Chapter 22. Growth, Thyroid, and Gonadal Pharmacology

The endocrine system integrates major organ systems with each other and with the nervous system. The endogenous ligands that the endocrine system uses to perform this integrative task are called hormones. Hormones are released from specialized cells, circulate in the blood, and regulate physiologic processes in one or more target organs. In many endocrine systems, several hormones act in series to regulate organ function. The release of one hormone in the series regulates the release of the next hormone. A series of this type provides multiple levels of regulation and integration and also provides the opportunity for negative feedback, in which the last hormone in the series can reduce the production of earlier hormones in the series and thereby regulate its own production (Figure 22–1). The endocrine system provides many useful therapeutic targets and many drugs either mimic or block the effects of naturally occurring hormones.

This chapter will focus on drugs that regulate three related endocrine systems. These are (1) the hypothalamic-pituitary endocrine system, which exerts control over many integrative functions and other endocrine tissues and interacts directly with the nervous system; (2) the thyroid gland, an essential regulator of growth, development, and normal function of many organ systems; and (3) the gonadal system, which regulates the development and function of reproductive tissues. Separate chapters will cover the pharmacology of drugs that influence the function of hormones produced by the adrenal gland (Chapter 23), hormones that regulate blood glucose (Chapter 24), and those involved with bone mineralization (Chapter 25).

The overall control of metabolism, growth, and reproduction is mediated by a combination of neural and endocrine systems located in the hypothalamus and pituitary gland. The pituitary consists of an anterior lobe (adenohypophysis) and a posterior lobe (neurohypophysis). The pituitary is connected to the hypothalamus by a stalk of neurosecretory fibers and blood vessels, including a portal venous system that drains the hypothalamus and perfuses the anterior pituitary. The portal venous system carries small regulatory peptide releasing hormones from the hypothalamus to the anterior pituitary. These releasing hormones regulate release of anterior pituitary hormones, which subsequently regulate target tissues throughout the body (Table 22–1). The hormones released from the posterior lobe of the pituitary (oxytocin and vasopressin) are synthesized in the hypothalamus and transported via neurosecretory fibers in the pituitary stalk to the posterior lobe from which they are released into the circulation (Table 22–1).

Hypothalamic and pituitary hormones, and their synthetic analogs, have pharmacologic applications in three areas: (1) replacement therapy for hormone deficiency states, (2) antagonist therapy for diseases resulting from excessive production of, or response to, pituitary hormones, and (3) diagnostic tools for performing stimulation tests.

Growth Hormone–Releasing Hormone

Growth hormone–releasing hormone (GHRH) is a hypothalamic hormone that stimulates the release of growth hormone (GH) from the anterior pituitary. GH (also known as somatotropin) is an important regulator of growth in children and tissue maintenance in adults. Two short synthetic peptides with activity similar to GHRH are available for clinical use. In normal individuals, these peptides produce a rapid increase in plasma GH concentrations. They are occasionally used as a diagnostic tool in patients with GH deficiency to determine whether the cause of GH deficiency is due to a problem in the hypothalamus, pituitary, or tissues targeted by GH.

Somatostatin

Somatostatin (somatotropin release-inhibiting hormone, SRIF), a 14-amino-acid peptide, is found in the pancreas and other parts of the gastrointestinal system as well as in the central nervous system. This hormone inhibits the release of a number of hormones including GH, glucagon, insulin, and gastrin. Because of its short duration of action, somatostatin itself is of no clinical value. Octreotide, a synthetic somatostatin analog with a longer duration of action, is used to reduce symptoms caused by certain tumors that produce excessive concentrations of hormones. Tumors that are partially responsive to octreotide’s inhibitory effects include GH-secreting tumors that cause acromegaly, carcinoid tumors, gastrinoma, and glucagonoma. Regular octreotide must be administered subcutaneously two to four times daily. Once a brief course of regular octreotide has been demonstrated to be effective and tolerated, a slow-release intramuscular (IM) formulation is administered every 4 weeks for long-term therapy. Adverse effects associated with octreotide primarily involve the gastrointestinal system and the heart.

Thyrotropin-Releasing Hormone

Thyrotropin-releasing hormone (TRH), or protirelin, is a tripeptide that stimulates thyrotropin (thyroid-stimulating hormone, TSH) release from the anterior pituitary. TRH also increases prolactin production by the anterior pituitary, but has no effect on the release of GH or adrenocorticotropin (ACTH). TRH has been used in diagnostic testing of thyroid dysfunction.

Corticotropin-Releasing Hormone

Corticotropin-releasing hormone (CRH) is a 41-amino-acid peptide that stimulates secretion of both ACTH and the closely related peptide β-endorphin from the anterior pituitary. CRH is used to diagnose the source of ACTH secretion abnormalities. ACTH-secreting tumors located within the pituitary usually respond to exogenous CRH with an increase in ACTH secretion. In contrast, ACTH secretion by tumors located outside the pituitary rarely responds to exogenous CRH.

Gonadotropin-Releasing Hormone

Gonadotropin-releasing hormone (GnRH), a decapeptide, coordinates reproductive function in males and females by regulating release of two gonadotropins—luteinizing hormone (LH) and follicle-stimulating hormone (FSH)—from the anterior pituitary. When administered in a pulsatile fashion that mimics the endogenous pattern of secretion, recombinant GnRH stimulates gonadotropin release. Pulsatile GnRH administration is used to determine the basis of delayed puberty in adolescents and, rarely, to treat infertility caused by hypothalamic dysfunction in both sexes.

Leuprolide was the first of several synthetic peptides with GnRH agonist activity. When given in pulsatile doses, these synthetic peptides, like GnRH, stimulate gonadotropin release. In contrast, steady dosing inhibits gonadotropin release by causing down-regulation of GnRH receptors in pituitary cells that normally release gonadotropins. Steady dosage of GnRH agonists is used to suppress gonadotropin secretion in patients with prostatic carcinoma or other gonadal steroid-sensitive tumors, endometriosis, or precocious puberty. GnRH agonists are also used to suppress endogenous gonadotropin release in women undergoing controlled ovarian hyperstimulation and in assisted reproduction technology such as in vitro fertilization.

Ganirelix and cetrorelix are new GnRH antagonists that can be used to prevent premature surges of LH during controlled ovarian hyperstimulation. These GnRH antagonists may also be effective in disorders that are currently treated with GnRH agonists, including endometriosis, uterine fibroids, and prostatic cancer.

Prolactin-Inhibiting Hormone

Dopamine (also called prolactin-inhibiting hormone, PIH) is the primary physiologic regulator of prolactin release. Acting through D2 dopamine receptors, dopamine inhibits prolactin release. Dopamine itself is not used to treat hyperprolactinemia. Instead, bromocriptine and other orally active ergot derivatives such as pergolide are used to reduce prolactin secretion from normal glands as well as from prolactinomas.

Growth Hormone (Somatotropin)

Recombinant forms of human GH are somatropin and somatrem; the latter is somatotropin with an extra methionine added to the protein. Recombinant growth hormone is used to treat GH deficiency in children and adults. Girls with Turner’s syndrome treated with GH frequently achieve increased final adult height. GH treatment also improves growth in children with failure to thrive secondary to chronic renal failure or HIV infection. Growth hormone is also helpful in treating adults with acquired immune deficiency syndrome (AIDS)–associated wasting.

Thyroid-Stimulating Hormone

In thyroid cells, thyroid-stimulating hormone (TSH) increases iodine uptake and production of thyroid hormones. TSH has been used as a diagnostic tool to distinguish primary from secondary hypothyroidism.

Adrenocorticotropin Hormone

Adrenocorticotropin (ACTH) is a large peptide formed from a larger precursor peptide, pro-opiomelanocortin. This precursor is also the source of α-melanocyte-stimulating hormone, β-endorphin, and met-enkephalin. Cosyntropin, a synthetic ACTH analog, is used for diagnostic purposes in patients with abnormal corticosteroid production.

Follicle-Stimulating Hormone

Follicle-stimulating hormone (FSH) is a glycoprotein that stimulates gametogenesis and follicle development in women and spermatogenesis in men. Two preparations are available for clinical use. Urofollitropin can be purified from the urine of postmenopausal women and is available in a recombinant form, follitropin-α (rFSH). These products are used in combination with other drugs to treat infertility in both sexes.

Luteinizing Hormone

In women, luteinizing hormone (LH) acts in concert with FSH to regulate gonadal steroid production, follicular development, and ovulation. In men, LH regulates testosterone production. A recombinant form of LH is available for clinical use. Human chorionic gonadotropin (hCG), which is almost identical to LH in structure, is used for treatment of hypogonadism in men and women and as part of controlled ovarian hyperstimulation and assisted reproductive technology programs.

Menotropins

Menotropins are human menopausal gonadotropins that consist of a mixture of FSH and LH purified from the urine of postmenopausal women. The product is used in combination with hCG in the treatment of hypogonadal states and as part of controlled ovarian hyperstimulation and assisted reproductive technology programs.

The thyroid gland secretes two types of hormones. The first is calcitonin, a peptide that is important in calcium metabolism and bone mineralization; calcitonin is discussed in Chapter 25. The second type of thyroid hormone consists of two iodine-containing hormones, thyroxine (T4) and triiodothyronine (T3), which have broad effects on growth, development, and metabolism (Figure 22–2).

Thyroid Hormones

Control, Synthesis, Transport, and Mechanism of Action

Thyroid function is controlled by TSH release from the anterior pituitary and by iodine availability. High levels of thyroid hormones inhibit TSH release, providing an effective negative feedback control mechanism. Iodine, derived from food or iodine supplements, is necessary for the synthesis of thyroid hormones. Iodine uptake is an active process, and the iodide ion is highly concentrated in the thyroid gland (Figure 22–3). The tyrosine residues of the protein thyroglobulin are iodinated in the gland to form monoiodotyrosine (MIT) or diiodotyrosine (DIT). Whereas T4 is formed from the combination of 2 molecules of DIT, T3 is formed from the combination of one molecule each of MIT and DIT. Inadequate iodine intake results in a diffuse enlargement of the thyroid gland called goiter. Higher than normal iodide concentrations inhibit iodination of tyrosine, an effect that is useful in the treatment of thyroid disease. In Graves’ disease, lymphocytes release a thyroid-stimulating immunoglobulin that causes thyrotoxicosis. Because these lymphocytes are not susceptible to negative feedback, blood concentrations of thyroid hormone may become very high.

The thyroid gland secretes both T3 and T4. Although the T3 released from the thyroid is active, most circulating T3 is formed by the deiodination of T4 in the tissues. Both T3 and T4 are transported in the blood by thyroxine-binding globulin (TBG), a protein synthesized by the liver. T3 is about 10 times more potent than T4. Because T4 is converted to T3 in target cells, the liver, and the kidneys, most of the effect of circulating T3 is probably due to deiodination of T4 in the tissues.

Thyroid hormone binds to intracellular receptors that control expression of genes responsible for many metabolic processes. Proteins synthesized under T3 control differ depending on the tissue involved. These proteins include Na+/K+ ATPase, specific contractile proteins in smooth muscle and the heart, enzymes involved in lipid metabolism, and important developmental components in the brain. In addition, T3 may also have a separate membrane receptor-mediated effect in some tissues.

Physiologic Effects

The actions of thyroid hormones include normal growth and development of the nervous, skeletal, and reproductive systems and regulation of metabolism of fats, carbohydrates, proteins, and vitamins. The key features of excess thyroid activity (hyperthyroidism) and insufficient thyroid function (hypothyroidism) are listed in Table 22–2.

Clinical Use

Thyroid hormone therapy can be accomplished with either T4 or T3. Synthetic T4 (levothyroxine) is usually the first choice. T3 acts more quickly, but has a shorter half-life and is more expensive.

Adverse Effects

Toxicity due to excessive supplementation of thyroid hormones is expressed as hyperthyroidism (Table 22–2). Older patients, those with cardiovascular disease, and those with long-standing hypothyroidism are highly sensitive to the stimulatory effects of T4 on the heart, and this sensitivity should be considered in the rehabilitation process associated with these patients.

Antithyroid Drugs

Thioamides

Propylthiouracil (PTU) and methimazole are small sulfur-containing molecules that inhibit thyroid hormone production by several mechanisms. The most important mechanism is blocking iodination of the tyrosine residues of thyroglobulin (Figure 22–3). In addition, these drugs may block coupling of DIT and MIT. The thioamides can be taken orally and are effective in most patients with uncomplicated hyperthyroidism. Because synthesis (rather than release) of thyroid hormone is inhibited, the onset of activity of these drugs is usually slow, often requiring 3 to 4 weeks for full effect. However, high-dose PTU also inhibits the conversion of T4 to T3. PTU is less likely than methimazole to cross the placenta and enter breast milk, but it should be used cautiously in pregnant and nursing women. The most common toxic effect is skin rash. Rarely, severe immune reactions occur, but these are usually reversible. These include vasculitis, hypoprothrombinemia , and agranulocytosis.

Iodide Salts and Iodine

Iodide salts inhibit thyroid hormone release; possibly by inhibiting thyroglobulin proteolysis (Figure 22–3). These salts also decrease the size and vascularity of the hyperplastic thyroid gland. Because iodide salts inhibit release as well as synthesis of thyroid hormones, their onset of action occurs relatively rapidly—within 2 to 7 days. However, their effects are transient; the thyroid gland “escapes” from the iodide block after several weeks of treatment. Iodide salts are used to manage severe hyperthyroidism, a “thyroid storm” (life-threatening sudden acute exacerbation of all of the symptoms of hyperthyroidism), and to prepare patients for surgical resection of a hyperactive thyroid. The usual forms of this drug are oral solutions such as Lugol’s solution (iodine and potassium iodide) or saturated solution of potassium iodide.

Radioactive Iodine and Iodinated Radiocontrast Media

Radioactive iodine (131I) is taken up and concentrated in the thyroid gland so avidly that a dose large enough to damage the gland severely can be given without endangering other tissues. Unlike the thioamides and iodide salts, an effective dose of 131I can produce a permanent cure of hyperthyroidism without surgery. 131I should not be used in pregnant or nursing women.

Certain iodinated radiocontrast media, such as ipodate, effectively suppress the conversion of T4 to T3 in the liver, kidney, and other peripheral tissues (Figure 22–3). Inhibition of hormone release from the thyroid may also play a part. Ipodate is useful for rapidly reducing T3 concentrations in hyperthyroidism.

Other Drugs

Other agents used in the treatment of hyperthyroidism include the β-adrenergic receptorantagonists (Chapter 6). These agents are particularly useful in controlling the tachycardia and other cardiac abnormalities of severe hyperthyroidism. Propranolol also inhibits the conversion of T4 to T3 (Figure 22–3). Finally, a number of other drugs not used in the treatment of thyroid dysfunction may affect thyroid hormone levels by altering thyroid hormone synthesis, transport, or metabolism (Table 22–3).

The gonadal hormones include the steroids of the ovary (estrogens and progesterone) and testis (chiefly testosterone) (Figure 22–4). Because of their use as contraceptives, many synthetic estrogens and progesterone receptoragonists have been produced. These include receptor agonists, partial agonists, antagonists, and some drugs with mixed effects. Drugs with mixed effects demonstrate agonist effects in some tissues and antagonist effects in other tissues. Mixed agonists with estrogenic effects are called selective estrogen receptor modulators (SERMs). Synthetic androgens, all of which have anabolic activity, are also available for clinical use. A diverse group of drugs with antiandrogenic effects are also used in the treatment of prostatic cancer, benign prostatic hyperplasia, and hirsutism in women.

Ovarian Hormones

The ovary is the primary source of sex hormones in women during the childbearing years (i.e., between puberty and menopause). During each menstrual cycle, in response to FSH and LH from the anterior pituitary, a follicle in the ovary matures, secretes increasing amounts of estrogen, releases an ovum, and finally transforms into a progesterone-secreting corpus luteum. If the ovum is not fertilized and implanted, the corpus luteum degenerates. The uterine endometrium, which proliferated as a result of stimulation by estrogen, is shed as part of the menstrual flow, and the cycle repeats. Both estrogen and progesterone enter into cells and bind to cytosolic receptors. The receptor–hormone complex translocates into the nucleus, where it modulates gene expression.

Estrogens

The major ovarian estrogen in women is estradiol. Although estradiol has low oral bioavailability, its bioavailability is increased in a micronized form. The drug can also be administered via transdermal patch or vaginal cream. Long-acting esters of estradiol that are converted in the body to estradiol, such as estradiol cypionate, can be administered by IM injection. Mixtures of conjugated estrogens from biologic sources (e.g., Premarin) are used orally for hormone replacement therapy (HRT). Ethinyl estradiol and mestranol are synthetic estrogens with high bioavailability that are used in hormonal contraceptives.

Physiologic Effects

Estrogen is essential for normal female sexual development. The hormone is responsible for growth of the vagina, uterus, and uterine tubes during childhood, appearance of secondary sexual characteristics, and the growth spurt associated with puberty. Estrogen also has multiple metabolic effects. The hormone modifies serum protein levels and reduces bone resorption. Estrogen also enhances blood coagulability and increases plasma triglyceride and high-density lipoprotein (HDL) cholesterol levels while reducing low-density lipoprotein (LDL) cholesterol. Continuous administration of estrogen, especially in combination with a progestin, inhibits the secretion of gonadotropins from the anterior pituitary (Figure 22–5).

Clinical Use

Estrogens are used in the treatment of hypogonadism in young females (Table 22–4). Another use is as HRT in women with estrogen deficiency resulting from premature ovarian failure, menopause, or surgical removal of the ovaries. HRT ameliorates hot flushes and atrophic changes in the urogenital tract. Estrogen is also effective in preventing bone loss and osteoporosis; however, there is an increased risk of adverse cardiovascular events and breast cancer when estrogen is used by postmenopausal women for this pharmacologic effect. Finally, the estrogens are components of hormonal contraceptives (see discussion below).

Adverse Effects

In hypogonadal girls, the dose of estrogen must be adjusted carefully to prevent premature closure of the epiphyses of the long bones, resulting in short stature. The relationship between long-term estrogen therapy and cancer continues to be actively investigated. When used alone for HRT in women with a uterus, estrogen increases the risk of endometrial cancer. However, this effect can be prevented by combining estrogen with a progestin. Estrogen use by postmenopausal women is also associated with a small increase in the risk of breast cancer, myocardial infarction, and stroke. These increased risks are not ameliorated by concurrent progestin therapy. Dose-dependent toxicities include nausea, breast tenderness, increased risk of migraine headache, thromboembolic events (e.g., deep vein thrombosis), gallbladder disease, hypertriglyceridemia, and hypertension.

Progestins

Progesterone is the major progestin in humans. Micronized form is used orally for HRT and progesterone-containing vaginal creams are also available. Synthetic progestins (e.g., medroxyprogesterone) have improved oral bioavailability. The 19-nortestosterone compounds differ primarily in their degree of androgenic effects. Older drugs such as l-norgestrel and norethindrone are more androgenic than the newer progestins such as norgestimate and desogestrel.

Physiologic Effects

Progesterone induces secretory changes in the endometrium and is required for the maintenance of pregnancy. Other progestins also stabilize the endometrium but do not support pregnancy. Progestins do not significantly affect plasma proteins, but they affect carbohydrate metabolism and stimulate fat deposition. High doses suppress gonadotropin secretion and often prevent ovulation.

Clinical Use

Progestins are used as contraceptives, either alone or in combination with an estrogen. As previously discussed, they are used in combination with an estrogen in HRT to prevent estrogen-induced endometrial cancer. Progesterone is used in assisted reproductive technology programs to promote and maintain pregnancy.

Adverse Effects

The toxicity of progestins is low. However, they may increase blood pressure and decrease high-density plasma lipoprotein (HDL) cholesterol. Long-term use of high doses in premenopausal women is associated with a reversible decrease in bone density and delayed resumption of ovulation after termination of therapy.

Hormonal Contraceptives

Hormonal contraceptives contain either a combination of an estrogen and a progestin or a progestin alone. Hormonal contraceptives are available in a variety of preparations, including oral pills, long-acting injections, transdermal patches, vaginal rings, and intrauterine devices (IUDs) (Table 22–4). Three different types of oral contraceptives for women are available in the United States. Monophasic preparations are a combination of estrogen-progestin tablets that are taken in constant dosage throughout the menstrual cycle. Biphasic and triphasic preparations are combination preparations in which the progestin or estrogen dosage, or both, changes during the month to more closely mimic hormonal changes in a menstrual cycle. The third type of preparation contains only progestin.

The postcoital contraceptives (also known as “emergency contraception”) will prevent pregnancy if administered within 72 hours after unprotected sexual intercourse. Several types of oral preparations are effective: estrogens alone, l-norgestrel (progestin alone), combination pills containing an estrogen and a progestin, and mifepristone (RU 486), a progesteroneantagonist.

Mechanism of Action

The combination hormonal contraceptives have several actions. The primary action is inhibition of ovulation. Additional changes in the cervical mucus glands, uterine tubes, and endometrium also decrease the likelihood of fertilization and implantation. Progestin-only agents do not always inhibit ovulation and instead act through the other mechanisms listed. The mechanisms of action of postcoital contraceptives are not well understood. When administered before the LH surge, they inhibit ovulation. They also affect cervical mucus, tubal function, and endometrial lining.

Other Clinical Uses and Beneficial Effects

Additional clinical uses of combination hormonal contraceptives are presented in Table 22–4. Combination hormonal contraceptives are used to prevent estrogen deficiency in young women with primary hypogonadism after their growth has been achieved. Combinations of hormonal contraceptives and progestins are used to treat acne, hirsutism, dysmenorrhea, and endometriosis. Users of combination hormonal contraceptives have reduced risks of ovarian cysts, ovarian and endometrial cancer, benign breast disease, and pelvic inflammatory disease as well as a lower incidence of ectopic pregnancy, iron deficiency anemia, and rheumatoid arthritis.

Adverse Effects

The incidence of dose-dependent toxicity has fallen since the introduction of the low-dose combined oral contraceptives. The most notable adverse effects include thromboembolism and a potentially increased risk of developing breast cancer at a younger age.

Increased risk of thromboembolism results from the effect of the combined hormonal contraceptives’ estrogenic component on liver synthesis of blood coagulation factors. There is a well-documented increase in the risk of thromboembolic events in older women, smokers, women with a personal or family history of such problems, and women with genetic defects that affect the production or function of clotting factors. This increased risk results in an elevated potential for myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism. However, risk of thromboembolism incurred by the use of combined hormonal contraceptives is usually less than that imposed by pregnancy.

Evidence also suggests that the lifetime risk of breast cancer in women who are current or past users of hormonal contraceptives is not affected by oral contraceptive use, but there may be an earlier onset of breast cancer.

The potential for other toxicities also exists. The low-dose combined oral and progestin-only contraceptives cause significant breakthrough bleeding, especially during the first few months of therapy. Other toxicities of the hormonal contraceptives include nausea, breast tenderness, headache, skin pigmentation, and depression. Preparations containing older, more androgenic progestins can cause weight gain, acne, and hirsutism. The high dose of estrogen in the estrogen-containing postcoital contraceptives is associated with significant nausea.

Selective Estrogen Receptor Modulators

Selective estrogen receptor modulators (SERMs) are mixed estrogen receptor ligands that act as agonists in some tissues and as partial agonists or antagonists in other tissues.

Tamoxifen is a SERM effective in the treatment of hormone-responsive breast cancer, where it acts as an antagonist to prevent receptor activation by endogenous estrogens (Figure 22–5). Prophylactic use of tamoxifen reduces the incidence of breast cancer in women who are at very high risk. However, tamoxifen acts as an agonist at endometrial estrogen receptors, causing hyperplasia and increasing the risk of endometrial cancer. Tamoxifen can cause hot flushes, reflecting an antagonist effect, whereas it also increases risk of venous thrombosis, an agonist effect. In bone, tamoxifen has more agonist than antagonist estrogenic actions, thus preventing osteoporosis in women who are taking the drug for breast cancer. Toremifene is structurally related to tamoxifen and has similar properties, indications, and toxicities.

Raloxifene, which is approved for prevention of osteoporosis in postmenopausal women and the prevention of breast cancer in high-risk women, has a partial agonist effect on bone. Like tamoxifen, raloxifene has antagonist effects in breast tissue and reduces the incidence of breast cancer in women who are at very high risk. Unlike tamoxifen, the drug has no estrogenic effects on endometrial tissue. Adverse effects also include hot flushes and increased risk of venous thrombosis.

Other Estrogen and Progesterone Agonists, Antagonists, and Synthesis Inhibitors

Clomiphene is used to induce ovulation in anovulatory women who wish to become pregnant. The drug is a nonsteroidal compound with tissue-selective actions. By selectively blocking estrogen receptors in the anterior pituitary, clomiphene reduces negative feedback and increases FSH and LH secretion. This increase in gonadotropins stimulates ovulation.

Mifepristone (RU 486) is an orally active steroid antagonist of progesterone and glucocorticoidreceptors. Mifepristone is primarily used as an abortifacient in early pregnancy, up to 49 days after the last menstrual period. When given as a single oral dose followed by administration of a prostaglandin E or prostaglandin F analog, a very high percentage of complete abortion is achieved with a low incidence of serious toxicity.

Danazolis a weak partial agonist that binds to progestin, androgen, and glucocorticoidreceptors. Danazol also inhibits several P450 enzymes involved in gonadal steroid synthesis. The drug is sometimes used in the treatment of endometriosis and fibrocystic breast disease.

Aromatase inhibitors such as anastrozole and related compounds are nonsteroidal inhibitors of aromatase, the enzyme required for estrogen synthesis. These drugs are used in the treatment of breast cancer (Chapter 31).

Androgens

The hypothalamic-pituitary control of the secretion of testosterone and related androgens is presented in Figure 22–6. Testosterone and related androgens are produced in the testis, the adrenal gland, and, to a small extent, the ovary. Testosterone is synthesized from progesterone and dehydroepiandrosterone (DHEA). The latter also has a sulfated form (DHEAS). In the plasma, testosterone is partly bound to a transport protein, sex hormone–binding globulin (SHBG). Testosterone itself is active in some tissues, but it is converted in several organs (such as the prostate gland) to dihydrotestosterone (DHT), which is the active hormone in those tissues. Because of rapid hepatic metabolism, orally administered testosterone has little effect. The drug may be given by injection of long-acting esters or as a transdermal patch. Orally active variants are also available (Table 22–4).

Many androgens have been synthesized in an effort to increase anabolic effects (increasing muscle mass) without increasing androgenic actions (producing masculine characteristics). Oxandrolone and stanozolol are examples of drugs that, in laboratory testing, have an increased ratio of anabolic:androgenic action. However, all of the so-called anabolic steroids have androgenic agonist effects when used in humans.

Physiologic Effects

Like the steroid hormones discussed previously, androgens enter cells and bind to cytosolic receptors (Figure 22–6). The hormone–receptor complex enters the nucleus and modulates the expression of target genes. Testosterone is necessary for normal development of the male fetus and infant and is responsible for major changes in the male at puberty. These changes include growth of the penis, larynx, and skeleton; development of facial, pubic, and axillary hair; darkening of skin; and enlargement of muscle mass. After puberty, testosterone maintains secondary sex characteristics, fertility, and libido. Finally, testosterone (as dihydrotestosterone) acts on hair cells to cause male-pattern baldness.

The major effect of androgens, in addition to development and maintenance of normal male characteristics, is an anabolic action that involves increased muscle size and strength and increased red blood cell production. Urea excretion is reduced, and nitrogen balance becomes more positive. Testosterone also helps maintain normal bone density.

Clinical Use

The primary clinical use of the androgens is for replacement therapy in hypogonadism (Table 22–4). They have also been used to stimulate red blood cell production in certain anemias and to promote weight gain in patients with wasting syndromes (e.g., AIDS-associated wasting). The anabolic effects have been exploited illicitly by athletes in attempts to increase muscle mass and strength and enhance athletic performance. Therefore, they are banned by amateur and professional athletic organizations.

Adverse Effects

Use of androgens by females results in menstrual irregularity and virilization, which includes hirsutism, enlarged clitoris, and deepening of the voice. In women who are pregnant with a female fetus, exogenous androgens can cause virilization of the fetus’ external genitalia. Paradoxically, excessive doses of androgens in men can result in feminization, which is characterized by gynecomastia, testicular shrinkage, and infertility. This feminization results from feedback inhibition of the anterior pituitary and conversion of exogenous androgens to estrogens. High doses in males also cause behavioral changes including hostility and aggression (“roid rage”) (Chapter 21). In both sexes, high doses of anabolic steroids can cause cholestatic jaundice, elevation of liver enzyme levels, possibly hepatocellular carcinoma, increased lipid levels (resulting in atherosclerosis), and sodium retention (resulting in hypertension).

Antiandrogens

Decreasing the effects of androgens is an important mode of therapy for both benign and malignant prostate disease, precocious puberty, hair loss, and hirsutism. Several drugs are available that act at different sites in the androgen pathway (Figure 22–6).

Gonadotropin-Releasing Hormone Analogs

A reduction in gonadotropin secretion, especially LH secretion, lowers the production of testosterone. As described earlier, this can be effectively accomplished with long-acting depot preparations of leuprolide or similar GnRHagonists. These analogs are used in prostatic carcinoma. During the first week of therapy, an androgenreceptorantagonist such as flutamide is added to prevent the tumor flare that can result from the surge in testosterone synthesis caused by the initial agonist action of the GnRH analog. Within several weeks, testosterone production falls to normal and then far below normal.

Inhibitors of Steroid Synthesis

All steroid hormones are derivatives of cholesterol. Steroid hormones include the gonadal hormones discussed here and the corticosteroids discussed in Chapter 23. Ketoconazole, an antifungal agent (Chapter 29), inhibits cytochrome P450 enzymes necessary for the synthesis of gonadal and adrenal steroids. Ketoconazole has been used to suppress adrenal steroid synthesis in patients with steroid-responsive metastatic tumors. Part of the antiandrogen effect of spironolactone, a drug used principally as a potassium-sparing diuretic (Chapter 7), is due to its inhibition of 17α-reductase, an enzyme involved in androgen synthesis.

5α-Reductase Inhibitors

Testosterone is converted to DHT by the enzyme 5α-reductase. Some tissues, most notably the prostate and hair follicles, depend on DHT rather than testosterone for androgenic stimulation. 5α-Reductase is inhibited by finasteride, a drug used to treat benign prostatic hyperplasia and, at a lower dose, to prevent hair loss in men. Because the drug does not interfere with the action of testosterone, it is less likely than other antiandrogens to cause impotence, infertility, and loss of libido.

Receptor Inhibitors

Flutamide and related drugs are nonsteroidal compounds that act as competitive antagonists at androgenreceptors. These drugs are used to decrease the action of endogenous androgens in patients with prostate carcinoma. The diuretic spironolactone also inhibits androgen receptors, and is used in the treatment of hirsutism.

Combined Hormonal Contraceptives

Combined hormonal contraceptives exert an antiandrogenic effect when they are used in women with hirsutism, which is caused by excess production of androgenic steroids. The estrogen in the contraceptive causes the liver to increase production of sex hormone–binding globulin, which in turn acts to reduce the concentration of free androgen in the blood.

Many endocrine drugs directly influence the practice of the physical therapist, while others directly influence patients’ responses to the rehabilitation process.

Many postmenopausal women use estrogens and progestins for HRT. A small number of these women experience breast or endometrial cancers, or cardiovascular events to which the HRT contributed. Subsequent rehabilitation may be required by these patients. Androgen supplementation in geriatric males with hypogonadism or decreased testosterone levels improves bone mineral density and exercise tolerance. However, abuse of these drugs by athletes promotes abnormal distribution of cholesterol in serum lipoproteins and increases the risk of atherosclerosis and cardiovascular morbidities. Physical therapists should be aware of these adverse effects and counsel athletes appropriately.

Drugs that affect endocrine function may also directly influence the response of the patient to rehabilitation. For example, excessive supplementation with thyroxine (T4) presents as hyperthyroidism. The cardiovascular and respiratory dysfunction caused by hyperthyroidism may not appear at rest, but can be precipitated with exercise.

Adverse Drug Reactions

• Thyroid hormones
  • • Exercise intolerance associated with both hyperthyroidism and hypothyroidism
  • • Intolerance to temperature changes
  • • Hypothyroidism: cold intolerance
  • • Hyperthyroidism: heat intolerance
• Estrogens and progesteronereceptors agonists
  • • Deep vein thrombosis
  • • Myocardial infarction
  • • Hypertension

Effects Interfering with Rehabilitation

• • Decreased capacity to participate in aerobic conditioning due to thyroid dysfunction
• • Increased risk for embolic event during therapy
• • Increased risk of myocardial infarction during therapy

Possible Therapy Solutions

• • Examine for potential deep vein thrombosis prior to therapy.
• • Check heart rate and blood pressure prior to and following therapy.

Potentiation of Functional Outcomes Secondary to Drug Therapy

• • Progressive resistance training has been shown to augment increases in strength and lean body mass by testosterone analogs in certain patient populations with cachexia (i.e., wasting).

Brief History: The patient is a 53-year-old female with a 10-year history of mild hypertension that is stabilized with current medications. She also has a 1-year history of bipolar disorder that is being pharmacologically treated. The patient was diagnosed 3 weeks ago with fibromyalgia. She is working with a physical therapist at an outpatient clinic and wellness center to develop an exercise program to assist in pain relief prior to an alternative treatment option of strong analgesics. The patient has been actively participating in the exercise program at the wellness center. She has an appointment with the therapist on a weekly basis for review of the exercise program and assessment of her fibromyalgia symptoms.

Current Medical Status and Drug Therapy: Recent blood pressure measurements were 130/82 mm Hg with a heart rate of 80 beats per minute. Medications include enalapril and hydrochlorothiazide/amiloride combination for hypertension. Bipolar disorder is being treated with lithium carbonate. One week ago, the patient was also diagnosed with functional hypothyroidism that probably resulted from the lithium treatment. The patient was prescribed levothyroxine and started the medication that day.

Rehabilitation Setting: The patient arrived for the weekly assessment with the physical therapist. She complained that within the past week her muscle weakness increased and her ability to perform the exercise program decreased significantly. Specifically, she was short of breath during her work on the stationary bicycle. Additionally, pain complaints associated with her fibromyalgia increased. The therapist measured her blood pressure and heart rate at 142/86 mm Hg and 96 beats per minute and irregular.

Problem/Clinical Options: The exogenous thyroid medication the patient recently started has resulted in hyperthyroidism. The adverse effects of the medication did not manifest until the patient was exercising. Hyperthyroidism decreased the patient’s exercise tolerance directly through an effect on skeletal muscles and indirectly through decreased cardiac and pulmonary function. Finally, the chronic pain associated with the fibromyalgia was heightened. The therapist should recommend that the patient discontinue her exercise program until she is reevaluated by her physician. Because atrial fibrillation is likely, the therapist should immediately inform the physician of these signs and symptoms of hyperthyroidism.

Hypothalamic and Pituitary Agents

Bromocriptine (Parlodel)

Oral: 2.5-mg tablets, 5-mg capsules

Cabergoline (Dostinex)

Oral: 0.5-mg scored tablets

Cetrorelix (Cetrotide)

Parenteral 0.25, 3 mg/vial with diluent for subcutaneous injection

Chorionic gonadotropin (hCG) (generic, Profasi, A.P.L., Pregnyl, others)

Parenteral powder to reconstitute 500, 1000, 2000 units/mL for injection

Corticorelin ovine (Acthrel)

Parenteral 0.1 mg for IV injection

Corticotropin (H.P. Acthar Gel)

Parenteral 80 units/mL

Cosyntropin (Cortrosyn)

Parenteral 0.25 mg/vial with diluent for IV or IM injection

Follitropin alfa (Gonal-F)

Parenteral 37.5, 150 IU powder for injection

Follitropin beta (FSH) (Follistim)

Parenteral 75 IU powder for injection

Ganirelix (Antagon)

Parenteral 500 mcg/mL for injection

Gonadorelin acetate (GnRH) (Lutrepulse)

Parenteral powder to reconstitute for injection via Lutrepulse pump (0.8, 3.2 mg/vial)

Gonadorelin hydrochloride (GnRH) (Factrel)

Parenteral 100, 500 mg for injection

Goserelin acetate (Zoladex)

Parenteral 3.6-, 10.8-mg subcutaneous implant

Histrelin (Supprelin)

Parenteral 120, 300, 600 mg for subcutaneous injection

Leuprolide (generic, Lupron)

Parenteral 5 mg/mL for subcutaneous injection

Parenteral depot suspension (Lupron Depot, Depot-Ped, Depot-3, Depot-4): lyophilized microspheres to reconstitute for IM injection (3.75, 7.5, 11.25, 15, 22.5, 30 mg/vial)

Parenteral implant: 72 mg

Menotropins (hMG) (Pergonal, Repronex)

Parenteral 75 IU FSH and 75 IU LH activity, 150 IU FSH and 150 IU LH activity, each with diluent

Nafarelin (Synarel)

Nasal: 2 mg/mL (200 mcg/spray)

Octreotide (Sandostatin)

Parenteral 0.05, 0.1, 0.2, 0.5, 1 mg/mL for subcutaneous or IV administration

Parenteral depot injection (Sandostatin LAR Depot): 10, 20, 30 mg for IM injection only

Pergolide (Permax)

Oral: 0.05-, 0.25-, 1-mg tablets

Protirelin (Thypinone, Relefact TRH, Thyrel TRH)

Parenteral 500 mg/mL for injection

Sermorelin (Geref)

Parenteral 0.5, 1 mg for subcutaneous injection; 50-mcg powder to reconstitute for intravenous injection

Somatrem (Protropin)

Parenteral 5, 10 mg/vial with diluent for subcutaneous or IM injection

Somatropin (Genotropin, Humatrope, Nutropin, Nutropin Aq, Norditropin, Serostim, Saizen)

Parenteral 0.2, 0.4, 0.6, 0.8, 1.0, 1.2, 1.4, 1.5, 1.6, 1.8, 2, 4, 5, 5.8, 6, 8, 10, 12, 13.5, 13.8, 15, 18, 22.5, 24 mg/vial with diluent for subcutaneous or IM injection

Thyrotropin alpha (Thyrogen)

Parenteral 1.1 mg (4 IU)/vial with diluent for IM injection

Triptorelin (Trelstar)

Parenteral 3.75, 11.25 mg for IM injection

Urofollitropin (Fertinex, Bravelle)

Parenteral powder to reconstitute for injection, 75, 150 IU FSH activity per ampule

Thyroid Agents

Levothyroxine (T4) (generic, Levoxyl, Levo-T, Synthroid, Unithroid)

Oral: 0.025-, 0.05-, 0.075-, 0.088-, 0.1-, 0.112-, 0.125-, 0.137-, 0.15-, 0.175-, 0.2-, 0.3-mg tablets

Parenteral 200, 500 mcg per vial (100 mcg/mL when reconstituted) for injection

Liothyronine (T3) (generic, Cytomel, Triostat)

Oral: 5-, 25-, 50-mcg tablets

Parenteral 10 mcg/mL

Liotrix (a 4:1 ratio of T4:T3) (Thyrolar)

Oral: tablets containing 12.5, 25, 30, 50, 60, 100, 120, 150, 180 mcg T4 and one-fourth as much T3

Thyroid desiccated (USP) (generic, Armour Thyroid, Thyroid Strong, Thyrar, S-P-T)

Oral: tablets containing 15, 30, 60, 90, 120, 180, 240, 300 mg; capsules (S-P-T) containing 120, 180, 300 mg

Antithyroid Agents

Diatrizoate sodium (Hypaque)

Parenteral 25% (150 mg iodine/mL); 50% (300 mg iodine/mL) (unlabeled use)

Iodide (131I) sodium (Iodotope, Sodium Iodide I131 Therapeutic)

Oral: available as capsules and solution

Iopanoic acid (Telepaque)

Oral: 500-mg tablets (unlabeled use)

Ipodate sodium (Oragrafin Sodium, Bilivist)

Oral: 500-mg capsules (unlabeled use)

Methimazole (Tapazole)

Oral: 5-, 10-mg tablets

Potassium Iodide

Oral solution (generic, SSKI): 1 g/mL

Oral solution (Lugol solution): 100 mg/mL potassium iodide plus 50 mg/mL iodine

Oral syrup (Pima): 325 mg/5 mL

Oral controlled-action tablets (Iodo-Niacin): 135 mg potassium iodide plus 25 mg niacinamide hydroiodide

Oral potassium iodide tablets (generic, IOSAT, RAD-Block, Thyro-Block): 65, 130 mg

Propylthiouracil (PTU) (Generic)

Oral: 50-mg tablets

Thyrotropin; Recombinant Human TSH (Thyrogen)

Parenteral 0.9 mg per vial

Estrogens

Conjugated Estrogens (Premarin)

Oral: 0.3-, 0.625-, 0.9-, 1.25- 2.5-mg tablets

Parenteral 25 mg/5 mL for IM, IV injection

Vaginal: 0.625 mg/g cream base

Dienestrol (Ortho Dienestrol, Dv)

Vaginal: 10 mg/g cream

Diethylstilbestrol Diphosphate (Stilphostrol)

Oral: 50-mg tablets

Parenteral 50 mg/mL injection

Esterified Estrogens (Menest, Estratab)

Oral: 0.3-, 0.625-, 1.25-, 2.5-mg tablets

Estradiol Cypionate in Oil (Generic, Depo-Estradiol Cypionate)

Parenteral 5 mg/mL for IM injection

Estradiol (Generic, Estrace)

Oral: 0.5-, 1-, 2-mg tablets

Vaginal: 0.1 mg/g cream

Estradiol Transdermal (Estraderm, Others)

Transdermal: patches with 0.025, 0.0375, 0.05, 0.075, 0.1 mg/d release rates

Estradiol Valerate in Oil (Generic)

Parenteral 10, 20, 40 mg/mL for IM injection

Oral contraceptives are listed in Table 22–3.

Estrone Aqueous Suspension (Generic, Kestrone 5)

Parenteral 5 mg/mL for injection

Estropipate (Generic, Ogen)

Oral: 0.625-, 1.25-, 2.5-, 5-mg tablets

Vaginal: 1.5 mg/g cream base

Ethinyl Estradiol (Estinyl)

Oral: 0.02-, 0.05-, 0.5-mg tablets

Progestins

Etonogestrel (Implanon)

Kit for subcutaneous implant; 1 rod of 68 mg

Hydroxyprogesterone Caproate (Generic, Hylutin)

Parenteral 125, 250 mg/mL for IM injection

Medroxyprogesterone Acetate (Generic, Provera)

Oral: 2.5-, 5-, 10-mg tablets

Parenteral (Depo-Provera): 150, 400 mg/mL for IM injection

Megestrol Acetate (Generic, Megace)

Oral: 20-, 40-mg tablets; 40 mg/mL suspension

Norethindrone Acetate (Generic, Aygestin)

Oral: 5-mg tablets

Norgestrel (Ovrette) (Also Table 22–3)

Oral: 0.075-mg tablets

Progesterone (Generic)

Oral: 100-mg capsules

Topical: 8% vaginal gel

Parenteral 50 mg/mL in oil for IM injection

Androgens and Anabolic Steroids

Fluoxymesterone (Generic, Halotestin)

Oral: 2-, 5-, 10-mg tablets

Methyltestosterone (Generic)

Oral: 10-, 25-mg tablets; 10-mg capsules; 10-mg buccal tablets

Parenteral 200 mg/mL injection

Nandrolone Decanoate (Deca-Durabolin, Others)

Parenteral 100, 200 mg/mL in oil for injection

Oxandrolone (Oxandrin)

Oral: 2.5-mg tablets

Oxymetholone (Androl-50)

Oral: 50-mg tablets

Stanozolol (Winstrol)

Oral: 2-mg tablets

Testolactone (Teslac)

Oral: 50-mg tablets

Testosterone Aqueous (Generic, Others)

Parenteral 25, 50, 100 mg/mL suspension for IM

Testosterone Cypionate in Oil (Generic, Others)

Parenteral 100, 200 mg/mL for IM injection

Testosterone Enanthate in Oil (Generic)

Parenteral 200 mg/mL for IM injection

Testosterone Propionate in Oil (Generic, Testex)

Parenteral 100 mg/mL for IM injection

Testosterone transdermal system

Patch (Testoderm): 4, 5, 6 mg/24 h release rate

Patch (Androderm): 2.5, 5 mg/24 h release rate

Gel (Androgel): 25, 50 mg total

Testosterone pellets (Testopel)

Parenteral 75 mg/pellet for parenteral injection (not IV)

SERMs, Antagonists, and Inhibitors

Anastrozole (Arimidex)

Oral: 1-mg tablets

Bicalutamide (Casodex)

Oral: 50-mg tablets

Clomiphene (Generic, Clomid, Serophene, Milophene)

Oral: 50-mg tablets

Danazol (Generic, Danocrine)

Oral: 50-, 100-, 200-mg capsules

Dutasteride (Avodart)

Oral: 0.5-mg tablets

Exemestane (Aromasin)

Oral: 25-mg tablets

Finasteride

Oral: 1-mg tablets (Propecia); 5-mg tablets (Proscar)

Flutamide (Eulexin)

Oral: 125-mg capsules

Fulvestrant (Faslodex)

Parenteral 50 mg/mL for IM injection

Letrozole (Femara)

Oral: 2.5-mg tablets

Mifepristone (Mifeprex)

Oral: 200-mg tablets

Nilutamide (Nilandron)

Oral: 50-, 150-mg tablets

Raloxifene (Evista)

Oral: 60-mg tablets

Tamoxifen (Generic, Nolvadex)

Oral: 10-, 20-mg tablets

Toremifene (Fareston)

Oral: 60-mg tablets