Pharmacology_Katzung

Pharmacology_Katzung. Ketoconazole has been used in the treatment of patients with Cushing’s syndrome due to several causes. Dosages of 200–1200 mg/d have caused a reduction in hormone levels and clinical improvement in some patients. This drug has some hepatotoxicity and should be started at 200 mg/d and slowly increased by 200 mg/d every 2–3 days up to a total daily dose of 1000 mg. Etomidate [R-1-(1-ethylphenyl)imidazole-5-ethyl ester] is used for induction of general anesthesia and sedation. At subhypnotic doses of 0.1 mg/kg per hour this drug inhibits adrenal steroidogenesis at the level of 11β-hydroxylase and has been used as the only parenteral medication available in the treatment of severe Cushing’s syndrome. FIGURE 39–5 Some adrenocortical blockers. Because of their toxicity, some of these compounds are no longer available in the United States.


Pharmacology_Katzung

Pharmacology_Katzung. Metyrapone (Figure 39–5) is a relatively selective inhibitor of steroid 11-hydroxylation, interfering with cortisol and corticosterone synthesis. In the presence of a normal pituitary gland, there is a compensatory increase in pituitary ACTH release and adrenal 11-deoxycortisol secretion. This response is a measure of the capacity of the anterior pituitary to produce ACTH and has been adapted for clinical use as a diagnostic test. Although the toxicity of metyrapone is much lower than that of mitotane (see text that follows), the drug may produce transient dizziness and gastrointestinal disturbances. This agent has not been widely used in the treatment of Cushing’s syndrome. However, in doses of 0.25 g twice daily to 1 g four times daily, metyrapone can reduce cortisol production to normal levels in some patients with endogenous Cushing’s syndrome. Thus, it may be useful in the management of severe manifestations of cortisol excess while the cause of this condition is being determined


Pharmacology_Katzung

Pharmacology_Katzung. levels in some patients with endogenous Cushing’s syndrome. Thus, it may be useful in the management of severe manifestations of cortisol excess while the cause of this condition is being determined or in conjunction with radiation or surgical treatment. Metyrapone is the only adrenal-inhibiting medication that can be administered to pregnant women with Cushing’s syndrome. The major adverse effects observed are salt and water retention and hirsutism resulting from diversion of the 11-deoxycortisol precursor to DOC and androgen synthesis.


Pharmacology_Katzung

Pharmacology_Katzung. Metyrapone is commonly used in tests of adrenal function. The blood levels of 11-deoxycortisol and the urinary excretion of 17-hydroxycorticoids are measured before and after administration of the compound. Normally, there is a twofold or greater increase in the urinary 17-hydroxycorticoid excretion. A dosage of 300–500 mg every 4 hours for six doses is often used, and urine collections are made on the day before and the day after treatment. In patients with Cushing’s syndrome, a normal response to metyrapone indicates that the cortisol excess is not the result of a cortisol-secreting adrenal carcinoma or adenoma, since secretion by such tumors produces suppression of ACTH and atrophy of normal adrenal cortex.


Pharmacology_Katzung

Pharmacology_Katzung. Pituitary function may also be tested by administering metyrapone, 2–3 g orally at midnight and by measuring the level of ACTH or 11-deoxycortisol in blood drawn at 8 am or by comparing the excretion of 17-hydroxycorticosteroids in the urine during the 24-hour periods preceding and following administration of the drug. In patients with suspected or known lesions of the pituitary, this procedure is a means of estimating the ability of the gland to produce ACTH. Metyrapone has been withdrawn from the market in the United States but is available on a compassionate basis.


Pharmacology_Katzung

Pharmacology_Katzung. Trilostane is a 3β-17 hydroxysteroid dehydrogenase inhibitor that interferes with the synthesis of adrenal and gonadal hormones and is comparable to aminoglutethimide. Trilostane’s adverse effects are predominantly gastrointestinal; adverse effects occur in about 50% of patients with both trilostane and aminoglutethimide. There is no cross-resistance or crossover of side effects between these compounds. Trilostane is not available in the United States. Abiraterone is the newest of the steroid synthesis inhibitors to be approved. It blocks 17α-hydroxylase (P450c17) and 17,20-lyase (Figure 39–1), and predictably reduces synthesis of cortisol in the adrenal and gonadal steroids in the gonads. A compensatory increase occurs in ACTH and aldosterone synthesis, but this can be prevented by concomitant administration of dexamethasone. Abiraterone is an orally active steroid prodrug and is approved for the treatment of refractory prostate cancer.


Pharmacology_Katzung

Pharmacology_Katzung. The search for a glucocorticoid receptor antagonist finally succeeded in the early 1980s with the development of the 11β-aminophenyl-substituted 19-norsteroid called RU-486, later named mifepristone. Unlike the enzyme inhibitors previously discussed, mifepristone is a pharmacologic antagonist at the steroid receptor. This compound has strong antiprogestin activity and initially was proposed as a contraceptive-contragestive agent. High doses of mifepristone exert antiglucocorticoid activity by blocking the glucocorticoid receptor, since mifepristone binds to it with high affinity, causing (1) some stabilization of the hspglucocorticoid receptor complex and inhibition of the dissociation of the RU-486–bound glucocorticoid receptor from the hsp chaperone proteins; and (2) alteration of the interaction of the glucocorticoid receptor with coregulators, favoring the formation of a transcriptionally inactive complex in the cell nucleus. The result is inhibition of glucocorticoid receptor


Pharmacology_Katzung

Pharmacology_Katzung. interaction of the glucocorticoid receptor with coregulators, favoring the formation of a transcriptionally inactive complex in the cell nucleus. The result is inhibition of glucocorticoid receptor activation.


Pharmacology_Katzung

Pharmacology_Katzung. The mean half-life of mifepristone is 20 hours. This is longer than that of many natural and synthetic glucocorticoid agonists (dexamethasone has a half-life of 4–5 hours). Less than 1% of the daily dose is excreted in the urine, suggesting a minor role of kidneys in the clearance of the compound. The long plasma half-life of mifepristone results from extensive and strong binding to plasma proteins. Less than 5% of the compound is found in the free form when plasma is analyzed by equilibrium dialysis. Mifepristone can bind to albumin and α1-acid glycoprotein, but it has no affinity for corticosteroid-binding globulin.


Pharmacology_Katzung

Pharmacology_Katzung. In humans, mifepristone causes generalized glucocorticoid resistance. Given orally to several patients with Cushing’s syndrome due to ectopic ACTH production or adrenal carcinoma, it was able to reverse the cushingoid phenotype, eliminate carbohydrate intolerance, normalize blood pressure, correct thyroid and gonadal hormone suppression, and to ameliorate the psychological sequelae of hypercortisolism in these patients. At present, this use of mifepristone can only be recommended for inoperable patients with ectopic ACTH secretion or adrenal carcinoma who have failed to respond to other therapeutic manipulations. Its pharmacology and use in women as a progesterone antagonist are discussed in Chapter 40.


Pharmacology_Katzung

Pharmacology_Katzung. Mitotane (Figure 39–5), a drug related to the DDT class of insecticides, has a nonselective cytotoxic action on the adrenal cortex in dogs and to a lesser extent in humans. This drug is administered orally in divided doses up to 12 g daily. About one-third of patients with adrenal carcinoma show a reduction in tumor mass. In 80% of patients, the toxic effects are sufficiently severe to require dose reduction. These include diarrhea, nausea, vomiting, depression, somnolence, and skin rashes. The drug has been withdrawn from the market in the United States but is available on a compassionate basis. In addition to agents that interfere with aldosterone synthesis (see above), there are steroids that compete with aldosterone for its receptor and decrease its effect peripherally. Progesterone is mildly active in this respect.


Pharmacology_Katzung

Pharmacology_Katzung. Spironolactone is a 7α-acetylthiospirolactone. Its onset of action is slow, and the effects last for 2–3 days after the drug is discontinued. It is used in the treatment of primary aldosteronism in dosages of 50–100 mg/d. This agent reverses many of the manifestations of aldosteronism. It has been useful in establishing the diagnosis in some patients and in ameliorating the signs and symptoms when surgical removal of an adenoma is delayed. When used diagnostically for the detection of aldosteronism in hypokalemic patients with hypertension, dosages of 400–500 mg/d for 4–8 days—with an adequate intake of sodium and potassium—restore potassium levels to or toward normal. Spironolactone is also useful in preparing these patients for surgery. Dosages of 300–400 mg/d for 2 weeks are used for this purpose and may reduce the incidence of cardiac arrhythmias.


Pharmacology_Katzung

Pharmacology_Katzung. Spironolactone is also an androgen antagonist and as such is sometimes used in the treatment of hirsutism and acne in women. Dosages of 50–200 mg/d cause a reduction in the density, diameter, and rate of growth of facial hair in patients with idiopathic hirsutism or hirsutism secondary to androgen excess. The effect can usually be seen in 2 months and becomes maximal in about 6 months. Spironolactone as a diuretic is discussed in Chapter 15. The drug has benefits in heart failure greater than those predicted from its diuretic effects alone (see Chapter 13). Adverse effects reported for spironolactone include hyperkalemia, cardiac arrhythmia, menstrual abnormalities, gynecomastia, sedation, headache, gastrointestinal disturbances, and skin rashes.


Pharmacology_Katzung

Pharmacology_Katzung. Eplerenone, another aldosterone antagonist, is approved for the treatment of hypertension and heart failure (see Chapters 11, 13, and 15). Like spironolactone, eplerenone has also been found to reduce mortality in heart failure. This aldosterone receptor antagonist is somewhat more selective than spironolactone and has no reported effects on androgen receptors. The standard dosage in hypertension is 50–100 mg/d. The most common toxicity is hyperkalemia, but this is usually mild. Drospirenone, a progestin, is an oral contraceptive (see Chapter 40), and also antagonizes the effects of aldosterone. Betamethasone sodium phosphate Generic, Celestone Phosphate Budesonide Generic, Entocort EC Dexamethasone Generic, Decadron Hydrocortisone (cortisol) Generic, Cortef Hydrocortisone sodium succinate Generic, Solu-Cortef, others Methylprednisolone Generic, Medrol Methylprednisolone acetate Generic, Depo-Medrol Methylprednisolone sodium Generic, Solu-Medrol, others succinate


Pharmacology_Katzung

Pharmacology_Katzung. Methylprednisolone Generic, Medrol Methylprednisolone acetate Generic, Depo-Medrol Methylprednisolone sodium Generic, Solu-Medrol, others succinate Prednisolone Generic, Prelone, others Prednisolone acetate Generic, Flo-Pred Prednisolone sodium phosphate Generic, Hydeltrasol Prednisone Generic, Deltasone, Prednicot Triamcinolone acetonide Generic, Kenalog, Azmacort Ketoconazole Generic, Nizoral Mifepristone Mifeprex, Korlym Glucocorticoids for respiratory use: See Chapter 20. Glucocorticoids for dermatologic use: See Chapter 61. Glucocorticoids for gastrointestinal use: See Chapter 62. Alesci S et al: Glucocorticoid-induced osteoporosis: From basic mechanisms to clinical aspects. Neuroimmunomodulation 2005;12:1. Bamberger CM, Schulte HM, Chrousos GP: Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids. Endocr Rev 1996;17:245.


Pharmacology_Katzung

Pharmacology_Katzung. Bamberger CM, Schulte HM, Chrousos GP: Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids. Endocr Rev 1996;17:245. Charmandari E et al: Peripheral CLOCK regulates target-tissue glucocorticoid receptor transcriptional activity in a circadian fashion in man. PLoS One 2011;6:e25612. Charmandari E, Kino T: Chrousos syndrome: A seminal report, a phylogenetic enigma and the clinical implications of glucocorticoid signaling changes. Eur J Clin Invest 2010;40:932. Charmandari E, Nicolaides NC, Chrousos GP: Adrenal insufficiency. Lancet. 2014;383:2152. Charmandari E, Tsigos C, Chrousos GP: Neuroendocrinology of stress. Ann Rev Physiol 2005;67:259. Chrousos GP: Stress and disorders of the stress system. Nat Rev Endocrinol 2009;5:374.


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Pharmacology_Katzung. Charmandari E, Tsigos C, Chrousos GP: Neuroendocrinology of stress. Ann Rev Physiol 2005;67:259. Chrousos GP: Stress and disorders of the stress system. Nat Rev Endocrinol 2009;5:374. Chrousos GP, Kino T: Glucocorticoid signaling in the cell: Expanding clinical implications to complex human behavioral and somatic disorders. In: Glucocorticoids and mood: Clinical manifestations, risk factors, and molecular mechanisms. Proc NY Acad Sci 2009;1179:153. Cutolo M, Chrousos GP, Pincus T: Special issue on glucocorticoid therapy in rheumatic diseases. Neuroimmunomodulation. 2015;22:3. Elenkov IJ, Chrousos GP: Stress hormones, TH1/TH2 patterns, pro/anti-inflammatory cytokines and susceptibility to disease. Trends Endocrinol Metab 1999;10:359. Elenkov IJ et al: Cytokine dysregulation, inflammation, and wellbeing. Neuroimmunomodulation 2005;12:255. Franchimont D et al: Glucocorticoids and inflammation revisited: The state of the art. Neuroimmunomodulation 2002–2003;10:247.


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Pharmacology_Katzung. Franchimont D et al: Glucocorticoids and inflammation revisited: The state of the art. Neuroimmunomodulation 2002–2003;10:247. Graber AL et al: Natural history of pituitary-adrenal recovery following long-term suppression with corticosteroids. J Clin Endocrinol Metab 1965;25:11. Hochberg Z, Pacak K, Chrousos GP: Endocrine withdrawal syndromes. Endocr Rev 2003;24:523. Kalantaridou S, Chrousos GP: Clinical review 148: Monogenic disorders of puberty. J Clin Endocrinol Metab 2002;87:2481. Kino T, Charmandari E, Chrousos G (editors): Glucocorticoid action: Basic and clinical implications. Ann NY Acad Sci 2004;1024. Kino T et al: The GTP-binding (G) protein β interacts with the activated glucocorticoid receptor and suppresses its transcriptional activity in the nucleus. J Cell Biol 2005;20:885. Koch CA, Chrousos GP (editors): Endocrine hypertension: Underlying mechanisms and therapy. In: Contemporary Endocrinology, vol XIII. Springer, 2013.


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Pharmacology_Katzung. Koch CA, Chrousos GP (editors): Endocrine hypertension: Underlying mechanisms and therapy. In: Contemporary Endocrinology, vol XIII. Springer, 2013. Koch CA, Pacak K, Chrousos GP: The molecular pathogenesis of hereditary and sporadic adrenocortical and adrenomedullary tumors. J Clin Endocrinol Metab 2002;87:5367. Mao J, Regelson W, Kalimi M: Molecular mechanism of RU 486 action: A review. Mol Cellular Biochem 1992;109:1. Marik PE et al: Clinical practice guidelines for the diagnosis and management of corticosteroid insufficiency in critical illness: Recommendations of an international task force. Crit Care Med 2008;36:1937. Markou A et al: Stress-induced aldosterone hyper-secretion in a substantial subset of patients with essential hypertension. J Clin Endocrinol Metab. 2015;100:2857.


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Pharmacology_Katzung. Markou A et al: Stress-induced aldosterone hyper-secretion in a substantial subset of patients with essential hypertension. J Clin Endocrinol Metab. 2015;100:2857. Meduri GU et al: Activation and regulation of systemic inflammation in ARDS: Rationale for prolonged glucocorticoid therapy. Chest 2009;136:1631. Meduri GU et al: Steroid treatment in ARDS: A critical appraisal of the ARDS network trial and the recent literature. Intens Care Med 2008;34:61. 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. Nader N, Chrousos GP, Kino T: Interactions of the circadian CLOCK system and the HPA axis. Trends Endocrinol Metab 2010;21:277. Papanastasiou L et al: Primary aldosteronism in hypertensive patients: Clinical implications and target therapy. Eur J Clin Invest. 2014;44:697.


Pharmacology_Katzung

Pharmacology_Katzung. Papanastasiou L et al: Primary aldosteronism in hypertensive patients: Clinical implications and target therapy. Eur J Clin Invest. 2014;44:697. Pervanidou P, Kanaka-Gantenbein C, Chrousos GP: Assessment of metabolic profile in a clinical setting. Curr Opin Clin Nutr Metab Care 2006;9:589. Preda VA et al: Etomidate in the management of hypercortisolaemia in Cushing’s syndrome: A review. Eur J Endocrinol 2012;167:137. Tsigos C, Chrousos GP: Differential diagnosis and management of Cushing’s syndrome. Annu Rev Med 1996;47:443. Whitaker MJ et al: An oral multiparticulate, modified-release, hydrocortisone replacement therapy that provides physiological cortisol exposure. Clin Endocrinol (Oxf) 2014;80:554. Zannas AS, Chrousos GP. Glucocorticoid signaling drives epigenetic and transcription factors to induce key regulators of human parturition. Sci Signal 2015;8:fs19.


Pharmacology_Katzung

Pharmacology_Katzung. Zannas AS, Chrousos GP. Glucocorticoid signaling drives epigenetic and transcription factors to induce key regulators of human parturition. Sci Signal 2015;8:fs19. The patient should be placed on replacement oral hydrocor-tisone at 10 mg/m2 per day and fludrocortisone at 75 mcg/d. He should be given a MedicAlert bracelet and instructions for increased treatment at 2 times standard glucocorticoid dosage for 24 hours for minor stress and 10 times replace-ment of hydrocortisone for major stress over 48 hours. The Gonadal Hormones & Inhibitors George P. Chrousos, MD


Pharmacology_Katzung

Pharmacology_Katzung. The Gonadal Hormones & Inhibitors George P. Chrousos, MD A 25-year-old woman with menarche at 13 years and menstrual periods until about 1 year ago complains of hot flushes, skin and vaginal dryness, weakness, poor sleep, and scanty and infrequent menstrual periods of a year’s dura-tion. She visits her gynecologist, who obtains plasma levels of follicle-stimulating hormone and luteinizing hormone, both of which are moderately elevated. She is diagnosed with premature ovarian failure, and estrogen and pro-gesterone replacement therapy is recommended. A dual-energy absorptiometry scan (DEXA) reveals a bone density t-score of <2.5 SD, ie, frank osteoporosis. How should the ovarian hormones she lacks be replaced? What extra mea-sures should she take for her osteoporosis while receiving treatment? ■ THE OVARY (ESTROGENS, PROGESTINS, OTHER OVARIAN HORMONES, ORAL CONTRACEPTIVES, INHIBITORS & ANTAGONISTS, & OVULATIONINDUCING AGENTS)


Pharmacology_Katzung

Pharmacology_Katzung. ■ THE OVARY (ESTROGENS, PROGESTINS, OTHER OVARIAN HORMONES, ORAL CONTRACEPTIVES, INHIBITORS & ANTAGONISTS, & OVULATIONINDUCING AGENTS) The ovary has important gametogenic functions that are integrated with its hormonal activity. In the human female, the gonad is relatively quiescent during childhood, the period of rapid growth and maturation. At puberty, the ovary begins a 30to 40-year period of cyclic function called the menstrual cycle because of the regular episodes of bleeding that are its most obvious manifestation. It then fails to respond to gonadotropins secreted by the anterior pituitary gland, and the cessation of cyclic bleeding that occurs is called menopause.


Pharmacology_Katzung

Pharmacology_Katzung. The mechanism responsible for the onset of ovarian function at the time of puberty is thought to be neural in origin, because the immature gonad can be stimulated by gonadotropins already present in the pituitary and because the pituitary is responsive to exogenous hypothalamic gonadotropin-releasing hormone (GnRH). Despite extensive research in the field, the mechanism of puberty initiation still remains an enigma. Pulsatile pituitary gonadotropin secretion under the guidance of GnRH definitely constitutes a sine qua non for pubertal onset. However, the secretion of GnRH in the human hypothalamus is regulated by kisspeptin and its receptor, as well as by permissive or opposing signals mediated by neurokinin B and dynorphin acting on their respective receptors. These three supra-GnRH regulators compose the Kisspeptin, Neurokinin B, and Dynorphin neuron (KNDy) system, a key player in pubertal onset and progression. Recently, makorin ring finger protein 3 (MKRN3) was also implicated in


Pharmacology_Katzung

Pharmacology_Katzung. compose the Kisspeptin, Neurokinin B, and Dynorphin neuron (KNDy) system, a key player in pubertal onset and progression. Recently, makorin ring finger protein 3 (MKRN3) was also implicated in pubertal onset by contributing to the regulation of the KNDy system. However, the inhibitory (gamma-amino butyric acid, neuropeptide Y, and RFamide-related peptide-3) and stimulatory (glutamate) signals acting upstream of KNDy call into question the primary role of MKRN3 as the gatekeeper of puberty. Recently, epigenetic mechanisms involving derepression of genes, such as that of kisspeptin, have been implicated in pubertal onset. Ultimately, withdrawal of a childhood-related inhibitory effect upon hypothalamic arcuate nucleus neurons allows these neurons to produce GnRH in pulses with the appropriate amplitude, which stimulate the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (see Chapter 37). At first, small amounts of the latter two hormones are released during


Pharmacology_Katzung

Pharmacology_Katzung. amplitude, which stimulate the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (see Chapter 37). At first, small amounts of the latter two hormones are released during the a corpus albicans. The endometrium, which proliferated during the follicular phase and developed its glandular function during the luteal phase, is shed in the process of menstruation. These events are summarized in Figure 40–1.


Pharmacology_Katzung

Pharmacology_Katzung. The ovary normally ceases its gametogenic and endocrine function with time. This change is accompanied by a cessation in uterine bleeding (menopause) and occurs at a mean age of 52 years in the United States. Although the ovary ceases to secrete estrogen, significant levels of estrogen persist in many women as a result of conversion of adrenal and ovarian steroids such as androstenedione to estrone and estradiol in adipose and possibly other nonendocrine tissues. A. Disturbances in Ovarian Function


Pharmacology_Katzung

Pharmacology_Katzung. A. Disturbances in Ovarian Function Disturbances of cyclic function are common even during the peak years of reproduction. A minority of these result from inflammatory or neoplastic processes that influence the functions of the uterus, ovaries, or pituitary. Many of the minor disturbances leading to periods of amenorrhea or anovulatory cycles are night, and the limited quantities of ovarian estrogen secreted in response start to cause breast development. Subsequently, FSH and LH are secreted throughout the day and night, causing secretion of higher amounts of estrogen and leading to further breast enlargement, alterations in fat distribution, and a growth spurt that culminates in epiphyseal closure in the long bones. The change of ovarian function at puberty is called gonadarche.


Pharmacology_Katzung

Pharmacology_Katzung. A year or so after gonadarche, sufficient estrogen is produced to induce endometrial changes and periodic bleeding (menarche). After the first few irregular cycles, which may be anovulatory, normal cyclic function is established. At the beginning of each cycle, a variable number of follicles Days (vesicular follicles), each containing an ovum, begin to enlarge in response to FSH. After 5 or 6 days, one follicle, called the dominant follicle, begins to develop more rapidly. The outer theca and inner granulosa cells of this follicle multiply and, under the influence of LH, synthesize and release estrogens at an increasing rate. The estrogens appear to inhibit FSH release and may lead to regression of the smaller, less mature follicles.


Pharmacology_Katzung

Pharmacology_Katzung. The mature dominant ovarian follicle consists of an ovum surrounded by a fluid-filled antrum lined by granulosa and theca cells. The estrogen secretion reaches a peak just before midcycle, and the granulosa cells begin to secrete progesterone. These changes stimulate the brief surge in LH and FSH release that precedes and causes ovulation. When the follicle ruptures, the ovum is released into the abdominal cavity near the opening of the uterine tube. Following the above events, the cavity of the ruptured fol licle fills with blood (corpus hemorrhagicum), and the luteinized theca and granulosa cells proliferate and replace the blood to form the corpus luteum. The cells of this structure produce estrogens and progesterone for the remainder of the cycle, or longer if pregnancy occurs.


Pharmacology_Katzung

Pharmacology_Katzung. If pregnancy does not occur, the corpus luteum begins to degenerate and ceases hormone production, eventually becoming self-limited. They are often associated with emotional or physical stress and reflect temporary alterations in the stress centers in the brain that control the secretion of GnRH. Anovulatory cycles are also associated with eating disorders (bulimia, anorexia nervosa) and with severe exercise such as distance running and swimming. Among the more common organic causes of persistent ovulatory disturbances are pituitary prolactinomas and syndromes and tumors characterized by excessive ovarian or adrenal androgen production. Normal ovarian function can be modified by androgens produced by the adrenal cortex or tumors arising from it. The ovary also gives rise to androgen-producing neoplasms such as arrhenoblastomas, as well as to estrogen-producing granulosa cell tumors.


Pharmacology_Katzung

Pharmacology_Katzung. 80 60 40 20 0 400 200 0 20 0 mIU/mLpg/mLng/mL Gonadotropins Estradiol Progesterone LH FSH 1 7 14 21 28 FIGURE 40–1 The menstrual cycle, showing plasma levels of pituitary and ovarian hormones and histologic changes.


Pharmacology_Katzung

Pharmacology_Katzung. Estrogenic activity is shared by a large number of chemical substances. In addition to the variety of steroidal estrogens derived from animal sources, numerous nonsteroidal estrogens have been synthesized. Many phenols are estrogenic, and estrogenic activity has been identified in diverse forms of life including those found in ocean sediments. Estrogen-mimetic compounds (flavonoids) are found in many plants, including saw palmetto, and soybeans and other foods. A diet rich in these plant products may cause slight estrogenic effects. Additionally, some compounds used in the manufacture of plastics (bisphenols, alkylphenols, phthalate phenols) have been found to be estrogenic. It has been proposed that these agents are associated with an increased breast cancer incidence in both women and men in the industrialized world.


Pharmacology_Katzung

Pharmacology_Katzung. The major estrogens produced by women are estradiol (estradiol17β, E2), estrone (E1), and estriol (E3) (Figure 40–2). Estradiol is the major secretory product of the ovary. Although some estrone is produced in the ovary, most estrone and estriol are formed in the liver from estradiol or in peripheral tissues from androstenedione and other androgens (see Figure 39–1). As noted above, during the first part of the menstrual cycle estrogens are produced in the ovarian follicle by the theca and granulosa cells. After ovulation, the estrogens as well as progesterone are synthesized by the luteinized granulosa and theca cells of the corpus luteum, and the pathways of biosynthesis are slightly different.


Pharmacology_Katzung

Pharmacology_Katzung. During pregnancy, a large amount of estrogen is synthesized by the fetoplacental unit—consisting of the fetal adrenal zone, secreting androgen precursor, and the placenta, which aromatizes it into estrogen. The estriol synthesized by the fetoplacental unit is released into the maternal circulation and excreted into the urine. Repeated assay of maternal urinary estriol excretion has been used in the assessment of fetal well-being. One of the most prolific natural sources of estrogenic substances is the stallion, which liberates more of these hormones than the pregnant mare or pregnant woman. The equine estrogens— equilenin and equilin—and their congeners are unsaturated in the B as well as the A ring and are excreted in large quantities in urine, from which they can be recovered and used for medicinal purposes.


Pharmacology_Katzung

Pharmacology_Katzung. In normal women, estradiol is produced at a rate that varies during the menstrual cycle, resulting in plasma levels as low as 50 pg/mL in the early follicular phase to as high as 350–850 pg/mL at the time of the preovulatory peak (Figure 40–1). A variety of chemical alterations have been applied to the natural estrogens. The most important effect of these alterations has been to increase their oral effectiveness. Some structures are shown in Figure 40–3. Those with therapeutic use are listed in Table 40–1. In addition to the steroidal estrogens, a variety of nonsteroidal compounds with estrogenic activity have been synthesized and used clinically. These include dienestrol, diethylstilbestrol, benzestrol, hexestrol, methestrol, methallenestril, and chlorotrianisene.


Pharmacology_Katzung

Pharmacology_Katzung. When released into the circulation, estradiol binds strongly to an α2 globulin (sex hormone–binding globulin [SHBG]) and with lower affinity to albumin. Bound estrogen is relatively unavailable for diffusion into cells, and it is the free fraction that is physiologically active. Estradiol is converted by the liver and other tissues to estrone and estriol (Figure 40–2) and their 2-hydroxylated derivatives and conjugated metabolites (which are too insoluble in lipid to cross the cell membrane readily) and excreted in the bile. Estrone and estriol have low affinity for the estrogen receptor. Steroidal, natural Steroidal, synthetic CCH3CH3COOHOH3CCHC2H5OH3CCCClOCH3OCH3HOCCCH2CH2CH3CH3HONonsteroidal,synthetic FIGURE 40–3 Compounds with estrogenic activity. TABLE 40–1 Commonly used estrogens. Conjugated, esterified, or mixed estrogenic substances: Oral 0.3–1.25 mg/d Injectable 0.2–2 mg/d Transdermal Patch Quinestrol 0.1–0.2 mg/week


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 40–1 Commonly used estrogens. Conjugated, esterified, or mixed estrogenic substances: Oral 0.3–1.25 mg/d Injectable 0.2–2 mg/d Transdermal Patch Quinestrol 0.1–0.2 mg/week However, the conjugates may be hydrolyzed in the intestine to active, reabsorbable compounds. Estrogens are also excreted in small amounts in the breast milk of nursing mothers. Because significant amounts of estrogens and their active metabolites are excreted in the bile and reabsorbed from the intestine, the resulting enterohepatic circulation ensures that orally administered estrogens will have a high ratio of hepatic to peripheral effects. As noted below, the hepatic effects are thought to be responsible for some undesirable actions such as synthesis of increased clotting factors and plasma renin substrate. The hepatic effects of estrogen can be minimized by routes that avoid first-pass liver exposure, ie, vaginal, transdermal, or by injection. A. Mechanism


Pharmacology_Katzung

Pharmacology_Katzung. A. Mechanism Estrogens in the blood and interstitial fluid are bound to SHBG, from which they dissociate to cross the cell membrane, enter the nucleus, and bind to their receptor. Two genes code for two estrogen receptor isoforms, α and β, which are members of the superfamily of steroid, sterol, retinoic acid, and thyroid receptors. Unlike glucocorticoid receptors, estrogen receptors are found predominantly in the nucleus, where they are bound to heat shock proteins that stabilize them (see Figure 39–4).


Pharmacology_Katzung

Pharmacology_Katzung. Binding of the hormone to its receptor alters the receptor’s conformation and releases it from the stabilizing proteins (predominantly Hsp90). The receptor-hormone complex forms dimers (usually ERα-ERα, ERβ-ERβ, or ERα-ERβ) that bind to a specific sequence of nucleotides, called estrogen response elements (EREs), in the regulatory regions of various genes and regulate their transcription. The ERE is composed of two half-sites arranged as a palindrome separated by a small group of nucleotides called the spacer. The interaction of a receptor dimer with the ERE also involves a number of nuclear proteins, the coregulators, as well as components of the transcription machinery. Complex interactions with various coregulators appear to be responsible for some of the tissue-specific effects that govern the actions of selective estrogen receptor modulators (SERMs, see below). The receptor may also bind to other transcription factors to influence the effects of these factors on their responsive


Pharmacology_Katzung

Pharmacology_Katzung. the actions of selective estrogen receptor modulators (SERMs, see below). The receptor may also bind to other transcription factors to influence the effects of these factors on their responsive genes. Interestingly, although ERβ has its own separate actions from ERα, it also acts as a dominant negative inhibitor of ERα. Thus, while ERα has many growth-promoting properties, ERβ has anti-growth effects. Many phytoestrogens act via the ERβ protecting cells from the pro-growth effects of ERα.


Pharmacology_Katzung

Pharmacology_Katzung. The relative concentrations and types of receptors, receptor coregulators, and transcription factors confer the cell specificity of the hormone’s actions. The genomic effects of estrogens are mainly due to proteins synthesized by translation of RNA transcribed from a responsive gene. Some of the effects of estrogens are indirect, mediated by the autocrine and paracrine actions of autacoids such as growth factors, lipids, glycolipids, and cytokines produced by the target cells in response to estrogen. Rapid estrogen-induced effects such as granulosa cell Ca2+ uptake and increased uterine blood flow do not require gene activation. These appear to be mediated by nongenomic effects of the classic estrogen receptor-estrogen complex, influencing several intracellular signaling pathways.


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Pharmacology_Katzung. Recently, all steroid receptors except the mineralocorticoid receptors were shown to have palmitoylation motifs that allow enzymatic addition of palmitate and increased localization of the receptors in the vicinity of plasma membranes. Such receptors are available for direct interactions with, and effects on, various membrane-associated or cytoplasmic proteins without the need for entry into the nucleus and induction of transcriptional actions. B. Female Maturation


Pharmacology_Katzung

Pharmacology_Katzung. B. Female Maturation Estrogens are required for the normal sexual maturation and growth of the female. They stimulate the development of the vagina, uterus, and uterine tubes as well as the secondary sex characteristics. They stimulate stromal development and ductal growth in the breast and are responsible for the accelerated growth phase and the closing of the epiphyses of the long bones that occur at puberty. They contribute to the growth of axillary and pubic hair and alter the distribution of body fat to produce typical female body contours. Larger quantities also stimulate development of pigmentation in the skin, most prominent in the region of the nipples and areolae and in the genital region. C. Endometrial Effects


Pharmacology_Katzung

Pharmacology_Katzung. C. Endometrial Effects In addition to its growth effects on uterine muscle, estrogen plays an important role in the development of the endometrial lining. When estrogen production is properly coordinated with the production of progesterone during the normal human menstrual cycle, regular periodic bleeding and shedding of the endometrial lining occur. Continuous exposure to estrogens for prolonged periods leads to hyperplasia of the endometrium that is usually associated with abnormal bleeding patterns. D. Metabolic and Cardiovascular Effects


Pharmacology_Katzung

Pharmacology_Katzung. D. Metabolic and Cardiovascular Effects Estrogens have a number of important metabolic and cardiovascular effects. They seem to be partially responsible for maintenance of the normal structure and function of the skin and blood vessels in women. Estrogens also decrease the rate of resorption of bone by promoting the apoptosis of osteoclasts and by antagonizing the osteoclastogenic and pro-osteoclastic effects of parathyroid hormone and interleukin 6. Estrogens also stimulate adipose tissue production of leptin and are in part responsible for the higher levels of this hormone in women than in men.


Pharmacology_Katzung

Pharmacology_Katzung. In addition to stimulating the synthesis of enzymes and growth factors leading to uterine and breast growth and differentiation, estrogens alter the production and activity of many other proteins in the body. Metabolic alterations in the liver are especially important, so that there is a higher circulating level of proteins such as transcortin (corticosteroid-binding globulin [CBG]), thyroxine-binding globulin (TBG), SHBG, transferrin, renin substrate, and fibrinogen. This leads to increased circulating levels of thyroxine, estrogen, testosterone, iron, copper, and other substances.


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Pharmacology_Katzung. Alterations in the composition of the plasma lipids caused by estrogens are characterized by an increase in the high-density lipoproteins (HDL), a slight reduction in the low-density lipoproteins (LDL), and a reduction in total plasma cholesterol levels. Plasma triglyceride levels are increased. Estrogens decrease hepatic oxidation of adipose tissue lipid to ketones and increase synthesis of triglycerides. E. Effects on Blood Coagulation Estrogens enhance the coagulability of blood. Many changes in factors influencing coagulation have been reported, including increased circulating levels of factors II, VII, IX, and X and decreased antithrombin III, partially as a result of the hepatic effects mentioned above. Increased plasminogen levels and decreased platelet adhesiveness have also been found (see Hormonal Contraception, below). F. Other Effects


Pharmacology_Katzung

Pharmacology_Katzung. F. Other Effects Estrogens induce the synthesis of progesterone receptors. They are responsible for estrous behavior in animals and may influence behavior and libido in humans. Administration of estrogens stimulates central components of the stress system, including the production of corticotropin-releasing hormone and the activity of the sympathetic system, and promotes a sense of well-being when given to women who are estrogen-deficient. They also facilitate the loss of intravascular fluid into the extracellular space, producing edema. The resulting decrease in plasma volume causes a compensatory retention of sodium and water by the kidney. Estrogens also modulate sympathetic nervous system control of smooth muscle function. A. Primary Hypogonadism Estrogens have been used extensively for replacement therapy in estrogen-deficient patients. The estrogen deficiency may be due to primary failure of development of the ovaries, premature menopause, castration, or menopause.


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Pharmacology_Katzung. * The use of estrogens in contraception is discussed later in this chapter. CHAPTER 40 The Gonadal Hormones & Inhibitors 725 Treatment of primary hypogonadism is usually begun at 11–13 years of age in order to stimulate the development of secondary sex characteristics and menses, to stimulate optimal growth, to prevent osteoporosis, and to avoid the psychological consequences of delayed puberty and estrogen deficiency. Treatment attempts to mimic the physiology of puberty. It is initiated with small doses of estrogen (0.3 mg conjugated estrogens or 5–10 mcg ethinyl estradiol) on days 1–21 each month and is slowly increased to adult doses and then maintained until the age of menopause (approximately 51 years of age). A progestin is added after the first uterine bleeding. When growth is completed, chronic therapy consists mainly of the administration of adult doses of both estrogens and progestins, as described below. B. Postmenopausal Hormonal Therapy


Pharmacology_Katzung

Pharmacology_Katzung. B. Postmenopausal Hormonal Therapy In addition to the signs and symptoms that follow closely upon the cessation of normal ovarian function—such as loss of menstrual periods, vasomotor symptoms, sleep disturbances, and genital atrophy—there are longer-lasting changes that influence the health and well-being of postmenopausal women. These include an acceleration of bone loss, which in susceptible women may lead to vertebral, hip, and wrist fractures; and lipid changes, which may contribute to the acceleration of atherosclerotic cardiovascular disease noted in postmenopausal women. The effects of estrogens on bone have been extensively studied, and the effects of hormone withdrawal have been well-characterized. However, the role of estrogens and progestins in the cause and prevention of cardiovascular disease, which is responsible for 350,000 deaths per year, and breast cancer, which causes 35,000 deaths per year, is less well understood.


Pharmacology_Katzung

Pharmacology_Katzung. When normal ovulatory function ceases and the estrogen levels fall after menopause, oophorectomy, or premature ovarian failure, there is an accelerated rise in plasma cholesterol and LDL concentrations, while LDL receptors decline. HDL is not much affected, and levels remain higher than in men. Very-low-density lipoprotein and triglyceride levels are also relatively unaffected. Since cardiovascular disorders account for most deaths in this age group, the risk for these disorders constitutes a major consideration in deciding whether hormonal “replacement” therapy (HRT, also correctly called HT) is indicated and influences the selection of hormones to be administered. Estrogen replacement therapy has a beneficial effect on circulating lipids and lipoproteins, and this was earlier thought to be accompanied by a reduction in myocardial infarction by about 50% and of fatal strokes by as much as 40%. These findings, however, have been disputed by the results of a large study from the


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Pharmacology_Katzung. to be accompanied by a reduction in myocardial infarction by about 50% and of fatal strokes by as much as 40%. These findings, however, have been disputed by the results of a large study from the Women’s Health Initiative (WHI) project showing no cardiovascular benefit from estrogen plus progestin replacement therapy in perimenopausal or older postmenopausal patients. In fact, there may be a small increase in cardiovascular problems as well as breast cancer in women who received the replacement therapy. Interestingly, a small protective effect against colon cancer was observed. Although current clinical guidelines do not recommend routine hormone therapy in postmenopausal women, the validity of the WHI report has been questioned. In any case, there is no increased risk for breast cancer if therapy is given immediately after menopause and for the first 7 years, while the cardiovascular risk depends on the degree of atherosclerosis at the onset of therapy. Transdermal or vaginal


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Pharmacology_Katzung. if therapy is given immediately after menopause and for the first 7 years, while the cardiovascular risk depends on the degree of atherosclerosis at the onset of therapy. Transdermal or vaginal administration of estrogen may be associated with decreased cardiovascular risk because it bypasses the liver circulation. Women with premature menopause should definitely receive hormone therapy.


Pharmacology_Katzung

Pharmacology_Katzung. In some studies, a protective effect of estrogen replacement therapy against Alzheimer’s disease was observed. However, several other studies have not supported these results. Progestins antagonize estrogen’s effects on LDL and HDL to a variable extent. However, one large study has shown that the addition of a progestin to estrogen replacement therapy does not influence the cardiovascular risk. Optimal management of the postmenopausal patient requires careful assessment of her symptoms as well as consideration of her age and the presence of (or risks for) cardiovascular disease, osteoporosis, breast cancer, and endometrial cancer. Bearing in mind the effects of the gonadal hormones on each of these disorders, the goals of therapy can then be defined and the risks of therapy assessed and discussed with the patient.


Pharmacology_Katzung

Pharmacology_Katzung. If the main indication for therapy is hot flushes and sleep disturbances, therapy with the lowest dose of estrogen required for symptomatic relief is recommended. Treatment may be required for only a limited period of time and the possible increased risk for breast cancer avoided. In women who have undergone hysterectomy, estrogens alone can be given 5 days per week or continuously, since progestins are not required to reduce the risk for endometrial hyperplasia and cancer. Hot flushes, sweating, insomnia, and atrophic vaginitis are generally relieved by estrogens; many patients experience some increased sense of well-being; and climacteric depression and other psychopathologic states are improved.


Pharmacology_Katzung

Pharmacology_Katzung. The role of estrogens in the prevention and treatment of osteoporosis has been carefully studied (see Chapter 42). The amount of bone present in the body is maximal in the young active adult in the third decade of life and begins to decline more rapidly in middle age in both men and women. The development of osteoporosis also depends on the amount of bone present at the start of this process, on vitamin D and calcium intake, and on the degree of physical activity. The risk of osteoporosis is highest in smokers who are thin, Caucasian, and inactive and have a low calcium intake and a strong family history of osteoporosis. Depression also is a major risk factor for development of osteoporosis in women.


Pharmacology_Katzung

Pharmacology_Katzung. Estrogens should be used in the smallest dosage consistent with relief of symptoms. In women who have not undergone hysterectomy, it is most convenient to prescribe estrogen on the first 21–25 days of each month. The recommended dosages of estrogen are 0.3–1.25 mg/d of conjugated estrogen or 0.01–0.02 mg/d of ethinyl estradiol. Dosages in the middle of these ranges have been shown to be maximally effective in preventing the decrease in bone density occurring at menopause. From this point of view, it is important to begin therapy as soon as possible after the menopause for maximum effect. In these patients and others not taking estrogen, calcium supplements that bring the total daily calcium intake up to 1500 mg are useful.


Pharmacology_Katzung

Pharmacology_Katzung. Patients at low risk of developing osteoporosis who manifest only mild atrophic vaginitis can be treated with topical preparations. The vaginal route of application is also useful in the treatment of urinary tract symptoms in these patients. It is important to realize, however, that although locally administered estrogens escape the first-pass effect (so that some undesirable hepatic effects are reduced), they are almost completely absorbed into the circulation, and these preparations should be given cyclically.


Pharmacology_Katzung

Pharmacology_Katzung. As noted below, the administration of estrogen is associated with an increased risk of endometrial carcinoma. The administration of a progestational agent with the estrogen prevents endometrial hyperplasia and markedly reduces the risk of this cancer. When estrogen is given for the first 25 days of the month and the progestin medroxyprogesterone (10 mg/d) is added during the last 10–14 days, the risk is only half of that in women not receiving hormone replacement therapy. On this regimen, some women will experience a return of symptoms during the period off estrogen administration. In these patients, the estrogen can be given continuously. If the progestin produces sedation or other undesirable effects, its dose can be reduced to 2.5–5 mg for the last 10 days of the cycle with a slight increase in the risk for endometrial hyperplasia. These regimens are usually accompanied by bleeding at the end of each cycle. Some women experience migraine headaches during the last few days of the


Pharmacology_Katzung

Pharmacology_Katzung. increase in the risk for endometrial hyperplasia. These regimens are usually accompanied by bleeding at the end of each cycle. Some women experience migraine headaches during the last few days of the cycle. The use of a continuous estrogen regimen will often prevent their occurrence. Women who object to the cyclic bleeding associated with sequential therapy can also consider continuous therapy. Daily therapy with 0.625 mg of conjugated equine estrogens and 2.5–5 mg of medroxyprogesterone will eliminate cyclic bleeding, control vasomotor symptoms, prevent genital atrophy, maintain bone density, and show a favorable lipid profile with a small decrease in LDL and an increase in HDL concentrations. These women have endometrial atrophy on biopsy. About half of these patients experience breakthrough bleeding during the first few months of therapy. About 70–80% become amenorrheic after the first 4 months, and most remain so. The main disadvantage of continuous therapy is the need for uterine


Pharmacology_Katzung

Pharmacology_Katzung. bleeding during the first few months of therapy. About 70–80% become amenorrheic after the first 4 months, and most remain so. The main disadvantage of continuous therapy is the need for uterine biopsy if bleeding occurs after the first few months.


Pharmacology_Katzung

Pharmacology_Katzung. As noted above, estrogens may also be administered vaginally or transdermally. When estrogens are given by these routes, the liver is bypassed on the first circulation, and the ratio of the liver effects to peripheral effects is reduced. In patients in whom estrogen replacement therapy is contraindicated, such as those with estrogen-sensitive tumors, relief of vasomotor symptoms may be obtained by the use of clonidine. C. Other Uses Estrogens combined with progestins can be used to suppress ovulation in patients with intractable dysmenorrhea or when suppression of ovarian function is used in the treatment of hirsutism and amenorrhea due to excessive secretion of androgens by the ovary. Under these circumstances, greater suppression may be needed, and oral contraceptives containing 50 mcg of estrogen or a combination of a low-estrogen pill with GnRH suppression may be required.


Pharmacology_Katzung

Pharmacology_Katzung. Adverse effects of variable severity have been reported with the therapeutic use of estrogens. Many other effects reported in conjunction with hormonal contraceptives may be related to their estrogen content. These are discussed below. A. Uterine Bleeding Estrogen therapy is a major cause of postmenopausal uterine bleeding. Unfortunately, vaginal bleeding at this time of life may also be due to carcinoma of the endometrium. To avoid confusion, patients should be treated with the smallest amount of estrogen possible. It should be given cyclically so that bleeding, if it occurs, will be more likely to occur during the withdrawal period. As noted above, endometrial hyperplasia can be prevented by administration of a progestational agent with estrogen in each cycle. B. Cancer


Pharmacology_Katzung

Pharmacology_Katzung. The relation of estrogen therapy to cancer continues to be the subject of active investigation. Although no adverse effect of short-term estrogen therapy on the incidence of breast cancer has been demonstrated, a small increase in the incidence of this tumor may occur with prolonged therapy. Although the risk factor is small (1.25), the impact may be great since this tumor occurs in 10% of women, and addition of progesterone does not confer a protective effect. Studies indicate that following unilateral excision of breast cancer, women receiving tamoxifen (an estrogen partial agonist, see below) show a 35% decrease in contralateral breast cancer compared with controls. These studies also demonstrate that tamoxifen is well tolerated by most patients, produces estrogen-like alterations in plasma lipid levels, and stabilizes bone mineral loss. Studies bearing on the possible efficacy of tamoxifen and raloxifene in postmenopausal women at high risk for breast cancer show decreases of risk


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Pharmacology_Katzung. lipid levels, and stabilizes bone mineral loss. Studies bearing on the possible efficacy of tamoxifen and raloxifene in postmenopausal women at high risk for breast cancer show decreases of risk for at least 5 years, but of unknown further duration. Another study showed that postmenopausal hormone replacement therapy with estrogens plus progestins was associated with greater breast epithelial cell proliferation and breast epithelial cell density than estrogens alone or no replacement therapy. Furthermore, with estrogens plus progestins, breast proliferation was localized to the terminal duct-lobular unit of the breast, which is the main site of development of breast cancer. Thus, further studies are needed to conclusively assess the possible association between progestins and breast cancer risk.


Pharmacology_Katzung

Pharmacology_Katzung. Many studies show an increased risk of endometrial carcinoma in patients taking estrogens alone. The risk seems to vary with the dose and duration of treatment: 15 times greater in patients taking large doses of estrogen for 5 or more years, in contrast with two to four times greater in patients receiving lower doses for short periods. However, as noted above, the concomitant use of a progestin prevents this increased risk and may in fact reduce the incidence of endometrial cancer to less than that in the general population.


Pharmacology_Katzung

Pharmacology_Katzung. There have been a number of reports of adenocarcinoma of the vagina in young women whose mothers were treated with large doses of diethylstilbestrol early in pregnancy. These cancers are most common in young women (ages 14–44). The incidence is less than 1 per 1000 women exposed—too low to establish a cause-andeffect relationship with certainty. However, the risks for infertility, ectopic pregnancy, and premature delivery also are increased. It is now recognized that there is no indication for the use of diethylstilbestrol during pregnancy, and it should be avoided. It is not CHAPTER 40 The Gonadal Hormones & Inhibitors 727 known whether other estrogens have a similar effect or whether the observed phenomena are peculiar to diethylstilbestrol. This agent should be used only in the treatment of cancer (eg, of the prostate) or as a “morning after” contraceptive (see page 736). C. Other Effects


Pharmacology_Katzung

Pharmacology_Katzung. C. Other Effects Nausea and breast tenderness are common and can be minimized by using the smallest effective dose of estrogen. Hyperpigmentation also occurs. Estrogen therapy is associated with an increase in frequency of migraine headaches as well as cholestasis, gallbladder disease, and hypertension. Estrogens should not be used in patients with estrogen-dependent neoplasms such as carcinoma of the endometrium or in those with—or at high risk for—carcinoma of the breast. They should be avoided in patients with undiagnosed genital bleeding, liver disease, or a history of thromboembolic disorder. In addition, the use of estrogens should be avoided by heavy smokers.


Pharmacology_Katzung

Pharmacology_Katzung. The dosages of commonly used natural and synthetic preparations are listed in Table 40–1. Although all of the estrogens produce almost the same hormonal effects, their potencies vary both between agents and depending on the route of administration. As noted above, estradiol is the most active endogenous estrogen, and it has the highest affinity for the estrogen receptor. However, its metabolites estrone and estriol have weak uterine effects.


Pharmacology_Katzung

Pharmacology_Katzung. For a given level of gonadotropin suppression, oral estrogen preparations have more effect on the circulating levels of CBG, SHBG, and a host of other liver proteins, including angiotensinogen, than do transdermal preparations. The oral route of administration allows greater concentrations of hormone to reach the liver, thus increasing the synthesis of these proteins. Transdermal preparations were developed to avoid this effect. When administered transdermally, 50–100 mcg of estradiol has effects similar to those of 0.625–1.25 mg of conjugated oral estrogens on gonadotropin concentrations, endometrium, and vaginal epithelium. Furthermore, the transdermal estrogen preparations do not significantly increase the concentrations of renin substrate, CBG, and TBG and do not produce the characteristic changes in serum lipids. Combined oral preparations containing 0.625 mg of conjugated estrogens and 2.5 mg of medroxyprogesterone acetate are available for menopausal replacement therapy.


Pharmacology_Katzung

Pharmacology_Katzung. changes in serum lipids. Combined oral preparations containing 0.625 mg of conjugated estrogens and 2.5 mg of medroxyprogesterone acetate are available for menopausal replacement therapy. Tablets containing 0.625 mg of conjugated estrogens and 5 mg of medroxyprogesterone acetate are available to be used in conjunction with conjugated estrogens in a sequential fashion. Estrogens alone are taken on days 1–14 and the combination on days 15–28.


Pharmacology_Katzung

Pharmacology_Katzung. Natural Progestins: Progesterone Progesterone is the most important progestin in humans. In addition to having important hormonal effects, it serves as a precursor to the estrogens, androgens, and adrenocortical steroids. It is TABLE 40–2 Properties of some progestational agents. 1Interpretation: + = active; – = inactive; sl = slightly active. Activities have been reported in various species using various end points and may not apply to humans. 2Not available in USA. synthesized in the ovary, testis, and adrenal cortex from circulating cholesterol. Large amounts are also synthesized and released by the placenta during pregnancy.


Pharmacology_Katzung

Pharmacology_Katzung. synthesized in the ovary, testis, and adrenal cortex from circulating cholesterol. Large amounts are also synthesized and released by the placenta during pregnancy. In the ovary, progesterone is produced primarily by the corpus luteum. Normal males appear to secrete 1–5 mg of progesterone daily, resulting in plasma levels of about 0.03 mcg/dL. The level is only slightly higher in the female during the follicular phase of the cycle, when only a few milligrams per day of progesterone are secreted. During the luteal phase, plasma levels range from 0.5 mcg/dL to more than 2 mcg/dL (Figure 40–1). Plasma levels of progesterone are further elevated and reach their peak levels in the third trimester of pregnancy.


Pharmacology_Katzung

Pharmacology_Katzung. A variety of progestational compounds have been synthesized. Some are active when given by mouth. They are not a uniform group of compounds, and all of them differ from progesterone in one or more respects. Table 40–2 lists some of these compounds and their effects. In general, the 21-carbon compounds (hydroxyprogesterone, medroxyprogesterone, megestrol, and dimethisterone) are the most closely related, pharmacologically as well as chemically, to progesterone. A new group of third-generation synthetic progestins has been introduced, principally as components of oral contraceptives. These “19-nor, 13-ethyl” steroid compounds include desogestrel (Figure 40–4), gestodene, and norgestimate. They are claimed to have lower androgenic activity than older synthetic progestins.


Pharmacology_Katzung

Pharmacology_Katzung. Progesterone is rapidly absorbed following administration by any route. Its half-life in the plasma is approximately 5 minutes, and small amounts are stored temporarily in body fat. It is almost completely metabolized in one passage through the liver, and for that reason it is quite ineffective when the usual formulation is administered orally. However, high-dose oral micronized progesterone preparations have been developed that provide adequate progestational effect.


Pharmacology_Katzung

Pharmacology_Katzung. In the liver, progesterone is metabolized to pregnanediol and conjugated with glucuronic acid. It is excreted into the urine as pregnanediol glucuronide. The amount of pregnanediol in the urine has been used as an index of progesterone secretion. This measure has been very useful despite the fact that the proportion of secreted progesterone converted to this compound varies from day to day and from individual to individual. In addition to progesterone, 20αand 20β-hydroxyprogesterone (20αand 20β-hydroxy-4-pregnene-3-one) also are found. These compounds have about one-fifth the progestational activity of progesterone in humans and other species. Little is known of their physiologic role, but 20α-hydroxyprogesterone is produced in large amounts in some species and may be of some importance biologically.


Pharmacology_Katzung

Pharmacology_Katzung. The usual routes of administration and durations of action of the synthetic progestins are listed in Table 40–2. Most of these agents are extensively metabolized to inactive products that are excreted mainly in the urine. FIGURE 40–4 Progesterone and some progestational agents in clinical use. A. Mechanism


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 40–4 Progesterone and some progestational agents in clinical use. A. Mechanism The mechanism of action of progesterone—described in more detail above—is similar to that of other steroid hormones. Progestins enter the cell and bind to progesterone receptors that are distributed in the nucleus and the cytoplasm. The ligand-receptor complex binds to a progesterone response element (PRE) to activate gene transcription. The response element for progesterone appears to be similar to the corticosteroid response element, and the specificity of the response depends upon which receptor is present in the cell as well as upon other cell-specific receptor coregulators and interacting transcription factors. The progesterone-receptor complex forms a dimer before binding to DNA. Like the estrogen receptor, it can form heterodimers as well as homodimers between two isoforms, A and B. These isoforms are produced by alternative splicing of the same gene. B. Effects of Progesterone


Pharmacology_Katzung

Pharmacology_Katzung. B. Effects of Progesterone Progesterone has little effect on protein metabolism. It stimulates lipoprotein lipase activity and seems to favor fat deposition. The effects on carbohydrate metabolism are more marked. Progesterone increases basal insulin levels and the insulin response to glucose. There is usually no manifest change in carbohydrate tolerance. In the liver, progesterone promotes glycogen storage, possibly by facilitating the effect of insulin. Progesterone also promotes ketogenesis.


Pharmacology_Katzung

Pharmacology_Katzung. Progesterone can compete with aldosterone for the mineralocorticoid receptor of the renal tubule, causing a decrease in Na+ reabsorption. This leads to an increased secretion of aldosterone by the adrenal cortex (eg, in pregnancy). Progesterone increases body temperature in humans. The mechanism of this effect is not known, but an alteration of the temperature-regulating centers in the hypothalamus has been suggested. Progesterone also alters the function of the respiratory centers. The ventilatory response to CO2 is increased by progesterone but synthetic progestins with an ethinyl group do not have respiratory effects. This leads to a measurable reduction in arterial and alveolar Pco2 during pregnancy and in the luteal phase of the menstrual cycle. Progesterone and related steroids also have depressant and hypnotic effects on the brain.


Pharmacology_Katzung

Pharmacology_Katzung. Progesterone is responsible for the alveolobular development of the secretory apparatus in the breast. It also participates in the preovulatory LH surge and causes the maturation and secretory changes in the endometrium that are seen following ovulation (Figure 40–1). Progesterone decreases the plasma levels of many amino acids and leads to increased urinary nitrogen excretion. It induces changes in the structure and function of smooth endoplasmic reticulum in experimental animals. Other effects of progesterone and its analogs are noted below in the section, Hormonal Contraception. C. Synthetic Progestins


Pharmacology_Katzung

Pharmacology_Katzung. Other effects of progesterone and its analogs are noted below in the section, Hormonal Contraception. C. Synthetic Progestins The 21-carbon progesterone analogs antagonize aldosteroneinduced sodium retention (see above). The remaining compounds (“19-nortestosterone” third-generation agents) produce a decidual change in the endometrial stroma, do not support pregnancy in test animals, are more effective gonadotropin inhibitors, and may have minimal estrogenic and androgenic or anabolic activity (Table 40–2; Figure 40–4). They are sometimes referred to as “impeded androgens.” Progestins without androgenic activity include desogestrel, norgestimate, and gestodene. The first two of these compounds are dispensed in combination with ethinyl estradiol for oral contraception (Table 40–3) in the United States. TABLE 40–3 Some oral and implantable contraceptive agents in use.1


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 40–3 Some oral and implantable contraceptive agents in use.1 TABLE 40–3 Some oral and implantable contraceptive agents in use.1 (Continued) 1The estrogen-containing compounds are arranged in order of increasing content of estrogen. Other preparations are available. (Ethinyl estradiol and mestranol have similar potencies.) Oral contraceptives containing the progestin cyproterone acetate (also an antiandrogen) in combination with ethinyl estradiol are investigational in the United States. A. Therapeutic Applications


Pharmacology_Katzung

Pharmacology_Katzung. A. Therapeutic Applications The major uses of progestational hormones are for hormone replacement therapy (see above) and hormonal contraception (see below). In addition, they are useful in producing long-term ovarian suppression for other purposes. When used alone in large doses parenterally (eg, medroxyprogesterone acetate, 150 mg intramuscularly every 90 days), prolonged anovulation and amenorrhea result. This therapy has been employed in the treatment of dysmenorrhea, endometriosis, and bleeding disorders when estrogens are contraindicated, and for contraception. The major problem with this regimen is the prolonged time required in some patients for ovulatory function to return after cessation of therapy. It should not be used for patients planning a pregnancy in the near future. Similar regimens will relieve hot flushes in some menopausal women and can be used if estrogen therapy is contraindicated.


Pharmacology_Katzung

Pharmacology_Katzung. Medroxyprogesterone acetate, 10–20 mg orally twice weekly— or intramuscularly in doses of 100 mg/m2 every 1–2 weeks—will prevent menstruation, but it will not arrest accelerated bone maturation in children with precocious puberty. Progestins do not appear to have any place in the therapy of threatened or habitual abortion. Early reports of the usefulness of these agents resulted from the unwarranted assumption that after several abortions the likelihood of repeated abortions was over 90%. When progestational agents were administered to patients with previous abortions, a salvage rate of 80% was achieved. It is now recognized that similar patients abort only 20% of the time even when untreated. On the other hand, progesterone was given experimentally to delay premature labor with encouraging results.


Pharmacology_Katzung

Pharmacology_Katzung. Progesterone and medroxyprogesterone have been used in the treatment of women who have difficulty in conceiving and who demonstrate a slow rise in basal body temperature. There is no convincing evidence that this treatment is effective. Preparations of progesterone and medroxyprogesterone have been used to treat premenstrual syndrome. Controlled studies have not confirmed the effectiveness of such therapy except when doses sufficient to suppress ovulation have been used. B. Diagnostic Uses Progesterone can be used as a test of estrogen secretion. The administration of progesterone, 150 mg/d, or medroxyprogesterone, 10 mg/d, for 5–7 days, is followed by withdrawal bleeding in amenorrheic patients only when the endometrium has been stimulated by estrogens. A combination of estrogen and progestin can be given to test the responsiveness of the endometrium in patients with amenorrhea. Contraindications, Cautions, & Adverse Effects


Pharmacology_Katzung

Pharmacology_Katzung. Contraindications, Cautions, & Adverse Effects Studies of progestational compounds alone and with combination oral contraceptives indicate that the progestin in these agents may increase blood pressure in some patients. The more androgenic progestins also reduce plasma HDL levels in women. (See Hormonal Contraception, below.) Two recent studies suggest that combined progestin plus estrogen replacement therapy in postmenopausal women may increase breast cancer risk significantly compared with the risk in women taking estrogen alone. These findings require careful examination and if confirmed will lead to important changes in postmenopausal hormone replacement practice.


Pharmacology_Katzung

Pharmacology_Katzung. The normal ovary produces small amounts of androgens, including testosterone, androstenedione, and dehydroepiandrosterone. Of these, only testosterone has a significant amount of biologic activity, although androstenedione can be converted to testosterone or estrone in peripheral tissues. The normal woman produces less than 200 mcg of testosterone in 24 hours, and about one-third of this is probably formed in the ovary directly. The physiologic significance of these small amounts of androgens is not established, but they may be partly responsible for normal hair growth at puberty, for stimulation of female libido, and, possibly, for metabolic effects. Androgen production by the ovary may be markedly increased in some abnormal states, usually in association with hirsutism and amenorrhea as noted above.


Pharmacology_Katzung

Pharmacology_Katzung. The ovary also produces inhibin and activin. These peptides consist of several combinations of α and β subunits and are described in greater detail later. The αβ dimer (inhibin) inhibits FSH secretion while the ββ dimer (activin) increases FSH secretion. Studies in primates indicate that inhibin has no direct effect on ovarian steroidogenesis but that activin modulates the response to LH and FSH. For example, simultaneous treatment with activin and human FSH enhances FSH stimulation of progesterone synthesis and aromatase activity in granulosa cells. When combined with LH, activin suppressed the LH-induced progesterone response by 50% but markedly enhanced basal and LH-stimulated aromatase activity. Activin may also act as a growth factor in other tissues. The physiologic roles of these modulators are not fully understood.


Pharmacology_Katzung

Pharmacology_Katzung. Relaxin is another peptide that can be extracted from the ovary. The three-dimensional structure of relaxin is related to that of growth-promoting peptides and is similar to that of insulin. Although the amino acid sequence differs from that of insulin, this hormone, like insulin, consists of two chains linked by disulfide bonds, cleaved from a prohormone. It is found in the ovary, placenta, uterus, and blood. Relaxin synthesis has been demonstrated in luteinized granulosa cells of the corpus luteum. It has been shown to increase glycogen synthesis and water uptake by the myometrium and to decrease uterine contractility. In some species, it changes the mechanical properties of the cervix and pubic ligaments, facilitating delivery. In women, relaxin has been measured by immunoassay. Levels were highest immediately after the LH surge and during menstruation. A physiologic role for this peptide has not been established.


Pharmacology_Katzung

Pharmacology_Katzung. In women, relaxin has been measured by immunoassay. Levels were highest immediately after the LH surge and during menstruation. A physiologic role for this peptide has not been established. Clinical trials with relaxin have been conducted in patients with dysmenorrhea. Relaxin has also been administered to patients in premature labor and during prolonged labor. When applied to the cervix of a woman at term, it facilitates dilation and shortens labor. Several other nonsteroidal substances such as corticotropinreleasing hormone, follistatin, and prostaglandins are produced by the ovary. These probably have paracrine effects within the ovary. ■ HORMONAL CONTRACEPTION (ORAL, PARENTERAL, & IMPLANTED CONTRACEPTIVES)


Pharmacology_Katzung

Pharmacology_Katzung. ■ HORMONAL CONTRACEPTION (ORAL, PARENTERAL, & IMPLANTED CONTRACEPTIVES) A large number of oral contraceptives containing estrogens or progestins (or both) are now available for clinical use (Table 40–3). These preparations vary chemically and pharmacologically and have many properties in common as well as definite differences important for the correct selection of the optimum agent. Two types of preparations are used for oral contraception: (1) combinations of estrogens and progestins and (2) continuous progestin therapy without concomitant administration of estrogens. The combination agents are further divided into monophasic forms (constant dosage of both components during the cycle) and biphasic or triphasic forms (dosage of one or both components is changed once or twice during the cycle). The preparations for oral use are all adequately absorbed, and in combination preparations the pharmacokinetics of neither drug is significantly altered by the other.


Pharmacology_Katzung

Pharmacology_Katzung. Only one implantable contraceptive preparation is available at present in the USA. Etonogestrel, also used in some oral contraceptives, is available in the subcutaneous implant form listed in Table 40–3. Several hormonal contraceptives are available as vaginal rings or intrauterine devices. Intramuscular injection of large doses of medroxyprogesterone also provides contraception of long duration. A. Mechanism of Action


Pharmacology_Katzung

Pharmacology_Katzung. A. Mechanism of Action The combinations of estrogens and progestins exert their contraceptive effect largely through selective inhibition of pituitary function that results in inhibition of ovulation. The combination agents also produce a change in the cervical mucus, in the uterine endometrium, and in motility and secretion in the uterine tubes, all of which decrease the likelihood of conception and implantation. The continuous use of progestins alone does not always inhibit ovulation. The other factors mentioned, therefore, play a major role in the prevention of pregnancy when these agents are used. B. Effects on the Ovary Chronic use of combination agents depresses ovarian function. Follicular development is minimal, and corpora lutea, larger follicles, stromal edema, and other morphologic features normally seen in ovulating women are absent. The ovaries usually become smaller even if enlarged before therapy.


Pharmacology_Katzung

Pharmacology_Katzung. The great majority of patients return to normal menstrual patterns when these drugs are discontinued. About 75% will ovulate in the first posttreatment cycle and 97% by the third posttreatment cycle. About 2% of patients remain amenorrheic for periods of up to several years after administration is stopped. The cytologic findings on vaginal smears vary depending on the preparation used. However, with almost all of the combined drugs, a low maturation index is found because of the presence of progestational agents. C. Effects on the Uterus After prolonged use, the cervix may show some hypertrophy and polyp formation. There are also important effects on the cervical mucus, making it more like postovulation mucus, ie, thicker and less copious.


Pharmacology_Katzung

Pharmacology_Katzung. Agents containing both estrogens and progestins produce further morphologic and biochemical changes of the endometrial stroma under the influence of the progestin, which also stimulates glandular secretion throughout the luteal phase. The agents containing “19-nor” progestins—particularly those with the smaller amounts of estrogen—tend to produce more glandular atrophy and usually less bleeding. D. Effects on the Breast Stimulation of the breasts occurs in most patients receiving estrogen-containing agents. Some enlargement is generally noted. The administration of estrogens and combinations of estrogens and progestins tends to suppress lactation, but when the doses are small, the effects on breast-feeding are not appreciable. Studies of the transport of the oral contraceptives into breast milk suggest that only small amounts of these compounds cross into the milk, and they have not been considered to be of importance. E. Other Effects of Oral Contraceptives 1.


Pharmacology_Katzung

Pharmacology_Katzung. E. Other Effects of Oral Contraceptives 1. Effects on the central nervous system—The central nervous system effects of the oral contraceptives have not been well studied in humans. A variety of effects of estrogen and progesterone have been noted in animals. Estrogens tend to increase excitability in the brain, whereas progesterone tends to decrease it. The thermogenic action of progesterone and some of the synthetic progestins is also thought to occur in the central nervous system. It is very difficult to evaluate any behavioral or emotional effects of these compounds in humans. Although the incidence of pronounced changes in mood, affect, and behavior appears to be low, milder changes are commonly reported, and estrogens are being successfully employed in the therapy of premenstrual tension syndrome, postpartum depression, and climacteric depression. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Effects on endocrine function—The inhibition of pituitary gonadotropin secretion has been mentioned. Estrogens also alter adrenal structure and function. Estrogens given orally or at high doses increase the plasma concentration of the α2 globulin that binds cortisol (corticosteroid-binding globulin). Plasma concentrations may be more than double the levels found in untreated individuals, and urinary excretion of free cortisol is elevated. These preparations cause alterations in the renin-angiotensinaldosterone system. Plasma renin activity has been found to increase, and there is an increase in aldosterone secretion.


Pharmacology_Katzung

Pharmacology_Katzung. These preparations cause alterations in the renin-angiotensinaldosterone system. Plasma renin activity has been found to increase, and there is an increase in aldosterone secretion. Thyroxine-binding globulin is increased. As a result, total plasma thyroxine (T4) levels are increased to those commonly seen during pregnancy. Since more of the thyroxine is bound, the free thyroxine level in these patients is normal. Estrogens also increase the plasma level of SHBG and decrease plasma levels of free androgens by increasing their binding; large amounts of estrogen may decrease androgens by gonadotropin suppression.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Effects on blood—Serious thromboembolic phenomena occurring in women taking oral contraceptives gave rise to a great many studies of the effects of these compounds on blood coagulation. A clear picture of such effects has not yet emerged. The oral contraceptives do not consistently alter bleeding or clotting times. The changes that have been observed are similar to those reported in pregnancy. There is an increase in factors VII, VIII, IX, and X and a decrease in antithrombin III. Increased amounts of coumarin anticoagulants may be required to prolong prothrombin time in patients taking oral contraceptives. There is an increase in serum iron and total iron-binding capacity similar to that reported in patients with hepatitis. Significant alterations in the cellular components of blood have not been reported with any consistency. A number of patients have been reported to develop folic acid deficiency anemias. 4.


Pharmacology_Katzung

Pharmacology_Katzung. Significant alterations in the cellular components of blood have not been reported with any consistency. A number of patients have been reported to develop folic acid deficiency anemias. 4. Effects on the liver—These hormones also have profound effects on the function of the liver. Some of these effects are deleterious and will be considered below in the section on adverse effects. The effects on serum proteins result from the effects of the estrogens on the synthesis of the various α2 globulins and fibrinogen. Serum haptoglobins produced in the liver are depressed rather than increased by estrogen. Some of the effects on carbohydrate and lipid metabolism are probably influenced by changes in liver metabolism (see below).


Pharmacology_Katzung

Pharmacology_Katzung. Important alterations in hepatic drug excretion and metabolism also occur. Estrogens in the amounts seen during pregnancy or used in oral contraceptive agents delay the clearance of sulfobromophthalein and reduce the flow of bile. The proportion of cholic acid in bile acids is increased while the proportion of chenodeoxycholic acid is decreased. These changes may be responsible for the observed increase in cholelithiasis associated with the use of these agents. 5.


Pharmacology_Katzung

Pharmacology_Katzung. 5. Effects on lipid metabolism—As noted above, estrogens increase serum triglycerides and free and esterified cholesterol. Phospholipids are also increased, as are HDL; levels of LDL usually decrease. Although the effects are marked with doses of 100 mcg of mestranol or ethinyl estradiol, doses of 50 mcg or less have minimal effects. The progestins (particularly the “19-nortestosterone” derivatives) tend to antagonize these effects of estrogen. Preparations containing small amounts of estrogen and a progestin may slightly decrease triglycerides and HDL. 6.


Pharmacology_Katzung

Pharmacology_Katzung. 6. Effects on carbohydrate metabolism—The administration of oral contraceptives produces alterations in carbohydrate metabolism similar to those observed in pregnancy. There is a reduction in the rate of absorption of carbohydrates from the gastrointestinal tract. Progesterone increases the basal insulin level and the rise in insulin induced by carbohydrate ingestion. Preparations with more potent progestins such as norgestrel may cause progressive decreases in carbohydrate tolerance over several years. However, the changes in glucose tolerance are reversible on discontinuing medication. 7.


Pharmacology_Katzung

Pharmacology_Katzung. 7. Effects on the cardiovascular system—These agents cause small increases in cardiac output associated with higher systolic and diastolic blood pressure and heart rate. The pressure returns to pretreatment levels when treatment is terminated. Although the magnitude of the pressure change is small in most patients, it is marked in a few. It is important that blood pressure be followed in each patient. An increase in blood pressure has been reported to occur in a few postmenopausal women treated with estrogens alone. 8.


Pharmacology_Katzung

Pharmacology_Katzung. 8. Effects on the skin—The oral contraceptives have been noted to increase pigmentation of the skin (chloasma). This effect seems to be enhanced in women with dark complexions and by exposure to ultraviolet light. Some of the androgen-like progestins might increase the production of sebum, causing acne in some patients. However, since ovarian androgen is suppressed, many patients note decreased sebum production, acne, and terminal hair growth. The sequential oral contraceptive preparations as well as estrogens alone often decrease sebum production.


Pharmacology_Katzung

Pharmacology_Katzung. The most important use of combined estrogens and progestins is for oral contraception. A large number of preparations are available for this specific purpose, some of which are listed in Table 40–3. They are specially packaged for ease of administration. In general, they are very effective; when these agents are taken according to directions, the risk of conception is extremely small. The pregnancy rate with combination agents is estimated to be about 5–12 per 100 woman-years at risk. (Under conditions of perfect adherence, the pregnancy rate would be 0.5–1 per 100 woman-years.) Contraceptive failure has been observed in some patients when one or more doses are missed, if phenytoin is also being used (which may increase catabolism of the compounds), or if antibiotics are taken that alter enterohepatic cycling of metabolites.


Pharmacology_Katzung

Pharmacology_Katzung. Progestins and estrogens are also useful in the treatment of endometriosis. When severe dysmenorrhea is the major symptom, the suppression of ovulation with estrogen alone may be followed by painless periods. However, in most patients this approach is inadequate. The long-term administration of large doses of progestins or combinations of progestins and estrogens prevents the periodic breakdown of the endometrial tissue and in some cases will lead to endometrial fibrosis and prevent the reactivation of implants for prolonged periods. As is true with most hormonal preparations, many of the undesired effects are physiologic or pharmacologic actions that are objectionable only because they are not pertinent to the situation for which they are being used. Therefore, the product containing the smallest effective amounts of hormones should be selected for use.


Pharmacology_Katzung

Pharmacology_Katzung. The incidence of serious known toxicities associated with the use of these drugs is low—far lower than the risks associated with pregnancy. There are a number of reversible changes in intermediary metabolism. Minor adverse effects are frequent, but most are mild and many are transient. Continuing problems may respond to simple changes in pill formulation. Although it is not often necessary to discontinue medication for these reasons, as many as one third of all patients started on oral contraception discontinue use for reasons other than a desire to become pregnant. A. Mild Adverse Effects 1. Nausea, mastalgia, breakthrough bleeding, and edema are related to the amount of estrogen in the preparation. These effects can often be alleviated by a shift to a preparation containing smaller amounts of estrogen or to agents containing progestins with more androgenic effects. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Changes in serum proteins and other effects on endocrine function (see above) must be taken into account when thyroid, adrenal, or pituitary function is being evaluated. Increases in sedimentation rate are thought to be due to increased levels of fibrinogen. 3. Headache is mild and often transient. However, migraine is often made worse and has been reported to be associated with an increased frequency of cerebrovascular accidents. When this occurs or when migraine has its onset during therapy with these agents, treatment should be discontinued. 4. Withdrawal bleeding sometimes fails to occur—most often with combination preparations—and may cause confusion with regard to pregnancy. If this is disturbing to the patient, a different preparation may be tried or other methods of contraception used. B. Moderate Adverse Effects Any of the following may require discontinuance of oral contraceptives: 1.


Pharmacology_Katzung

Pharmacology_Katzung. B. Moderate Adverse Effects Any of the following may require discontinuance of oral contraceptives: 1. Breakthrough bleeding is the most common problem in using progestational agents alone for contraception. It occurs in as many as 25% of patients. It is more frequently encountered in patients taking low-dose preparations than in those taking combination pills with higher levels of progestin and estrogen. The biphasic and triphasic oral contraceptives (Table 40–3) decrease breakthrough bleeding without increasing the total hormone content. 2. Weight gain is more common with the combination agents containing androgen-like progestins. It can usually be controlled by shifting to preparations with less progestin effect or by dieting. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Weight gain is more common with the combination agents containing androgen-like progestins. It can usually be controlled by shifting to preparations with less progestin effect or by dieting. 3. Increased skin pigmentation may occur, especially in dark-skinned women. It tends to increase with time, the incidence being about 5% at the end of the first year and about 40% after 8 years. It is thought to be exacerbated by vitamin B deficiency. It is often reversible upon discontinuance of medication but may disappear very slowly. 4. Acne may be exacerbated by agents containing androgen-like progestins (Table 40–2), whereas agents containing large amounts of estrogen usually cause marked improvement in acne. 5. Hirsutism may also be aggravated by the “19-nortestosterone” derivatives, and combinations containing nonandrogenic progestins are preferred in these patients. 6. Ureteral dilation similar to that observed in pregnancy has been reported, and bacteriuria is more frequent.


Pharmacology_Katzung

Pharmacology_Katzung. 6. Ureteral dilation similar to that observed in pregnancy has been reported, and bacteriuria is more frequent. 7. Vaginal infections are more common and more difficult to treat in patients who are using oral contraceptives. 8. Amenorrhea occurs in some patients. Following cessation of administration of oral contraceptives, 95% of patients with normal menstrual histories resume normal periods and all but a few resume normal cycles during the next few months. However, some patients remain amenorrheic for several years. Many of these patients also have galactorrhea. Patients who have had menstrual irregularities before taking oral contraceptives are particularly susceptible to prolonged amenorrhea when the agents are discontinued. Prolactin levels should be measured in these patients, since many have prolactinomas.


Pharmacology_Katzung

Pharmacology_Katzung. C. Severe Adverse Effects 1. Vascular disorders—Thromboembolism was one of the earliest of the serious unanticipated effects to be reported and has been the most thoroughly studied.


Pharmacology_Katzung

Pharmacology_Katzung. a. Venous thromboembolic disease—Superficial or deep thromboembolic disease in women not taking oral contraceptives occurs in about 1 patient per 1000 woman years. The overall incidence of these disorders in patients taking low-dose oral contraceptives is about threefold higher. The risk for this disorder is increased during the first month of contraceptive use and remains constant for several years or more. The risk returns to normal within a month when use is discontinued. The risk of venous thrombosis or pulmonary embolism is increased among women with predisposing conditions such as stasis, altered clotting factors such as antithrombin III, increased levels of homocysteine, or injury. Genetic disorders, including mutations in the genes governing the production of protein C (factor V Leiden), protein S, hepatic cofactor II, and others, markedly increase the risk of venous thromboembolism. The incidence of these disorders is too low for cost-effective screening by current methods,


Pharmacology_Katzung

Pharmacology_Katzung. Leiden), protein S, hepatic cofactor II, and others, markedly increase the risk of venous thromboembolism. The incidence of these disorders is too low for cost-effective screening by current methods, but prior episodes or a family history may be helpful in identifying patients with increased risk.


Pharmacology_Katzung

Pharmacology_Katzung. The incidence of venous thromboembolism appears to be related to the estrogen but not the progestin content of oral contraceptives and is not related to age, parity, mild obesity, or cigarette smoking. Decreased venous blood flow, endothelial proliferation in veins and arteries, and increased coagulability of blood resulting from changes in platelet functions and fibrinolytic systems contribute to the increased incidence of thrombosis. The major plasma inhibitor of thrombin, antithrombin III, is substantially decreased during oral contraceptive use. This change occurs in the first month of treatment and lasts as long as treatment persists, reversing within a month thereafter.


Pharmacology_Katzung

Pharmacology_Katzung. b. Myocardial infarction—The use of oral contraceptives is associated with a slightly higher risk of myocardial infarction in women who are obese, have a history of preeclampsia or hypertension, or have hyperlipoproteinemia or diabetes. There is a much higher risk in women who smoke. The risk attributable to oral contraceptives in women 30–40 years of age who do not smoke is about 4 cases per 100,000 users per year, as compared with 185 cases per 100,000 among women 40–44 who smoke heavily. The association with myocardial infarction is thought to involve acceleration of atherogenesis because of decreased glucose tolerance, decreased levels of HDL, increased levels of LDL, and increased platelet aggregation. In addition, facilitation of coronary arterial spasm may play a role in some of these patients. The progestational component of oral contraceptives decreases HDL cholesterol levels, in proportion to the androgenic activity of the progestin. The net effect, therefore, will depend on


Pharmacology_Katzung

Pharmacology_Katzung. patients. The progestational component of oral contraceptives decreases HDL cholesterol levels, in proportion to the androgenic activity of the progestin. The net effect, therefore, will depend on the specific composition of the pill used and the patient’s susceptibility to the particular effects. Recent studies suggest that risk of infarction is not increased in past users who have discontinued oral contraceptives.


Pharmacology_Katzung

Pharmacology_Katzung. c. Cerebrovascular disease—The risk of stroke is concentrated in women over age 35. It is increased in current users of oral contraceptives but not in past users. However, subarachnoid hemorrhages have been found to be increased among both current and past users and may increase with time. The risk of thrombotic or hemorrhagic stroke attributable to oral contraceptives (based on older, higher-dose preparations) has been estimated at about 37 cases per 100,000 users per year. In summary, available data indicate that oral contraceptives increase the risk of various cardiovascular disorders at all ages and among both smokers and nonsmokers. However, this risk appears to be concentrated in women 35 years of age or older who are heavy smokers. It is clear that these risk factors must be considered in each individual patient for whom oral contraceptives are being considered. Some experts have suggested that screening for coagulopathy should be performed before starting oral contraception.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Gastrointestinal disorders—Many cases of cholestatic jaundice have been reported in patients taking progestin-containing drugs. The differences in incidence of these disorders from one population to another suggest that genetic factors may be involved. The jaundice caused by these agents is similar to that produced by other 17-alkyl-substituted steroids. It is most often observed in the first three cycles and is particularly common in women with a history of cholestatic jaundice during pregnancy. Jaundice and pruritus disappear 1–8 weeks after the drug is discontinued. These agents have also been found to increase the incidence of symptomatic gallbladder disease, including cholecystitis and cholangitis. This is probably the result of the alterations responsible for jaundice and bile acid changes described above.


Pharmacology_Katzung

Pharmacology_Katzung. It also appears that the incidence of hepatic adenomas is increased in women taking oral contraceptives. Ischemic bowel disease secondary to thrombosis of the celiac and superior and inferior mesenteric arteries and veins has also been reported in women using these drugs. 3. Depression—Depression of sufficient degree to require cessation of therapy occurs in about 6% of patients treated with some preparations. 4.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Depression—Depression of sufficient degree to require cessation of therapy occurs in about 6% of patients treated with some preparations. 4. Cancer—The occurrence of malignant tumors in patients taking oral contraceptives has been studied extensively. It is now clear that these compounds reduce the risk of endometrial and ovarian cancer. The lifetime risk of breast cancer in the population as a whole does not seem to be affected by oral contraceptive use. Some studies have shown an increased risk in younger women, and it is possible that tumors that develop in younger women become clinically apparent sooner. The relation of risk of cervical cancer to oral contraceptive use is still controversial. It should be noted that a number of recent studies associate the use of oral contraceptives by women who are infected with human papillomavirus with an increased risk of cervical cancer.