Jasmin A. answered • 08/02/22
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Androgen therapy, using injectable, oral and more recently, transdermal preparations, has been available to physicians for many years to treat a variety of male disorders; to a lesser degree, their use has been extended to some female indications. Unlike female sex hormone therapies, which have found extensive use and applications in the fields of hormone replacement, reproductive disorders, gynecological cancers, and contraception, androgen therapy has not been widespread.
A more widely accepted use of androgen therapy has been hampered by the lack of orally active preparations with good efficacy and, particularly, a safe profile. Progress has been limited over the last three decades in developing synthetic molecules that could separate androgenic activities considered desirable (i.e., anabolic) from others that were undesirable or had dose-limiting side effects (1). The abuse of synthetic anabolic steroids by athletes and body builders has contributed to the general perception of certain negative side effects (i.e.,aggressive behavior), effects that we do not expect to see with replacement regimens of testosterone or other androgen receptor agonists that target judicious restoration of physiological functions normally regulated by endogenous androgens.
Recent advances clearly indicate that androgen therapy is about to experience a fundamental change, both in the extent of use and in the range of applications that may benefit from these upcoming advances. Several factors have and will continue to contribute to this change. First, the significant advances of hormone replacement therapy (HRT) in postmenopausal females and the expansion and application of HRT to treat and prevent major disorders such as osteoporosis, cardiovascular disease, breast cancer, mood and cognition, among others, have clearly established the value of novel HRT therapies for improving women’s health (2–4), and by extrapolation, they clearly point out the potential for similar approaches to address men’s health disorders. Second, the development and marketing of novel selective estrogen receptor modulators (SERMs) has provided both preclinical and clinical proof-of-concept that we can develop molecules with a great degree of tissue selectivity targeting the estrogen receptor to eliminate undesired side effects and to maintain (and in the future to enhance) the positive, protective effects of selective transcriptional receptor activation (3–7). Third, significant advances in our understanding of nuclear receptor activation and function have provided the molecular underpinnings for new drug development efforts to design and bring forward a new generation of tissue-selective molecules targeting steroid and other nuclear receptors. Proof-of-concept for tissue selectivity has now been extended to many compounds interacting with different nuclear receptors, such as the estrogen (ER), progesterone (PR), androgen (AR), retinoid (RAR/RXR), and peroxisome proliferation activated receptors (PPARs), among others (6–11).
With the information described above, we have been able to chart a development path and create a profile of desired activity and selective indications for a new class of molecules targeting the androgen receptor. We have chosen the term selective androgen receptor modulators (SARMs) after the terminology currently used for similar molecules targeting the estrogen receptor. Below we briefly describe the molecular mechanisms underlying the potential for selective modulation of AR by different ligands and the opportunities that novel SARMs bring to therapies for broad, as well as selective, uses of androgen therapy, in men as well as in women.
