Androgen responsive genes as they affect hair growth.

Finasteride has been shown to be an effective treatment for men with androgenetic alopecia (AGA) as it restores hair growth to miniaturized hair follicles on the top of the scalp [1]. Caspases are regulators of programmed cell death, and very likely some specific caspases may function as mediators of the hair growth cycle. It is unclear whether finasteride influences the regulation of apoptosis via caspases in the hair follicle. Very little information is available regarding the role of caspases present in human hair follicles in normal scalp and in androgenetic alopecia. In this study we have analyzed the family of caspases, 1-10 along with usurpin, and XIAP, in men with normal scalp and in men with androgenetic alopecia before and after 6 months treatment with 1 mg oral finasteride treatment. Caspases 1, 3, 8 and 9 were detected predominantly within the isthmic and infundibular hair follicle area for both normal and AGA patients, however the expression of all factors, especially caspase 3 was greater in the AGA group than in the normal scalp group. AGA men had the same caspase factors but with greater expression. In the same AGA men treated with finasteride for 6 months, the expression of these factors was similar to levels in the normal group. Results from our study indicate caspase 3 to be of primary importance in normal hair homeostasis and that DHT may be signaling greater expression of caspases, inducing apoptosis in androgenetic alopecia. In conclusion, DHT may selectively regulate the caspase genes which play an important role in signaling programmed cell death, affecting the hair growth cycle.

Idiopathic hirsutism.

Hirsutism, the presence of terminal (coarse) hairs in females in a male-like pattern, affects between 5% and 10% of women. Of the sex steroids, androgens are the most important in determining the type and distribution of hairs over the human body. Under the influence of androgens hair follicles that are producing vellus-type hairs can be stimulated to begin producing terminal hairs (i.e., terminalized). The activity of local 5alpha-reductase (5alpha-RA) determines to a great extent the production of dihydrotestosterone (DHT), and consequently the effect of androgens on hair follicles. While there are two distinct 5alpha-RA isoenzymes, type 1 and type 2, the activity of these in the facial or abdominal skin of hirsute women remains to be determined. Although the definition of idiopathic hirsutism (IH) has been an evolving process, the diagnosis of IH should be applied only to hirsute patients with normal ovulatory function and circulating androgen levels. A history of regular menses is not sufficient to exclude ovulatory dysfunction, since up to 40% of eumenorrheic hirsute women are anovulatory. The diagnosis of IH, when strictly defined, will include less than 20% of all hirsute women. The pathophysiology of IH is presumed to be a primary increase in skin 5alpha-RA activity, probably of both isoenzyme types, and possibly an alteration in androgen receptor function. Therapeutically, these patients respond to antiandrogen or 5alpha-RA inhibitor therapy. Pharmacological suppression of ovarian or adrenal androgen secretion may be of additional, albeit limited, benefit. New therapeutic strategies such as laser epilation or the use of new biological response modifiers may play an important role in offering a more effective means of treatment to remove unwanted hair. Further investigations into the genetic, molecular, and metabolic aspects of this disorder, including only well defined patients, are needed.

Androgenetic alopecia. New approved and unapproved treatments.

Although there are new FDA-approved drug therapies to treat hair loss, there are many unapproved agents with claims of effectively treating hair loss. A variety of new over-the-counter agents are available for consumers to use; however, it is difficult to assess how these agents work, costs of these agents, and efficacy. This article covers the new approved and the large multitude of unapproved treatments that are used to treat hair loss.

Novel agents for the treatment of alopecia.

Recent approval in the United States of two new products, Propecia (Merck Co, Rahway, NJ) and Rogaine Extra Strength 5% (Pharmacia & UpJohn Co, Kalamazoo, MI), indicated in men to promote scalp hair growth, have added a new dimension to treatment options offered by physicians in treating androgenetic alopecia (AGA). The search for new and effective agents to treat many different hair loss problems has been intensified by the increase in hair biology research taking place worldwide, from university academic institutions to the pharmaceutical companies. All have a desire to profit from marketing such drugs that have been termed, "cosmeceuticals". Millions of men and women of every race suffer from various forms of alopecia, the most common being AGA where the target tissue active androgen, 5 alpha-dihydrotestosterone (DHT) aggravates genetically programmed scalp hair follicles that results in short, fine, miniaturized hairs. Currently available to treat alopecia are drugs indicated for other disease processes because no other agents are accessible; some have severe side-effects and many are minimally effective. 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. These agents continue to be used clinically to treat patients with various forms of alopecia. As a result, a variety of new agents are emerging in the patient application process to gain protection and approval specifically for various forms of alopecia. This report reviews the most recently approved products, some of the more promising compounds in clinical trial development, as well as those in the over-the-counter (OTC) "natural" treatments category.

Androgen receptor polymorphisms (CAG repeat lengths) in androgenetic alopecia, hirsutism, and acne.

BACKGROUND: The androgen receptor (AR) is a structurally conserved member of the nuclear receptor superfamily. The amino-terminal domain is required for transcriptional activation and contains a region of polyglutamine encoded by CAG trinucleotide repeats. In humans, the number of CAG repeats is polymorphic. Expansion of CAG repeats in the AR has clinical implications for human disease. OBJECTIVE: Androgens influence androgenetic alopecia (AGA), hirsutism, and acne; the polymorphisms in CAG repeat length may affect the clinical course of patients with these cutaneous disorders. The purpose of this study is to test for an association between these disorders and CAG repeat length. METHODS: We analyzed normal lymphocyte genomic DNA from a total of 48 men and 60 women. The CAG repeat region of the AR was amplified by polymerase drain reaction (PCR) and the products were sized on polyacrylamide gels. RESULTS: In normal men and women controls, a range of 12 to 29 trinucleotide repeats was found, with men having 22 +/- 4 (M 6 SD), women 21 +/- 3. Men with AGA had 19 +/- 3, whereas women with AGA had 17 +/- 3. Men with acne had 21 +/- 3, whereas women had 20+/- 3; men with AGA and acne had 18 +/- 4; and women with hirsutism had 16 +/- 3. Women with a combination of at least two disorders also had 16 +/- 3 trinucleotide repeats. CONCLUSION: associated with the development of androgen-mediated skin disorders in men and women. These data suggest that CAG-repeat length in AR may affect androgen mediated gene expression in hair follicles and sebaceous glands in men and women with these androgenic skin disorders.

Different levels of 5alpha-reductase type I and II, aromatase, and androgen receptor in hair follicles of women and men with androgenetic alopecia.

In this study, 12 women and 12 men, ages 18-33 y, with androgenetic alopecia were selected for biopsies from frontal and occipital scalp sites. The androgen receptor, type I and II 5alpha-reductase, cytochrome P-450-aromatase enzyme were measured and analyzed in hair follicles from these scalp biopsies. Findings revealed that both women and men have higher levels of receptors and 5alpha-reductase type I and II in frontal hair follices than in occipital follicles, whereas higher levels of aromatase were found in their occipital follicles. There are marked quantitative differences in levels of androgen receptors and the three enzymes, which we find to be primarily in the outer root sheath of the hair follicles in the two genders. Androgen receptor content in female frontal hair follicles was approximately 40% lower than in male frontal hair follicle. Cytochrome P-450-aromatase content in women's frontal hair follicles was six times greater than in frontal hair follicles in men. Frontal hair follicles in women had 3 and 3.5 times less 5alpha-reductase type I and II, respectively, than frontal hair follicles in men. These differences in levels of androgen receptor and steroid-converting enzymes may account for the different clinical presentations of androgenetic alopecia in women and men.

Clinical updates in hair.

It is now known that there are major differences in the systemic and cellular mechanisms that mediate hair loss in women versus men. The severity or degree of hair loss in women with androgenetic alopecia is usually much less than in men. It is usually assumed that the hormonal basis for androgenetic alopecia in women is the same as in men; that is, the same target tissue-active androgens, testosterone and dihydrotestosterone, are being produced systemically to aggravate scalp hair follicles, resulting in hair loss. This article reviews some of the latest findings in androgenetic alopecia for both men and women, along with new and old treatments and drugs, doses, and effectiveness. Research findings indicate that levels of androgen-metabolizing enzymes and receptors differ in the scalps of women versus men, which may be important in formulating more effective hair growth treatments in the future.

CD44 expression in alopecia areata and androgenetic alopecia.

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.

Biochemical mechanisms regulating human hair growth.

The human hair follicle cycles in active growth and resting phases controlled by a complex network of biochemical processes, yet to be fully understood. It is well known that hair follicles on scalp respond to androgens by a shortening of the anagen growth phase causing hairs to regress to a finer, thinner texture. The target tissue androgens, testosterone, and dihydrotestosterone can circulate systemically to skin or can be formed locally in hair follicles and sebaceous glands by specific enzymes in the steroid cascade. Kinetic constants have been evaluated for several enzymes which mediate dihydrotestosterone formation, including 5a-reductase, and the cytochrome P-450 aromatase enzyme in isolated human hair follicles and sebaceous glands from scalp of men and women with androgenetic alopecia. The levels of these enzymes differed between men and women, and from frontal versus occipital sites within the same patient, indicating that similar steroid mechanisms may be taking place in men and women, but the amount or level of enzymes vary, perhaps explaining why men have more severe patterns of hair loss than women. Knowing the differences between men and women with androgenetic alopecia could shape more effective treatment options in the future.

The antiandrogens. When and how they should be used.

This article is a useful guide for treating androgen-related skin disorders such as androgenetic alopecia, acne, and hirsutism. All available antiandrogens are discussed, as well as treatment doses, efficacy, and mode of action.

Immunohistochemical distribution of aromatase and 3B-hydroxysteroid dehydrogenase in human hair follicle and sebaceous gland.

Human hair follicles (HF) and sebaceous glands (SG) were assessed for the presence and distribution of the cytochrome P-450-aromatase (AR) and 3B-hydroxysteroid dehydrogenase (3B-HSD) enzymes. Immunohistochemical methods were used to examine both enzymes in male and female human skin specimens at various ages and different body sites. AR was found in the external root sheath of anagen, terminal HF, and in SG, whereas the 3B-HSD was found only in the SG. AR was rarely found in telogen HF. The expression of both enzymes, AR and 3B-HSD, did not vary with body site or sex. Localizing AR in the external root sheath of anagen HF suggests that AR may have a function in the HF cycle. We hypothesize that AR may be one of many enzymes or factors that play a role in the HF cycle by regulating the level of androgens formed locally, whereas 3B-HSD is localized in SG, converting weak androgen precursors to potent androgens, stimulating lipogenesis.

Purification of androgen receptors in human sebocytes and hair.

Human sebaceous glands (SG) and hair follicles (HF) are target structures in the skin for androgen action. They contain steroid enzymes, capable of transforming weak androgens into the target-tissue-active androgens testosterone (T) and dihydrotestosterone (DHT), which bind to the androgen receptor (AR) to regulate cellular transcription. The AR from HF and SG from human scalp tissue has been purified greater than 86,000 times by phenyl-sepharose, DEAE-sephacel, gel filtration chromatography, and ultrafiltration. Sucrose density gradient analysis and non-denaturing gradient polyacrylamide gel electrophoresis (PAGE) and sodium dodecyl sulfate (SDS)-PAGE revealed two molecular species of AR, an active form called monomer, capable of binding DHT with great specificity (4S, m = 62,000 Da, Kd = 0.6 nM, Bmax 8260 fmol/micrograms protein), and the other, an inactive form of the monomer called tetramer (10.8S, m = 252,000 Da, Kd = 2.9 nM). The two species are interconvertible, and after purification each appeared as a single band on SDS-PAGE. The conversion of the monomer to the tetramer AR form is influenced by reduced and oxidized glutathione, and possibly by an endogenous disulfide converting factor (DCF). Furthermore, biochemical events in the androgenic signal transduction sequence were shown to be stimulated by androgens via the AR. These include the total nuclear AR content, chromatin binding of AR complexes, and stimulation of RNA polymerase II, thus influencing gene expression, which is important in understanding regulation of HF growth and SG proliferation.

Interleukin 1 protects hair follicles from cytarabine (ARA-C)-induced toxicity in vivo and in vitro.

ImuVert, a biologic response modifier, and interleukin 1 (IL 1) have been shown to protect the young rat from alopecia induced by cytarabine (ARA-C). In the present study the inhibition by ARA-C of DNA synthesis in hair follicles (HFs) and the protective effect of ImuVert and IL 1 were investigated in vivo and in vitro. Both ImuVert and IL 1 were equally effective in protecting rats from ARA-C-induced alopecia. DNA synthesis in HFs isolated from ARA-C-treated animals was 10-20% of untreated controls. Follicles isolated from animals given either ImuVert or IL 1 before ARA-C exhibited normal DNA synthesis. In vitro, the incubation of normal rat HF with ARA-C resulted in 80% inhibition of [3H]-thymidine uptake. Preincubation of the follicles for 1 hr with IL 1 before the addition of ARA-C completely blocked the inhibition. Preincubation with imuVert, however, was less effective in blocking the inhibition from ARA-C.

Steroid chemistry and hormone controls during the hair follicle cycle.

Human hair follicles contain several steroid enzymes capable of transforming weak androgens, such as dehydroepiandrosterone, into more potent target tissue androgens, such as testosterone and dihydrotestosterone. Kinetic constants have been evaluated for the 3-alpha, 3-beta, and 17-beta hydroxysteroid dehydrogenase enzymes, 5a-reductase, and the aromatase enzyme in isolated human HF from scalp of men and women with androgenetic alopecia. The apparent Km values did not differ for each enzyme whether present in bald, receded HF or thick, anagen HF of men or women. However, levels of specific activity varied greatly in the frontal versus occipital HF analyzed. The androgen receptor content and activation factors also differ between men and women. The steroid mechanisms influencing AGA in men and women may be similar, but differences in the specific activity/amounts of enzymes, receptors, and activation factors differ between men and women. These findings may explain the varied clinical presentations of men and women with AGA, and may shape treatment options for the future.

Increased androgen binding capacity in sebaceous glands in scalp of male-pattern baldness.

Sebaceous glands were isolated by manual dissection under a microscope from surgical specimens of scalp skin with male pattern baldness and skin specimens of hairy and bald scalp obtained at autopsy. The 800 X g pellet (nuclear fraction) and the 164,000 X g supernatant fraction (cytosol) of homogenates of the sebaceous glands were used for measurements of androgen binding characteristics, using dextran-coated charcoal and sucrose gradient methods. Scatchard plots showed high affinity binding for [3H]dihydrotestosterone (DHT) and [3H]methyltrienolone (R1881). Nuclei prepared from bald scalp contained greater total androgen binding capacity than nuclei of hairy scalp, although Kd values of type I binding were similar (0.68 vs 0.56 nM, respectively). On sucrose gradient, the binding protein from cytosol was found in the 7 to 8S density range. Androgen binding by cytosol of sebaceous glands of hairy scalp had Kd of 1.89 +/- .79 and 2.05 +/- .56 nM for DHT and R1881, respectively, and Bmax of 18.7 +/- 4.4 and 20.0 +/- 4.6 fmol/mg protein for DHT and R1881, respectively. Cytosol from sebaceous glands of bald scalp had Kd values approximately half those of hairy scalp, and Bmax values 50%-100% higher. The bound 3H labeled DHT and R1881 could be partially displaced by testosterone (40-50%), moxestrol (28-32%), promegestone (19-26%), and delta 4-androstenedione (6-12%), but not by dehydroepiandrosterone. These data demonstrate the presence of specific androgen binding protein in sebaceous glands, and that sebaceous glands of bald scalp have greater binding affinity and capacity for androgens than those in hairy scalp. This difference may explain the greater androgenic response in androgenic alopecia.

delta 5-3 beta-hydroxysteroid dehydrogenase activity in sebaceous glands of scalp in male-pattern baldness.

Sebaceous glands were isolated by manual dissection using a stereomicroscope from skin specimens of bald scalp of men with male-pattern baldness undergoing hair transplant or scalp reduction surgery and also from specimens taken from hairy and bald areas of scalp at autopsy of adult male victims of accidental death within 3 h post mortem. Homogenates of the isolated glands exhibited activities of delta 5-3 beta-hydroxysteroid dehydrogenase (3 beta HSD), 17 beta-hydroxysteroid dehydrogenase, and testosterone 5 alpha-reductase by the conversion of [3H]dehydroepiandrosterone (DHA) to 3H-delta 4-androstenedione (AD), [3H]testosterone, and [3H]dihydrotestosterone. Homogenates of glands from bald (B) scalp had greater 3 beta HSD activity than homogenates of glands from hairy (H) scalp. After differential centrifugation, 3 beta HSD activity was found mainly in the microsomal and 105,000 X g supernatant fractions. Specific activity of the enzyme based on protein mass was highest in the microsomal fraction; however, the total 3 beta HSD activity in the 105,000 X g supernatent of B glands was significantly (p less than .01) greater than that of H glands. 3 beta HSD activity in sebaceous glands isolated from autopsy specimens did not differ from that of glands isolated from surgical specimens in apparent Km (0.13-0.14 microM), pH optima (8.0), or coenzyme requirement for NAD. Since substantial 3 beta HSD activity was present in the cytosol, and cytosol of B glands showed increased 3 beta HSD activity, the increased conversion of DHA to AD may be a critical step for androgenic action and may be responsible for excessive androgenicity in male-pattern baldness.