Marty E. Sawaya’s research while affiliated with University of Miami and other places

Circulating androgens can profoundly influence target cutaneous structures such as the pilosebaceous unit (hair follicle and sebaceous gland), and play a central role in the pathogenesis of cutaneous disorders of hyperandrogenism (CHA) which include androgenetic alopecia (AGA), acne vulgaris, and hirsutism. Therapeutically, two main categories of drugs affect androgens and their activity. The first are ‘antiandrogens’ which are agents that block the androgen receptor (AR) and include spironolactone, flutamide, and cyproterone acetate. The second are ‘androgen inhibitors,’ which block androgen synthesis, and include finasteride and dutasteride (these are specific 5-α reductase inhibitors, that inhibit formation of dihydrotestosterone [DHT]), as well as leuprolide, (which is a gonadotropin-releasing hormone (GnRH) agonist, and works at the level of the ovary and pituitary). In this chapter ‘antiandrogens’ is the term used for specific AR blockers, and the term ‘androgen inhibitors’ will be used to distinguish those compounds that work by suppressing or inhibiting the formation of DHT. Other agents such as progestins and combined oral contraceptives (COC) are both antiandrogens and androgen inhibitors. The various drugs discussed in this chapter are categorized by their most important clinical mode of action. This chapter provides an overview of various antiandrogens (drugs that block the AR) and androgen inhibitors (enzyme inhibitors and other mechanisms). How these specific compounds work, their approved and off-label indications, dosing, and adverse effects will be presented. Particular emphasis is given to spironolactone, finasteride, dutasteride, and oral contraceptives.

Inflammasomes that activate caspase-1 govern the innate immune inflammatory response. Whether hair loss associated with androgenetic alopecia (AGA) involves caspase-1 activation is not known. Immunohistochemical staining for caspase-1 was performed on scalp tissue sections, and protein lysates were analyzed from individuals with AGA (no treatment), and individuals with AGA taking finasteride with apparent hair growth, individuals with AGA taking finasteride without noted hair growth, and normal controls. In vitro studies of human keratinocytes were conducted to establish effects of finasteride, dihydrotestosterone (DHT), and testosterone on caspase-1 levels using immunoblot analysis. Caspase-1 is expressed in normal human adult epidermal keratinocytes. Caspase-1 expression is greater in men with AGA. In contrast, in men taking finasteride, caspase-1 levels were lower and were similar to those in normal controls. In vitro studies showed that keratinocytes treated with finasteride in combination with testosterone or DHT resulted in a significant decrease in caspase-1 expression. In vivo and in vitro finasteride treatment resulted in lower caspase-1 expression, supporting the idea that androgens influence innate immunity involved in the hair cycle in AGA. These findings may provide a basis for development of novel treatments for inflammatory skin and hair diseases.

CD44 is a widely distributed cell surface protein thought to be involved in multiple steps of normal immune cell function, including T-cell activation, and in cellular adhesion where it mediates cell attachment to hyaluronate. In normal skin, CD44 is found by immunohistochemical means to be primarily in eccrine coil cells. In this study, we have looked at the expression of CD44 in normal scalp and in two different hair disorders, androgenetic alopecia and alopecia areata. In normal scalp and androgenetic alopecia, CD44 was found in its normal distribution in eccrine coil cells. In scalp of 30 patients with alopecia areata, there was no expression of this glycoprotein. Patients were also assessed pre and post treatment for their alopecia areata, and even though they had no significant hair regrowth, 2 patients regained expression of CD44, indicating a variable expression of this protein in the alopecia areata disease process. The absence of CD44 expression in alopecia areata-affected scalp may give further information regarding the pathogenesis of this disease.

Recently, the search for new and effective agents for the treatment of alopecia has become significantly more intense. The increase in hair biology research worldwide seen in both academic institutions and pharmaceutical companies stems from the desire to profit from the marketing of drugs that have been termed cosmeceuticals. Millions of men and women from every ethnic group suffer from various forms of alopecia, the most common being androgenetic alopecia (AGA), where the target tissue active androgen, 5α-dihydrotestosterone (DHT) aggravates genetically programmed scalp hair follicles, resulting in hair loss. Currently available drugs indicated for other disease processes are still commonly used to treat the various forms of alopecia because no other agents are available; some of these compounds have severe side-effects and many also exhibit minimal efficacy. These prescription drugs were not originally indicated for alopecia and have not been adequately tested in controlled clinical trials to assess for efficacy, safety and toxicity. Despite this, these agents continue to be used clinically for the treatment of patients with various forms of alopecia. To combat the problems associated with the currently prescribed drugs a variety of new agents have emerged in patent applications. This report reviews nearly 70 patent applications submitted since 1995 for AGA, immunomodulatory related hair diseases and antichemotherapeutic alopecia agents (preventing hair loss during chemotherapy) and discusses the mechanisms of action targetted by research and their implications regarding efficacy.

Excessive sebum production is a central aspect of the pathophysiology of acne vulgaris. Sebaceous gland function is under androgen control and it is hypothesized that dihydrotestosterone is formed by the action of 5 alpha-reductase. Type I is the controlling isoenzyme. This study describes a 3-month, multicenter, randomized, placebo-controlled clinical trial with a potent, selective inhibitor of type I 5 alpha-reductase used alone and in combination with systemic minocycline. Inhibition of type I 5 alpha-reductase was not associated with clinical improvement of acne when used alone and did not enhance the clinical benefit of systemic minocycline. These results indicate the need for further work at the molecular level to better understand the action of androgens on sebaceous gland function.

This article contains a brief review of hair follicle biology, followed by a presentation of the workup of elderly patients who present with hair loss or hirsutism. Common hair disorders, such as graying, telogen effluvium, androgenic alopecia, senescent alopecia, alopecia arcuata, hirsutism, and hypertrichosis, are discussed.

Background A number of studies have provided evidence that apoptosis is a central element in the regulation of hair follicle regression. In androgenetic alopecia (AGA), the exact location and control of key players in the apoptotic pathways remains obscure. Objective In the present study, we used a panel of antibodies and investigated the spatial and cellular pattern of expression of caspases and inhibitors of apoptosis (IAPs), such as XIAP and FLIP, in men with normal scalp and in men with AGA before and after 6 months of treatment with 1 mg oral finasteride treatment. Methods and Results Constitutive expression of caspases-1, −3, −8, and −9 and XIAP was detected predominantly within the isthmic and infundibular hair follicle area, basilar layer of the epidermis, and eccrine and sebaceous glands. AGA-affected tissues showed an increase in caspase (−1, −3, −6, −9) immunoreactivity with a concomitant decrease in XIAP staining. After 6 months of finasteride treatment, both caspases and XIAP were similar to levels exhibited by normal subjects. Immunoblot analysis was performed to determine antibody specificity and cellular expression of caspases. Purified populations of keratinocytes, melanocytes, dermal papilla, and dermal fibroblasts derived from human hair follicles were cultured in vitro and treated with 0.5 μm staurosporin. Time-course experiments revealed that processing of caspase-3 is a principal event during apoptosis of these hair cell types. Conclusion These data suggest that alterations in levels of caspases and IAPs regulate hair follicle homeostasis. Moreover, finasteride appears to influence caspase and XIAP expression in hair follicle cells thus signaling anagen, active growth in the hair cycle.

A number of studies have provided evidence that apoptosis is a central element in the regulation of hair follicle regression. In androgenetic alopecia (AGA), the exact location and control of key players in the apoptotic pathways remains obscure. In the present study, we used a panel of antibodies and investigated the spatial and cellular pattern of expression of caspases and inhibitors of apoptosis (IAPs), such as XIAP and FLIP, in men with normal scalp and in men with AGA before and after 6 months of treatment with 1 mg oral finasteride treatment. Constitutive expression of caspases-1, -3, -8, and -9 and XIAP was detected predominantly within the isthmic and infundibular hair follicle area, basilar layer of the epidermis, and eccrine and sebaceous glands. AGA-affected tissues showed an increase in caspase (-1, -3, -6, -9) immunoreactivity with a concomitant decrease in XIAP staining. After 6 months of finasteride treatment, both caspases and XIAP were similar to levels exhibited by normal subjects. Immunoblot analysis was performed to determine antibody specificity and cellular expression of caspases. Purified populations of keratinocytes, melanocytes, dermal papilla, and dermal fibroblasts derived from human hair follicles were cultured in vitro and treated with 0.5 mm staurosporin. Time-course experiments revealed that processing of caspase-3 is a principal event during apoptosis of these hair cell types. These data suggest that alterations in levels of caspases and IAPs regulate hair follicle homeostasis. Moreover, finasteride appears to influence caspase and XIAP expression in hair follicle cells thus signaling anagen, active growth in the hair cycle.