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PHYSIOLOGY 03028 WEEKS 11 THROUGH 13: ENDOCRINE AND REPRODUCTIVE SYSTEMS

Cormack: Chs. 4, 9; Guyton and Hall: Chs. 74-82; Michael and Rovick: Unit 8; van Wysberghe and Cooley:

Cases 25-34 4/6/00

W. Crone (303 FTZ, 629-7439, cronewil@hvcc.edu, http://www.hvcc.edu/academ/faculty/crone/index.html)

Web sites: http://www.mcl.tulane.edu/classware/pathology/medical_pathology/endocrine_cases/casesTop.html

(case studies-a bit more detailed than what I expect, but good practice for CS and Lab Medicine too)

http://www-medlib.med.utah.edu/kw/human_reprod/ (contains lectures and cases in human reproduction)

THE THIRD LECTURE EXAM WILL COVER THROUGH THIS MATERIAL

Generally, what we will see in terms of endocrine disorders is the following:⁵

INSULIN AND GLUCAGON:

In the endocrine islets of Langerhans, 60% are b cells that secrete insulin, 25% are a cells that secrete glucagon, and 15% are d cells that secrete somatostatin (seems to regulate the a , b cells). Autonomic nervous system effects on the islets:

parasympathetic stimulates insulin secretion

sympathetic stimulates glucagon and inhibits insulin secretion, so a"stress hyperglycemia"

Skeletal muscles don't use blood glucose as an energy source at rest (it's saved for the brain), and glycogen is stored in the liver. In contrast, exercise can enhance muscle uptake of glucose without insulin via the contractions, hence exercise is useful for diabetics.⁶

diabetes mellitus: chronic hyperglycemia, from either the insufficient secretion of insulin by beta cells or the inability of secreted insulin to stimulate the cellular uptake of glucose from blood:

type 1 diabetes mellitus (IDDM) (type I diabetes, insulin-dependent diabetes, IDDM, juvenile diabetes): 10% of diabetics, beta cells destroyed, so lack of insulin production.

type 2 diabetes mellitus (NIDDM) (type II diabetes, non-insulin dependent diabetes, NIDDM, adult-onset diabetes): 90% of diabetics, insulin production adequate, but insulin resistance in tissues.

Acute complications of diabetes include:⁶

1. osmotic diuresis from glucosuria
2. ketoacidosis from elevated ketone body concentration. Given that fatty acids are now the energy source, ketone bodies are a resulting residue.
3. polyphagia from inadequate incorporation of nutrients into cells

Chronic complications of diabetes include:^3,6

1. increased risk of atherosclerosis from alterations in lipid metabolism
2. microangiopathy: thickening of capillary basement membrane from glycosylation, so obstruction and rupture of capillaries (retinas, kidneys). Microinfarcts may compromise nerve function.
3. infections: increased glucose as a medium for bacteria, e.g., UTIs.
4. other metabolic disruptions: with the hyperglycemia, additional substrate for a polyol pathway to produce excessive sorbitol, which is then deposited in nerves. Additionally, decreased myoinositol levels also contribute to decreased nerve conduction, e.g., symmetrical distal polyneuropathy.

hypoglycemia: often caused by an overdose of insulin. Fatty acids can't cross BBB and so neural symptoms from lack of sufficient glucose.⁴

OVERVIEW OF ENDOCRINE AXIS:

Hypothalamus: in endocrine context, the hypothalamus is a source of releasing/inhibiting factors that travel down a specialized capillary bed to the anterior pituitary. In contrast, ADH and oxytocin are produced in hypothalamic nuclei and transported axonally down to the posterior pituitary.

The hypothalamus is a major factor in hormone regulation via releasing and inhibitory factors that act on the pituitary. The pituitary will control other endocrine organs by supplying trophic hormones. Hormones of the hypothalamus and of the anterior pituitary can both be controlled by the hormones of the target glands, mostly through negative feedback inhibition.

Hypothalamic control over the anterior lobe is through the vascular hypothalamo-hypophyseal portal system. As a result, there are:

The anterior pituitary secretes trophic hormones, so that high levels of them cause their target organs to hypertrophy (and vice-versa).

1. Growth hormone (GH, somatotropin). Promotes movement of animo acids into cells and their incorporation into proteins, hence stimulating organ growth.

Growth hormone secretion (done in a pulsatile fashion), is stimulated by an increase in the plasma concentrations of amino acids and by a decrease in plasma glucose concentration. GH stimulates the cellular uptake of amino acids and protein synthesis. GH stimulates lipolysis in fat cells, and opposes insulin by opposing glucose uptake. Somatomedins (which are insulin-like growth factors) are mediators for many of growth hormone's effects, e.g., the liver produces IGF-1 in response to GH. IGF-1 stimulates cell division and growth in cartilage, so gigantism before fusion of the epiphyseal plates and acromegaly later in life with GH oversecretion.⁶

2. Thyroid-stimulating hormone (TSH, thyrotropin). Stimulates thyroid to produce and secrete thyroxine (T₄) and triiodothryonine (T₃).

The thyroid gland consists of many follicles containing colloid. In the colloid, iodide is accumulated, oxidized to iodine, and attached to thyroglobulin. With TSH stimulation, follicular cells endocytize some colloid, and hydrolyze off T₃ and T₄. The thyroid hormones are bound to serum proteins (e.g., TBG, thyroxine-binding globulin), with only a small percentage free in the serum. This allows for a large buffer pool of thyroid hormone and, with protection against metabolic degradation, allows for a longer half-life.

T₃ is the more active hormone of the two, generally leading to increased rates of nuclear transcription rates. Thyroid hormones set the basal metabolic rate (BMR) by increasing cellular activities, e.g., at the sodium pump.⁶ Thyroid hormones also stimulate protein synthesis throughout the body, which is especially important for early brain development, otherwise cretinism. Hypothyroidism later in life leads to myxedema. Other illnesses:¹

goiter:	From iodine deficiency, so lack of negative inhibition of TSH stimulation, and enlarged thyroid gland.
Grave's disease:	Autoimmune TSH-like stimulation

Parathyroid hormone (PTH) from parathyroid hormones promotes a rise in blood Ca²⁺ levels by actions on the bones, kidneys, and intestines.

bone:	PTH stimulates osteoclasts to resorb bone and thus break down the hydroxyapatite crystals of calcium and phosphate.
kidney:	PTH stimulates Ca2+ reabsorption, inhibit PO43- reabsorption
intestine:	PTH promotes the formation of 1,25-dihydroxyvitamin D3 in the kidney, so that this substance can then increase the intestinal absorption of Ca2+ and PO43-.

Vitamin D₃ is produced in the skin under the influence of sunlight. Final hydroxylation and activation occurs in the kidney, an activity which is stimulated by PTH. The primary function of 1,25-dihydroxyvitamin D₃ is the stimulation of intestinal absorption of calcium and phosphate. Osteomalacia and rickets occur as defective mineralization of bones, because of vitamin D deficiency. This contrasts with osteoporosis, where there is reduction in bone mass as a whole, rather than just the mineral content.

Calcitonin, made in parafollicular cells in the thyroid, lowers blood calcium levels, and may have a larger role with the rapid bone remodeling levels seen in children.⁶

The bivalent calcium ion affects sodium channels, so that in hypocalcemia, the sodium channels are more permeable and tetany can occur (carpopedal spasms, anyone?). Much of plasma calcium is bound to albumin, and with alkalosis, there can be more binding and hence fewer ionized calcium ions in the plasma. Hypercalcemia leads to decreased sodium channel permeability, and hence, nervous system depression.⁶ Given, the inverse relationships between calcium and phosphate, you can probably predict the effects of hyperphosphatemia and hypophosphatemia, right?

QUICK INTERLUDE ON SOME BONE THOUGHTS

Major histologic differences between hyaline cartilage and compact bone. Endochondral bone formation of long bones involves ends (epiphyses) separated by from the shaft (diaphysis) via epiphyseal plates.

Bone is constantly being remodeled by:

osteoblasts: cells that produce bone matrix

osteocytes: osteoblasts that are buried in their matrix (connected by canaliculi, right?)

osteoclasts: derived from fused monocytes, these"bone chewers" resorb bone

Periosteal and endosteal layers contain osteogenic cells, and can contribute to bone fracture repair via formation of bony callus.¹

3. Adrenocorticotropic hormone (ACTH, corticotropin). Stimulates adrenal cortex to secrete glucocorticoids (e.g., cortisol).

Adrenal cortex: secretion of corticosteriods (corticoids). Three functional categories:

1. mineralcorticoids that regulate Na⁺ and K⁺ balance, e.g., aldosterone
2. glucocorticoids that regulate the metabolism of glucose and the like, e.g., corticosterone and cortisol

Excess secretion: Cushing's disease/syndrome. Inadequate secretion: Addison's disease:

Cushing's: with an overproduction (or iatrogenic oversupply) of glucocorticoids, suppression of immune response, thinning of hair, redistribution of fat, etc.

Addison's: main concerns over lack of stress response or lack of aldosterone response

3. sex steroids that supplement the production from the gonads (e.g., masculinization in congenital adrenal hyperplasia).

Steroid hormone biochemistry; two general directions from cholesterol:⁷

cholesterol à pregnenoloneà 17-OH^- pregnenolone à androgens. Testosterone à estradiol (estrogen). OR cholesterol à pregnenolone à progesterone à glucocorticoids. Corticosterone à aldosterone (mineralcorticoid).

Adrenal androgens usually don't matter much in males, but in females, they can be a problem if certain enzymes are missing (particularly 21-hydroxylase that lead from progesterone to glucocorticoids). Resulting clinical picture of CAH (congenital adrenal hyperplasia, autosomal recessive).⁷ With high ACTH levels without negative inhibition, the adrenal cholesterol precursors instead get turned into androgens, which are masculizing to the female fetus (this virilized child also with risk of Addisonian crisis, from lack of mineralcorticoids).

STRESS

stress: reactions of the body to forces of a deleterious nature, infections, and various abnormal states that tend to disturb its normal physiologic equilibrium (homeostasis)

Stress is perceived by brain and sensory receptors and can be considered from both a short-term and a long-term perspective. In the short-term, catecholamines predominate; in the long-term, cortisol predominates.⁵

Adrenal medulla: catecholamines produce"fight or flight" syndrome, intense and short duration (liver degradation of epinephrine in 3 min). Cortisol secretion at this time enhances catecholamine function.

Vasoconstriction to shift blood flow away from digestion. BP, HR, RR, airway diameter all increased. and time for clotting reduced. Catecholamines also stimulate glycogen release from liver.

Hypothalamus releases CRH à pituitary releases ACTH à adrenal cortex produces cortisol

The increased amount of cortisol helps the body deal with stress:

1. protein catabolism, so amino acids released as energy source and a means of tissue repair in case of injury
2. amino acids can be used for gluconeogenesis, since in stress eating and digesting are reduced
3. lipolysis adds another food source

1. Follicle stimulating hormone (FSH, folliculotropin). Stimulates growth of ovarian follicles and sperm production.
2. Lutenizing hormone (LH, luteotropin, ICSH, interstitial cell-stimulating hormone).

LH promotes ovulation and conversion of that ovulated follicle into a corpus luteum and secretion of testosterone from Leydig cells.

The gonadotropic hormones FSH and LH are stimulated by GnRH (gonadotropin-releasing hormone) from the hypothalamus.

3. Prolactin (PRL). Stimulation of milk production after delivery of a baby.

Why changes at puberty? There are rises in FSH, LH secretion from:²

1. maturational changes in brain that result in increased GnRH
2. upregulation of GnRH receptors in anterior pituitary
3. decreased sensitivity of gonadotropin secretion to (-) feedback effects of sex steroids

The pulsatile secretions of FSH and LH lead to increased production of testosterone and estradiol-17b (estradiol being the main form of estrogen) and leads to secondary sex characteristics.

Average age of menarche (first menstrual flow) is 12.6 years, depending on amount of body fat, and so is later in very active girls. Physically active women may also have irregular cycles or amenorrhea. Exercise may not only lower body fat, but may also inhibit GnRH, FSH, and LH secretion via endorphin production.⁶

Male reproduction

Testis has two compartments:

1. seminiferous tubules for spermatogenesis (90%)
2. interstitial tissue for testosterone production from Leydig cells (10%)

Cellular receptors for FSH are found only in seminiferous tubules, at the Sertoli cells, with cellular receptors for LH only in Leydig cells.

Sertoli cells produces inhibin, a peptide hormone that supresses FSH secretion, as well. Negative feedbacks with testosterone and inhibin allow a more constant secretion of testosterone, vs. the cyclic secretion of gonadotropins and sex steroids in women.

Testosterone is the major androgen. Androgens are sometimes known as anabolic steroids. In the testis, testosterone acts in an autocrine fashion, so that it is required for spermatogenesis.

The Sertoli cells assist in spermiogenesis (spermatids à sperm). The Sertoli cells form a continuous layer (blood-testis layer) around the tubule, which prevents autoimmune destruction of sperm. Sertoli cells phagocytose much of the cytoplasm of the spermatids. Sertoli cells also produce androgen binding protein (ABP) in the lumen of the seminiferous tubules, to concentrate testosterone there. Typical sperm count is 60-150 million per ml of semen (typically 1.5 - 5ml in ejaculation). Oligospermia < 20 million per ml, with a total count < 50 million per ejaculate a concern for infertility.⁶

Ovary and follice development: primary oocytes that still need further meiotic divisions to reach maturity are contained in primordial/primary follicles, with layer/layers of granulosa cells. With FSH stimulation, these grow and form vesicles to become secondary follicles, and then on to mature Graafian follicles with one large antrum. Under FSH stimulation, the granulosa cells secrete estrogen as follicles grow. Another layer of cells, the theca interna cells, surrounded the granulosa cells. Under LH stimulation, theca cells produce progesterone and androgen precursors for estrogens.

Ovulation: 10-14 days after the first day of menstruation, one follicle has matured into a Graafian follicle (the other secondary follicles regress)... the one follicle enlarges, and ruptures to pop out the secondary oocyte. Under the influence of LH, the empty follicle changes into a corpus luteum, which secretes both estrogen and progesterone.

Cyclic changes in the secretion of FSH, LH from anterior pituitary cause ovarian changes during the monthly cycle. This ovarian cycle also affects the uterine endometrium during the menstrual cycle. The average cycle: 28 days. First day of menstruation: day 1 of the cycle. Follicular phase for ovaries until ovulation, when they are then in the luteal phase.

Follicular phase: One follicle matures as discussed above, and the granulosa cells secrete an increasing amount of estradiol (the principal estrogen), reaching a peak value at day 12 (2 days before ovulation). FSH stimulates the number of FSH receptors on granulosa cells, as does the increasing amounts of estradiol. The FSH and estradiol stimulate the number of LH receptors in the Graafian follicle. Positive estradiol feedback leads to a LH surge to tigger ovulation.⁶

Luteal phase: After ovulation, the empty follicle is stimulated by LH to become a corpus luteum, which now secretes both estradiol and progesterone, with the progesterone levels reaching a peak 1 week after ovulation. This high level of progesterone combined with estradiol create negative feedback inhibition on FSH, LH so that new ovulation doesn't occur. These high levels of progesterone and estradiol do not persist and soon drop off, causing menstruation and a new round of follicle development.

The endometrium is cycling as well. Three phases:

Proliferative phase: while ovary in follicular phase. The estradiol stimulates production of the stratum functionale of the endometrium, with development of spiral arteries.

Secretory phase: while ovary in luteal phase. The increased progesterone promotes uterine gland development, to promote their secretory activity. The endometrium is thick, vascular.

Menstrual phase: coincides with fall of hormone levels in late luteal phase. Necrosis and sloughing of stratum functionale, via constriction of spiral arteries.

Oral contraceptives: pills taken after menstrual period to increase the levels of ovarian hormones and so with negative feedback inhibition of gonadotropin secretion, ovulation never occurs (like a false luteal phase) vs. Menopause: fall in estradiol since no more follicles, so that FSH and LH levels are high without the negative feedback inhibition.⁶

Pregnancy testing: embryonic trophoblast cells secrete hCG (human chorionic gonadotropin), which is identical to LH in its effects, so as to maintain the corpus luteum and maintain its high levels of estradiol and progesterone that prevent menstruation. hCG secretion by trophoblast cells declines by 10th week of pregnancy, with the placenta taking over the hormone-secreting role within a few weeks.

Nursing helps to stimulate a neuroendocrine reflex to inhibit PIH and so maintain high levels of prolactin. Suckling also increases the release of oxytocin, which results in milk let-down (milk ejection reflex).

1. DH Cormack, Clinically Integrated Histology (Lippincott-Raven, Philadelphia, 1998), pp, 96, 97, 239.
2. SI Fox, Human Physiology, 5th ed. (WCB McGraw-Hill, Boston, 1998), pp. 649, 650, 660, 661.
3. JL Funk, KR Feingold, Disorders of the Endocrine Pancreas, pp. 367-392, in SJ McPhee et al., eds. Pathophysiology of Disease: An Introduction to Clinical Medicine (Appleton & Lange, Norwalk, CT, 1995).
4. S Goldberg, Clinical Physiology Made Ridiculously Simple (MedMaster, Miami, 1995), p. 142
5. BE Gould, Pathophysiology for the Health-Related Professions (WB Saunders, 1997), pp. 135, 378-380, 385-388.
6. Pp. 380, 938-940, 972, 973, 978, 988, 995, 1027, 1029.
7. SJ McPhee, Disorders of the adrenal cortex, pp. 320-345 in SJ McPhee et al., eds. Pathophysiology of Disease: An Introduction to Clinical Medicine (Appleton & Lange, Norwalk, CT, 1995).

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