Color Atlas of Physiology 2003 thieme

C. Synthesis, storage and mobilization of the thyroid hormones

Plate 11.12 Thyroid Hormones II

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11 Hormones and Reproduction

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!

cium deposition (e.g., in the kidneys). Ca2+ conc. exceeding 3.5 mmol/L lead to coma, renal insufficiency and cardiac arrhythmias.

tion and increased renal excretion of the just absorbed Ca2+. Calcitonin also acts on the kidneys (!D6).

Calcitriol (1,25-(OH)2-cholecalciferol) is a lipophilic, steroid-like hormone synthesized as follows (! C): Cholecalciferol (vitamin D3) is produced from hepatic 7-dehydrocholesterol in the skin via an intermediate product (previtamin D) in response to UV light (sun, tanning lamps). Both substances bind to vitamin D-binding protein (DBP) in the blood, but cholecalciferol is preferentially transported because of its higher affinity. Previtamin D therefore remains in the skin for a while after UV light exposure (short-term storage). Calcidiol (25-OH-cholecalciferol) and calcitriol bind to DBP. An estrogen-dependent rise in DBP synthesis occurs during pregnancy.

Cholecalciferol (vitamin D3) is administered to compensate for inadequate UV exposure. The recommended daily dosage in children is approximately 400 units = 10 µg; adults receive half this amount. Plant-derived ergocalciferol (vitamin D2) is equally effective as animal-derived vitamin D3. The following actions apply for both forms.

Cholecalciferol is converted to calcidiol (25- 292 OH-cholecalciferol) in the liver. Vitamin D is mainly stored as calcidiol because the plasma

conc. of calcidiol is 25 µg/L, and its half-life is 15 days. Calcitriol (1,25-(OH)2-cholecalciferol), the hormonally active form, is mainly synthesized in the kidneys (!C), but also in the placenta. The plasma conc. of calcitriol is regulated by renal 1-α-hydroxylase (final step of synthesis) and by 24-hydroxylase, an enzyme that deactivates calcitriol.

The calcitriol concentration rises in response to hy- pocalcemia-related PTA secretion (!D2), to phosphate deficiency and to prolactin (lactation). All three inhibit 24-hydroxylase and activate 1-α-hy- droxylase. It decreases due to several negative feedback loops, i.e. due to the fact that calcitriol (a) directly inhibits 1-α-hydroxylase, (b) inhibits parathyroid hormone secretion, and (c) normalizes the (decreased) plasma conc. of Ca2+ and phosphate by increasing the intestinal absorption of Ca2+ and phosphate (see below). Calcium and phosphate inhibit 1-α-hydroxylase, while phosphate activates 24hydroxylase.

Target organs. Calcitriol’s primary target is the gut, but it also acts on the bone, kidneys, placenta, mammary glands, hair follicles, skin etc. It binds with its nuclear receptor and induces the expression of calcium-binding protein and Ca2+-ATPase (! pp. 278 and 36). Calcitriol has also genomic effects. Calcitriol increases the intestinal absorption of Ca2+ (!D4) and promotes mineralization of the bone, but an excess of calcitriol leads to decalcification of the bone, an effect heightened by PTH. Calcitriol also increases the transport of Ca2+ and phosphate at the kidney (!p. 178), placenta and mammary glands.

In transitory hypocalcemia, the bones act as a temporary Ca2+ buffer (!D) until the Ca2+ deficit has been balanced by a calcitriol-mediated increase in Ca2+ absorption from the gut. If too little calcitriol is available, skeletal demineralization will lead to osteomalacia in adults and rickets in children. Vitamin D deficiencies are caused by inadequate dietary intake, reduced absorption (fat maldigestion), insufficient UV light exposure, and/or reduced 1-α- hydroxylation (renal insufficiency). Skeletal demineralization mostly occurs due to the prolonged increase in parathyroid hormone secretion associated with chronic hypocalcemia (compensatory hyperparathyroidism).

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Plate 11.14 Calcium and Phosphate Metabolism II

11 Hormones and Reproduction

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Adrenal Cortex and Glucocorticoid

Synthesis

etc.

CRH and ACTH regulate cortisol synthesis and secretion (! A4, A5; see also p. 270). ACTH ensures also structural preservation of the adrenal cortex and supplies cortisol precursors, e.g., by forming cholesterol from its esters, by de novo synthesis of cholesterol and by converting it to progesterone and 17α-hy- droxyprogesterone (!pp. 256 and 294). ACTH secretion is stimulated by CRH and epinephrine and inhibited (negative feedback control) by cortisol with or without the aid of CRH (!A; see also p. 273 A).

A circadian rhythm of CRH secretion and thus of ACTH and cortisol secretion can be observed. The peak secretion is in the morning (!B, mean values). Continuous hormone conc. sampling at short intervals have shown that ACTH and cortisol are secreted in 2–3-hour episodes (!B).

Receptor proteins (!p. 278) for glucocorticoids can be found in virtually every cell. Glucocorticoids are vital hormones that exert numerous effects, the most important of which are listed below.

Carbohydrate and amino acid (AA) metabolism (see also pp. 283 A and 285 C): Cortisol uses AA derived from protein degradation to

296increase the plasma glucose concentration (gluconeogenesis), which can lead to the so-

called steroid diabetes in extreme cases. Thus, cortisol has a catabolic effect (degrades proteins) that results in the increased excretion of urea.

Cardiovascular function: Glucocorticoids increase myocardial contractility and vasoconstriction due to enhancement of catecholamine effects (!pp. 194 and 214). These are described as permissive effects of cortisol. Cortisol increases the synthesis of epinephrine in the adrenal medulla (!A6) and of angiotensinogen in the liver (!p. 184).

Especially when administered at high doses, glucocorticoids induce anti-inflam- matory and anti-allergic effects because they stabilize lymphokine synthesis and histamine release (!p. 100). On the other hand, inter- leukin-1, interleukin-2 and TNF-α (e.g., in severe infection) leads to increased secretion of CRH and high cortisol conc. (see below).

Renal function: Glucocorticoids delay the excretion of water and help to maintain a normal glomerular filtration rate. They can react also with aldosterone receptors but are converted to cortisone by 11!-hy- droxysteroid oxidoreductase in aldosterone target cells. Normal cortisol conc. are therefore ineffective at the aldosterone receptor. High conc., however, have the same effect as aldosterone (!p. 182).

Gastric function: Glucocorticoids weaken the protective mechanisms of the gastric mucosa. Thus, high-dose glucocorticoids or stress (see below) increase the risk of gastric ulcers (!p. 242).

Cerebral function: High glucocorticoid conc. change hypothalamic (!A) and electrical brain activity (EEG) and lead to psychic abnormalities.

Stress: Physical or mental stress increases cortisol secretion as a result of increased CRH secretion and increased sympathetic tone (!A). Many of the aforementioned effects of cortisol therefore play a role in the body’s response to stress (activation of energy metabolism, increase in cardiac performance, etc.). In severe physical (e.g., sepsis) or mental stress (e.g., depression), the cortisol plasma conc. remains at a very high level (up to 10 times the normal value) throughout the day.

Oogenesis and the Menstrual Cycle

In addition to general changes in the body and mood, the following changes occur in the ovaries, uterus and cervix during the menstrual cycle (!A):

Day 1: Start of menstruation (lasting about 2–6 days).

Days 1–14 (variable, see above): The follicular phase starts on the first day of menstruation. The endometrium thickens to become prepared for the implantation of the fertilized ovum during the luteal phase (!A5), and about 20 ovarian follicles mature under the influence of FSH. One of these becomes the dominant follicle, which produces increasing quantities of estrogens (!A4 and p. 300). The small cervical os is blocked by a viscous mucous plug.

Day 14 (variable, see above): Ovulation. The amount of estrogens produced by the follicle increases rapidly between day 12 and 13 (! A2). The increased secretion of LH in response to higher levels of estrogen leads to ovulation (!A1, A4; see also p. 300). The basal body temperature (measured on an empty stomach before rising in the morning) rises about 0.5!C about 1–2 days later and remains elevated until the end of the cycle (!A3). This temperature rise generally indicates that ovulation has occurred. During ovulation, the cervical mucus is less viscous (it can be stretched into long threads—spinnbarkeit) and the cervical os opens slightly to allow the sperm to enter.

Days 14–28: The luteal phase is characterized by the development of a corpus luteum (!A4), which secretes progesterone, (!A2); an increase in mucoid secretion from the uterine glands also occurs (! A5). The endometrium is most responsive to progesterone around the 22nd day of the cycle, which is when nidation should occur if the ovum has been fertilized. Otherwise, progesterone and estrogens now inhibit Gn-RH secretion (!p. 300), resulting in degeneration of the corpus luteum. The subsequent rapid decrease in the plasma concentrations of estrogens and progesterone (!A2) results in constriction of endometrial blood vessels and ischemia. This ultimately leads to the breakdown and discharge of the uterine lining and to bleeding, i.e., menstruation (! A5).