subunit common to both. Using the electron microscope, the gonadotrophs are oval, small to mid-sized cells relative to surrounding cell types producing other (nongonadotropic) hormones. The gonadotroph nucleus is spherical or ovoid, with the cytoplasm containing a well-developed RER that has highly dilated cisternae containing fine granular substance. The RER cisternae may occupy up to 15% of the cytoplasmic area in a particular cell. The Golgi complex is large and ring-shaped, with immature secretory granules observed within the latter. Mature secretory granules are usually 250–300 nm, although larger ones (400–450 nm) are also seen with some regularity. Gonadotrophs enlarge and become vacuolated when the gonads are removed and sex steroid production is curtailed. Electron microscopic examination of these ‘‘castration cells’’ reveals that a large portion (more than 50%) of this cellular enlargement is due to dilation of the RER and the Golgi complex. When visible secretory granules are present in these castration cells, they are displaced to the periphery as a result of the organelle dilation. Normal gonadotrophs are often found adjacent to lactotrophs (PRL-secreting cells), suggesting a potential paracrine relationship between these two cell types. In addition to the six cell types associated with hormone production, there are additional cell types found in the adenohypophysis of humans and some lower animals Asa et al (2001). Follicular cells are epithelioid-like in that they present a free surface and junctional specializations, but lack a defined basement membrane. These follicular cells are joined together to form acinus (‘‘grape’’) structures that may resemble a hollow ball or true follicular sphere. The function of these cells, which usually lack secretory granules, is
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unclear Horvath et al (1974). Folliculostellate cells, which are also known as stellate cells, are believed to have both a supportive role and a paracrine function. With respect to the latter, there is some experimental evidence for paracrine release of cytokines that modulate hormone production locally in the pituitary Baes et al (1987). Immunoreactive S100 and glial fibrillary acidic protein (GFAP) have been identified in human folliculostellate cells Hofler et al (1984), Girod et al (1985).
Abnormalities Affecting The Structure of the Anterior Pituitary Several abnormalities affect the structure of the anterior pituitary and, in some cases, may be associated with alterations in hormone secretion Asa et al (2001). Vascular Lesions: Hemorrhages in the anterior lobe, while uncommon, are sometimes found in association with head injuries or with rapidly growing tumors. The latter may alter pressure within the pituitary causing vascular compression, redistribution of blood circulation, or frank hypoxia and cell death. Infarcts due to interruption of the blood supply to the anterior lobe are often found at autopsy (1–6% of unselected cases). Small infarcts generally are clinically irrelevant and are only recognized by histological examination. Infarcts of the anterior lobe are more often detected in patients with diabetes mellitus, head injury, cerebrovascular accidents, or increased intracranial pressure. More frequent occurrences of adenohypophyseal infarcts are found in patients maintained on mechanical ventilators.
Hyperplasias Somatotrophs: GH-secreting hyperplasia is associated with hypersecretion of GHReleasing Hormone (GHRH) that may be produced by various endocrine neoplasms. Hypersecretion of GH associated with somatotroph hyperplasia is usually associated with acromegaly or gigantism. Lactotrophs: PRL-secreting hyperplasia may accompany neoplastic or non-neoplastic anterior pituitary lesions, such as corticotroph adenomas, thyrotroph hyperplasia, or any suprasellar (above the pituitary) mass enlargement that may impinge on the pituitary stalk. The effects of pressure on the stalk may interrupt the inhibitory action of hypothalamic dopamine on the release of PRL. Thyrotrophs: TSH-secreting hyperplasia is common in patients with untreated hypothyroidism and is sometimes associated with measurable anterior pituitary enlargement. Treatment with thyroid hormone causes regression of this type of anterior pituitary enlargement. Corticotrophs: The proliferation of corticotrophs may be dispersed and, therefore, not lead to changes in tissue architecture. There is also a nodular form of corticotroph hyperplasia that can lead to changes in tissue architecture. Massive nodular corticotroph hyperplasia may occur in cases of ectopic production of corticotropin-releasing hormone (CRH). Inflammatory Lesions:Inflammatory lesions may cause massive destruction of the anterior pituitary gland. Infectious diseases, such as tuberculosis and syphilis, as well as opportunistic infections in those with acquired immunodeficiency, are capable of causing destructive inflammatory lesions in the adenohypophysis. An autoimmune mechanism has been postulated as the cause of lymphatic hypophysitis, a chronic inflammatory disorder that occurs most often in women. Pituitary Neoplasms: Neoplasms account for approximately 10% of all intracranial tumors. They can be primary or secondary, benign or malignant, hormone producing, or functionally inactive.
The Anterior Pituitary and its Hormones
Anterior Pituitary Hormones
Growth Hormone (GH) While several different forms of growth hormone are present in the anterior pituitary, some of the reported forms are artifacts of analytical procedures. Approximately 75% of pituitary GH is a nonglycosylated single chain 191 amino acid, 22-kd protein with two intramolecular disulfide bonds. Approximately 5–10% of pituitary GH is a 20-kd form produced by alternate splicing of the second coding exon that deletes the codons for amino acids 32–46 from the RNA Cooke et al (1988), DeNoto et al (1981). Remaining percentages occur as monomeric, dimeric, tri-, tetra-, and pentameric forms, as well as complexed 22-kd and 20-kd forms. GH is released in a pulsatile pattern that is regulated by two hypothalamic regulatory hormones, GHRH and somatostatin. GHRH controls GH synthesis, whereas somatostatin determines the timing and amplitude of GH pulses, but has no effect on GH synthesis. The actions of GH are manifold. GH increases linear growth, amino acid uptake, protein synthesis, fatty acid release (from adipose tissue), insulin resistance, and blood glucose. Moreover, GH reduces glucose uptake into muscle.
Prolactin (PRL) Human PRL consists of 199 amino acids and has three intramolecular disulfide bonds, one more than human G H. Only 16% of PRL amino acids are homologous with those of G H. PRL circulates in blood predominantly in a monomeric form (‘‘little prolactin’’, 22-kd), but also exists in dimeric (‘‘big prolactin’’, 48–56-kd) and polymeric (>100-kd) forms. Glycosylated PRL also exists. The biologic significance of these different forms is unclear, although the larger ones may have reduced receptor-binding affinity and biologic activity. As with all anterior pituitary hormones, PRL is secreted in an episodic manner. Its secretion is inhibited by dopamine (DA) and enhanced by various prolactin-releasing factors. Unique among the anterior pituitary hormones, it is under tonic hypothalamic inhibition by way of DA produced by tuberoinfundibular neurons. PRL acts through prolactin receptors located throughout the body, including the breast, liver, ovary, testis, and prostate. In humans, these receptors are also stimulated by GH, which displays an affinity equal to PR L. The main site of PRL action is in the mammary gland where it initiates and maintains lactation. Its actions at nonbreast locations are poorly understood. It also acts in the hypothalamus to regulate DA turnover and to influence gonadotropin secretion.
Thyrotropin (TSH) The three anterior pituitary glycoprotein hormones are TSH, FSH, and L H. Each consists of two noncovalently linked subunits, alpha and beta. Although the alpha subunit is common to all three, the beta subunit is unique for each and confers biologic specificity. The subunits are synthesized as separate peptides from distinct mRNAs. Microheterogeneity of the carbohydrate constituents of the individual hormones cause differences in receptor affinity, biologic potency, and metabolic clearance Thorner et al (1998). The
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alpha subunits are approximately 20–22kd and have 92 amino acid residues in humans. There are two N-linked carbohydrate groups. The TSH beta subunit is approximately 18kd, consists of 110 amino acids, and contains one N-linked complex carbohydrate. The mRNAs that encode alpha and beta thyrotropin subunits are regulated by thyroid hormones, with the degree of suppression of TSH beta by thyroid hormone being greater than suppression of the alpha subunit. Thyrotropin Releasing Hormone (TRH) from the hypothalamus increases TSH alpha and beta mRNA levels within 30 minutes, with the levels declining thereafter. The extent of stimulation by TRH for both alpha and beta is equal. Secretion of TSH is regulated by both hypothalamic hormones and circulating thyroid hormones. The principal regulator of TSH is feedback by thyroid hormones Thorner et al (1998). TSH regulates both the synthesis and secretion of thyroid hormones by increasing the size and vascularity of the gland. This results in an increase in iodide transport, thyroglobulin synthesis, iodotyrosine, iodothyronine formation, thyroglobulin proteolysis, and T4 and T3 release (thyroxine and triiodothyronine).
Gonadotropins (LH and FSH) The beta subunits of both LH and FSH are composed of 115 amino acids and have two carbohydrate side chairs. The structure of the beta subunit of LH is similar to that of human chorionic gonadotropin (hCG), except that the hCG subunit has an additional 32 amino acids and additional carbohydrate residues on the COOH end. A terminal sialic acid is frequently present on the carbohydrate side chairs of the beta subunit of hCG and FS H. Thorner et al (1998). Secretion from the gonadotrope is regulated by integration of the luteinizing hormone-releasing hormone (LHRH) (also known as GnRH) from the hypothalamus and feedback effects of gonadal steroid and peptides (e.g., inhibin). LHRH (GnRH) interacts with a gonadotrope membrane receptor to regulate both LH and FSH release and synthesis and is necessary for gonadotrope function. Both gonadal steroids and inhibin are ineffective alone in regulating release. There is uncertainty regarding the mechanism of LHRH (GnRH) action. LH regulates gonadal steroid production by Leydig cells of the testis and by the ovarian follicles. The preovulatory surge of LH in women produces rupture and luteinization of the follicle. FSH stimulates gametogenesis and Sertoli cells, which have an important role in spermatogenesis. FSH is also critical for development of ovarian follicles.
Corticotropin (ACTH) Corticotropin is a 39 amino acid peptide synthesized as part of a large, 241-amino acid precursor molecule, pro-opiomelanocortin (POMC). POMC undergoes extensive posttranslational processing, including glycosylation, enzymatic cleavage, phosphorylation, NH2-terminal acetylation, and COOH-terminal amination of certain cleared peptides. This processing is species and tissue specific. In the human anterior pituitary, POMC is cleaved at dibasic amino acids into beta-lipotropin, corticotropin, joining peptide, and NH2-terminal peptide. The first 18 amino acids have full biologic activity and the first 24 amino acids are identical across species. Secretion of ACTH is stimulated by corticotropin-releasing hormone (CRH) produced in hypothalamic neurons and released into the primary capillary network located in the infundibulum, which is situated in the floor of the hypothalamus. When ACTH is
The Anterior Pituitary and its Hormones
secreted in bursts that cause similar sharp peaks in plasma cortisol released by the adrenal. CRH rapidly releases ACTH and related peptides and increases POMC gene transcription and POMC synthesis. The pulsatile release of ACTH increases in frequency after 3–5 hr of sleep in humans, are maximal prior to waking and for about one hour after waking. Corticotropin (ACTH) is also under circadian control that is regulated by several factors. In normal individuals, ACTH levels decline during the morning, reaching a nadir in the evening. The rhythm is established after the first year of life and the timing of the peak level of ACTH is shifted to 3 hr earlier in the elderly. The circadian rhythm is otherwise quite resilient and is unaffected by short-term sleep deprivation, continuous feeding, prolonged bed rest, or even working on a night shift, provided a normal sleep pattern is preserved on weekends. The rhythm can be disrupted by a major time shift, as may occur after traveling across several time zones. Psychological and physical stress activates the hypothalamic-pituitary-adrenal (HPA) axis, resulting in the increased secretion of both ACTH and adrenal cortisol. Ordinarily, glucocorticoids, like cortisol, inhibit ACTH secretion at multiple sites within the corticotrope pituitary cell, including inhibition of the corticotropin response to CRH and inhibition of ACTH synthesis by blockade of the POMC gene transcription and POMC synthesis. Glucocorticoids also inhibit arginine vasopressin (AVP) secreted by hypothalamic, which, by itself, is a weak secretogogue of ACTH Thorner et al (1998). Corticotropin (ACTH) stimulates cortisol synthesis and secretion. Acute effects of ACTH on the adrenal include an increase on adrenal blood flow and stimulation of the initial rate-limiting step of cholesterol conversion to pregnenolone. There is also an acute effect of ACTH on increasing the supply of cholesterol esters and more prolonged effects of corticotropin on the maintenance and growth of the adrenal through an increase in the synthesis of proteins, including the enzymes involved in steroid biosynthesis.
Treatment of Hypopituitarism Endocrine replacement therapy should be designed to mimic the normal hormonal milieu as much as is possible. The goal is to improve symptoms while avoiding overtreatments. Growth Hormone Deficiency: Current practice in most clinics is to offer GH therapy only in severely GH-deficient adult patients who present with symptoms of fatigue, reduced vitality, or who have significant osteopenia or osteoporosis. Until 1989, the sole indication for GH therapy was in children with GH deficiency. The availability of recombinant DNA-derived GH has gradually changed the approach to GH therapy to include adults. The majority of modern regimens recommend a low starting dose (0.27 mg/day subcutaneously) followed by an increase every 4–6 weeks based on clinical response until a steady replacement dose is reached. Only those patients showing a definite improvement should continue treatment Lissett and Shalet (2001). Gonadotropin Deficiency: In adult patients not desiring fertility, the most appropriate form of replacement therapy is sex steroid therapy. In the hypogonadotropic hypogonadal patient, fertility can be achieved with gonadotropin therapy provided primary gonadal dysfunction does not coexist. In the male, excellent success rates can usually be achieved. The choices range from gonadotropin replacement to gonadotropin-releasing hormone (GnRH). In the case of the former, initial LH-like activity is provided by human chorionic gonadotropin (HCG) administered subcutaneously (SC) or intramuscularly (IM) (dosage range between 1000 and 2000 IU) 2–3 times per week, continued for 6 months. Sperm counts usually show improvements during the months 3–6 of the therapy. If adequate spermatogenesis is not achieved, then FSH in the form of human menopausal gonadotropin (HMG), or a more purified preparation of FSH, is added to the treatment. The dose of FSH is increased if adequate spermatogenesis is not achieved in 6 months of
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combined (FSH plus HCG) treatment. The alternate therapy for idiopathic hypogonadotropic hypogonadism and in Kallmann’s syndrome is pulsatile GnRH therapy (GnRH administered SC via a catheter attached to a minipump). Use of the latter therapy implies that there is a hypothalamic defect with essentially normal pituitary gonadotrophs Lissett and Shalet (2001). In women with hypogonadotropic hypogonadism, pregnancy rates of 83% after pulsatile GnRH or gonadotropins therapy are reported. These are better pregnancy rates than those that are achieved in women having ovulation induced for other pathologic conditions. As for males (see above), the range of choices lie between GnRH therapy and gonadotropin therapy, but in women with enough residual gonadotroph function, pulsatile GnRH therapy is more likely than hMG to result in ovulation of a single follicle, thereby reducing the chances of hyperstimulation and multiple gestation Lissett and Shalet (2001). ACTH Deficiency: This is the most life-threatening feature of hypopituitarism. In addition to other causes of pituitary failure, functional ACTH deficiency may occur after discontinuation of exogenous glucocorticoids or ACTH, even when these hormones have been administered for only a few weeks. Isolated deficiencies of ACTH are very rare, and tests for ACTH deficiency, as is the case for testing of the hypothalamo-pituitary-adrenal (HPA) axis in general, are not infallible. Nonetheless, the replacement hormone of choice for ACTH deficiency, once it is established, is hydrocortisone (10 mg morning, 5 mg noon, 5 mg evening, to 10 mg), total daily dose being 20 mg to start. Monitoring of therapy usually involves the use of an 8-hour hydrocortisone day curve or a modified three-point day curve, with the goal being to normalize cortisol levels. Monitoring of this therapy permits detection of minor degrees of over- or under replacement, which are unlikely to be clinically obvious Lissett and Shalet (2001). Thyroid Stimulating Hormone (TSH) Deficiency: Hypothyroidism secondary to low or absent pituitary TSH secretion is treated the same way as hypothyroidism attributable to primary thyroid gland failure to secrete thyroid hormones, with thyroxine (T4) replacement therapy. The normal beginning dose of T4 in a young patient without evidence of cardiac disease is 100 mg/day. In elderly patients, or in a patient with evidence of ischemic heart disease, T4 therapy should be started at lower (25–50 mg/day) doses. The objective is to restore serum free T4 to its normal range. In a patient with suspected hypopituitarism involving multiple hormones, T4 therapy should be delayed until ACTH deficiency has been excluded or treated, as there is a risk of worsening the features of cortisol deficiency Lissett and Shalet (2001). Prolactin (PRL) Deficiency: When PRL deficiency occurs, it is normally one component of a combined pituitary hormone deficiency, although there have been a few cases in women of PRL deficiency without evidence of other pituitary defects. No cases of isolated PRL deficiency in men have been reported. Prolactin Hypersecretion: Hypersecretion of PRL is among the most common of pituitary disorders. The causes are manifold: (1) physiologic (sleep, stress, pregnancy nursing, orgasm); (2) pharmacologic (dopamine receptor blockers—phenothiazines, butyrophenones, thioxanthenes, tiaprides, dopamine synthesis inhibitors, catecholamine depletors, opioids, Histamine (H2) antagonists, imipramines, serotonin reuptake inhibitors, calcium antagonists, estrogens); (3) Pathologic (lesions of the hypothalamus or pituitary stalk), pituitary lesions, primary hypothyroidism, polycystic ovary syndrome, neurogenic, chronic renal failure, and liver cirrhosis. Medications that elevate PRL secretion by antagonizing dopamine (DA) action or by elevating serotonin or endorphin bioactivity (commonly used antiemetics, antidepressants, and narcotics) are manifold: reserpine and methyldopa increase PRL secretion due to DA depletion; DA receptor antagonists such as haloperidol and phenylthiazines increase PRL secretion; serotonin reuptake inhibitors such as fluoxetine elevate serum
The Anterior Pituitary and its Hormones
PR L. It is uncommon for any of these medications to cause clinical signs of hyperprolactemia because the levels of PRL seldom reach more than 30 to 50 ng/ml with these drugs. There may be subtle hormonal effects after long-term treatments with these drugs Horseman (2001). Summary:The anterior pituitary regulates most endocrine glands in the body. This is accomplished by integrating signals from the brain and the feedback effects of peripheral hormones produced by the target endocrine glands, such as the thyroid or adrenal. The anterior pituitary synthesizes six major tropic hormones that, in turn, stimulate the target endocrine organs to produce their hormonal products that are then released into the peripheral circulation. With the possible exception of prolactin, anterior pituitary hormones are under feedback regulation through the integration of target organ hormones and signals from the brain (releasing hormones). Thus, signals from the brain and the periphery interact to regulate anterior pituitary hormone secretion and maintain a normal endocrine state. If a target organ fails, reduction in the negative feedback leads to an augmented secretion of the tropic brain (hypothalamic) hormone, resulting in the enhancement of pituitary tropic hormone secretions. All anterior pituitary hormones are secreted in a pulsatile fashion. The concept of a link between the hypothalamus and the anterior pituitary was first suggested, and later demonstrated, by Geoffrey Harris. The existence of a tiny series of blood capillary vessels in a hypothalamo-hypophyseal portal vascular arrangement, leading from the base of the hypothalamus to the anterior pituitary, was demonstrated by Harris in an elegant series of studies Harris (1955). This neurovascular arrangement constitutes the substrate for brain regulation of the cells producing tropic hormones for secretion by the anterior pituitary.
Other Information – Web Sites Site is a good structural and functional review of pituitary gland: http://www.emc. maricopa.edu/faculty/f
Journal Citations Baes, M., Allaerts, W., Denef, C., 1987. Evidence for functional communication between folliculo-stellate cells and hormone-secreting cells in perifused anterior pituitary aggregates. Endocrinology, 120, 685–691. Cooke, N.E., Ray, J., Watson, M. A. et al., 1988. Human growth hormone gene and the highly homologous growth hormone variant gene display different splicing patterns. J. Clin. Invest., 82, 270–275. DeNoto, F.M., Moore, D.D., Goodman, H.M., 1981. Human growth hormone DNA sequence and mRNA structure: possible alternative splicing. Nucleic Acids Res., 9, 3719–3730. Girod, C., Trouillas, J., Dubois, M.P., 1985. Immunocytochemical localization of S-100 protein in stellate cells (follicle-stellate cells) of the anterior lobe of the normal human pituitary. Cell Tiss. Res., 241, 505–511. Hofler, H., Walter, G.F., Denk, H., 1984. Immunohistochemistry of folliculo-stellate cells in normal human adenohypophyses and in pituitary adenomas. Acta Neuropathol. (Berl), 65, 35–40. Horvath, E., Kovacs, K., Penze, G., Ezrin, C., 1974. Origin, possible function and fate of ‘‘;follicular cells’’ in the anterior lobe of the human pituitary. Am. J. Pathol., 27, 199–212.
Book Citations Asa, S.L., Horvath, E., Kovacs, K.T., 2001. Functional Pituitary Anatomy and Histology. DeGroot, L.J., Jameson, J.L. (Ed.), Endocrinology, Edition 4, pp. 167–182, W. B. Saunders, Philadelphia, PA. Harris, G.W., 1955. Bayliss, L.E., Feldberg, W., Hodgkin, A.L. (Ed.), Neural Control of the Pituitary Gland, Monographs of the Physiological Society, Edition 3, pp. 1–298, Edward Arnold Publishers, London.
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The Anterior Pituitary and its Hormones Thorner, M.O., Vance, M.L., Laws, E.R., Horvath, E., Kovacs, K., 1998. The Anterior Pituitary. Wilson, J.D., Foster, D.W., Kronenberg, H.M., Larsen, P.R. (Ed.), Williams Textbook of Endocrinology, Edition 9, pp. 249–340, W. B. Saunders, Philadelphia, PA. Lissett, C.A., Shalet, S.M., 2001. Hypopituitarism. DeGroot, L.J., Jameson, J.L. (Ed.), Endocrinology, Edition 4, pp. 289–299, W. B. Saunders, Philadelphia, PA. Horseman, N.O., 2001. Prolactin. DeGroot, L.J., Jameson, J.L. (Ed.), Endocrinology, Edition 4, pp. 209–220, W. B. Saunders, Philadelphia, PA.