Pituitary Disorders

Question 1

What are the main disorders affecting the pituitary gland

Answer 1

Hypopituitarism underproduction of any of the ant. pituitary hormones e.g. Growth Hormone Deficiency leading Childhood Dwarfism, Panhypopituitarism with their various causes and clinical manifestation
• Hyperpituitarism (most commonly pituitary adenoma) overproduction of hormones giving rise to pituitary disorders e.g. Childhood Gigantism, Acromegally
•The importance of laboratory diagnosis of pituitary disorders e.g. CAPFT

Question 2

What are the hormones of the anterior pituitary gland

Answer 2

Posterior Pituitary Anti-Diuretic Hormone (ADH) Oxytocin
•Anterior Pituitary Adrenocorticotrophic Hormone (ACTH) Thyroid-Stimulating Hormone (TSH) Luteinising Hormone (LH) Follicle-Stimulating Hormone (FSH) Prolactin (PRL) Growth Hormone (GH) Melanocyte-Stimulating Hormone (MSH)

Question 3

What is pituitary dwarfism in childhood

Answer 3

The lack of growth hormone in childhood results in dwarfism

Question 4

What are some causes of pituitary dwarfism

Answer 4

Idiopathic(i.e. the cause of which is not really known)
•Secondary to tumours in and around the pituitary e.g. craniopharyngioma
•In the idiopathic type, shortness of stature first noticed at the age of 2 to 3 years. The body proportions are normal
•There is usually delay in tooth eruption and bone show retarded growth. As years go by, height remains shorter even when compared to bone age, more so to chronological age
•The facial features are immature. Muscle bulk is below normal
•There is also sexual infantilism(underdevelopment of sex organs with absence of 20 sex cx’s

Question 5

What is panhypopituitarism in adult life

Answer 5

The syndrome of panhypopituitarism is often due to atrophy or degeneration of the anterior pituitary and is also known as Simmond’s disease. In some instances the cause of the anterior pituitary involvement may be due to;
•Granulomatous lesions
•Invasion of tumour
•Surgery or radiation
The resulting lack of trophic hormone e.g. gonadotropins, corticotropin etc. become manifest in due course

Question 6

What are the clinical manifestations of panhypopituitarism in adult life

Answer 6

Gradual loss of 20 sex CX’s
•Loss of pubic auxiliary hair
•Genital hypoplasia
•Secondary amenorrhoea
•Sensitivity to cold
•Absence of sweating, depigmentation with pallor of skin
•Poor tolerance of infection, tendency to coma

Question 7

What are some causes of pituitary hypofunction

Answer 7

Tumour
•Infarction
•Trauma
•Congenital malformation
•Infection
•Hypothalamic disorder

Question 8

What is pituitary gigantism

Answer 8

Gigantism results from excessive production of growth hormone in the prepubertal period and this is usually associated with eosinophilic adenoma of the pituitary, CAH, Hyperthyroidism or inherited disorders such as Klinefelter’s syndrome
•Tallness can be to the extent of 7 to 9 feet usually with postural defects. Normal pubertal growth is absent. Hands and feet may be very large

Question 9

What is acromegaly

Answer 9

Acromegally results from over-function of the pituitary hormones especially in the production of somatotropin in adult life. The most likely cause is a pituitary adenoma
The clinical manifestation are:
•Overgrowth of endochondral bone and skeletal changes become most marked in acral portions
•Skin is thickened, coarse and greasy. Increase in folds especially on the forehead gives a bull-dog like appearance
•Hands and feet become spatulate in appearance
•Body hair may increase and result in mild hirsutism
•Protruding jaw (prognathism)
•Larynx changes result in alteration which become deep and gruffly
•Sweating
•Impaired glucose tolerance
• or DM, Goitre, hypertension, adrenal hyperfunction, gonadal hypofunction
•Headaches, visual defects due to pressure defects

Question 10

How do you diagnose acromegaly

Answer 10

X-ray of the pituitary fossa
•Assessment of heel-pad thickness and assay of GH(the basal serum are elevated)
•GTT- A normal person will suppress GH in response to glucose load (expected metabolic response) The acromegallic patient’s GH levels do not suppress in response to a high glucose load
•IGF1- Elevated levels of IGF1 in serum confirm
the diagnosis of acromegally
5. The Triple function test

Question 11

What is the triple function test

Answer 11

This involves the silmultaneous administration of: Insulin(stimulates ACTH, GH and Prolactin), TRH(stimulates TSH and Prolactin) and GnRH(stimulates FSH and LH).
•Measure baseline and at time 30,60, 90, and 120 of all hormones.
•Results- Normal Response, Cortisol- x5 fold increase,
•GHx50 Fold increase, LH x 20 fold, FSH x 5fold, TSH x20 fold.
• Draw Graphs

Question 12

What is the anatomy of the pituitary gland

Answer 12

The pituitary gland (hypophysis) is located at the base of
turcica (Turkish saddle). The gland is small-1 cm or less in height and width -and weighs approximately 500 mg.
It is anatomically divided into the anterior (adenohypophysis) and the posterior (neurohypophysis) lobes. A third lobe (the intermediate lobe is present in most vertebrates and in the human fetus; this lobe is rudimentary in the adult human.

Arterial blood reaches the pituitary gland via the superior hypophyseal artery. Venous blood, carryingneurosecretoryhor-mones from the hypothalamus, reaches the pituitary through the hypothalamic hypophyseal portal system. These hypotha lamic factors stimulate or inhibit the release of hormones from the adenohypophysis.
The pituitary gland regulates the endocrine system by integrating chemical signals from the brain with regulatory feedback from the concentration of hormones in the circulation to stimulate intermittent hormone release from target endocrine glands.’ Historically, because the Dituitary gland is intimatelv involved in the regulation of (1) growth, (2) development, (3) thyroid function, (4) adrenal function, (5) gonadal function, and (6) water and salt homeostasis, it has been called the
“master endocrine organ.»,I
The adenohypophysis secretes (I) growth hormone (GH),
(2) prolactin (PRL), (3) thyrotropin (TSH), (4) adrenocor-ticotropin (ACTH), (5) follicle-stimulating hormone (FSH), and (6) luteinizing hormone (LH), all of which are proteins or peptides (Table 39-1). The adenohypophysis also secretes B-lipotropin (B-LPH) and a number of smaller peptides of undetermined significance.’ Vasopressin (ADH) and oxytocin are produced in the hypothalamus and are carried through the neurohypophyseal nerve axons to the neurohypophysis. Thus the neurohypophysis is not a discrete endocrine organ, but rather functions as a reservoir for these two hormones.
Of the six major hormones from the adenohypophysis, GH and PRL act primarily on diffuse target tissue, with TSH, ACTH, and the gonadotropins (LH and FSH) acting primarily on specific target endocrine glands such as the thyroid gland, adrenal cortex, and gonads, respectively. These peptide hormones originating from the pituitary and related hormones elaborated by the placenta during pregnancy have been classified based on their molecular structure and biochemical evolution.

Question 13

How is the hypothalamus regulated

Answer 13

Secretion of hormones from the anterior lobe of the pituitary gland is controlled by the hypothalamus, which manufactures small peptide hormones known as releasing or inhibitory factors (Figure 39-2). Several have been characterized includ-ing: (1) corticotropin-releasing hormone (CRH),’ (2) thyrotcopin-releasing hormone (TRH), (3) GH-releasing hormone (GH-RH), (4) somatostatin (also called somatotropin release-inhibiting factor (SRIF]), (5) gonadotropin-releasing hormone (Gn-RH, also called luteinizing hormone-releasing hormone), and (6) PRL-inhibiting factor (PIF) that is actually the neurotransmitter dopamine. In addition, Gn-RH stimulates the secretion of FSH and LH. However, a separate and distinct releasing factor for FSH has not yet been established, although negative feedback control of this gonadotropin is affected by inhibin, a peptide of gonadal origin.
CRH, GH-RH, Gn-RH, and TRH have all been used to test for pituitary hormone reserve. In addition, pulsatile On-RH administration is used to initiate puberty and to induce ovulation or spermatogenesis.Alternately, Gn-RH antagonists that inhibit the action of endogenous Gn-RH are used to treat patients with (1) precocious puberty, (2) endometriosis, (3) uterine fibroids, and (4) prostate carcinoma. GH-RH is yet another hypothalamic peptide that is used to treat patients with GH deficiency caused by hypothalamic disease.
The neurons that elaborate hypophysiotropic hormones are themselves influenced by hypothalamic neurotransmitters, such as (1) dopamine, (2) norepinephrine, (3) serotonin, (4) acetylcholine, and (5) endorphins. These neurotransmitters also modify the secretory activity of anterior pituitary hormones (Table 39-2). Indeed basal and episodic secretion, diurnal rhythm, and nocturnal release of pituitary hormones are all considered to be secondary to central nervous system events that are mediated through hypothalamic hormones.
In addition to higher center regulation of the hypothalamic-pituitary axis by classic neurotransmitters, chemical mediators released by inflammatory cells (cytokines)+ have been discovered that participate in altering the control mechanisms associated with the neuroendocrine axis. For example, modulation of the feedback loop between the hypothalamic-pituitary-adrenal axis by cytokines, such as interleukin 1 (IL-1) and IL-6, released as a result of infection or stress has been shown to diminish the immune system.
Control of the functional relationship between the pituitary gland and its target organs is based on the principle of feedback control, which is primarily negative between the blood concentration of circulating hormones and the pituitary gland and hypothalamus (Figure 39-2). The effect of negative feedback is typically opposite to that of the initial stimulus. For example, an elevated concentration of cortisol (initial stimulus) reduces the synthesis and release of CRH, resulting in decreased secretion of ACTH and, ultimately, reduced secretion of cortisol (final response). Such feedback control maintains an optimal concentration of hormone in the blood under a fluctuating variety of circumstances.

Question 14

What is growth hormone and IGFs

Answer 14

The most abundant hormone produced by the adenohypophy-sis is GH. Insulin-like growth factors (IGFs) I and I are polypeptides synthesized and release in response to GH that have considerable amino acid sequence and functional similarity to insulin.

Question 15

How is the secretion of growth hormone regulated

Answer 15

The release of G H is thought to be controlled by hypothalamic
GH-RH and SRIF. The former stimulates GH release and the latter inhibits G H release. SRIF is also found in the delta cells of the pancreatic islets and in many other sites in the digestive tract. It has important effects on gastrointestinal hormone secretion and causes inhibition of insulin and glucagon release.
The hypothalamic influence on G H release appears to be primarily inhibitory through the action of SRIF (Figure 39-3).
Release of these two hypothalamic factors is in turn influenced by higher centers of the brain. Thus different stimuli, such as
(1) exercise, (2) physical and emotional stress, (3) hypoglyce-mia, (4) increased circulating amino acid concentrations (par-ticularly arginine), and (5) hormones, such as testosterone, estrogens, and thyroxine, evoke an increase in GH secretion (see Figure 39-3). In the presence of abnormally high concentrations of glucocorticoids, GH secretion is suppressed. Other hypothalamic hormones, such as TH and Gn-RH, do not affect GH release in healthy subjects, but may provoke GH release in patients with acromegaly.
Isolation and discovery of ghrelin support another control system for G H release in addition to GH-RH and SRIF. Ghrelin is a small 28-amino acid peptide released from neuroendocrine cells in the gastric mucosa that binds to the G H secretagogue receptor to induce the secretion of both GH-RH and G H itself.
Ghrelin also induces food intake and the development of obesity.

Question 16

What are the physiological actions of growth hormone

Answer 16

The overall physiological effect of GH is to promote growth in soft tissue, cartilage, and bone. This action results from stimulation of protein synthesis that is partly induced by an increase in amino acid transport through cell membranes. The effects of G H on hone and muscle are exerted both directly and through the effects of IFs that are produced primarily in the liver and other tissues under the influence of GH (e.g., bone). The increased growth of soft tissue and the skeleton is accompanied by changes in electrolyte metabolism, including a (1) positive nitrogen and phosphorus balance, (2) rise in plasma phosphorus concentrations, and (3) fall in blood urea nitrogen and amino acid concentrations. Additional responses to G H include increased intestinal absorption of calcium and decreased urinary excretion of sodium and potassium. The metabolic changes are most likely a result of the increased uptake of these ions by growing tissue. GH has other effects on intermediary metabolism. For example, GH stimulates the uptake of nonesterified fatty acids by muscle and accelerates the mobilization and metabolism of fat from adipose tissue to the liver. Acutely, GH causes a decrease in blood glucose con-centrations; however, chronic G H excess stimulates hepatic glycogenolysis and antagonizes the effect of insulin on glucose uptake by peripheral cells. This leads to an increase in blood glucose concentrations. GH and insulin induce growth in a similar manner because both have protein anabolic effects and stimulate the transport of amino acids into peripheral cells.
Their respective effects on glucose homeostasis, however, oppose each other. Most growth-promoting GH effects are delayed rather than immediate and are exerted primarily through IGF-I.
The most important of the ICFs is IGF-I. In addition to its growth-promoting effects on cartilage, IGF-I also shows insulin-like activitv in other tissue. IGF-I increases elucose oxidation in adipose tissue and stimulates glucose and amino acid transport into diaphragmatic muscle and heart muscle. Synthesis of collagen and proteoglycans is enhanced by IGF-I, which also has positive effects on calcium, magnesium, and potassium homeostasis.
Plasma concentrations of immunoreactiveIGF-I rise during childhood and achieve adult concentrations by the time of puberty. During puberty IGF-I concentrations have been observed to be two to three times the adult concentration.
During adolescence IGF-I concentrations show a gradual decline, reaching a steady state in the third decade of life.
IGF-I concentrations are increased as expected in patients with acromegaly and are reduced in GH-deficiency states and in many other forms including (1) growth retardation, (2) hypothyroidism, (3) chronic illness, (4) nutritional deficiency, and (5) liver disease.

Question 17

What is the clinical significance of growth hormone

Answer 17

Clinically important states of Gil excess or deficiency are
relatively uncommon and often difficult to diagnose. concentrations vary widely under normal circumstances,so the measurement of G H under random conditions is not generally considered useful. A single GH measurement should not be used to distinguish normal fluctuations from the low or high concentrations that are seen in various disease states. GH measurements are best determined as part of dynamic testing that involves the use of pharmacological or physiological provocative stimuli to stimulate or suppress G H release.”
In contrast to GH, a single measurement of IGF-I is considered an accurate reflection of IGF-I production.
13 Serum
concentrations of IGF-I are influenced by age, degree of sexual maturation, and nutritional status. As mentioned previously, IGF-I concentrations are low in states of G H deficiency, but also in patients with acute or chronic protein or caloric deprivation.

Question 18

What is the effect of growth hormone being produced in excess

Answer 18

Excess GH production is associated with eosinophilic or chro-mophobe adenomas? of the pituitary gland. These tumors are sufficiently large to be demonstrated using computed tomography or magnetic resonance imaging in approximately 75% of patients. Prolonged exposure to G H excess causes an overgrowth of the skeleton and soft tissue. This occurs most commonly in adults and is known as acromegaly. When G H excess is seen before long-bone growth is complete, the condition is called pituitary gigantism. With pituitary gigantism, in addition to the overgrowth of bone and soft tissue particularly evident in the face and extremities, there is a striking acceleration of linear growth. In severe or advanced cases of GH excess, the diagnosis is made on the basis of physical appearance alone. The physical changes are often subtle and gradual so that a high degree of clinical suspicion is needed to make an early diagnosis. The reversibility of the tissue changes depends largely on the duration of the disease. In addition to the soft-tissue changes, acromegaly may cause severe disability or death from cardiac or neurological sequelae. The most important requirement for the diagnosis of acromegaly is the demonstration of inappropriate and excessive G H secretion.”
GH-secreting pituitary tumors account for most of the cases of acromegaly. Patients who have pituitary tumors that produce GH are frequently shown to release GH in response to other hypothalamic peptides (TRH and Gn-RH) that under normal circumstances do not elicit a release of GH. On occasion pituitary tumors that produce excess amounts of both G H and PRL are observed. Few cases of acromegaly, however, are due to GH-RH hypersecretion by tumors.
As many as 10% of patients with active acromegaly have random serum GH concentrations that fall within the health reference interval. Essentially, all patients with acromegaly have an abnormal response to oral glucose. Patients with acromegaly typically show either no change in their basal concentration of GH or demonstrate a paradoxical increase in GH.10 Healthy individuals, on the other hand, show suppression of GH concentrations to <1 ng/mL after the oral ingestion of glucose.
Serum IGF-I concentrations are elevated in active acro-megaly. IGF-I concentrations often correlate better with the
clinical severity of acromegaly than with glucose-suppressedor
basal GH concentrations.

Question 19

What is the effect of growth hormone deficiency

Answer 19

Children who have inadequate G H production or a GH receptor defect do not grow normally. G H deficiency may be (1) congenital or acquired, (2) idiopathic or caused by anatomical damage to the pituitary gland or hypothalamus, or (3) caused by isolated or associated deficiencies of other pituitary hor-mones. In one reversible GH deficiency state known as psychosocial dwarfism, environmental stress has been shown to inhibit pituitary and hypothalamic function, leading to GH suppression and growth retardation. Children with this disorder show clinical and chemical evidence of growth deficiency when first evaluated, but usually have normal pituitary function after a few days of hospital stay. G H deficiency is not a common cause of growth retardation. About one half of the children evaluated for growth retardation have no specific organic cause.
Approximately, 15% of children with growth retardation have endocrine problems, and approximately one half of these (about 8% of all children with short stature) have GH defi-ciency. However, children with growth retardation or pituitary dwarfism with no clear explanation should at least be screened for G H deficiency. With the availability of recombinant GH for therapeutic use, many children with short stature are now being selectively treated with GH to advance their growth pattern to closer toward normal.
GH deficiency in adults is probably the most common demonstrable abnormality in patients with large pituitary ade-nomas? or patients who have undergone pituitary irradiation.
In adults it has been known to lead to (1) premature mortality,
(2) abnormal body composition, (3) impaired serum lipids, (4) decreased bone density with an increase in fracture risk, and
(5) overall a n impaired quality of life. Thus GH replacement therapy is an important clinical intervention in GH-deficient adults and considered the standard of care.

Insensitivity to G H results in growth failure despite normal or increased serum GH concentrations. Patients who have familial short stature and high serum GH or low serum IGF-I concentrations probably represent many different defects in genetic coding for the G H receptor that result in the absence of or defective G H receptors. In affected individuals, exogenous GH fails to produce any appreciable metabolic changes or to promote growth. In healthy individuals, the basal concentration of G H is usually low, and the half-life of circulating G H is approximately 20 minutes. Moreover, GM is secreted by the pituitary gland in short pulses or bursts. Thus assays of GH performed on a single random or fasting specimen may not distinguish patients with abnormally low concentrations from healthy subjects who have GH values at the low end of the reference interval. When evaluating G H reserve, provocative tests are frequently used to sort out a true deficiency. Although a normal G H response to a provocative test is a strong indication for the absence of G H deficiency, no single test is considered diagnostic in this situation. For example, as many as 30% of subjects with normal G H secretion fail to show the expected elevation in serum GH in response to a specific provocative stimulus at any given time. Consequently, to diagnose GH deficiency as a cause of growth retardation, it is necessary to demonstrate that the serum concentration of G H remains low after the use of at least two different provocative stimuli. The definition of subnormal responses, however, is arbitrarily defined and assay dependent. In general a G H response >7 to 10 ng/mL after stimulation is considered normal.
A number of physiological and pharmacological circumstances provoke GH release (see Figure 39-3). In one simple screening test, the patient performs 20 minutes of vigorous exercise, and then a sample is obtained for a GH measurement.

Question 20

What is prolactin

Answer 20

Prolactin (PRL) is a hormone secreted by specialized cells within the adenohypophysis. PRL’s primary role is to stimulate and sustain lactation in postpartum mammals. PRL has many other effects, including essential roles in the maintenance of the immune system and an important role in ovarian steroido-genesis. PRL is also known as (I) lactogen, (2) lactotropin, (3) luteotropin, (4) mammotropin, or (5) galactopoietic, lactation, lactogenic, or luteotropic hormone.

Question 21

What is the physiological action of prolactin

Answer 21

PRL is the principal hormone that controls the initiation and maintenance of lactation. However, for an appropriate expression of PRL action, breast tissue requires priming by estrogens, progestins, corticosteroids, thyroid hormone, and insulin. PRL induces ductal growth, development of the breast lobular alveolar system, and the synthesis of specific milk proteins, including casein and Y-lactalbumin. PRL has effects on the immune system and is important in the control of osmolality and various metabolic events, including (1) the metabolism of subcutaneous fat, (2) carbohydrate metabolism, (3) calcium and vitamin D metabolism, (4) fetal lung development, and (5) steroido-genesis. This last function may be related to its antigonado-tropic effect.
PRL, like other pituitary hormones, binds to a specific recedtor on the cell membrane of its target oreans breast. adrenal, ovaries, testes, prostate, kidney, and liver). However, the exact intracellular mechanism of PRL action is not known.

Question 22

What is the clinical significance of prolactin

Answer 22

Hyperprolactinemia is the most common hypothalamic-pituitary disorder encountered in clinical endocrinology. PRI concentrations also may be elevated in women who have only subtle alterations of fertility, such as (1) anovulation with or without menstrual irregularity, (2) amenorrhea and galactor-rhea, or (3) galactorrhea alone. PRL excess in men is frequently manifested as oligospermia or impotence or both. In addition, men with PRL-secreting pituitary adenomas more often have macroadenomas along with visual field disturbances as a result of a larger tumor pressing on the optic chiasm. Men do not have the subtle reminder of an irregular menstrual period that frequently exposes a microadenoma in women. Elevated PRL concentrations are observed in as many as 30% of patients with polycystic ovarian syndrome and patients with clinically silent pituitary adenomas. Other causes of PRL elevation are shown in Figure 39-4 and should be kept in mind when evaluating patients who have an elevated concentration of PRL. There is no reliable stimulation or suppression test as with other pituitary hormones to distinguish tumor from benign causes of PRL elevation.
Basal gonadotropin concentrations are low in most patients with hyperprolactinemia; most studies suggest that PRL inhibits the release of Gn-RH, resulting in a state of functional hypogonadotropism. Other pituitary function tests are usually normal in patients with hyperprolactinemia, except in individuals with very large tumors.
Clinically, medications that stimulate PRL release are the single most common cause for creating a biochemical picture of a prolactinoma in an otherwise healthy individual. When a significant elevation of PRL is confirmed, a careful history must be recorded to rule out the possibility that medications are not the cause for the elevation in PRL.
Finding an elevated PRL concentration in a patient with a pituitary tumor does not establish a cause-and-effect relation-ship. Usually a PRL concentration in excess of 200 ng/mL is sufficient evidence to strongly suspect a PRL-secreting pituitary tumor. However, “pseudoprolactinomas” do occur and are large nonsecretory tumors that press on the pituitary stalk, disrupting the normal inhibitory flow of dopamine from the hypothalamus, resulting in modest elevations in PRL concentrations (typically between 50 and 200 Mg/L).

Question 23

What is adrenocorticotropin and related peptides

Answer 23

Adrenocorticotropic hormone (ACTH) is a peptide hormone secreted by the adenohypophysis as one of the derivatives of pro-opiomelanocortin (POMC). It acts primarily on the adrenal cortex, stimulating its growth and the synthesis and secretion of corticosteroids. ACTH production is increased during times of stress. It is also known as corticotropin, corti-cotrophin, adrenocorticotrophin, and adrenocorticotropin.

Question 24

What is the clinical significance of ACTH secretion

Answer 24

With adrenal insufficiency, the pituitary release of POMC and ACTH is increased significantly. Individuals with Addison disease will demonstrate increased circulating concentrations of ACTH and MSH as a result of the lack of negative feedback to the pituitary from cortisol. The increased concentrations of MSH have been observed to result in hyperpigmentation and darkening of the skin, a characteristic feature of individuals with Addison disease.
In addition, because ACTH synthesis originates from the POMC precursor peptide, its production by the pituitary is closely tied to the secretion of endogenous opiate peptides, such as B-endorphin. The physiological effects of endogenous opiates include (1) sedation, (2) an increased threshold of pain, and (3) autonomic regulation of respiration, blood pres-sure, and heart rate. These peptides are also involved in modifying endocrine responses to stress and water balance and may play a role in the regulation of reproduction and the immune system. No diseases, however, have been clearly linked with disordered metabolism of opioid peptides, but changes in their plasma concentrations may accompany other disorders, such as Cushing disease and depression (increased -endorphin con-centrations) or pheochromocytoma (increased enkephalin concentrations). Altered concentrations of opioids in cerebrospinal fluid may reflect disorders such as chronic pain syn-dromes, schizophrenia, and depression.

Question 25

Give some examples of gonadotropins

Answer 25

LH
FSH

Question 26

What are gonadotropins

Answer 26

Follicle-stimulating hormone (FSH) is synthesized in the adenohypophysis and (1) stimulates the growth and maturation of ovarian follicles, (2) stimulates estrogen secretion, (3) promotes the endometrial changes characteristic of the first phase (proliferative phase) of the mammalian menstrual cycle, and (4) stimulates spermatogenesis in the male (see Chapter
42). It is also called follitropin. Luteinizing hormone (LH) is also synthesized in the adenohypophysis and acts with FSH to promote ovulation and secretion of androgens and progesterone. It initiates and maintains the second (secretory) phase of the mammalian estrus and menstrual cycle. In females it is concerned with corpus luteum formation, and in males it stimulates the development and functional activity of testicular Leydig cells (see Chapter 42). LH is also called interstitial cell-stimulating hormone and lutropin.

Question 27

What is the physiological action for gonadotropins

Answer 27

In females FSH stimulates the growth of ovarian follicles and, in the presence of LH, promotes secretion of estrogens by the maturing follicles. LH in females causes ovulation and release of the ovum from the ovarian follicle, which has previously ripened under the influence of FSH, and causes luteinization of the ruptured follicle to form the corpus luteum. The corpus luteum then secretes both progesterone and estradiol under the influence of pulsatile LH release. In males FSH stimulates spermatogenesis by the germ cells in the testes, and LH is responsible for the production of testosterone by the Leydig cells of the testes.

Question 28

What is thyrotropin

Answer 28

Thyrotropin is a glycoprotein hormone synthesized by the thy-rotroph cells of the adenohypophysis that promotes the growth and uptake of iodine by the thyroid gland and stimulates the synthesis and secretion of thyroid hormones from the thyroid gland. It is also called thyroid-stimulating hormone (TSH).
It is a peptide with a molecular weight of 26.6 kDa. A molecule of TSH consists of two noncovalently linked a- and B-subunits with the a-subunit chemically similar to the a-subunits of LH, FSH, and hCG. TSH (1) stimulates the growth and vascularity of the thyroid gland, (2) stimulates the growth of thyroid fol licular cells, and (3) promotes a number of the steps involved in thyroid hormone synthesis. These include the (1) uptake of iodine, (2) organification of iodine onto tyrosine, (3) coupling of tyrosines, and (4) proteolytic release of stored thyroid hormone from thytoglobulin stores.

Question 29

What is arginine vasopressin

Answer 29

AVP is formed by neuronal cells of hypothalamic nuclei and stored in the neurohypophysis. In humans it contains arginine at position 8. (In the pig and hippopotamus, lysine is found at position 8.) AVP (1) stimulates contraction of the muscles of capillaries and arterioles, raising blood pressure; (2) promotes contraction of the intestinal musculature, increasing peristal-sis; (3) exerts contractile influence on the uterus; and (4) has a specific effect on the epithelial cells of renal collecting tubules, augmenting resorption of water independently of solutes to cause concentration of urine and dilution of blood serum. Its rate of secretion is regulated chiefly hy the osmolat-ity of the plasma.

Question 30

How is vasopressin secretion regulated

Answer 30

Osmolality of the blood is the main regulator of A VP secretion.
Osmoreceptors located in cell bodies in or near the magnicel-lular nuclei of the hypothalamus respond to changes in plasma osmolality. As little as a 2% increase in extracellular fluid osmolality causes shrinkage of osmoreceptor cells with stimulation of AVP release from the posterior pituitary lobe (Figure
39-9). A plasma osmolality above 280 mOsm/kg is considered the osmotic threshold for A VP release.
Besides the osmoreceptor mechanism, the physiological regulation of AVP secretion also involves a pressure-volume mechanism that is distinct from the osmotic sensor. In this second process, A VP release is regulated by barorecrptors that respond to alterations in blood volume. For example, a reduction in plasina volume or arterial pressure, or both, stimulates AVP secretion. Other nonosmotic stimuli for AVP release include (1) pain, (2) stress, (3) sleep, (4) exercise, and (5) chemical agents, such as catecholamines, angiotensin I1, opiates, prostaglandins, anesthetics, nicotine, and barbiturates.
Agents such as alcohol, phenytoin, and glucocorticoids are known to inhibit A VP release, leading to a water diuresis and physiological dehydration.
The thirst center is regulated by many of the same factors that determine A VP release. This center has a higher set-point than the osmoreceptors and responds to osmolalities above 290 mOsm/kg. Responses involving A VP, thirst, and the kidney are coordinated in a complex scheme to maintain plasma osmolality in healthy individuals within a narrow range (284 to 295 mOsm/kg).

Question 31

What are some physiological actions of vasopressin

Answer 31

The major physiological function of AVP is the control of water homeostasis, which allows the kidney to reabsorb water and concentrate urine (see Figure 39-9). When released in sufficient quantity, AVP also induces a generalized vasoconstriction that leads to a rise in arterial blood pressure. A VP is believed to play an important role in the maintenance of arterial blood pressure during blood loss. Release of A VP into the pituitary portal system also augments the action of CRH in stimulating the release of ACTH from the adenohypophysis.
However, A VP does not appear to affect the release of other anterior pituitary hormones.

Question 32

What is the clinical significance for vasopressin

Answer 32

Disorders of A VP activity have been divided into hypofunction (polyuric) and hyperfunction (syndrome of inappropriate antidiuretic hormone secretion [SIADH1).
Polyuric States
Deficient production or action of AVP results in polyuria caused by the failure of the renal tubules to reabsorb solute-free water. Under normal circumstances, urine output is largely dependent on fluid intake. Thus an arbitrary limit for normal urine output is difficult to define When urine output is >2.5 L/ day, an investigation is usually indicated; with complete deficiency of A VP, urine output may approach 1 L/hr. If the thirst response is normal, increased ingestion of fluid (polydipsia) will follow. If access to water is not restricted, plasma osmolal-ity and serum electrolytes will usually remain normal.
Polyuric states are divided into three main categories: (1) deficient A VP production (hypothalamic diabetes insipidus [HDI]), (2) deficient A VP action on the kidney (nephrogenic diabetes insipidus (NDI]), and (3) excessive water intake (psy-chogenic polydipsia). An osmotic diuresis may also produce polvuria and polydipsia. Uncontrolled diabetes mellitus with a high glucose load to the kidney is a common cause of an osmotic diurcsis.
Hypothalamic Diabetes Insipidus. HDI is also called neu-rogenic, central, or cranial diabetes insipidus. It is caused by a failure of the pituitary gland to secrete normal amounts of A VP in response to osmoregulatory factors. The incidence of HDI is about 1 in 25,000 people. In 30% of patients, HDI occurs without apparent cause; other cases are associated with (1) neoplastic diseases, (2) neurological surgery, (3) head trauma,
(4) ischemic or hypoxic disorders, (5) granulomatous diseases,
(6) infections, or (7) autoimmune disorders.
Nephrogenic Diabetes Insipidus. NDI results from the failure of the kidney to respond to normal or increased concentrations of AVP. In the majority of these patients, A VP is incapable of stimulating cyclic adenosine monophosphate (cAMP) formation. Mutation in the AV P receptor and mutations in the aquaporin-2 water channels are thought to be responsible for this disorder. The A VP receptor mutation form of NDI is an X-chromosome-linked disorder that mostly affects males. Females are more likely to have the aquaporin-2 water channel gene defect on chromosome 12,q12-13, which produces an autosomal recessive disease. Acquired forms of NDI may be caused by (1) metabolic disorders (hypokalemia, hyper-calcemia, and amyloidosis), (2) drugs (lithium, demeclocy-cline, and barbiturates), and (3) renal diseases (polycystic disease and chronic renal failure). NDI may also be seen in the absence of these factors (idiopathic).
Psychogenic or Primary Polydipsia. A chronic, excessive intake of water suppresses A VP secretion and produces hypotonic polyuria. The polyuria and polydipsia are usually not as sustained as in HDI or NDI. Nocturnal polyuria also is less frequent. Psychogenic factors are most commonly associated with this disorder, but hypothalamic disease affecting the thirst center may be a cause. Drugs also affect the thirst center and result in primary polydipsia.

Syndrome of Inappropriate Antidiuretic
Hormone Secretion
Syndrome of inappropriate antidiuretic hormone (SIADH) refers to the autonomous, sustained production of A VP in the absence of known stimuli for its release. In this syndrome, plasma AVP concentrations are “inappropriately increased relative to a low plasma osmolality and to a normal or increased plasma volume. SIADH may be the result of (1) production of AVP by a malignancy (such as a small cell carcinoma of the lung), (2) the presence of acute and chronic diseases of the central nervous system, (3) pulmonary disorders, or (4) a side effect of certain drug therapies. In addition, as many as 10% of patients undergoing pituitary surgery have a transient SIADH approximately 8 to 9 days after surgery (when the patient is at home), which responds to water restriction (2 to 3 days) and resolves without recurrence. In SIADH a primary excess of A VP, coupledwithunrestricted fluid intake, promotes increased reabsorption of free water by the kidney. The result is a decreased urine volume and an increased urine sodium concentration and urine osmolality. As a consequence of water retention, these patients become modestly volume expanded.
The increase in intravascular volume causes hemodilution accompanied by dilutional hyponatremia and a low plasma osmolality. Volume expansion also decreases renal sodium reabsorption and thus further increases the urine sodium concentration.
The most common cause of hyponatremia in hospital patients is SIADH.” However, other disorders cause dilutional hyponatremia and must be differentiated from SIADH. These conditions include (1) congestive heart failure, (2) renal insuf-ficiency, (3) nephrotic syndrome, (4) liver cirrhosis, and (5) hypothyroidism. Excessive administration of hypotonic fluids and treatment with drugs that stimulate AVP (e.g., chlorpro-pamide, vincristine, clofibrate, carbamazepine, nicotine, phe-nothiazines, and cyclophosphamide) also have been known to cause dilutional hyponatremia. Hyponatremia may also occur from renal or extrarenal sodium losses (depletional hyponatre-mia) as a result of vomiting, diarrhea, excessive sweating, diuretic abuse., salt-losing nephropathy, or mineralocorticoid deficiency.
The clinical manifestations of hyponatremia are nonspe-cific. Weakness and apathy occur in mild cases, and central nervous system changes (lethargy, coma, and seizures) are present in more severe cases. No signs or symptoms are specific for SIADH. History, physical examination, and routine laboratory test results often suggest that hyponatremia is due to dilution or depletion.

Question 33

What is oxytocin

Answer 33

Oxytocin is a nonapeptide that promotes uterine contractions and milk ejection and contributes to the second stage of labor in pregnancy.
Biochemistry
Oxytocin is synthesized in the hypothalamus as part of a preprohormone, along with a separate neurophysin-binding protein. These molecular complexes are packaged into secretory granules that migrate down the nerve axons for 12 to 14 hours before reaching the posterior pituitary lobe for storage.
Release of oxytocin into the portal circulation occurs via calcium-dependent exocytosis on nerve cell stimulation. Oxytocin exists in plasma mainly in unbound forms.
Secretion
The primary stimulus for oxytocin release is suckling. Stimulation of tactile receptors located around the nipples of the breasts initiates an action potential that propagates along affer-ent nerve fibers through the spinal cord and midbrain to the hypothalamus. The cell bodies in the paraventricular nucleus are then stimulated, resulting in the episodic release of oxyto-cin. Stretch receptors in the uterus and possibly in the vaginal mucosa may also initiate action potentials in afferent nerve fibers that ultimately stimulate the release of oxytocin from the neurohypophysis. Estrogens enhance the response of oxytocin to these stimuli. The influence of other parts of the brain on the release of oxytocin has been reported; emotional stress, for instance, inhibits lactation.

Question 34

What are some physiological actions of oxytocin

Answer 34

Oxytocin is present in males and females, but its physiological effects are known only for females. Oxytocin stimulates contraction of the uterine myometrium only in the estrogen-primed uterus and activates the smooth muscles associated with milk let-down with nursing. Thus the effects of oxytocin appear limited to events of parturition and lactation. Oxytocin has been used as a therapeutic agent to induce labor, but the physiological mechanism whereby it induces uterine contractions remains obscure. There is some evidence to show that oxytocin stimulates prostaglandin production, which may be the vehicle through which myometrial contractility is enhanced. There is evidence indicating that oxytocin may affect the central nervous system and thus modulate human behavior. Progestins are believed to counteract the actions of oxytocin.

Question 35

What is the hypothalamic pituitary adrenal axis

Answer 35

normal morning serum cortisol concentration is usually adequate evidence that the hypothalamic-pituitary-adrenal axis is intact and functioning properly. On occasion, however, the Synacthen (a potent analogue of ACTH) stimulation test is used when the morning cortisol results are low or equivocal (<5 ug/dL) or when there is a strong clinical suspicion of adrenal insufficiency This provocative test is performed by obtaining a baseline blood specimen for cortisol followed by the intravenous (IV) administration of 250 Mg of Synacthen (ACTH). Specimens for cortisol are then obtained at 30 and 60 minutes after IV administration of the synthetic ACTH. A peak value for plasma cortisol of >18 ug/dL. is considered a normal response to ACTH administration.

Question 36

What is the hypothalamic pituitary thyroid axis

Answer 36

When the serum free throxine concentration (FI4) or ultrasensitive TSH result is normal, the hypothalamic-pituitary-thyroidaxis is assumed to be intact. If primary hypo-thyroidismissuspectedclinically, however, asinglemeasurement of a basal TSH concentration may be sufficient r confirm the diagnosis. In patients with a history of pituitary disease and secondary hypothyroidism, the serum TSH concentration is frequently normal; thus in this situation, an FL concentration is the better test to gauge normality of the hypothalamic-pituitary-thyroidaxis. Improvements in the sensitivity of third-generation TSH tests allow for the detection of abnormalities of the hypothalamic-pituitary-thyroid axis much earlier in the disease process than ever before.

Question 37

What is the hypothalamic pituitary gonadal axis

Answer 37

History and physical examination are extremely helpful in evaluating the status of the hypothalamic-pituitary-gonadal axis, particularly in women during their reproductive years.’ Normal menstrual cycles are usually indicative of an intact hypothalamic-pituitary-gonadal axis in reproductive-age women. Baseline laboratory assessment for hypothalamic-pituitary-gonadaldysregulationshould include measurement of serum gonadotropins (LH and FSH) and sex steroids (estradiol in females and testosterone in males). Provocative testing of this axis with Gn-RH and measurements of FSH and LH are useful in selected patients. These tests, however, are known to be unreliable in differentiating pituitary disorders from hy-pothalamic dysfunction; thus the physician is usually depen-dent on an accurate determination of gonadotropins and sex steroids along with clinical judgment.