Osteoporosis Prevention And Treatment104106

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Osteoporosis is an enormous public health problem, responsible for approximately 1.5 million fractures in the United States each year. Because of the prevalence of osteoporosis, especially in older women, the prevention and treatment of this condition have received much attention. Prior to menopause, a good diet and exercise are essential for young women, to decrease the risk of osteoporosis later in life. After menopause, supplemental estrogens can have a positive effect relative to osteoporosis. Estrogens mainly act by decreasing bone resorption, so estrogens are better at preventing bone loss than restoring bone mass. Estrogens taken after menopause (often with a supplemental progestin) have been unequivocally shown to greatly decrease the incidence and severity of osteoporosis, especially when combined with good nutrition and exercise. The long-term use of estrogens plus a progestin for preventing osteoporosis, however, should be carefully evaluated in light of the WHI studies examining HRT for lowering the risk of heart disease (see next page). Alternatives to estrogens for the prevention of osteoporosis, such as raloxifene and bisphosphonates, should also be considered.

TABLE 25.4 Combined Progestin/Estrogen Hormone Replacement Therapy Products (Available in Tablets or a Transdermal Patch)

Brand

Progestin

Estrogen

Prempro

Medroxyprogesterone acetate, 2.5 or 5 mg

Conjugated estrogens, 0.625 mg

Premphasea

Medroxyprogesterone acetate, 5 mg

Conjugated estrogens, 0.625 mg

Femhrt

Norethindrone acetate, 1 mg

Ethinyl estradiol, 5 pg

Activella

Norethindrone acetate, 0.5 mg

Estradiol, 1 mg

Ortho-Prefestb

Norgestimate, 0.09 mg

Estradiol, 1 mg

CombiPatch

Norethindrone acetate, 0.14 or 0.25 mg

Estradiol, 50 pg

"Premphase is dosed 14 days of estrogen-only tablets (0.625-mg conjugated estrogens), followed by 14 days of combined progestin/estrogen.

hOrtho-Prefest is dosed 15 days of estradiol (1 mg) alone, then 15 days of the combined progestin/estrogen.

"Premphase is dosed 14 days of estrogen-only tablets (0.625-mg conjugated estrogens), followed by 14 days of combined progestin/estrogen.

hOrtho-Prefest is dosed 15 days of estradiol (1 mg) alone, then 15 days of the combined progestin/estrogen.

HORMONE REPLACEMENT THERAPY, HEART DISEASE, AND CANCER—WOMEN'S HEALTH INITIATIVE TRIALS107,108

After years of general recommendations for the beneficial use of estrogens after menopause for lowering the risk of heart disease, the results of a long-term study with conjugated estrogens supplemented with a progestin have indicated that the risks of this approach outweigh the benefits. The WHI trial, which enrolled over 16,000 postmenopausal women between 1993 and 1998, was terminated early in 2002 because of an unacceptably high level of adverse effects relative to the benefits gained. With long-term use (average follow-up of 5.2 years), there was a slight increase in the incidence of coronary heart disease, as well as an increase in breast cancer risk. Although there was a slight decrease in the risk of colorectal cancer and fewer hip fractures, the effects on the heart and breast argue against the use of estrogens plus a progestin for the prevention of coronary heart disease in postmenopausal women. A second WHI trial with estrogen alone in postmenopausal women without a uterus was halted in 2004. In this study, with an average of 7 years of follow-up, no effect was seen on heart disease, but there was an increase in stroke risk as well as a decrease in hip fractures. In both studies, a single drug regimen was used (0.625 mg of conjugated equine estrogens alone or with 2.5 mg of MPA), so care should be taken in extending these results to other regimens and products. Several years after the studies were stopped, the medical profession is still analyzing and debating the results of the WHI trials.108,109 It is fair to say that there are many important health issues associated with HRT and each patient should discuss the costs and benefits of HRT with their physicians and pharmacists. In addition to the WHI studies indicating an increase in breast cancer risk, the Million Women Study conducted in the United Kingdom indicated an additional risk of ovarian cancer for women using HRT, with an increase in risk correlating with the duration of use.110

O ANDROGENS111 Endogenous Androgens

Testosterone and its more potent reduction product 5a-DHT are produced in significantly greater amounts in males than in females, but females also produce low amounts of these "male" sex hormones. These endogenous compounds have two important activities: androgenic activity (promoting male sex characteristics) and anabolic activity (muscle building).

DHEA and androstenedione are referred to as adrenal androgens, although this nomenclature is somewhat misleading. DHEA and androstenedione are biosynthetic precursors to the androgens but have only low affinity for the AR themselves.112,113 Therefore, DHEA or androstenedione can have androgenic actions, but only after in vivo conversion to testosterone and DHT. DHEA and androstenedione are, however, also precursors to the estrogens, so estrogenic actions may also occur.

Biosynthesis

As shown in Figure 25.5, testosterone can be synthesized through pregnenolone, DHEA, and androstenedione. About

7 mg/d is synthesized by young human adult males. Labeling experiments have also shown that it can be biosyn-thesized from androst-5-ene-3j6,17j6-diol, a reduction product of DHEA.

Testosterone is primarily produced by the interstitial cells of the testes, synthesized largely from cholesterol made in Sertoli cells. DHT is also secreted by the testes, as well as being produced in other tissues. The ovaries and adrenal cortex synthesize androstenedione and DHEA, which can be rapidly converted to testosterone in many tissues. Testosterone levels in the plasma of men are 5 to 100 times higher than those in the plasma of women.

Testosterone is produced in the testes in response to LH release by the anterior pituitary, as shown in Figure 25.10. Testosterone and DHT inhibit the production of LH and FSH by a feedback-inhibition process. This is quite similar to the feedback inhibition by estrogens and progestins in FSH and LH production.

Metabolism of Androgens

Testosterone is rapidly converted to 5a-DHT in many tissues by the action of 5a-reductase. Depending on the tissue, this is either to activate testosterone to the more potent androgen, DHT (e.g., in the prostate), or a step in the metabolic inacti-vation of this androgen. The primary route for metabolic in-activation of testosterone and DHT is oxidation to the 17-one. The 3-one group is also reduced to the 3a- (major) and 3^-ols (minor). The metabolites are shown in Figure 25.21. Androsterone is the major urinary metabolite and was the first "androgenic" steroid isolated. These metabolites are excreted mainly as the corresponding glucuronides. Other minor metabolites have also been detected.111

Biological Activities of Androgens114

Testosterone and DHT cause pronounced masculinizing effects, even in the male fetus. They induce the development of the prostate, penis, and related sexual tissues. At puberty, the secretion of testosterone by the testes increases greatly, leading to an increase in facial and body hair, deepening of the voice, increased protein anabolic activity and muscle mass, rapid growth of long bones, and loss of some subcutaneous fat. Spermatogenesis begins, and the prostate and seminal vesicles increase in activity. Sexual organs increase in size. The skin becomes thicker, and sebaceous glands increase in number, leading to acne in many young people. The androgens also play important roles in male psychology and behavior. In women, testosterone plays a role in libido, mood, muscle mass and strength, as well as bone density.115,116

Structural Classes: Anabolic Androgenic Steroids

The androgens, also known as anabolic androgenic steroids (AAS), include all of the therapeutic agents whose main actions are mediated by the AR. The inclusion of both anabolic and androgenic in referring to these compounds reflects the fact that no products are currently available in which the anabolic properties of androgens can be separated from the androgenic properties. The commonly used AAS are shown in Figure 25.22. Several recent reviews on AAS have been published.111,117

Testosterone

5a-dihydrotestosterone (DHT) 3a-HSD

Testosterone

17/3-HSD

17/3-HSD

Androstenedione

1) 5a-reductase

Androstenedione

1) 5a-reductase

Epiandrosterone Pathway

Figure 25.21 • Metabolism of testosterone and 5a-DHT (conjugates of the metabolites are also formed). (HSD, hydroxysteroid dehydrogenase.)

Androsterone

Epiandrosterone

Etiocholanolone

Androsterone

Epiandrosterone

Etiocholanolone

Figure 25.21 • Metabolism of testosterone and 5a-DHT (conjugates of the metabolites are also formed). (HSD, hydroxysteroid dehydrogenase.)

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