figure 26.1 organization of the endocrine system hormones are secreted into the blood by endocrine...

Figure 26.1 Organization of the Endocrine System Hormones are secreted into the blood by endocrine organs throughout the body, affecting physiological function at various target sites. ACTH, adrenocorticotropic hormone; ADH, antidiuretic hormone; CCK, cholecystokinin; CRH, corticotropin-releasing hormone; FSH, follicle-

stimulating hormone; GH, growth hormone; GHRH, growth hormone-releasing hormone; GIP, gastric inhibitory peptide; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; MSH, melanocyte-stimulating hormone; PRL, prolactin; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone.

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Figure 26.2 Overview of Hormone Action Hormones act at target cells by binding to specific cell membrane or cytosolic receptors, initiating a cascade of events that produces a physiological change (A). Binding to the receptor may result in generation of second messengers (e.g., cAMP, cGMP, IP3) or regulation of gene transcription.

True hormones (endocrine secretions) are released by "ductless glands" and are carried by the bloodstream to their sites of action. They are part of a larger group of substances that includes autocrine, paracrine, and neuroendocrine secretions (B).


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Figure 26.3 Structure of Hypothalamus and Pituitary The anterior pituitary (adenohypophysis) and posterior pituitary (neurohypophysis) are derived from different embryonic tissues and function as separate glands. Axons from hypothalamic nuclei extend to the posterior pituitary, where hormones (oxytocin and vasopressin) are

stored until released into the systemic bloodstream; other axons from hypothalamic nuclei extend to the median eminence, where they release hormones into the hypophyseal portal circulation, which carries them directly to the anterior pituitary. At the anterior pituitary, these hormones inhibit or stimulate the release of various

trophic hormones into the systemic blood.


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Figure 26.4 Overview of Anterior Pituitary Function The anterior pituitary gland is controlled by releasing and inhibitory hormones secreted into the hypophyseal portal circulation; these hormones reach the anterior pituitary directly through this portal circulation without entering the general circulation. Under control of these factors,

specific secretory cell types of the anterior pituitary secrete six major trophic hormones (TSH, ACTH, FSH, LH, prolactin, and GH), which act on distal endocrine glands. Trophic hormones and the target gland hormones have feedback effects on these endocrine systems, designed to regulate blood levels of the target gland hormone. ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; GH, growth hormone; IGF, insulin-like growth factor; LH, luteinizing hormone; TSH, thyroid-

stimulating hormone.


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Figure 26.5 Negative and Positive Feedback Regulation In most cases, a hypothalamic- pituitary-target gland axis is regulated by negative feedback, whereby the trophic hormone of the anterior pituitary gland has negative feedback effects on the hypothalamus, and the target gland hormone has negative feedback effects on both the

hypothalamus and the anterior pituitary. Through these mechanisms, illustrated for the hypothalamus-pituitary-testes axis, levels of the target gland hormone are maintained within the normal physiological range. In a few specific cases, positive feedback can also occur. For example, during the late follicular and ovulatory phases of the menstrual cycle, high levels of estradiol actually cause greater secretion of the hypothalamic releasing hormone and trophic hormones in that system, resulting in

the surge in pituitary hormone release that is responsible for ovulation at midcycle.


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Figure 26.6 Posterior Pituitary Function (ADH) Antidiuretic hormone (ADH; also known as vasopressin) is synthesized mainly in the supraoptic nuclei (and also the paraventricular nuclei) of the hypothalamus and is stored and released at the posterior pituitary. Its main function is in water balance; it is released in response to

increased osmolarity of extracellular fluid and decreased blood pressure and has the major effect of promoting water reabsorption by the kidney. When ADH levels in plasma are high, a low volume of concentrated urine is produced.


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Figure 26.7 Posterior Pituitary Function (Oxytocin) Oxytocin is synthesized mainly in the paraventricular nuclei (and also the supraoptic nuclei) of the hypothalamus and is stored and released at the posterior pituitary. Its main functions are to stimulate milk let-down and uterine contraction.


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Figure 26.8 Growth Hormone Growth hormone release by the anterior pituitary is controlled by GHRH and somatostatin. Growth hormone has an important role in growth and development of children and regulation of metabolism. Its effects are mediated by somatomedins produced by the liver or by specific target tissues. AA, amino acids;

FFA, free fatty acids; GH, growth hormone; GHRH, growth hormone-releasing hormone; IGF, insulin-like growth factor.


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Growth Hormone-Secreting Adenomas The effects of growth hormone-secreting adenomas vary depending on size and growth rate as well as invasiveness. Large tumors cause destruction of the pituitary and deficiency of other pituitary hormones and may affect the optic chiasm and vision. Growth hormone excess produces

acromegaly in adults (right panel), with protrusion of the jaw, macroglossia, and other effects.


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Figure 26.9 Prolactin Prolactin synthesis and release by the anterior pituitary is mainly under tonic negative control by dopamine (prolactin inhibitory factor, PIF). Its major functions are in breast development, pregnancy, and lactation. Its levels are elevated during fetal development, pregnancy, and the postpartum period (if the woman is

breastfeeding). TRH, thyrotropin-releasing hormone.


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Figure 27.1 Thyroid Gland Structure The thyroid gland is a highly vascularized structure located anterior to the trachea and inferior to the cricoid cartilage. In about 15% of the population, a small pyramidal lobe is present (as seen).


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Figure 27.2 Structure of T3 and T4 The two main types of thyroid hormones (TH), thyroxine (T4) and triiodothyronine (T3), differ from each other by the addition of one iodine in T4. The majority of circulating TH is T4, and almost all of the circulating TH is bound to a thyroxine-binding protein.


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Figure 27.3 Synthesis and Regulation of Thyroid Hormones The thyroid gland is composed of follicular epithelial cells that synthesize and store thyroxine (T4) and triiodothyronine (T3) and release these hormones into the circulation. The synthesis is controlled by release of thyroid-stimulating hormone (TSH), which is under

negative feedback control by the thyroid hormones. Synthesis and storage of the thyroid hormones is outlined here and in the figure: (1) In the endoplasmic reticulum, thyroglobulin molecules are produced, packaged in vesicles by the Golgi, and exocytosed into the lumen of the follicle. (2) Iodide (I-) (from the diet) enters the follicle cell via basolateral Na+/I- cotransporters (the I-trap). The iodide exits the cell on the apical side into the lumen via I-/Cl- antiporters. (3) In the follicular lumen, I- is oxidized to iodine by thyroid peroxidase and substituted for H+ on the benzene ring of tyrosine residues of thyroglobulin. (4) Binding of one iodine will form monoiodotyrosine (MIT), and binding of two iodine moieties will form diiodotyrosine (DIT). This reaction is termed organification. Thyroid peroxidase also catalyzes the binding of DIT to another

DIT, forming T4. Some DIT will also bind to an MIT, forming T3. These products remain linked to the thyroglobulin (Tg). (5) The mature Tg, containing MIT, DIT, T4, and T3 (in order of greater to lesser abundance), is endocytosed back into the follicle cell and can be stored as colloid until secreted. (6) Proteolysis of the colloid is

stimulated by TSH and releases the constituent molecules. MIT and DIT reenters the synthetic pool, and T3 and T4 exit the basolateral membrane into the blood. TRH, thyrotropin-releasing hormone. Downloaded from: StudentConsult (on 27 October 2008 06:48 PM)

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Figure 27.4 Thyroid Hormone Action T4 is converted to active T3 at target tissue by 5'-deiodinase action. The T3 binds to nuclear receptors, initiating transcription of a variety of proteins and enzymes. The overall effects of thyroid hormone are to increase metabolic rate and O2 consumption, and the general effects in target organs are

illustrated.


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Hashimoto's Thyroiditis Hashimoto's thyroiditis is a common form of hypothyroidism and is caused by autoimmune antibodies directed against thyroglobulin or thyroid peroxidase. This results in low TH production (and high circulating TSH) and eventual destruction of the thyroid gland.


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Clinical Symptoms of Hyperthyroidism A, Hyperthyroidism, such as is seen in Graves' disease, affects most physiologic systems and can increase metabolic rate by 30% to 60% over normal. The elevated thyroid hormone causes a wide variety of symptoms as illustrated above. B, Goiter. Enlargement of the thyroid gland (goiter) can be

caused by both hypothyroid and hyperthyroid conditions and results from TSH, or immunoglobulin-mediated stimulation of hyperplastic growth of the thyrocytes.


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Figure 28.1 Adrenal Gland Structure The two adrenal glands are located above the kidneys and below the diaphragm in the retroperitoneal space. The outer cortex of the adrenal gland produces steroid hormones, whereas the inner medulla synthesizes and releases catecholamines.


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Figure 28.2 Adrenal Gland Histology The highly vascularized adrenal (suprarenal) glands comprise an outer cortex and inner medulla. The cortex synthesizes the steroid hormones aldosterone, cortisol, and androgens, respectively, in its zona glomerulosa, zona fasciculata, and zona reticularis. ACTH administration results in increased cell

size and steroid biosynthetic activity mainly in the zona fasciculata but also in the zona reticularis (A). The medullary chromaffin cells synthesize and release catecholamines (mainly epinephrine) into the bloodstream in response to sympathetic nervous system activation. The blood supply to the adrenal gland is provided by the

suprarenal arteries (B). ACTH, adrenocorticotropic hormone.


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Figure 28.3 Adrenal Cortical Hormones Adrenal mineralocorticoid (aldosterone), glucocorticoid (cortisol), and androgens (dehydroepiandrosterone and androstenedione) are synthesized from cholesterol through the biosynthetic pathways illustrated. ACTH stimulates the conversion of cholesterol to Δ5-pregnenolone by the enzyme

CYP11A1; the conversion of Δ5-pregnenolone to various products is dependent on additional enzymes in the various zones of the adrenal cortex. The adrenal gland also synthesizes small amounts of other steroids (e.g., testosterone and estradiol). Negative feedback on ACTH and the hypothalamic-releasing hormone CRH is

accomplished by cortisol. ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone.


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Figure 28.4 Actions of Cortisol Cortisol has a wide array of actions, including muscle wasting, gluconeogenesis, hyperglycemia, anti-inflammatory and anti-immune effects, and insulin resistance. It also has mineralocorticoid-like effects on the kidney at high concentrations.


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Corticosteroid Actions in Bronchial Asthma Anti-inflammatory effects are the basis for use of inhaled corticosteroids as preventive medication in patients who suffer frequent or severe asthma attacks.


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Causes of Cushing's Syndrome Cushing's syndrome may result from a variety of causes, all of which result in elevated plasma glucocorticoid level. ACTH, adrenocorticotropic hormone.


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Figure 28.5 Actions of Aldosterone The steroid hormone aldosterone has the important functions of regulating extracellular fluid volume and K+ levels. Synthesis and release of aldosterone is promoted by angiotensin II and hyperkalemia and is inhibited by atrial natriuretic peptide. Its action results in water and Na+ retention and K+

and H+ excretion by the kidney; it has similar effects on the intestine, sweat glands, and salivary glands.


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Chronic Primary Adrenocortical Insufficiency (Addison's Disease) In primary adrenocortical insufficiency, adrenocortical steroid production is low, due to adrenal atrophy, tubercular destruction of the adrenal, or other causes, and ACTH level is elevated (due to lack of negative feedback). Symptoms reflect deficiency of corticosteroids but also reflect excess of ACTH, which causes pigmentation due to its sequence homology with α-melanocyte-stimulating hormone (MSH). ACTH, adrenocorticotropic

hormone.


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Figure 28.6 Function of the Adrenal Medulla The adrenal medulla releases epinephrine (80%) and norepinephrine (20%) into the bloodstream during activation of the sympathetic nervous system. The effects of epinephrine and norepinephrine, including relative magnitude, are illustrated for various sites. BMR, basal metabolic rate.


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Figure 29.1 Structure of the Endocrine Pancreas The pancreas is a key component of the gastro-intestinal (GI) tract because of its exocrine function; it also provides the primary control of blood glucose because of its production of endocrine hormones. The vast majority of the pancreas (∼99%) is composed of acinar cells, which produce and secrete the buffers and enzymes through ducts into the GI tract (exocrine function) (micrograph on left). The endocrine pancreas is composed of cells that

form the islets of Langerhans. The cells of the islets produce insulin (β-cells), glucagon (α-cells), and somatostatin (δ-cells).


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Figure 29.2 Insulin Structure A illustrates the proinsulin molecule, which is composed of an A (blue) and B (red) chain of insulin, connected by two disulfide bridges (yellow). In the endoplasmic reticulum, the insulin chains are attached to the connecting "C"-peptide, which is cleaved in the Golgi apparatus to yield the insulin and C-

peptide and then packaged in secretory granules; the three-dimensional structure of active insulin is illustrated in B.


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Figure 29.3 Insulin Synthesis and Release Glucose is the most important factor regulating insulin synthesis and secretion, although gastrointestinal peptides and local glucagon and somatostatin also contribute to modulation of release. A depicts the action of glucose to increase Ca2+ influx, which stimulates insulin secretion. B

illustrates the receptor-mediated stimulation of insulin secretion by local glucagon, gut peptides (CCK and GLP-1), and ACh, and inhibition of insulin by local somatostatin. ACh, acetylcholine; CCK, cholecystokinin; GLP, glucagon-like peptide.


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Figure 29.4 Actions of Insulin Insulin is considered a "fuel storage" hormone, and therefore insulin promotes the storage of glucose (as glycogen) and fatty acids (as triglycerides [TG] in adipose tissue). Insulin stimulates the uptake of glucose into cells via GLUT4 transporters, and the glucose is used or stored as glycogen. The major glycogen stores are in muscle and liver. Insulin also stimulates fat synthesis and inhibition of lipolysis in adipose tissue, which maintains stores of TGs and reduces keto acid production. Lastly, insulin stimulates uptake of amino acids into skeletal muscle and storage as protein. The overall result is that insulin decreases plasma glucose,

fatty acids, and keto acids.


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Figure 29.5 Actions of Glucagon Glucagon is considered the "fuel mobilization" hormone, because it breaks down glycogen, protein, and lipids, releasing glucose, amino acids, fatty acids, and keto acids into the blood to serve metabolic demand. Glucagon is stimulated by low blood glucose and promotes glycogenolysis and

gluconeogenesis in the liver, increasing blood glucose. Glucagon also stimulates lipolysis and release of fatty acids from adipose tissue, which are oxidized to keto acids in the liver. Lastly, in muscle, glucagon inhibits protein synthesis providing amino acids for conversion to glucose via gluconeogenesis in the liver.


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Microvascular and Macrovascular Complications of Diabetes Vascular complications can occur with either type 1 or type 2 diabetes and include retinopathy (which can lead to blindness), cardiovascular disease, cerebrovascular disease, and diabetic nephropathy. These complications are responsible for the high morbidity in diabetes.


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Dietary Calcium Deficiency Inadequate dietary calcium intake (1) reduces plasma calcium concentration (2), which stimulates parathyroid hormone (PTH) secretion (3 and 4). PTH increases the renal production of active vitamin D (5) (which increases gut absorption of calcium) (8), increases renal calcium reabsorption and decreases

renal phosphate reabsorption (6), and increases bone resorption of calcium and phosphate (7). All of these mechanisms serve to increase the plasma calcium concentration to normal (9). When there is a sustained calcium deficiency, the plasma calcium is maintained at a cost of severe bone demineralization (10).


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Figure 30.1 Parathyroid Hormone Secretion Parathyroid hormone is synthesized in the chief cells of the parathyroid glands. The active hormone is packaged in vesicles and stored in the cytoplasm until released. PTH secretion is stimulated by small decreases in plasma calcium levels and provides rapid mobilization of calcium into the

extracellular fluid.


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Figure 30.2 Parathyroid Hormone and Vitamin D Actions on Plasma Calcium Concentrations Parathyroid hormone (PTH) is secreted from the parathyroid glands in response to a decrease in plasma ionized Ca2+. PTH acts rapidly (1) on bone to cause resorption and increase plasma Ca2+; and (2) on the kidney to increase Ca2+ reabsorption and decrease phosphate reabsorption and increase production of active vitamin D. The increase in vitamin D increases Ca2+ absorption in the gut and

promotes bone mineralization. Overall, the rapid effects of PTH increase Ca2+ in the blood, restoring homeostasis.


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Pathophysiology of Hyperparathyroidism Most cases of hyperparathyroidism arise from parathyroid tumors that cause hypersecretion of parathyroid hormone (PTH). The elevated PTH increases bone resorption, renal calcium reabsorption, and active vitamin D production (which increases intestinal calcium absorption). This causes

hypercalcemia, which can result in multiple symptoms ("stones," "bones," "groans," and "moans").


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Pathophysiology of Hypoparathyroidism Hypoparathyroidism is usually a result of thyroid or parathyroid surgery, and the lack of parathyroid hormone reduces the formation of active vitamin D, decreases renal calcium reabsorption, and alters bone resorption activity. Hypocalcemia develops, and the low plasma calcium levels

increase neuronal and muscle cell excitation, causing twitching, cramping, and in extreme cases tetany.


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Rickets The main manifestation of vitamin D deficiency is in bone mineralization. As depicted in the illustration, in children, this results in rickets. In adults, vitamin D deficiency leads to osteomalacia.


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Figure 31.1 Gonad and Genital Duct Formation The undifferentiated gonads and ducts of the early embryo differentiate into the male or female gonads and duct systems under the influence of various products encoded by the X and Y chromosomes. Notably, a product of the SRY gene of the Y chromosome results in differentiation of the

gonads into testes. Production of testosterone by the testes results in persistence and differentiation of the wolffian ducts. Müllerian-inhibiting factor secreted by the testes causes müllerian duct degeneration. In the female fetus, in the absence of testosterone the gonads develop into ovaries and the wolffian ducts degenerate.


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Figure 31.2 Differentiation of the External Genitalia In the absence of testosterone, the undifferentiated external genitalia develop into the female structures. Testosterone, after conversion to dihydrotestosterone, stimulates the formation of male external genitalia from the undifferentiated structures. Homologies between male

and female genital structures are color-coded.


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Figure 31.3 Menstrual Cycle During the female menstrual cycle, changes take place in the ovaries and uterus, under the control of the hypothalamus and anterior pituitary gland. During the follicular phase, several primary follicles undergo further development in response to FSH and synthesize androgens, which are converted to

estradiol under the influence of LH. Ultimately, one follicle fully matures and the others regress. The uterine endometrium proliferates in response to estradiol. Near midcyle, estradiol rises to a level that initiates positive feedback, and thus a surge in LH and FSH release by the anterior pituitary, which results in ovulation. During the

ensuing luteal phase, the mature follicle becomes the corpus luteum, which secretes progesterone and estradiol. The uterus undergoes further proliferative and secretory changes. Unless pregnancy occurs, endometrial sloughing and menstruation eventually occur, marking the beginning of a new cycle. FSH, follicle-stimulating hormone;

LH, luteinizing hormone.


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Figure 31.4 Ovary, Ova, and Follicles Until puberty, the ovary contains numerous primordial follicles that remain in a dormant state. After puberty, several follicles begin ripening with each menstrual cycle, in stages illustrated in the bottom panel. Only one follicle becomes a mature follicle; the others ultimately regress. After ovulation and

release of the ovum, the mature follicle involutes to form the corpus luteum, which persists to the end of the cycle.


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Causes of Abnormal Uterine Bleeding Abnormal uterine bleeding is associated with a variety of disease processes and disorders.


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Figure 31.5 Hormonal Regulation of the Menstrual Cycle The hypothalamic-pituitary-ovarian axis is characterized by both positive and negative feedback over the course of a menstrual cycle. Initially, GnRH stimulates release of LH and FSH by the pituitary; estrogen synthesized by developing ovarian follicles has negative feedback effects on the axis. However, in the late follicular phase (A), blood estradiol reaches a high level that initiates positive feedback and a surge in LH and FSH release,

provoking ovulation. In the luteal phase, the system is characterized by negative feedback (B). Estradiol, progesterone, and inhibin produced by the corpus luteum have negative feedback actions on gonadotropin release. FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone.


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Figure 31.6 Fertilization and Implantation Upon rupture of the graafian follicle, the ovum enters the fallopian tube. If fertilization occurs, it takes place within the fallopian tube, which transports the ovum or zygote to the uterus. A zygote will have reached the blastocyst stage by day 5 and will implant in the endometrial lining at that time.


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Figure 31.7 The Testes and Spermatogenesis The testes contain convoluted seminiferous tubules, where spermatogenesis takes place, and, between the tubules, Leydig cells, which synthesize testosterone in the mature male (left panel). Sertoli cells constitute the epithelium of the tubules (right panel). Differentiation of primary

spermatocytes to sperm cells begins between the Sertoli cells and is completed in the epididymis.


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Mature Spermatozoon The morphology of mature spermatozoa reflect their motility and ovumpenetrating functions.


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Testicular Failure in Klinefelter's Syndrome The presence of two X chromosomes (47, XXY genotype) results in seminiferous tubular dysgenesis and infertility, as well as primary hypogonadism (low testicular hormone levels, and as a result, high gonadotropin levels).


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Figure 31.8 Control of Testicular Function GnRH secreted by the hypothalamus stimulates LH and FSH secretion by the anterior pituitary. LH stimulates testosterone synthesis by the Leydig cells of the testes, whereas testosterone and FSH are required for spermatogenesis. FSH induces production of androgen-binding protein (ABG); androgen is concentrated in the tubules by binding to ABG, promoting spermatogenesis. Sertoli cells also produce inhibin, which, along with testosterone, exerts negative

feedback effects on the axis (inhibin specifically inhibits FSH secretion). FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone.


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figure 26.1 organization of the endocrine system hormones are secreted into the blood by endocrine...

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