187-2017

effects on maturation of central nervous system centers governing sexual development, particularly in the female. Administration of these drugs to pregnant women may lead to masculinization or undermasculinization of the external genitalia in the female and male fetus, respectively. Although the above-mentioned effects may be less marked with the anabolic agents, they do occur.

Sodium retention and edema are not common but must be carefully watched for in patients with heart and kidney disease.

Most of the synthetic androgens and anabolic agents are 17-alkyl-substituted steroids. Administration of drugs with this structure is often associated with evidence of hepatic dysfunction. Hepatic dysfunction usually occurs early in the course of treatment, and the degree is proportionate to the dose. Bilirubin levels may increase until clinical jaundice is apparent. The cholestatic jaundice is reversible upon cessation of therapy, and permanent changes do not occur. In older males, prostatic hyperplasia may develop, causing urinary retention.

Replacement therapy in men may cause acne, sleep apnea, erythrocytosis, gynecomastia, and azoospermia. Supraphysiologic doses of androgens produce azoospermia and decrease in testicular size, both of which may take months to recover after cessation of therapy. The alkylated androgens in high doses can produce peliosis hepatica, cholestasis, and hepatic failure. They lower plasma HDL and may increase LDL. Hepatic adenomas and carcinomas have also been reported. Behavioral effects include psychological dependence, increased aggressiveness, and psychotic symptoms.

Contraindications & Cautions

The use of androgenic steroids is contraindicated in pregnant women or women who may become pregnant during the course of therapy.

Androgens should not be administered to male patients with carcinoma of the prostate or breast. Until more is known about the effects of these hormones on the central nervous system in developing children, they should be avoided in infants and young children.

Special caution is required in giving these drugs to children to produce a growth spurt. In most patients, the use of somatotropin is more appropriate (see Chapter 37).

Care should be exercised in the administration of these drugs to patients with renal or cardiac disease predisposed to edema. If sodium and water retention occurs, it will respond to diuretic therapy.

Methyltestosterone therapy is associated with creatinuria, but the significance of this finding is not known.

Caution: Several cases of hepatocellular carcinoma have been reported in patients with aplastic anemia treated with androgen anabolic therapy. Erythropoietin and colony-stimulating factors (see Chapter 33) should be used instead.

ANDROGEN SUPPRESSION & ANTIANDROGENS

ANDROGEN SUPPRESSION

In contrast to the lack of strong indications for the use of androgen supplementation (except in the case of hypogonadism), the use of inhibitors of androgen synthesis and of androgen antagonists has

several well-documented applications. The treatment of advanced prostatic carcinoma often requires orchiectomy or large doses of estrogens to reduce available endogenous androgen. The psychological effects of the former and gynecomastia produced by the latter make these approaches undesirable. As noted in Chapter 37, the GnRH analogs, such as goserelin, nafarelin, buserelin, and leuprolide acetate, produce effective gonadal suppression when blood levels are continuous rather than pulsatile (see Chapter 37 and Figure 40–6).

ANTIANDROGENS

The potential usefulness of antiandrogens in the treatment of patients producing excessive amounts of testosterone has led to the search for effective drugs that can be used for this purpose. Several approaches to the problem, especially inhibition of synthesis and receptor antagonism, have met with some success.

Steroid Synthesis Inhibitors

Ketoconazole, used primarily in the treatment of fungal disease, is an inhibitor of adrenal and gonadal steroid synthesis, as described in Chapter 39. It does not affect ovarian aromatase, but it reduces human placental aromatase activity. It displaces estradiol and dihydrotestosterone from sex hormone-binding protein in vitro and increases the estradiol:testosterone ratio in plasma in vivo by a different mechanism. However, it does not appear to be clinically useful in women with increased androgen levels because of the toxicity associated with prolonged use of the 400–800 mg/d required. The drug has also been used experimentally to treat prostatic carcinoma, but the results have not been encouraging. Men treated with ketoconazole often develop reversible gynecomastia during therapy; this may be due to the demonstrated increase in the estradiol:testosterone ratio.

Inhibition of Conversion of Steroid Precursors to Androgens

Several compounds have been developed that inhibit the 17-hydroxylation of progesterone or pregnenolone, thereby preventing the action of the side chain-splitting enzyme and the further transformation of these steroid precursors to active androgens. A few of these compounds have been tested clinically but have been too toxic for prolonged use. As noted in Chapter 39, abiraterone, a newer 17α-hydroxylase inhibitor, has been approved for use in metastatic prostate cancer.

Since dihydrotestosterone—not testosterone—appears to be the essential androgen in the prostate, androgen effects in this and similar dihydrotestosterone-dependent tissues can be reduced by an inhibitor of 5α-reductase (Figure 40–6). Finasteride, a steroid-like inhibitor of this enzyme, is orally active and causes a reduction in dihydrotestosterone levels that begins within 8 hours after administration and lasts for about 24 hours. The half-life is about 8 hours (longer in elderly individuals). About 40–50% of the dose is metabolized; more than half is excreted in the feces. Finasteride has been reported to be moderately effective in reducing prostate size in men with benign prostatic hyperplasia and is

GnRH

– GnRH antagonists (1)

+/– GnRH agonists (2)

Pituitary gonadotrophs

LH

Testis

Dihydrotestosterone

Flutamide,

–– cyproterone, (5) spironolactone

Androgen-receptor complex

Androgen response element

Expression of appropriate genes in androgen-responsive cells

FIGURE 40 6 Control of androgen secretion and activity and some sites of action of antiandrogens: (1) competitive inhibition of GnRH receptors; (2) stimulation (+, pulsatile administration) or inhibition via desensitization of GnRH receptors (–, continuous administration); (3) decreased synthesis of testosterone in the testis; (4) decreased synthesis of dihydrotestosterone by inhibition of 5α-reductase;

(5) competition for binding to cytosol androgen receptors.

approved for this use in the United States. The dosage is 5 mg/d. Dutasteride is a similar orally active steroid derivative with a slow onset of action and a much longer half-life than finasteride. It is approved for treatment of benign prostatic hyperplasia at a dosage of 0.5 mg daily. These drugs are not approved for use in women or children, although finasteride has been used successfully in the treatment of hirsutism in women and is approved for treatment of early male pattern baldness in men (1 mg/d).

O NH H

Finasteride

Receptor Inhibitors

Flutamide, a substituted anilide, is a potent antiandrogen that has been used in the treatment of prostatic carcinoma. Although not a steroid, it behaves like a competitive antagonist at the androgen receptor. It is rapidly metabolized in humans. It frequently causes mild gynecomastia (probably by increasing testicular estrogen production) and occasionally causes mild reversible hepatic toxicity. Administration of this compound causes some improvement in most patients with prostatic carcinoma who have not had prior endocrine therapy. Preliminary studies indicate that flutamide is also useful in the management of excess androgen effect in women.

Bicalutamide, nilutamide, and enzalutamide are potent orally active antiandrogens that can be administered as a single daily dose and are used in patients with metastatic carcinoma of the prostate. Studies in patients with carcinoma of the prostate indicate that these agents are well tolerated. Bicalutamide is recommended (to reduce tumor flare) for use in combination with a GnRH analog and may have fewer gastrointestinal side effects than flutamide. A dosage of 150–200 mg/d (when used alone) is required to reduce prostate-specific antigen levels to those achieved by castration, but, in combination with a GnRH analog, 50 mg/d may be adequate. Nilutamide is administered in a dosage of 300 mg/d for 30 days followed by 150 mg/d. The dosage of enzalutamide is 160 mg/d orally.

Cyproterone and cyproterone acetate are effective antiandrogens that inhibit the action of androgens at the target organ. The acetate form has a marked progestational effect that suppresses the feedback enhancement of LH and FSH, leading to a more effective antiandrogen effect. These compounds have been used in women to treat hirsutism and in men to decrease excessive sexual drive and are being studied in other conditions in which the reduction of androgenic effects would be useful. Cyproterone acetate in a dosage of 2 mg/d administered concurrently with an estrogen is used in the treatment of hirsutism in women, doubling as a contraceptive pill; it has orphan drug status in the United States.

Spironolactone, a competitive inhibitor of aldosterone (see Chapter 15), also competes with dihydrotestosterone for the androgen receptors in target tissues. It also reduces 17α-hydroxylase activity, lowering plasma levels of testosterone and androstenedione. It is used in dosages of 50–200 mg/d in the treatment of hirsutism in women and appears to be as effective as finasteride, flutamide, or cyproterone in this condition.

CHEMICAL CONTRACEPTION IN MEN

Although many studies have been conducted, an effective and nontoxic oral contraceptive for men has not yet been found. For example, various androgens, including testosterone and testosterone enanthate, in a dosage of 400 mg per month, produced azoospermia in less than half the men treated. Minor adverse reactions, including gynecomastia and acne, were encountered. Testosterone in combination with danazol was well tolerated but no more effective than testosterone alone. Androgens in combination with a progestin such as medroxyprogesterone acetate were no more effective. However, preliminary studies indicate that the intramuscular administration of 100 mg of testosterone enanthate weekly together with 500 mg of levonorgestrel daily orally can produce azoospermia in 94% of men. Retinoic acid is important in the maturation of sperm and the testis contains a unique isoform of the alcohol dehydrogenase enzyme that converts retinol to retinoic acid but no nontoxic inhibitor of this enzyme has been found to date.

Cyproterone acetate, a very potent progestin and antiandrogen, also produces oligospermia; however, it does not cause reliable contraception.

At present, pituitary hormones—and potent antagonist analogs of GnRH—are receiving increased attention. A GnRH antagonist in combination with testosterone has been shown to produce reversible azoospermia in nonhuman primates.

GOSSYPOL

Extensive trials of this cottonseed derivative have been conducted in China. This compound destroys elements of the seminiferous epithelium but does not significantly alter the endocrine function of the testis.

In Chinese studies, large numbers of men were treated with

4 million/mL. Preliminary data indicate that recovery (return of normal sperm count) following discontinuance of gossypol administration is more apt to occur in men whose counts do not fall to extremely low levels and when administration is not continued for more than 2 years. Hypokalemia is the major adverse effect and may lead to transient paralysis. Because of low efficacy and significant toxicity, gossypol has been abandoned as a candidate male contraceptive.

P R E P A R A T I O N S

A V A I L A B L E *

ANTAGONISTS & INHIBITORS

(See also Chapter 37)

Abiraterone

Anastrozole

Bazedoxifene (in combination with conjugated equine estrogens)

Bicalutamide

Clomiphene

Danazol

Dutasteride

Enzalutamide

Exemestane

Finasteride

Flutamide

Fulvestrant

Letrozole

Mifepristone

Nilutamide

Raloxifene

Tamoxifen

Toremifene

Oral contraceptives are listed in Table 40–3.

†Withdrawn in the United States.

REFERENCES

Acconcia F et al: Palmitoylation-dependent estrogen receptor alpha membrane localization: Regulation by 17beta-estradiol. Mol Biol Cell 2005;16:231.

Anderson GL et al for the Women’s Health Initiative Steering Committee: Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. JAMA 2004;291:1701.

Bacopoulou F, Greydanus DE, Chrousos GP: Reproductive and contraceptive issues in chronically ill adolescents. Eur J Contracept Reprod Health Carez 2010;15:389.

Basaria S et al: Adverse events associated with testosterone administration. N Engl J Med 2010;363:109.

Baulieu E-E: Contragestion and other clinical applications of RU 486, an antiprogesterone at the receptor. Science 1989;245:1351.

Bechlioulis A et al: Endothelial function, but not carotid intima-media thickness, is affected early in menopause and is associated with severity of hot flushes. J Clin Endocrinol Metab 2010;95:1199.

Bhupathiraju SN et al: Exogenous hormone use: oral contraceptives, postmenopausal hormone therapy, and health outcomes in the Nurses’ Health Study. Am J Pub Health 2016;106:1631.

Binkhorst L, et al: Augmentation of endoxifen exposure in tamoxifen-treated women following SSRI switch. Clin Pharmacokin 2016;55:259.

Böttner M, Thelen P, Jarry H: Estrogen receptor beta: Tissue distribution and the still largely enigmatic physiological function. J Steroid Biochem Mol Biol 2014;139:245.

Burkman R, Schlesselman JJ, Zieman M: Safety concerns and health benefits associated with oral contraception. Am J Obstet Gynecol 2004;190(Suppl 4):S5.

Chlebowski RT et al: Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 2010;304:1684.

Chrousos GP: Perspective: Stress and sex versus immunity and inflammation. Sci Signal 2010;3:pe36.

Chrousos GP, Torpy DJ, Gold PW: Interactions between the hypothalamic- pituitary-adrenal axis and the female reproductive system: Clinical implications. Ann Intern Med 1998;129:229.

Coomarasamy A et al: A randomized trial of progesterone in women with recurrent miscarriages. N Engl J Med 2015;373:2141.

Cui J, Shen Y, Li R: Estrogen synthesis and signaling pathways during aging: From periphery to brain. Trends Mol Med 2013;19:197.

Cuzick J et al: SERM Chemoprevention of Breast Cancer Overview Group: Selective oestrogen receptor modulators in prevention of breast cancer: An updated meta-analysis of individual participant data. Lancet 2013;381:1827.

Diamanti-Kandarakis E et al: Pathophysiology and types of dyslipidemia in PCOS. Trends Endocrinol Metab 2007;18:280.

Finkelstein JS et al: Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med 2013;369:1011.

Fuqua SAW, Schiff R: Mechanisms of action of selective estrogen receptor modulators and down regulators. UpToDate 2016; topic 762.

Gomes MPV, Deitcher SR: Risk of venous thromboembolic disease associated with hormonal contraceptives and hormone replacement therapy: A clinical review. Arch Intern Med 2004;164:1965.

Hall JM, McDonnell DP, Korach KS: Allosteric regulation of estrogen receptor structure, function, and co-activator recruitment by different estrogen response elements. Mol Endocrinol 2002;16:469.

Harman SM et al: Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 2001;86:724.

Imai Y et al: Nuclear receptors in bone physiology and diseases. Physiol Rev 2013;93:481.

Kalantaridou S, Chrousos GP: Monogenic disorders of puberty. J Clin Endocrinol Metab 2002;87:2481.

Kalantaridou S et al: Premature ovarian failure, endothelial dysfunction, and estrogen-progesterone replacement. Trends Endocrinol Metab 2006;17:101.

Kalantaridou SN et al: Impaired endothelial function in young women with premature ovarian failure: Normalization with hormone therapy. J Clin Endocrinol Metab 2004;89:3907.

Kanaka-Gantenbein C et al: Assisted reproduction and its neuroendocrine impact on the offspring. Prog Brain Res 2010;182C:161.

Lidegaard Ø et al: Thrombotic stroke and myocardial infarction with hormonal contraception. N Engl J Med 2012;366:2257.

Livadas S, Chrousos GP: Control of the onset of puberty. Curr Opin Pediatr 2016;28:551.

Manson JE et al: Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003;349:523.

Martin KA, Barbieri RL: Menopausal hormone therapy: Benefits and risks. UpToDate 2016.

McDonnell DP, Wardell SE: The molecular mechanisms underlying the pharmacological actions of ER modulators: Implications for new drug discovery in breast cancer. Curr Opin Pharmacol 2010;10:620.

Merke DP et al: Future directions in the study and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Ann Intern Med 2002;136:320.

Naka KK et al: Effect of the insulin sensitizers metformin and pioglitazone on endothelial function in young women with polycystic ovary syndrome: A prospective randomized study. Fertil Steril 2011;95:203.

Nelson HD et al: Use of medication to reduce risk for primary breast cancer: A systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2013;158:604.

Paulmurugan R et al: In vitro and in vivo molecular imaging of estrogen receptor α and β homoand heterodimerization: exploration of new modes of receptor regulation. Mol Endocrinol 2011;25:2029.

Price VH: Treatment of hair loss. N Engl J Med 1999;341:964.

Rossouw JE et al: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321.

Scher HI et al: Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012;367:1187.

Smith RE: A review of selective estrogen receptor modulators in national surgical adjuvant breast and bowel project clinical trials. Semin Oncol 2003;30(Suppl 16):4.

Snyder PJ et al: Effect of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab 2000;85:2670.

Stegeman BH et al: Different combined oral contraceptives and the risk of venous thrombosis: Systematic review and network meta-analysis. Brit Med J 2013;347:f5298.

U.S. Preventive ServicesTask Force: Hormone therapy for the prevention of chronic conditions in postmenopausal women. Ann Intern Med 2005;142:855.

Wehrmacher WH, Messmore H: Women’s Health Initiative is fundamentally flawed. Gend Med 2005;2:4.

Zandi PP et al: Hormone replacement therapy and incidence of Alzheimer’s disease in older women. JAMA 2002;288:2123.

C A S E S T U D Y A N S W E R

The patient should be advised to start daily transdermal estradiol therapy (100 mcg/d) along with oral natural progesterone (200 mg/d) for the last 12 days of each 28-day cycle. On this regimen, her symptoms should disappear

and normal monthly uterine bleeding resume. She should also be advised to get adequate exercise and increase her calcium and vitamin D intake as treatment for her osteoporosis.

■ THE ENDOCRINE PANCREAS

The endocrine pancreas in the adult human consists of approximately 1 million islets of Langerhans interspersed throughout the pancreatic gland. Within the islets, at least five hormoneproducing cells are present (Table 41–1). Their hormone products include insulin, the storage and anabolic hormone of the body; islet amyloid polypeptide (IAPP, or amylin), which modulates appetite, gastric emptying, and glucagon and insulin secretion; glucagon, the hyperglycemic factor that mobilizes glycogen stores; somatostatin, a universal inhibitor of secretory cells; pancreatic peptide, a small protein that facilitates digestive processes by a mechanism not yet clarified; and ghrelin, a peptide known to increase pituitary growth hormone release.

■ INSULIN

Chemistry

Insulin is a small protein with a molecular weight in humans of 5808. It contains 51 amino acids arranged in two chains (A and B) linked by disulfide bridges; there are species differences in the amino acids of both chains. Proinsulin, a long single-chain protein molecule, is processed within the Golgi apparatus of beta cells and packaged into granules, where it is hydrolyzed into insulin and a residual connecting segment called C-peptide by removal of four amino acids (Figure 41–1).

Insulin and C-peptide are secreted in equimolar amounts in response to all insulin secretagogues; a small quantity of

TABLE 41 1 Pancreatic islet cells and their secretory products.

1Within pancreatic polypeptide-rich lobules of adult islets, located only in the posterior portion of the head of the human pancreas, glucagon cells are scarce (<0.5%) and F cells make up as much as 80% of the cells.

unprocessed or partially hydrolyzed proinsulin is released as well. Although proinsulin may have some mild hypoglycemic action, C-peptide has no known physiologic function. Granules within the beta cells store the insulin in the form of crystals consisting of two atoms of zinc and six molecules of insulin. The entire human pancreas contains up to 8 mg of insulin, representing approximately 200 biologic units. Originally, the unit was defined on the basis of the hypoglycemic activity of insulin in rabbits. With improved purification techniques, the unit is presently defined on the basis of weight, and present insulin standards used for assay purposes contain 28 units per milligram.

somatostatin, and leptin; α-adrenergic sympathetic activity; chronically elevated glucose; and low concentrations of fatty acids. Inhibitory drugs include diazoxide, phenytoin, vinblastine, and colchicine.

One mechanism of stimulated insulin release is diagrammed in Figure 41–2. As shown in the figure, hyperglycemia results in increased intracellular ATP levels, which close ATP-dependent potassium channels. Decreased outward potassium efflux results in depolarization of the beta cell and opening of voltage-gated calcium channels. The resulting increased intracellular calcium triggers secretion of the hormone. The insulin secretagogue drug group (sulfonylureas, meglitinides, and -phenylalanine) exploits parts of this mechanism.

Insulin Degradation

The liver and kidney are the two main organs that remove insulin from the circulation. The liver normally clears the blood of approximately 60% of the insulin released from the pancreas by virtue of its location as the terminal site of portal vein blood flow, with the kidney removing 35–40% of the endogenous hormone. However, in insulin-treated diabetics receiving subcutaneous insulin injections, this ratio is reversed, with as much as 60% of exogenous insulin being cleared by the kidney and the liver removing no more than 30–40%. The half-life of circulating insulin is 3–5 minutes.

Insulin Secretion

Insulin is released from pancreatic beta cells at a low basal rate and at a much higher stimulated rate in response to a variety of stimuli, especially glucose. Other stimulants such as other sugars (eg, mannose), amino acids (especially gluconeogenic amino acids, eg, leucine, arginine), hormones such as glucagon-like polypeptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon, cholecystokinin, high concentrations of fatty acids, and β-adrenergic sympathetic activity are recognized. Stimulatory drugs include sulfonylureas, meglitinide and nateglinide, isoproterenol, and acetylcholine. Inhibitory signals are hormones including insulin itself, islet amyloid polypeptide,

Circulating Insulin

Basal serum insulin values of 5–15 µU/mL (30–90 pmol/L) are found in normal humans, with a peak rise to 60–90 µU/mL (360–540 pmol/L) during meals.

The Insulin Receptor

After insulin has entered the circulation, it diffuses into tissues, where it is bound by specialized receptors that are found on the membranes of most tissues. The biologic responses promoted by these insulin-receptor complexes have been identified in the primary target tissues regulating energy metabolism, ie, liver, muscle,

and adipose tissue. The receptors bind insulin with high specificity and affinity in the picomolar range. The full insulin receptor consists of two covalently linked heterodimers, each containing an α subunit, which is entirely extracellular and constitutes the recognition site, and a β subunit that spans the membrane (Figure 41–3). The β subunit contains a tyrosine kinase. The binding of an insulin molecule to the α subunits at the outside surface of the cell activates the receptor and through a conformational change brings the catalytic loops of the opposing cytoplasmic β subunits into closer proximity. This facilitates mutual phosphorylation of tyrosine residues on the β subunits and tyrosine kinase activity directed at cytoplasmic proteins.

The first proteins to be phosphorylated by the activated receptor tyrosine kinases are the docking proteins: insulin receptor substrates (IRS). After tyrosine phosphorylation at several critical sites, the IRS molecules bind to and activate other kinases subserving energy metabolism—most significantly phosphatidylinositol- 3-kinase—which produce further phosphorylations. Alternatively, they may stimulate a mitogenic pathway and bind to an adaptor protein such as growth factor receptor–binding protein 2, which translates the insulin signal to a guanine nucleotide-releasing factor that ultimately activates the GTP binding protein, Ras, and the mitogen-activated protein kinase (MAPK) system. The particular IRS-phosphorylated tyrosine kinases have binding specificity with downstream molecules based on their surrounding 4–5 amino acid sequences or motifs that recognize specific Src homology 2 (SH2) domains on the other protein. This network of phosphorylations within the cell represents insulin’s second

message and results in multiple effects, including translocation of glucose transporters (especially GLUT 4, Table 41–2) to the cell membrane with a resultant increase in glucose uptake; increased glycogen synthase activity and increased glycogen formation; multiple effects on protein synthesis, lipolysis, and lipogenesis; and activation of transcription factors that enhance DNA synthesis and cell growth and division.

Various hormonal agents (eg, glucocorticoids) lower the affinity of insulin receptors for insulin; growth hormone in excess increases this affinity slightly. Aberrant serine and threonine phosphorylation of the insulin receptor β subunits or IRS molecules may result in insulin resistance and functional receptor down-regulation.

Effects of Insulin on Its Targets

Insulin promotes the storage of fat as well as glucose (both sources of energy) within specialized target cells (Figure 41–4) and influences cell growth and the metabolic functions of a wide variety of tissues (Table 41–3).

■ GLUCAGON

Chemistry & Metabolism

Glucagon is synthesized in the alpha cells of the pancreatic islets of Langerhans (Table 41–1). Glucagon is a peptide— identical in all mammals—consisting of a single chain of

Intestine

FIGURE 41 4 Insulin promotes synthesis (from circulating nutrients) and storage of glycogen, triglycerides, and protein in its major target tissues: liver, fat, and muscle. The release of insulin from the pancreas is stimulated by increased blood glucose, incretins, vagal nerve stimulation, and other factors (see text).

Glucagon is extensively degraded in the liver and kidney as well as in plasma and at its tissue receptor sites. Its half-life in plasma is between 3 and 6 minutes, which is similar to that of insulin.

Pharmacologic Effects of Glucagon

A. Metabolic Effects

FIGURE 41 3 Schematic diagram of the insulin receptor heterodimer in the activated state. IRS, insulin receptor substrate; MAP, mitogen-activated protein; P, phosphate; Tyr, tyrosine.

29 amino acids, with a molecular weight of 3485. Selective proteolytic cleavage converts a large precursor molecule of approximately 18,000 MW to glucagon. One of the precursor intermediates consists of a 69-amino-acid peptide called glicentin, which contains the glucagon sequence interposed between peptide extensions.

The first six amino acids at the amino terminal of the glucagon molecule bind to specific Gs protein–coupled receptors on liver cells. This leads to an increase in cAMP, which facilitates catabolism of stored glycogen and increases gluconeogenesis and ketogenesis. The immediate pharmacological result of glucagon infusion is to raise blood glucose at the expense of stored hepatic glycogen. There is no effect on skeletal muscle glycogen, presumably because of the lack of glucagon receptors on skeletal muscle. Pharmacological amounts of glucagon cause release of insulin from normal pancreatic beta cells, catecholamines from pheochromocytoma, and calcitonin from medullary carcinoma cells.

TABLE 41 3 Endocrine effects of insulin.

Effect on liver:

Reversal of catabolic features of insulin deficiency Inhibits glycogenolysis

Inhibits conversion of fatty acids and amino acids to keto acids Inhibits conversion of amino acids to glucose

Anabolic action

Promotes glucose storage as glycogen (induces glucokinase and glycogen synthase, inhibits phosphorylase)

Increases triglyceride synthesis and very-low-density lipoprotein formation

Effect on muscle:

Increased protein synthesis Increases amino acid transport

Increases ribosomal protein synthesis Increased glycogen synthesis

Increases glucose transport

Induces glycogen synthase and inhibits phosphorylase

Effect on adipose tissue:

Increased triglyceride storage

Lipoprotein lipase is induced and activated by insulin to hydrolyze triglycerides from lipoproteins

Glucose transport into cell provides glycerol phosphate to permit esterification of fatty acids supplied by lipoprotein transport

Intracellular lipase is inhibited by insulin

B. Cardiac Effects

Glucagon has a potent inotropic and chronotropic effect on the heart, mediated by the cAMP mechanism described above. Thus, it produces an effect very similar to that of β-adrenoceptor agonists without requiring functioning β receptors.

C. Effects on Smooth Muscle

Large doses of glucagon produce profound relaxation of the intestine. In contrast to the above effects of the peptide, this action on the intestine may be due to mechanisms other than adenylyl cyclase activation.

Clinical Uses

A. Severe Hypoglycemia

The major clinical use of glucagon is for emergency treatment of severe hypoglycemic reactions in patients with type 1 diabetes when unconsciousness precludes oral feedings and intravenous glucose treatment is not possible. Recombinant glucagon is currently available in 1-mg vials for parenteral (IV, IM, or SC) use (Glucagon Emergency Kit).

B. Endocrine Diagnosis

Several tests use glucagon to diagnose endocrine disorders. In patients with type 1 diabetes mellitus, a classic research test of pancreatic beta-cell secretory reserve uses 1 mg of glucagon

administered as an intravenous bolus. Because insulin-treated patients develop circulating anti-insulin antibodies that interfere with radioimmunoassays of insulin, measurements of C-peptide are used to indicate beta-cell secretion.

C. Beta-Adrenoceptor Blocker Overdose

Glucagon is sometimes useful for reversing the cardiac effects of an overdose of β-blocking agents because of its ability to increase cAMP production in the heart independent of β-receptor function. However, it is not clinically useful in the treatment of heart failure.

D. Radiology of the Bowel

Glucagon has been used extensively in radiology as an aid to x-ray visualization of the bowel because of its ability to relax the intestine.

Adverse Reactions

Transient nausea and occasional vomiting can result from glucagon administration. These are generally mild, and glucagon is relatively free of severe adverse reactions. It should not be used in a patient with pheochromocytoma.

■ DIABETES MELLITUS

Diabetes mellitus is defined as an elevated blood glucose associated with absent or inadequate pancreatic insulin secretion, with or without concurrent impairment of insulin action. The disease states underlying the diagnosis of diabetes mellitus are now classified into four categories: type 1, type 2, other, and gestational diabetes mellitus.

Type 1 Diabetes Mellitus

The hallmark of type 1 diabetes is selective beta cell (B cell) destruction and severe or absolute insulin deficiency. Type 1 diabetes is further subdivided into immune-mediated (type 1a) and idiopathic causes (type 1b). The immune form is the most common form of type 1 diabetes. Although most patients are younger than 30 years of age at the time of diagnosis, the onset can occur at any age. Type 1 diabetes is found in all ethnic groups, but the highest incidence is in people from northern Europe and from Sardinia. Susceptibility appears to involve a multifactorial genetic linkage, but only 10–15% of patients have a positive family history. Most patients with type 1 diabetes have one or more circulating antibodies to glutamic acid decarboxylase 65 (GAD 65), insulin autoantibody, tyrosine phosphatase IA2 (ICA 512), and zinc transporter 8 (ZnT8) at the time of diagnosis. These antibodies facilitate the diagnosis of type 1a diabetes and can also be used to screen family members at risk for developing the disease. Most type 1 patients with acute symptomatic presentation have significant beta cell loss and insulin therapy is essential to control glucose levels and to prevent ketosis.

Some patients have a more indolent autoimmune process and initially retain enough beta cell function to avoid ketosis.

They can be treated at first with oral hypoglycemic agents but then need insulin as their beta cell function declines. Antibody studies in northern Europeans indicate that up to 10–15% of “type 2” patients may actually have this milder form of type 1 diabetes (latent autoimmune diabetes of adulthood; LADA).

Type 2 Diabetes Mellitus

Type 2 diabetes is a heterogenous group of conditions characterized by tissue resistance to the action of insulin combined with a relative deficiency in insulin secretion. A given individual may have more resistance or more beta-cell deficiency, and the abnormalities may be mild or severe. Although the circulating endogenous insulin is sufficient to prevent ketoacidosis, it is inadequate to prevent hyperglycemia. Patients with type 2 diabetes can initially be controlled with diet, exercise and oral glucose lowering agents or non-insulin injectables. Some patients have progressive beta cell failure and eventually may also need insulin therapy.

Other Specific Types of Diabetes Mellitus

The “other” designation refers to multiple other specific causes of an elevated blood glucose: pancreatectomy, pancreatitis, nonpancreatic diseases, drug therapy, etc. For a detailed list the reader is referred to the reference Expert Committee, 2003.

Gestational Diabetes Mellitus

Gestational diabetes (GDM) is defined as any abnormality in glucose levels noted for the first time during pregnancy. Gestational diabetes is diagnosed in approximately 7% of all pregnancies in the United States. During pregnancy, the placenta and placental hormones create an insulin resistance that is most pronounced in the last trimester. Risk assessment for diabetes is suggested starting at the first prenatal visit. High-risk women should be screened immediately. Screening may be deferred in lower-risk women until the 24th to 28th week of gestation.

TABLE 41 4 Diagnostic criteria for diabetes.

Laboratory Findings

A. Plasma or Serum Glucose

A plasma glucose level of 126 mg/dL (7 mmol/L) or higher on more than one occasion after at least 8 hours of fasting is diagnostic of diabetes mellitus (Table 41–4). Fasting plasma glucose levels of 100–125 mg/dL (5.6–6.9 mmol/L) are associated with increased risk of diabetes (impaired fasting glucose tolerance).

If the fasting plasma glucose level is less than 126 mg/dL (7 mMol/L) but diabetes is nonetheless suspected, then a standardized oral glucose tolerance test may be done (Table 41–4). The patient should eat nothing after midnight prior to the test day. On the morning of the test, adults are then given 75 g of glucose in 300 mL of water; children are given 1.75 g of glucose per kilogram of ideal body weight. The glucose load is consumed within 5 minutes. Blood samples for plasma glucose are obtained at 0 and 120 minutes after ingestion of glucose. An oral glucose tolerance test is normal if the fasting venous plasma glucose value is less than 100 mg/dL (5.6 mmol/L) and the 2-hour value falls below 140 mg/dL (7.8 mmol/L). A fasting value of 126 mg/dL (7 mmol/L) or higher or a 2-hour value of greater than 200 mg/dL (11.1 mmol/L) is diagnostic of diabetes mellitus. Patients with 2-hour value of 140–199 mg/dL (7.8–11.1 mmol/L) have impaired glucose tolerance.

B. Hemoglobin A1c Measurements

When plasma glucose levels are in the normal range, about 4–6% of hemoglobin A has one or both of the N terminal valines of their beta chains irreversibly glycated by glucose—referred to as hemoglobin A1c (HbA1c). The HbA1c fraction is abnormally elevated in people with diabetes with chronic hyperglycemia. Since red cells have a lifespan of up to 120 days, the HbA1c value reflects plasma glucose levels over the preceding 8–12 weeks. In patients who monitor their glucose levels, the HbA1c value provides a valuable check on the accuracy of their monitoring. In patients who do not monitor their glucose levels, HbA1c measurements are essential for adjusting treatment. HbA1c can be used to