Androgens

CHAPTER 65


Androgens


Androgen hormones are produced by the testes, ovaries, and adrenal cortex. The major endogenous androgen is testosterone. Androgens are noted most for their ability to promote expression of male sex characteristics. However, androgens also influence sexuality in females. In addition, androgens have significant physiologic and pharmacologic effects unrelated to sex. The primary clinical application of the androgens is management of androgen deficiency in males. Principal adverse effects are virilization and hepatotoxicity.




Testosterone


Testosterone is the prototype of the androgen hormones. This compound is the principal endogenous androgen in both males and females. In addition to its physiologic role, testosterone is representative of the androgens employed clinically. The structural formula of testosterone is shown in Figure 65–1.


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Figure 65–1  Structural formulas of representative androgens.


Biosynthesis and secretion




Males.

Testosterone is made by Leydig cells of the testes. Daily production in men ranges from 2.5 to 10 mg. Synthesis is promoted by two hormones of the anterior pituitary: follicle-stimulating hormone (FSH) and luteinizing hormone (LH), also known as interstitial cell–stimulating hormone. Production of testosterone is regulated by negative feedback control: Rising plasma levels of testosterone act on the pituitary to suppress further release of FSH and LH, thereby decreasing the stimulus for further testosterone formation.


Some of the testosterone present in plasma is produced by the adrenals. However, androgenic activity of adrenal origin is much less than that of testicular origin. Hence, in males, adrenal androgens have minimal functional significance.


Testosterone production changes over time. Peak production occurs around age 17. Production then remains steady until age 30 or 40, after which it slowly declines. By the time a man reaches 80, testosterone production is only half what it was in his youth.





Physiologic and pharmacologic effects



Effects on sex characteristics in males


Pubertal transformation.

Increased production of testosterone promotes the transformations that signal puberty in males. Under the influence of testosterone, the testes enlarge, after which the penis and scrotum enlarge. Pubic and axillary hair appear, and hair on the trunk, arms, and legs assumes adult male patterns. Testosterone stimulates growth of bone and skeletal muscle, causing height and weight to increase rapidly. Testosterone also accelerates epiphyseal closure, causing bone growth to cease within a few years. The larynx enlarges, thereby deepening the voice. Sebaceous glands increase in number, causing the skin to become oily; acne results if the glands become clogged and infected. The final pubertal change is beard development. Several years are required for all of these changes to occur.







Clinical pharmacology of the androgens


In addition to testosterone, a few other androgens are employed clinically. All of these agents can bind to androgen receptors, and therefore all can elicit similar responses. Major differences among individual androgens pertain to route of administration, pharmacokinetics, adverse effects, and specific applications.



Classification


The androgens used clinically fall into two basic groups: (1) testosterone and testosterone esters, and (2) 17-alpha-alkylated compounds (noted for their hepatotoxicity). Androgens belonging to each group are listed in Table 65–1.



When speaking of testosterone-like compounds, it is traditional to distinguish between “androgens” and “anabolic steroids.” However, we will not make this distinction. Why? Because it is now clear that the receptor type that mediates the androgenic actions of the androgens is the same receptor type that mediates the anabolic actions of these hormones. Consequently, it has not been possible to separate anabolic activity from androgenic activity: Virtually all anabolic hormones are also androgenic. Accordingly, rather than creating two categories—androgens versus anabolic steroids—and assigning some agents to one category and some to the other, we will simply refer to all of the testosterone-like drugs as androgens.



Therapeutic uses


Individual androgens differ in their applications. No single androgen is employed for all of the uses discussed below. Specific applications of individual androgens are summarized in Table 65–1.




Male hypogonadism.

Hypogonadism in males is the principal indication for androgens. In this condition, the testes fail to produce adequate amounts of testosterone, and hence replacement therapy is required. Male hypogonadism may be hereditary or it may result from other causes, including pituitary failure, hypothalamic failure, and primary dysfunction of the testes.


When complete hypogonadism occurs in boys, puberty cannot take place—unless exogenous androgens are supplied. To induce puberty, a long-acting parenteral preparation (testosterone enanthate or testosterone cypionate) is chosen. Injections are given IM every 2 to 4 weeks for 3 to 4 years. Under the influence of these androgens, the normal sequence of pubertal changes occurs: growth is accelerated, the penis enlarges, the voice deepens, and other secondary sex characteristics become expressed. As in normal males, these changes take place over several years.



Replacement therapy.

Androgen replacement therapy is beneficial when testicular failure occurs in adult males. Treatment restores libido, increases ejaculate volume, and supports expression of secondary sex characteristics. However, treatment will not restore fertility. The principal drugs employed for testosterone replacement are testosterone itself and two testosterone esters: testosterone enanthate and testosterone cypionate. Preparations and dosages for replacement therapy are summarized in Table 65–2 and discussed below under Androgen Preparations for Male Hypogonadism. Replacement therapy in older males is discussed further in Box 65–1.



imageBOX 65–1    SPECIAL INTEREST TOPIC


TESTOSTERONE REPLACEMENT: CAN IT ENHANCE SEXUALITY IN MEN? OR WOMEN?


In men


More and more elderly men are taking testosterone, despite limited information on efficacy and safety. Why? Because they want to alleviate aging-related symptoms—specifically, erectile dysfunction, loss of libido, hot flushes, fatigue, muscle atrophy, and depression and other mood disturbances. Unfortunately, there’s little proof that testosterone replacement can help. In fact, there’s not even proof that low testosterone is the cause: Although these symptoms can occur in men with low testosterone levels, they can also occur in older men with normal levels.


In an effort to document the benefits and risks of testosterone replacement, a committee of the Institute of Medicine (IOM) conducted a systematic review of the medical literature. Unfortunately, the committee was unable to reach any firm conclusions. Why? Because even the best relevant studies were of short duration (most covered less than 12 months) and had few subjects (typically less than 50), and most were not placebo controlled. Hence, the committee couldn’t say with certainty that testosterone replacement is either safe or effective. To generate more reliable information, the committee recommended performing (1) short-term, randomized, placebo-controlled trials to evaluate the potential benefits of testosterone, followed by (2) long-term trials to evaluate potential risks.


Although the existing data on testosterone replacement are generally weak, do they tell us anything useful at all? According to the IOM committee, available data suggest—but don’t prove—that testosterone may enhance both libido and sexual function. There’s also pretty good evidence that testosterone can reduce body fat and increase muscle mass, although it may not increase muscle strength. Testosterone may also improve mood, increase energy, and promote a sense of well-being, but does not seem to improve cognition or memory. The IOM committee also identified potential risks. Testosterone stimulates production of red blood cells, and may thereby cause polycythemia. Testosterone can also increase LDL cholesterol (bad cholesterol) and reduce HDL cholesterol (good cholesterol), and may thereby promote cardiovascular disease. Perhaps the greatest concern is prostate cancer. Although testosterone doesn’t cause cancer, it can promote growth of prostate cancer cells.


Given our limited understanding of testosterone therapy, how should replacement be conducted? As with all other treatments, we want to balance benefits and risks. However, since we don’t know what the benefits and risks really are, a cautious approach would seem prudent. According to a recent Endocrine Society clinical practice guideline—2010 Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes—the following principles should be observed:



• Androgen deficiency should be diagnosed only in men with unquestionably low testosterone levels (below 220 ng/dL) plus classic symptoms and signs of testosterone deficiency.


• Testosterone therapy is recommended only for symptomatic men with classic androgen deficiency syndromes.


• The goal of testosterone therapy is to induce and sustain secondary sex characteristics and to improve sexual function, sense of well-being, muscle mass, muscle strength, and bone mineral density.


• Testosterone dosage should be adjusted to achieve serum testosterone levels in the mid-normal range (300 to 450 ng/dL).


• Testosterone therapy is not recommended for men expecting to improve fertility or for men with breast cancer, prostate cancer, a palpable prostate nodule, or poorly controlled heart failure.


These principles represent an interim approach. Once long-term studies on safety and efficacy have been conducted, development of more detailed guidelines should be possible.



In women


Can testosterone replacement enhance the sex lives of menopausal women? Yes. But the benefits are often modest, and only some women respond. Furthermore, the long-term risks are unknown. Nonetheless, testosterone has been used by millions of menopausal women for decades, and continues to be used by millions today.


Why do menopausal women take testosterone? When menopause occurs—either naturally or following oophorectomy (surgical removal of the ovaries)—many women experience a decline in libido. Reduced testosterone is believed to be the cause. Prior to menopause, women produce about 300 mcg of testosterone daily—half is made by the adrenals and half by the ovaries. After menopause, ovarian production stops, and hence testosterone levels drop about 50%. As a result, women may experience a decline in sexual desire, genital sensitivity, and sense of well-being, even with estrogen therapy.


What’s the effect of testosterone therapy? To answer this question, the manufacturer of Intrinsa (a testosterone patch designed for women) conducted clinical trials in women with low testosterone owing to bilateral oophorectomy. All of the women were receiving estrogen replacement and all were in monogamous sexual relationships. And they all suffered from documented hypoactive sexual desire disorder (HSDD), which began after surgically induced menopause. (HSDD is characterized by a persistent reduction in sexual desire that causes significant personal distress.) The testosterone trial was double-blinded, and the women were randomly assigned to receive either a placebo patch or Intrinsa, which delivers low-dose testosterone (only 300 mcg a day). The result? Women using Intrinsa had more sex and were happier about it. Testosterone increased the frequency of sexually satisfying encounters (from a baseline of three encounters per month up to five per month, versus four per month with placebo). In addition, testosterone increased sexual arousal, pleasure, responsiveness, and orgasms; decreased distress regarding sexual encounters; and improved self-image. Benefits began after 4 weeks of treatment, and reached a maximum by week 12. Results of other large studies mirrored those of the Intrinsa trials.


Is low-dose testosterone safe? In the Intrinsa trials, side effects from short-term use were common but generally mild. About 30% of users had application-site reactions. Less common effects were hirsutism (7.3% with Intrinsa vs. 5.9% with placebo), acne (6.7% vs. 5.1%), alopecia (4.2% vs. 2.9%), voice deepening (2.7% vs. 2.2%), migraine (2.7% vs. 1.5%), and weight gain (2% vs. 1.5%). There were no clinically significant effects on cardiovascular parameters, including serum lipid levels, coagulation, blood pressure, and hematology.


What about long-term safety? No one knows. Testing to date has not ruled out the possibility that testosterone therapy could increase the risk of stroke, heart disease, breast cancer, and other disorders. The absence of information on long-term safety is of special concern in light of data from the Women’s Health Initiative, which revealed that long-term estrogen therapy is less beneficial than previously believed—and more dangerous.


Who is a candidate for testosterone replacement? In 2005, after considering this study and many others, the North American Menopause Society (NAMS) issued a position statement on the role of testosterone therapy in women following spontaneous or surgically induced menopause. The statement notes that testosterone can have a positive effect on sexual function—primarily desire, arousal, and orgasmic response—and that women with no other identifiable cause of decreased desire may be candidates for testosterone therapy, provided that estrogen is taken as well. In 2006, The Endocrine Society released its own publication—Androgen Therapy in Women: An Endocrine Society Clinical Practice Guideline—which cautioned against generalized use of testosterone in women, but did recognize that testosterone can be appropriate for specific women, namely those with HSDD resulting from spontaneous or surgically induced menopause.


If a woman, after consultation with her prescriber, wants to try testosterone therapy, what options are available? In the United States, we have no formulations approved for women, and all of the formulations approved for men deliver more testosterone than women need. (Remember, the goal is to mimic premenopausal testosterone production—about 300 mcg/day.) What about Intrinsa? The patch is approved for use in countries in the European Union, but has been denied approval in the United States. Why? Because members of the Reproductive Health Drugs Advisory Committee of the FDA felt that the benefits of Intrinsa were only modest, and that there are concerns regarding possible long-term risks. If not Intrinsa, what can be used? Women still have several options. These include subdermal implantation of a testosterone pellet (eg, 50 mg every 4 to 6 months), IM injection with a long-acting testosterone ester, and use of a topical formulation custom made by a compounding pharmacist. Formulations for topical therapy include testosterone propionate (1% to 2%) in petrolatum and 2% micronized testosterone gel. The testosterone propionate formulation is applied to the genital mucosa. The micronized formulation is applied to the skin of the arm, thigh, or abdomen. For both formulations, the initial daily dosage is one-quarter teaspoon or less. Over time, the frequency of topical administration (genital or dermal) can be reduced to 3 or 4 times per week.

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Jul 24, 2016 | Posted by in NURSING | Comments Off on Androgens

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