Physiology, Pituitary Hormones

Cellular Level

The hormones of the pituitary gland are protein or polypeptide in nature and vary in complexity. 

Anterior Pituitary Hormones

Human Growth Hormone

Human growth hormone (HGH), also known as somatotropin, is a protein of 191 amino acid single chain polypeptides secreted by the acidophilic somatotropic cells of the anterior pituitary gland.[2] Its levels in the body are under tight regulation by the hypothalamus mediators, growth hormone-releasing hormone (GHRH), and growth hormone-inhibiting hormone (GHIH or somatostatin).

Prolactin

Prolactin is a protein hormone secreted by the acidophilic lactotroph cells of the anterior pituitary gland. Chemically, prolactin is similar to a growth hormone composing of 199 amino acids, and forms after a 28-amino acid signal peptide are proteolytically cleaved from the prolactin prohormone (pre-prolactin).[3] The secretion of prolactin by the anterior pituitary is tonically inhibited by dopamine from the tuberoinfundibular pathway of the hypothalamus and stimulated by thyrotropin-releasing hormone (TRH), estrogen, dopamine antagonist (antipsychotics), and multiple factors including suckling, stress, and sleep. 

Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH)

FSH and LH, also known as gonadotropins, are glycoprotein hormones secreted by the gonadotropin cells of the adenohypophysis. They are both glycoproteins made up of an alpha and beta subunit. The alpha subunits are identical between the two hormones, but the beta subunit of each is different and gives each hormone its biological specificity.[4] Particularly, the alpha subunit of LH is made up of 92 amino acids, and the beta subunit contains 120 amino acids.[4] The gonadotropic cells do not react well with acid or basic stains and thus appear either basophilic or chromophobic under the microscope.[4] The secretion of these hormones is regulated by the release of gonadotropin-releasing hormone secreted by the hypothalamus. 

Adrenocorticotrophic Hormone (ACTH)

The adrenocorticotrophic hormone is a polypeptide tropic hormone produced and secreted by the basophilic corticotropic cells of the anterior pituitary gland. ACTH is synthesized from Pro-opiomelanocortin (POMC) and consists of 39 amino acids. The hypothalamus-pituitary axis and secretion tightly regulate its production is in response to the corticotropin-releasing hormone. 

Thyroid-stimulating Hormone (TSH)

Thyroid-stimulating hormone is a peptide hormone secreted by the basophilic thyrotropes of the anterior pituitary gland. It is composed of 1 alpha chain and one beta chain.[5] The hypothalamus-pituitary axis regulates its release. The hypothalamus releases thyroid-releasing hormone (TRH), which stimulates thyrotrophs of the anterior pituitary to secrete TSH. 

Posterior Pituitary Hormones

Vasopressin & Oxytocin

Vasopressin, also known as antidiuretic hormone (ADH), is synthesized in the supraoptic nuclei of the hypothalamus while oxytocin synthesis occurs in the paraventricular nuclei of the hypothalamus. Both the posterior pituitary hormones are packaged in secretory granules and move down the axon where they are stored in the Herring bodies. These bodies are neurosecretory granules that represent the terminal ends of the axons coming from the hypothalamus. 

Development

The developmental origin of the pituitary gland is unique with a dual origin and begins in the fourth week of fetal development. The anterior pituitary, also called the adenohypophysis, is derived from embryonic ectoderm and is epithelial in origin, whereas the posterior pituitary, also known as neurohypophysis derives from neuroectoderm.[6] The development of the pituitary gland can broadly classify into the following stages:

• Formation of Rathke's pouch
• Evagination of Rathke's pouch and cell proliferation
• Cellular differentiation [6]

Function

Growth Hormone

The effects of HGH on the tissues of the body can generally be described as anabolic. Their primary function is to induce growth in almost all tissues and organs of the body, especially during adolescence. It increases the uptake of amino acids from the blood, enhances cellular proliferation, and reduces apoptosis. HGH also impacts metabolism, primarily by up-regulating the production of insulin-like growth factor-1 and its subsequent effect on peripheral cells.[2] It stimulates a diabetogenic effect by stimulating the liver to break down glycogen to glucose and releasing it into the blood. Furthermore, HGH stimulates lipolysis, breaking down stored fat and releasing it into the bloodstream. Subsequently, many tissues switch from glucose to fatty acid as their main energy source, resulting in increased levels of glucose in the bloodstream. 

Prolactin

Prolactin is best known for its multiple actions on the mammary gland with its two main functions; stimulation of milk production and development of breast tissues. During pregnancy, it contributes to the development and growth of the breast tissue with estrogen and progesterone and stimulates the enlargement of the alveoli in preparation for lactation. Prolactin stimulates milk production by inducing the enzyme that synthesizes the constituents of milk, such as lactose (the carbohydrate of milk), casein (the protein of milk), and lipids.[3] 

Follicle-stimulating Hormone and Luteinizing Hormone

The gonadotropins primarily regulate reproductive function and sexual development in both males and females. In the case of females, the onset and cessation of reproductive capacity are also dependent on these hormones.

FSH stimulates the production and maturation of sex cells, sperm in males, and ova in females. It also promotes follicular maturation in females during the ovarian cycle; these follicles then release estrogen in the female ovaries. LH triggers ovulation in women and causes the release of progesterone from the corpus luteum after ovulation. Furthermore, it causes the release of estrogen and progesterone from the ovaries. In males, LH stimulates the release of testosterone from the Leydig cells of the testes. 

Adrenocorticotrophic Hormone

ACTH primarily functions to regulate cortisol and androgen production. The ACTH released from the anterior pituitary acts on its target organ, the Adrenal gland, and stimulates the production of Glucocorticoids from the Zona Fasiculata and androgens from the Zona Reticularis. 

Thyroid-stimulating Hormone

TSH triggers the secretion of thyroid hormones thyroxine, or T4, and triiodothyronine, or T3 by stimulating receptors found in the follicular cells of the thyroid gland. Subsequently, the thyroid hormones promote bone and central nervous system maturation, increase basal metabolic rate, and heat production. TSH is also necessary to maintain the size of the thyroid follicles and their continued ability to produce thyroid hormones.[7] 

Vasopressin

Vasopressin acts as a water-saving hormone and is released into the bloodstream to vasoconstrict and reabsorb water from the kidney's collecting duct; this ensures the equilibrium of intracellular and extracellular contents.

Oxytocin

The polypeptide hormone oxytocin is commonly released in females during the process of childbirth. It allows the uterus to contract, which advances the fetus into the vagina for delivery. During lactation, oxytocin also releases milk from the breast tissue into the baby's oral cavity. Finally, oxytocin is also present in males during ejaculation and stimulates contraction of the vas deferens to push the semen and sperm forward.[1]

Mechanism

Growth Hormone

Growth Hormone has a direct and indirect mechanism of action. The direct effect of growth hormone involves growth hormone directly binding to its receptors on target cells to stimulate a response. The indirect effect is mediated by the action of insulin-like growth factor-1(IGF-1), which is secreted by the liver hepatocytes in response to growth hormone. Insulin-like growth factor-1 binds to its receptor, IGF-1R, on the cellular surface and activates a tyrosine kinase-mediated intracellular signaling pathway that phosphorylates various proteins intracellularly leading to increased anabolism, cellular replication and division, and metabolism.[2]

Prolactin

Prolactin initiates its effect by binding to the prolactin receptor found on various tissues across the body, including but not limited to mammillary glands, ovaries, skeletal muscle, uterus, and thymus. Upon the binding of prolactin to its receptor, Jannu kinase 2, a tyrosine kinase is activated that furthermore initiates the JAK-STAT pathway. 

FSH & LH

Both LH & FSH bind to G protein-coupled receptors. Upon binding to the receptor, adenylyl cyclase, an enzyme is activated, which goes on to produce cyclic-AMP. The intracellular concentrations of cyclic-AMP rise, which further activates a kinase molecule called protein kinase A. Protein kinase A primarily functions to phosphorylate specific intracellular proteins that then subsequently complete the physiological actions of FSH and LH. 

Adrenocorticotropic Hormone

ACTH interacts with G protein-coupled receptors found on the extracellular membranes of the zona fasciculata and zona reticularis of the adrenal cortex. cAMP is the secondary messenger system. Activation of the g-couple receptor activates adenylyl cyclase, thus increase cAMP production and subsequent activation of Protein Kinase A.[8]

Thyroid Stimulating Hormone (TSH)

TSH binds and activates the TSH receptor (TSHR) found on the basolateral surface of thyroid follicle cells. This binding site is a G-protein coupled receptor (GPCR), which couples to both Gs and Gq G-proteins, and hence activating both the cAMP pathway (via Gsa) and the phosphoinositol/calcium (IP/Ca2+; via Gq) second messenger signaling cascades. The Gs pathway activates iodide uptake,  increases thyroid hormone production, and enhances gland growth and differentiation. The Gq pathway is rate-limiting for hormone production by stimulating iodide organification.[5]

Vasopressin

Two regulating receptors, the subfornical organ and the organum vasculosum in the hypothalamus, sense water deprivation and signal for ADH secretion.[1] A small concentration of vasopressin is sufficient to generate water conservation in the renal tubules. The renal tubules are divided into the proximal, descending, ascending, distal regions, and the collecting duct. The most ADH-dependent segment of the renal tubule is the collecting duct, which has ADH receptors on its basolateral side for ADH to bind and stimulate the Gs protein. The Gs protein stimulates adenylyl cyclase, which further converts ATP into cAMP. High levels of cAMP cause the phosphorylation of protein kinase A, subsequently opening water channels known as aquaporins to allow passage of water from the luminal side to the basolateral side. 

Oxytocin

Oxytocin binds to its extracellular receptor present in the myometrium of the uterus, which then activates the Gq protein further leading to activation of phospholipase C. The phospholipase C functions to break down the phosphoinositol diphosphate into two components, Inositol triphosphate (IP3) which will release calcium from the sarcoplasmic reticulum and diacylglycerol (DAG) which will activate protein kinase C. The protein kinase C phosphorylates proteins specifically on the cell membrane to allow calcium entry from the extracellular space. The increased intracellular calcium generates enough energy to cause the contraction of the uterus. 

During lactation, when the newborn suckles, it transmits signals to the central nervous system to release oxytocin, a process known as the "milk letdown reflex." The oxytocin binds to the breast myoepithelial cell receptors and initiates the same Gq cascade similar to uterine contraction, and ejects milk into the baby's oral cavity. 

Pathophysiology

Growth Hormone

Dysfunction of the endocrine system control and release of growth hormone can result in several disorders. Hypersecretion of GH can cause acromegaly and gigantism, both of which are most commonly caused by a GH secreting adenoma of the pituitary gland. 

Acromegaly

Acromegaly typically is caused by a GH secreting pituitary adenoma that occurs after the closure of the epiphyseal growth plate. It leads to characteristic facies, large extremities, frontal bossing, diaphoresis, and impaired glucose tolerance. An increased insulin-like growth factor-1 (IGF-1) level establishes the diagnosis. Surgical excision is the first line of treatment for acromegaly. However, further medical treatment with somatostatin analogs or radiation is necessary as complete recovery is rare.[9]

Gigantism

Gigantism occurs when due to hypersecretion of growth hormone before the fusion of long bone epiphysis. It is characterized by tall stature and should be suspected when the patient's height is three standard deviations above normal mean height. 

Growth Hormone Deficiency

The effect of GH deficiency depends on the age at which the deficiency occurs. Onset in childhood is associated with decreased growth of all skeletal structures, subsequently leading to dwarfism. Adult-onset deficiency is more difficult to diagnose as it does not have a single identifying pathognomic factor. It usually presents with increased fat mass in visceral tissues and decreased skeletal muscle, as well as decreased bone density and remodeling, leading to osteoporosis.[2]

Prolactin

The pathology related to prolactin can be due to either prolactin excess or a deficiency of prolactin. 

Prolactin deficiency, most commonly due to pituitary destruction, presents with failure to lactate. 

Increased levels of prolactin can be physiological, pathological, or drug-induced. Physiological causes include pregnancy, exercise, sleep, stress, neonatal period, nipple stimulation and lactation, and sexual intercourse. Physiological hyperprolactinemia is transient and adaptive, and most patients may remain asymptomatic. Pharmacological and pathological hyperprolactinemia are symptomatic conditions (hypogonadism and galactorrhea) that have unwanted long-term consequences. Regardless of etiology, treatment options for prolactin excess include dopamine agonist medications such as bromocriptine and cabergoline.[3] 

Follicle-stimulating hormone and Luteinizing Hormone

Hyperfunctioning pituitary adenomas or unresponsive gonads can lead to increased FSH & LH. Decreased levels of FSH & LH can stem from pathology within either the hypothalamus or anterior pituitary.  

Adrenocorticotropic Hormone

Pathophysiology of ACTH can stem from either dysfunction of the pituitary, the adrenal glands, or ectopic secretions from a pathogenic source.[8]

Hypofunctioning or hyperfunctioning of the pituitary gland can lead to a decrease or increase of ACTH levels in the body, respectively. Common causes of decreased ACTH include pituitary insufficiency due to an adenoma compressing the pituitary gland, pituitary apoplexy, the sudden hemorrhage into the pituitary gland causing loss of ACTH, or Sheehan syndrome, a condition of pituitary infarction after blood loss during childhood.[8]

Thyroid-stimulating Hormone

A TSH assay is the recommended screening test for thyroid disease. It is the test of choice in patients suspected of having a deficiency (hypothyroidism) or excess (hyperthyroidism) of thyroid hormones. Abnormal levels indicate the pathological functioning of the thyroid gland.

When TSH levels are below normal levels, the primary diagnosis is hyperthyroidism. Low levels of TSH present in patients on steroids, dopamine, and somatostatin analogs. Patients with thyroid cancer who receive treatment with thyroxine can also have decreased levels of TSH. Graves disease is another common pathology that presents with low TSH levels and is due to an autoimmune disorder, which stimulates the thyroid gland to make excess thyroid hormones. The increased thyroid hormones cause feedback inhibition of TSH secretion by the anterior pituitary gland. 

Vasopressin

Central Diabetes Insipidus

Decreased levels of vasopressin can cause different pathological states. The most common form of pathology secondary to decreased ADH secretion from the pituitary gland is central diabetes insipidus. Low levels of ADH result in excess free water in the urine. There are no identifiable causes for the majority of the cases, and therefore, those cases are labeled as idiopathic central diabetes insipidus. Acquired forms of central diabetes insipidus include vascular and autoimmune diseases, craniopharyngioma, sarcoidosis, hypoxic brain injury, surgery, trauma, structural malformations, metastasis, Langerhans cell histiocytosis, or ischemia. Common presenting symptoms of patients include polyuria, polydipsia, and nocturia but may also include less common findings of weakness, lethargy, fatigue, and myalgias. 

Syndrome of Inappropriate Antidiuretic Hormone (SIADH)

Excess ADH from an ectopic source or the posterior pituitary leads to the syndrome of inappropriate antidiuretic hormone (SIADH). The excess ADH causes increased water retention and hypervolemic hyponatremia. Common etiologies behind SIADH include malignancies, trauma, stroke, infection, medications, and/or anesthesia. 

Oxytocin

Oxytocin insufficiency is not a common pathology but can occur rarely. Decreased levels of oxytocin slow down uterine contractions and reduce milk ejection during the birthing process. Panyypopituarism, a pathology in which both anterior and posterior hormone levels are below normal, can be the cause of oxytocin hyposecretion. 

Excess oxytocin is also rarely seen and causes an overactive uterus causing hypertrophy, which further leads to difficulty in maintaining pregnancy due to insufficient space for holding the fetus.[1]

Clinical Significance

Hormones secreted from the pituitary gland control blood pressure; growth; energy management; sex organs; thyroid glands; metabolism; some aspects of pregnancy, childbirth, breastfeeding; water/salt concentration at the kidneys; pain relief, and temperature regulation.

Pituitary Gland Associated Diseases

• Central diabetes insipidus (deficiency of vasopressin)
• Gigantism and acromegaly (excess of growth hormone) 
• Hypothyroidism (deficiency of thyroid-stimulating hormone)
• Hyperpituitarism (increased secretion of hormones produced by the pituitary gland)
• Hypopituitarism (decreased secretion of hormones produced by the pituitary gland)
• Panhypopituitarism (decreased secretion of pituitary hormones)

Pituitary Tumors

• Pituitary adenomas, noncancerous tumors that occur in the pituitary gland.

Dysfunction

• The pituitary gland mediates the stress response, via the hypothalamic–pituitary–adrenal axis.