Acne is much more complex than simply DHT levels.
DHT is not the sole contributor to whether one will experience such.
Genetics /sensitivity of the AR to androgens/DHT play a big role.
Genetically prone individuals can still experience acne even when using lower doses of testosterone.
What is new in the pathophysiology of acne, an overview
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Introduction
Acne is a chronic inflammatory disease of the pilosebaceous unit.1 It commonly occurs at puberty but is also observed in adults.
2 Its pathophysiology involves three actors, hyper-seborrhoea, abnormal follicular keratinization and Propionibacterium acnes proliferation in the pilosebaceous unit. As a result of their interaction, the cutaneous microenvironment changes and leads to inflammatory reactions of the host that foster acne lesion progression.2, 3 Recent research has put some new light on the involvement of the sebaceous gland, as well as on the pro‐inflammatory activity of the cutaneous microbiome in the pathophysiology of acne.
The objective of this article was to provide an update regarding the involvement of the sebaceous gland, the innate immunity and the cutaneous microbiome in acne. The second objective was to open a new perspective of treatment options.
The sebaceous gland
Sebum production is induced by different receptors expressed by the sebaceous gland. In addition to the well‐described histamine receptor activated by histamines, the hormonal DHT receptor, activated by androgens, and the neuromodulator receptor, mainly substance P and corticotrophin‐releasing hormone (CRH) receptor which are mainly activated by stress, recent molecular research has identified three other receptors that are expressed by the sebocyte and that control sebum production (Fig. 1).4-6
FIGURE 1
View attachment 9235
Receptors controlling sebum production (adapted from Zhang et al.7).
Each of these newly identified receptors is activated by a dietary substance. The peroxisome proliferator‐activated receptors (PPARα, β and γ) are stimulated by free fatty acids and cholesterol, the insulin‐like growth factor (IGF)‐1 receptor by sugar and leptin receptor by fat.
7-
9 Leptin is a hormone secreted by adipocytes that regulates bodyweight and is also known to link lipid metabolism with inflammation in various cell types. In the sebocyte, it is responsible for creating lipid droplets within the cell and has recently been shown to induce pro‐inflammatory enzyme and cytokine (interleukin (IL)‐6 and IL‐8) secretion as well.
9 This result suggests that leptin is a novel player in inducing inflammation and altering lipid profile in sebocytes and could be a link between diet and development of inflammatory acne.
The link between acne and diet is further supported by a recent case–control study of predictive factors for acne.
10 Apart from the well‐known relationship between family history and acne, the investigators found that a high body mass index (BMI) was also a predictive factor for an increased risk of developing moderate to severe acne in adolescents and young adults. Furthermore, a population‐based study of acne and BMI in adolescents reported that overweight as well as obesity may be potentially associated with acne in girls aged 18 and 19 years,
11 even though proofs are still lacking.
Dihydrotestosterone: Biochemistry, Physiology, and Clinical Implications of Elevated Blood Levels
Dihydrotestosterone: Biochemistry, Physiology, and Clinical Implications of Elevated Blood Levels
Skin
Skin possesses all of the requisite steroidogenic capabilities to ensure local homeostatic control of steroid hormones, suggesting an important paracrine role for T, DHT, and estradiol within the skin, the function of which is poorly understood (143). Likewise, skin contains metabolizing pathways (e.g., glucuronidation; sulphation) that inactivate DHT (144). Consequently, localized mechanisms in skin maintain concentrations of DHT that are not meaningfully influenced by circulating DHT levels, probably due to the fact that the DHT concentration gradient favors secretion into blood (143, 145). In men, androgen levels are highest in the scrotal skin followed by pubic skin and then thigh skin, a pattern paralleled by 5
α-reductase and low 3
α-reductase activity (and thus tissue DHT) (
146). In women, skin DHT concentrations are highest in the labia majora and clitoris followed by pubic skin and then thigh skin (
147).
Absorption of DHT (as is also true for T) across the skin is a passive process that follows Fick’s law (
148,
149). Accordingly, concentrations of DHT in skin to which DHT has been applied are extremely high during the period when DHT is absorbed into the bloodstream. A single transdermal DHT product is available in a handful of countries, and it is this formulation that has been used in clinical trials. Studies of topical DHT in hypogonadal or eugonadal men have not reported adverse effects on skin aside from mild irritation due to the high alcohol content, despite its direct application and sustained supraphysiological levels of DHT for up to 24 months (
51,
52,
54). These results are consistent with those from shorter-term transdermal DHT studies (
60,
103).
Male human skin and hair express an abundance of SRD5A type I in sebaceous glands, hair follicles, sweat glands, and the epidermis, whereas SRD5A type II is expressed in genital keratinocytes and hair follicles (
150).
The physiologic role of DHT in the skin is unclear, but it is hypothesized that sex steroids may influence the immune function of skin and locally influence inflammatory processes (143). Androgens clearly play a role in the pathogenesis of acne vulgaris, likely through increased sebum production, and may impact cutaneous wound healing (151); however, a specific role for DHT in many of these processes has not been demonstrated. An exception to this may be DHT-induced upregulation of inflammatory cytokines (e.g., IL-1, IL-6, and tumor necrosis factor-α) in acne (152). Studies of agents that reduce levels of DHT in skin clearly support a role for DHT in the development of male androgenic alopecia (MAA) (male pattern baldness). This is inferred, in part, by the effectiveness of 5AR-Is in suppressing the progression of MAA and the observations that castrated men and men with SRD5A deficiency do not develop baldness (153). However, the effectiveness of SRD5A therapy likely resides at the level of the hair follicle (i.e., lowered follicular concentrations of DHT) and not a reduction of circulating DHT because this has not been shown to correlate with MAA. Support for this conclusion is also found in a study of men exposed to exceptionally high levels of DHT in response to daily application of a DHT gel preparation for 24 months. DHT was not associated with acne, MAA, or other androgen-associated skin pathology (54). Instead, the most important factor in the pathogenesis of MAA is a genetic predisposition for AR polymorphisms [
e.g., synonymous nucleotide polymorphism in exon 1 (rs6152) of the AR] (
154,
155). In addition, differences in AR concentrations and steroid-converting enzymes in the hair follicle also appear to be play a significant role in MAA (
156).
