Once upon a time, knowledge of ancient Greek was mandatory if one wished to become a doctor. Perhaps that’s why so many scientific and medical terms have been generated using Greek words. The Greek verb hermao (ormaw) means “trigger a movement” and those molecules whose presence triggers some biochemical reactions are called “hormones.” Cortisol is the hormone that triggers awakening, melatonin is the hormone that signals sleeping, insulin increases glucose uptake and epinephrin increases blood flow to muscles and controls the “flight or fight” response. The hormones that are best known to the layperson are the so-called sex hormones (progesterone, estradiol, testosterone, etc.). Many lay people mistakenly hear “sex hormones” every time the word “hormone” is uttered.

What does all this have to do with skin and skin care? Well, sex hormones antagonists might be of interest in treating acne and uneven pigmentation.

Skin is a steroidogenic tissue. This means that the skin can chemically modify sex hormones and does react to their presence.¹ Skin enzymes such as 5a-reductase convert testosterone to de-hydro-testosterone and aromatases convert testosterone to estradiol.


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Estrogens exert their actions through intracellular receptors or via cell surface receptors, which activate specific second messenger signaling pathways. Estrogens seem to play a role in aging. As a matter of fact, estrogen binding to its receptors activates the NF-kB pathway and leads to the over expression of Mn SOD and GPx, two powerful antioxidant enzymes. Some authors think that this is the biochemical reason why women’s life expectancy is longer than men’s life expectancy.² Estradiol is also believed to play a role in skin aging, pigmentation, hair growth, sebum production and skin cancer.

The growth and the differentiation of sebocytes in sebaceous glands are modulated by androgens.³ Androgens also control epidermal barrier homeostasis and wound healing. To exert their action, androgens bind to nuclear androgen receptors. When there is an excess of androgens, one observes acne, seborrhea, hirsutism and androgenetic alopecia.

In addition to their role in reproduction, sex hormones seem, therefore, to be implicated in biochemical activities related to sebocyte differentiation and melanin synthesis.

Male Sex Hormones and Acne

Acne is considered to be a disfunction of sebo-genesis.⁴ Between the age of 6 to 9 years, androgens and insulin-like growth factor (IGF)-1 are produced. They trigger the synthesis of sebum5 and pilosebaceous follicles can become clogged. In clogged pores, anaerobic bacteria such as Propionibacterium acnes multiply and pro-inflammatory signals are released.

In the treatment of acne vulgaris, it had been suggested that spironolactone (a synthetic 17-lactone steroid) may reduce sebum production by blocking the binding of dihydrotestosterone to its androgen receptors, thereby inhibiting sebocytes proliferation.⁵ Indeed, it had been observed6 that spironolactone inhibits the binding of dihydrotestosterone to its receptors and it has been reported⁷ that spironolactone is an antagonist of testosterone and of 5a-dihydrotestosterone and that it inhibits the proliferation of sebocytes.

Another observation confirmed that antagonists to male steroids are likely to have anti-acne properties. Cimetidine has an interesting anti-acne behavior:⁸ the rate of sebum excretion of acneic patients is twice the rate in normal controls and returns to normal when patients are treated with cimetidine…and cimetidine has antiandrogenic activity.⁹ 

Female Sex Hormones and Pigmentation

That sex hormones play a role in pigmentation has been suggested because of the uneven skin pigmentations that may occur during pregnancy. Estradiol increases pigment production in human melanocytes and progesterone decreases it.¹⁰ Estrogen and progesterone regulate pigment production by binding to specific receptors. Targeting these receptors could be a reasonable strategy for treating pigmentation disorders.

Azelaic Acid & Acne

Azelaic acid at 20% is approved by the FDA as a prescription drug for treating acne.

Azelaic acid is a competitive inhibitor of mitochondrial oxidoreductases and of 5 a-reductase, inhibiting the conversion of testosterone to 5 a-dehydrotestosterone. A consequence of the presence of azelaic acid is that more testosterone is left to be converted in estradiol by aromatases. This suggests that perhaps structural and functional analogs of azelaic acid might have both anti-sebum and anti-pigmentation activities without unwanted side effects. 

References

1. Thiboutot et al (2003) Human skin is a steroidogenic tissue: steroidogenic enzymes and cofactors are expressed in the epidermis, normal sebocytes and in immortalized sebocytes cell line (SEB-1) J. Invest.Dermatol 120 : 905-914
2. Viña J, Gambini J, Lopez-Grueso R et al (2011) Females live longer than males: role of oxidative stress. Curr Pharm Des 17: 3959-65
3. Zouboulis CC et al (2007) Sexual hormones in Human Skin. Horm Metab Res 39 : 85-95
4. Khondker L, Khan SI. (2014) Acne vulgaris related to androgens: a review. Mymensingh Med J. 23 : 181–185. 
5. Layton AM et al. (2017) Oral Spironolactone for Acne Vulgaris in Adult Females: A Hybrid Systematic Review. Am J Clin Dermatol. 18 :169-191
6. Berardesca E et al. (1988) Topical spironolactone inhibits dihydrotestosterone receptors in human sebaceous glands: an autoradiographic study in subjects with acne vulgaris. Int J Tissue React.10 : 115–119. 
7. Akamatsu H et al. (1993) Spironolactone directly inhibits proliferation of cultured human facial sebocytes and acts antagonistically to testosterone and 5-alpha dihydrotestosterone in vitro. J Invest Dermatol. 100 : 660–662. doi: 10.1111/1523-1747.ep12472325.
8. LI He-Lian, YU Min (1993) Chinese J Dermatol Study of the Effect of Cimetidine and Ofloxacin Cream on Patients with Acne Vulgaris. 26 : 346-348
9. Liang T, Heiss CE (1981) Inhibition of 5a reductase, receptor binding and nuclear uptake of androgens in the prostate by a 4-Methyl-4-aza-steroid J Biol Chem 256 7998-8005
10. Natale CA et al. (2016) Sex steroids regulate skin pigmentation through nonclassical membrane-bound receptors. Elife. 5:e15104. doi: 10.7554/eLife.15104. PMID: 27115344; PMCID: PMC4863824.

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Paolo Giacomoni, PhD
Insight Analysis Consulting
[email protected]
516-769-6904
 
Paolo Giacomoni acts as an independent consultant to the skin care industry. He served as Executive Director of Research at Estée Lauder and was Head of the Department of Biology with L’Oréal. He has built a record of achievements through research on DNA damage and metabolic impairment induced by UV radiation as well as on the positive effects of vitamins and antioxidants. He has authored more than 100 peer-reviewed publications and has more than 20 patents. He is presently Head of R&D with L.RAPHAEL—The science of beauty—Geneva, Switzerland .