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At normal plasma concentrations 1 mg estradiol fast delivery menopause night sweats relief, calcium and phosphate are at or near chemical saturation levels discount 2 mg estradiol free shipping young women's health birth control. If PTH were to increase both calcium and phosphate levels, they would simply crystallize in bone or soft tissues as calcium phosphate, and the necessary increase in plasma calcium concentration would not occur. Thus, the effect of PTH to lower plasma phosphate is an important aspect of its role in regulating plasma calcium. Parathyroid hormone has several important actions in the The structures of vitamin D3 and vitamin kidneys (see Fig. Note that they differ only by a double bond the thick ascending limb and late distal tubule, decreasing between carbons 22 and 23 and a methyl group at position 24. It also inhibits phosphate reabsorption in the proximal lar cells) does not lead to overt clinical abnormalities of cal- tubule, leading to increased urinary phosphate excretion and cium homeostasis. Another important effect of from thyroid tumors involving parafollicular cells, does not PTH is to increase the activity of kidney 1 -hydroxylase, cause any overt problems. On a daily basis, calcitonin prob- which is involved in forming active vitamin D. In bone, PTH activates osteoclasts to increase bone re- The overall action of calcitonin is to decrease both cal- sorption and the delivery of calcium from bone into plasma cium and phosphate concentrations in plasma (Fig. In addition to stimulating active osteoclasts, The primary target of CT is bone, although some lesser ef- PTH stimulates the maturation of immature osteoclasts into fects also occur in the kidneys. PTH also inhibits collagen syn- creases the tubular reabsorption of calcium and phosphate. In bones, CT opposes the action of sorption are augmented by 1,25-dihydroxycholecalciferol. This leads PTH does not appear to have any major direct effects on to decreased bone resorption and an overall net transfer of the GI tract. However, because it increases active vitamin calcium from plasma into bone. Calcitonin has little or no D formation, it ultimately increases the absorption of both direct effect on the GI tract. The net effect of 1,25-dihydroxycholecalciferol is to in- Calcitonin is important in several lower vertebrates, but crease both calcium and phosphate concentrations in despite its many demonstrated biological effects in humans, plasma (Fig. The activated form of vitamin D prima- it appears to play only a minor role in calcium homeostasis. First, CT loss following surgical removal of the thyroid In the kidneys, 1,25-dihydroxycholecalciferol increases gland (and, therefore, removal of CT-secreting parafollicu- the tubular reabsorption of calcium and phosphate, pro- 642 PART IX ENDOCRINE PHYSIOLOGY Plasma calcium Parathyroid glands PTH secretion Plasma PTH Kidneys Phosphate 1,25-(OH)2 D3 Bone reabsorption formation resorption Calcium reabsorption Urinary excretion Plasma of phosphate 1,25-(OH)2 D3 Urinary excretion Release of calcium of calcium into plasma Intestine Calcium absorption FIGURE 36. Plasma calcium Parafollicular cells CT secretion Plasma CT Kidneys Phosphate Calcium Bone reabsorption reabsorption resorption Urinary excretion Urinary excretion Calcium of phosphate of calcium release FIGURE 36. CHAPTER 36 Endocrine Regulation of Calcium, Phosphate, and Bone Metabolism 643 Plasma calcium Plasma PTH Renal 1α-hydroxylase activity 1,25-(OH)2 D3 formation Plasma 1,25-(OH)2 D3 Kidneys Bone Phosphate Calcium promotes PTH reabsorption reabsorption action Intestine Urinary excretion Phosphate Calcium of phosphate absorption absorption Urinary excretion of calcium FIGURE 36. Osteoporosis involves a reduction in total this is a weak and probably only minor effect of the hor- bone mass with an equal loss of both bone mineral and or- mone. Several factors are known to contribute di- osteoclasts, increasing bone resorption (see Fig. Long-term dietary calcium defi- In the gastrointestinal tract, 1,25-dihydroxycholecalcif- ciency can lead to osteoporosis because bone mineral is erol stimulates calcium and phosphate absorption by the mobilized to maintain plasma calcium levels. Vitamin C de- small intestine, increasing plasma concentrations of both ficiency also can result in a net loss of bone because vitamin ions. This effect is mediated by increased production of cal- C is required for normal collagen synthesis to occur. A de- cium transport proteins resulting from gene transcription fect in matrix production and the inability to produce new events and usually requires several hours to appear. For reasons that are not entirely understood, a reduction in the me- chanical stress placed on bone can lead to bone loss. Im- ABNORMALITIES OF BONE mobilization or disuse of a limb, such as with a cast or paral- MINERAL METABOLISM ysis, can result in localized osteoporosis of the affected limb.

The Distributions of Calcium and Plasma phosphorus concentrations may fluctuate signif- Phosphorus Differ icantly during the course of a day generic estradiol 1mg with amex womens health 40, from 50 to 150% of the average value for any particular individual purchase estradiol 1 mg visa breast cancer stage 0 symptoms. The average adult body con- (expressed in terms of milligrams of phosphorus). Despite its critical role in excitation-contraction ganic orthophosphate (PO ). Nearly all plasma inorganic phosphate Of the roughly 600 g of phosphorus in the body, most is ultrafilterable. Compared with calcium, a much larger phate is present in small amounts in the plasma in organic percentage of phosphorus is located in cells (14%). Bones also contain a relatively high percentage of the to- The Homeostatic Pathways for Calcium tal body content of several other inorganic substances and Phosphorus Differ Quantitatively (Table 36. About 80% of the total carbonate in the body Both calcium and phosphate are obtained from the diet. This carbonate can be mobilized into ultimate fate of each substance is determined primarily by the blood to combat acidosis; thus, bone participates in pH the gastrointestinal (GI) tract, the kidneys, and the bones. Long-standing uncorrected acidosis can result in considerable loss of bone mineral. Significant percentages of the body’s magnesium and sodium and Calcium Handling by the GI Tract, Kidneys, and Bones. The approximate tissue distribution and average daily flux of calcium among tissues in a healthy adult are shown in Figure 36. Dietary intakes may vary widely, but an “aver- age” diet contains approximately 1,000 mg/day of calcium. Body Content and Tissue Distribution of Intakes up to twice that amount are usually well tolerated, TABLE 36. Only about one third of ingested calcium is actually absorbed from the GI tract; the remain- Calcium Phosphorus der is excreted in the feces. The efficiency of calcium up- Total Body Content 1,300 g 600 g take from the GI tract varies with the individual’s physio- Relative Tissue Distribution logical status. The percentage uptake of calcium may be (% of total body content) increased in young growing children and pregnant or nurs- Bones and teeth 99% 86% ing women; often it is reduced in older adults. Therefore, small changes in the amount of calcium reab- sorbed by the kidneys can have a dramatic impact on cal- Calcium in diet cium homeostasis. In marked contrast to calcium, most (1,300 Absorption Deposition mg/day) of this phosphorus is absorbed from the GI tract, 300 mg/day 500 mg/day typically as inorganic phosphate. There is an obligatory Extracellular fluid contribution of phosphorus to the contents of the GI tract Secretion 900 mg Resorption (about 200 mg/day), much like that for calcium, resulting in 150 mg/day 500 mg/day a net uptake of phosphorus of 1,100 mg/day and excretion of 300 mg/day via the feces. Thus, the majority of ingested phosphate is absorbed from the GI tract and little passes Glomerular through to the feces. Total cal- 200 mg/day 200 mg/day cium content in each compartment is shown in black. Note that the majority of ingested calcium is eliminated from the body via the feces. This component of the calcium flux partly results from sloughing of mucosal cells that line the GI tract and Fecal excretion 300 mg/day also from calcium that accompanies various secretions into Kidney the GI tract. This component of calcium metabolism is rel- atively constant, so the primary determinant of net calcium uptake from the GI tract is calcium absorption. Bone in an average individual contains approximately 1,000 g of calcium. Bone mineral is constantly resorbed and deposited in the remodeling process. As much as 500 mg/day of calcium may flow in and out of the bones (see Fig. Since bone calcium serves as a reservoir, both Urinary excretion bone resorption and bone formation are important in regu- 1,100 mg/day lating plasma calcium concentration. Fluxes of phosphorus (mg/day) are shown in eventually require elimination. Total phosphorus content in each compartment is shown nation is via the urine, and therefore, the kidneys play an in black. Note that the majority of ingested phosphorus is ab- important role in regulating calcium homeostasis. CHAPTER 36 Endocrine Regulation of Calcium, Phosphate, and Bone Metabolism 637 Because most ingested phosphate is absorbed, phos- bound to small diffusible anions.

Second generic estradiol 1 mg without a prescription menopause occurs when, phospholipids on the platelet plasma triggered when antigen is given systemically discount estradiol 1 mg online menopause 24 years old. Platelet activation results in the sequential responses of ad- HEMOSTASIS herence, aggregation, and secretion. Adherence is initiated when one or more substances, released from cells or activated Circulating in a high-pressure, closed system that communi- in plasma at the site of a hemorrhage, bind to receptors in the cates with all tissues and cells in the body, blood exchanges platelet plasma membrane. Receptor binding results, via sec- oxygen, nutrients, and wastes and provides necessary compo- ond messengers, in adherence (to other platelets and the in- nents for host defense. This communication takes place largely ner, endothelial surface of blood vessels) and secretion. Endothelial cells also rapidly de- fragile capillaries may result from minor tissue injury associ- ploy cellular adherence antigens known as integrins on the ated with normal physical activity or from massive tissue outer surface of their plasma membranes during wound trauma as a result of serious injury or infection, and may healing. These adherence antigens are deployed to the cell quickly lead to death. Any opening in the vascular network membrane by cellular processes set in motion by factors may lead to massive bruising or blood loss if left unrepaired. In turn, activated endothelial cells injury, components of the hemostatic system are activated. They may be activated on exposure to for- forming a bridge between cell surface receptors and colla- eign surfaces during bleeding, or by torn tissue at the site of gen in the subendothelial matrix. The protein thrombin, injury, or by products released from the interior of dam- which is generated by the plasma coagulation cascade, is a aged cells. Hemostasis can be viewed as four separate but potent activator of platelet adherence and secretion. Rup- interrelated events: tured cells at the site of tissue injury release adenosine • Compression and vasoconstriction, which act immedi- diphosphate (ADP), which causes platelets to aggregate at ately to stop the flow of blood the damaged site. These aggregates effectively stop the • Formation of a platelet plug flow of blood from the ruptured vessels. The fibrin network traps red cells, leuko- exerted by the tissue around the injured area, and vasocon- cytes, platelets, and serum at sites of vascular damage, striction. The degree of compression varies in different tis- thereby forming a blood clot. The stable, fibrin-based sues; for example, bleeding below the eye is not readily de- blood clot eventually replaces the unstable platelet ag- terred because the skin in this area is easily distensible. Fibrin is Back-pressure increases as blood which leaks out of the dis- an insoluble polymer of proteolytic products of the rupted capillaries accumulates. Fibrin molecules are cleaved uterus after childbirth, contraction of underlying muscles from fibrinogen by thrombin, which is generated in compresses blood vessels supplying the tissue and mini- plasma during clotting. Damaged cells at the site of tissue injury mation, thrombin cleaves four small peptides (fib- release potent substances that directly cause blood vessels rinopeptides) from each molecule of fibrinogen. The fib- to constrict, including serotonin, thromboxane A2, epi- rinogen molecule devoid of these fibrinopeptides is nephrine, and fibrinopeptide B. The fibrin monomers sponta- neously assemble into ordered fibrous arrays of fibrin, resulting in an insoluble matrix of fibrous strands. At this Platelets Form a Hemostatic Plug stage, the clot is held together by noncovalent forces. First, they form plasma enzyme, fibrin stabilizing factor (Factor XIII), multicellular aggregates linked by protein strands at sites of catalyzes the formation of covalent bonds between CHAPTER 11 Blood Components, Immunity, and Hemostasis 207 strands of polymerized fibrin, stabilizing and tightening the blood clot. Blood clotting is mediated by the sequential activation of a series of coagulation factors, proteins synthesized in the liver that circulate in the plasma in an inactive state. They are referred to by number (designated by a Roman numeral) in a sequence based on the order of the discovery of each factor. The plasma coagulation factors and their common names are listed in Table 11. The sequential activation of a series of inactive mole- cules resulting in a biological response is called a metabolic cascade. The sequential activation of coagulation factors resulting in the conversion of fibrinogen to fibrin (and, hence, clotting) is called the coagulation cascade.

A male with only concern for developmental anatomy are such topics as ectopic one such allele on his X chromosome order estradiol 2 mg amex menstrual weight gain, however generic 2 mg estradiol with visa breast cancer 78 year old, will show the pregnancies, so-called test-tube babies, multiple pregnancy, fetal characteristic. Because a male receives his X chromosome from monitoring, and congenital defects. Abnormal Implantation Sites Hemophilia is a sex-linked condition caused by a recessive al- lele. If H represents normal clotting and h rep- H side the uterus or in an abnormal site within the uterus resents abnormal clotting, then males with X Y will be normal and males with XhY will be hemophiliac. Occasionally, implantation occurs near the Knowledge Check cervix, where development of the placenta blocks the cervical opening. Define genetics, genotype, phenotype, allele, dominant, reces- serious bleeding. Ectopic pregnancies will not develop normally sive, homozygous, and heterozygous. List several dominant and recessive traits inherited in hu- the first trimester. Depending on the location and the stage of develop- for color blindness of an XcY male and an XCXc female. In Vitro Fertilization CLINICAL CONSIDERATIONS and Artificial Implantation Pregnancy and childbirth are natural events in human biology Reproductive biologists have been able to fertilize a human and generally progress smoothly without complications. Prenatal oocyte in vitro (outside the body), culture it to the blastocyst development is amazingly precise, and although traumatic, child- stage, and then perform artificial implantation, leading to a full- birth for most women in the world takes place without the aid of term development and delivery. The physician’s is used to aspirate the preovulatory egg from a mature vesicular knowledge of what constitutes normal development and what ovarian follicle. The oocyte is then placed in a suitable culture factors are responsible for congenital malformations ensures the medium, where it is fertilized with spermatozoa. When the zygote embryo and fetus every possible chance to develop normally. In vitro fertilization with what might be referred to as applied developmental biology. During the second trimester, fetal quickening can be de- tected, epidermal features are formed, and the vital body systems Twins occur about once in 85 pregnancies. At the end of the second trimester, two zygotes produced by the fertilization of two oocytes by two fetal length is about equal to the length of an adult’s hand. Monozy- fetus experiences a tremendous amount of growth and refine- gotic (identical) twins form from a single zygote (fig. Dizygotic twins always have two chorions and two am- Many clinical considerations are associated with prenatal nions, but the chorions and the placentas may be fused. Other developmental problems are geneti- cally related and will be mentioned only briefly. Developmental © The McGraw−Hill Anatomy, Sixth Edition Development Anatomy, Postnatal Companies, 2001 Growth, and Inheritance 786 Unit 7 Reproduction and Development Mesentery Small intestine I C D B E A Lumen of uterine tube X Body of F uterus H Ovarian ligament G (Implantation Ovary Fimbriae at isthmus of uterus) H (Cervical implantation) FIGURE 22. The normal implantation site is indicated by an X; the abnormal sites are indicated by letters in order of frequency of occurrence. Monozygotic twins have two amnions but only one chorion and a common placenta. If the embryoblast fails to completely divide, conjoined twins (Siamese twins) may form. Triplets occur about once in 7,600 pregnancies and may be (1) all from the same ovum and identical, (2) two identical and the third from another ovum, or (3) three zygotes from three dif- ferent ova. Fetal Monitoring Obstetrics has benefited greatly from advancements made in fetal monitoring in the last two decades. Before modern techniques became available, physicians could determine the welfare of the unborn child only by auscultation of the fetal heart and palpa- FIGURE 22. Currently, several tests may be used to gain in- erations, including the extraction of a preovulatory ovum. Fetal conditions that can now be diagnosed and evaluated include ge- netic disorders, hypoxia, blood disorders, growth retardation, pla- Monozygotic twins are of the same sex and are genetically cental functioning, prematurity, postmaturity, and intrauterine identical.