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5a reductase webinar


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Notes from 5a reductase webinar

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5a reductase webinar

  1. 1. Sebum has a central role in the pathogenesis of acne; it provides a medium for the proliferation of P. acnes. A correlation exists between the amount of sebum produced and the severity of acne. Sebaceous gland activity is under endocrine control and the main stimulus to the sebaceous glands is represented by androgens. The reduction of testosterone to dihydro-testosterone (DHT) by the enzyme 5a-reductase is the most important of the enzymatic processes involved in androgen activity; indeed DHT is a more potent androgen than is testosterone, due to its greater affinity for the androgen receptor. There are 2 types of isozymes of 5a reductase. Type 1 and type 2. Type 1 predominates in the sebaceous gland where it regulates sebum. Type 2 predominates in the prostate and also resides in the hair follicles. Higher levels of type 1 5a reductase are found in areas of the skin which are prone to acne. Acne skin has 20 times more dihydrotestosterone. Facial skin has a higher rate of conversion of DHT than back skin. Males have a higher rate of conversion than females. Inhibition of type 1 5a reductase represents a way of blocking the local production of dihydrotesterone within the sebaceous glands. This inhibition reduces sebum and improves acne. Apart from isotretinoin and hormonal therapies, there are few agents that can effectively reduce sebum production. This makes 5a reductase inhibitors a refreshing way of treating acne. Sebum is produced by the sebaceous glands under the control of androgens, mainly testosterone. Testosterone is converted to the more active 5αdihydrotestosterone (5α-DHT) by the enzyme type 1 5α-reductase. This more active androgen then stimulates increased sebum production • • The activity of 5a reductase type I is two to seven times greater in keratinocytes in the infrainfundibulum than in those in other parts of the epidermis. DHT is the most active androgen metabolite in the pilosebaceous unit with an affinity for the androgen receptor that is 5-10 times greater than that of testosterone. Androgens not only stimulate sebum they also stimulate the proliferation of keratinocytes of the ductus seboglandularis and the acroinfundibulum. Antiandrogens reduce the synthesis of sebaceous lipids and improve acne. Skin that is androgen insensitive skin possesses no functional androgen receptors and does not produce sebum nor develops acne.
  2. 2. DHT may also reach the androgen receptor without the influence of 5αreductase when the precursor molecules are already 5α-reduced. Milk contains at least 2 such molecules, 5α-androstanedione and 5αpregnanedione, and these are prime candidates as the long-term stimulants to pilosebaceous activity. There are several other likely precursors in milk (and its products), and the enzyme systems necessary for their conversion to DHT are all part of the pilosebaceous intracrine system. Elevations of plasma glucose, insulin, and IGF-1 are known to occur as a result of ingestion of a significant glycemic load, and these elevations can in turn cause a rise in testosterone and a decrease in sex hormone binding globulin, having the net effect of presenting the pilosebaceous units with more testosterone. This is the mechanism for the acnegenic effect of high glycemic load foods. The purpose of SHBG is to bind to oestrodiol (a type of oestrogen) and testosterone (particularly dihydrotestosterone or DHT. When SHBG is bound to these hormones, it inhibits their function, preventing them from floating around the bloodstream freely and being available to act on cell receptors. Low levels of SHBG result in increased activity of these hormones which can show up as excess body hair, head hair loss and acne. Testosterone metabolism to 5a-dihydrotestosterone and synthesis of sebaceous lipids is regulated by the peroxisome proliferator-activated receptor ligand linoleic acid in human sebocytes. The free fatty acid Linoleic acid is a PPAR agonist. PPAR agonists restore the normal lipid balance in the skin. PPARs are nuclear transcription factors involved in the control of lipid metabolism as well as in the control of inflammationc Sebaceous lipid synthesis is upregulated in the presence of androgens and certain fatty acids, ligands of proliferator-activated receptors (PPAR) . In fact, human sebaceous glands are equipped with both androgen receptors and with PPAR. Among the various PPAR subtypes PPARα and PPARγ are particularly involved in the regulation of lipid synthesis. A one-month topical application of linoleic acid, a PPARδ/γ ligand, resulted to almost 25% reduction of microcomedones in a clinical study. In sebaceous glands, androgen receptors (AR) are identified in basal and differentiating sebocytes. In addition, AR are present in pilosebaceous duct keratinocytes, suggesting that androgens may influence pilocebaceous duct keratinisation. Keratinocytes play an important role in the inflammatory reaction of the skin, synthesizing a number of cytokines, adhesion molecules and growth factors
  3. 3. In addition, it is known that keratinocytes play an important role in acne synthesizing a number of inflammatory cytokines. DHT is not only be involved in sebum production but also in production of pro-inflammatory cytokines in acne. DHT upregulates IL-6 and TNF-a . Women who have acne who have normal circulating androgens, have increased levels of the tissue-derived androgens. This supports the concept that target tissue androgens play a part in the pathogenesis of female acne. Reduced levels of linoleic acid have been found in acne patients and are also correlated with epidermal hyperplasia perhaps providing an explanation for the formation of ductal hypercornification. There is also a significantly higher sebum excretion rate among adult women with persistent acne, compared with non-acne female adults. Androgens regulate sebum production and may also play a role in the follicular hyperkeratinisation seen in acne. The activity of the enzyme type I 5α-reductase varies within regions of the PSU. Compared with interfollicular epidermal cells, infundibular keratinocytes have been shown to have an increased capacity for metabolising androgens, suggesting that androgen activity and follicular hyperkeratinisation are related. This association may in part be supported by the successful use of oral contraceptives in the treatment of acne. Enlargement of the sebaceous glands and increased production of sebum is stimulated by the increasing production of androgens at puberty. Of these, the most important androgen is testosterone, which is converted to the more active 5α-DHT by type 1 5α-reductase. The correlation between increased sebum production and acne is well established, and explains why the first signs of acne coincide with the onset of puberty. Furthermore, studies demonstrate that seborrhoea is more intense in individuals who are acneprone than in those who are free of acne. Increased sebum production seen in patients with acne is primarily as a result of individual increased sebaceous gland sensitivity to androgen to increased circulating levels of androgen or increased type I 5α-reductase activity. Type I 5α-reductase is most abundantly expressed in facial sebocytes, which may account for the prevalence of facial acne in all age groups. Androgen receptors have been localized to the basal layer of the sebaceous gland and the outer root sheath of the hair follicle. Androgens have been shown to trigger sebaceous gland growth and development and to stimulate sebum production. Clinical evidence supports the link between androgen and acne formation. Sebum production increases markedly during the prepubertal period, a time when serum levels of dihydroepiandrosterone sulfate (DHEAS), a precursor to testosterone, are also elevated. Individuals who are insensitive to androgen do not produce sebum and do not develop acne, and high androgen states are associated with acne formation.
  4. 4. In some studies, acne patients have higher circulating levels of free testosterone, DHEAS, 5a-reductase, and androgen receptors in the sebaceous gland compared with patients without acne. It is commonly believed, however, that hypersensitivity of the sebaceous glands to androgens is the underlying cause of acne. Testosterone and dihydrotestosterone (DHT) bind nuclear androgen receptors, which then interact with deoxyribonucleic acid (DNA) in the nucleus of sebaceous cells and ultimately regulate genes involved in cell proliferation and lipogenesis. Although these exact target genes are not known, they may include genes that encode growth factors and lipogenic enzymes. Peroxisome proliferator-activated receptor (PPAR) Ligands may also be implicated in regulation of lipid metabolic genes. Dihydrotestosterone is approximately 5 to 10 times more potent than testosterone in its interaction with the androgen receptor. Ingredients that inhibit 5a reductase Reishi (Ganoderma lucidum) Red reishi, commonly known as LingZhi in Chinese, is a mushroom thought to have many health benefits. In a research study exploring the anti-androgenic effects of 20 species of mushrooms, reishi mushrooms had the strongest action in inhibiting testosterone. That study found that reishi mushrooms significantly reduced levels of 5-alpha reductase, preventing conversion of testosterone into the more potent DHT. High levels of DHT are a risk factor for conditions such as benign prostatatic hypertrophy (BPH), acne, and baldness. Zinc Sulphate and Azelaic Acid Zinc is a potent inhibitor of 5a-reductase activity. At high concentrations, zinc could completely inhibit the enzyme activity. Azelaic acid was also a potent inhibitor of 5a reductase. When B6 was added as well there was a 90% inhibition of 5a-reductase activity was obtained. Eucalyptus Eucalyptus inhibits 5a reductase by 47%. 5a-Reductase inhibitory component from leaves Licorice (Glycyrrhiza glabra) Licorice affects the endocrine system because it contains isoflavones (phytoestrogens). Licorice can also reduce testosterone levels, which can contribute to hirsutism in women. Saw Palmetto (Serenoa repens)
  5. 5. Its extract is believed to be a highly effective anti-androgen as it contains phytosterols. This has been the subject of a great deal of research with regards to the treatment of BPH. Green Tea (Camellia sinensis) Beyond it’s antioxidant properties, green tea demonstrates anti-inflammatory as well as antimicrobial activity against p. acnes. It has also been shown to inhibit 5a reductase and reduce sebum production. A 2% green tea lotion has been shown to reduce total lesion count by 58% in 6 weeks for clients with mild to moderate acne. Inhibits interleukin-1, IL-8, IL-10, IL-12. Green tea has been associated with higher levels of sex hormone-binding globulin (SHBG). SHBG is a molecule that binds with high affinity to testosterone. Testosterone bound to SHBG is not bioactive and cannot bind to androgen receptors or be converted into DHT. Green tea may also have an effect on the type I 5 alpha reductase enzyme. References: • Testosterone metabolism to 5a-dihydrotestosterone and synthesis of sebaceous lipids is regulated by the peroxisome proliferator-activated receptor ligand linoleic acid in human sebocytes. British Journal of Dermatology 2007 156, pp428–432 • Differential rates of conversion of Testosterone to Dihydrotestosterone in Acne and Normal Skin – a possible pathogenic factor in acne. The Journal of Investigative Dermatology (1971) 56:366-372. • Effect of dihydrotestosterone on the upregulation of inflammatory cytokines in cultured sebocytes. Arch Dermatol Res (2010) 302:429–433 • Immunolocalization of 5a reductase Isozymes in Acne Lesions and normal skin. Archives of Dermatology (2000) 136:1125-1129. • Diet and acne. Clinics in Dermatology (2008) 26, 93–96 • Post-adolescent acne: a review of clinical features. British journal of Dermatology 1997; 136 • Post-adolescent acne. International Journal of Cosmetic Science, 2004, 26, 129–138 • Anti-Acne Effects of Oriental Herb Extracts: A Novel Screening Method to Select AntiAcne Agents. Skin Pharmacol Appl Skin Physiol 2003;16:84–90 • Current Concepts of the Pathogenesis of Acne Implications for Drug Treatment. Drugs 2003; 63 (15): 1579-1596 • Inhibition of 5a-reductase activity in human skin by zinc and azelaic acid. British Journal of Dermatology (1988) 119, 627-632 • 5a reductase inhibitory component of ARtocarpus Atilis. J Wood Science (2000) 46:385-389
  6. 6. • Pharmacologically Relevant Receptor Binding Characteristics and5a-Reductase Inhibitory Activity of Free Fatty Acids Contained in Saw Palmetto Extract Biol. Pharm. Bull. 32(4) 646—650 (2009) • Antioxidiants in Acne Vulgaris and Aging: Focus on Green Tea and Fever Few. (2012) Journal of Drugs in Dermatology. • Green tea and the skin (2005) American Academy of Dermatology, Inc. June. • Cosmeceuticals Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School •