Exploring the Interwoven Endocrinologic/Immunologic Mechanisms of Acne

woman with acne on her chin
woman with acne on her chin
A dive into the genesis of acne reveals a complex interplay of endocrinologic and immunologic mechanisms involving a marked disturbance in sebaceous gland activity.

Historically, acne in teenagers has been largely regarded as a natural rite of passage. The majority of acne cases occur in adolescents, with a  prevalence of 35% to 90%; 20% of men and 35% of women still experience acne throughout their twenties.1 Since the 1980s, the clinical perception of acne has recognized acne as a chronic inflammatory-based condition implicating the Propionibacterium acnes bacterium as the primary cause.2,3 This finding was the basis for extensive use of broad-spectrum antibiotics for treatment, which served to promote adverse reactions and the emergence of antibiotic-resistant strains.3

Recent studies however, have identified a much more complex interplay of endocrinologic and immunologic mechanisms involving a marked disturbance in sebaceous gland activity as the key to acne development and control. Dysfunction results from increased production and alterations in fatty acid concentrations of sebum in combination with mechanisms involving hormonal dysregulation of the microenvironment, hyperkeratinization of the follicles, and neuropeptide interactions that promote inflammation and disequilibrium of the innate and adaptive immune systems.4,5 These mechanisms are significantly genetically influenced and triggered by the actions of circulating hormones, cytokines, and even the Western diet.1

The Role of the Sebaceous Glands in Acne

The sebaceous glands are designed to produce a range of natural oils such as triglycerides and fatty acid breakdown products, as well as squalene, wax esters, cholesterol esters and cholesterol. Hormone production plays an obvious role in acne, as the androgenic effects of testosterone and estrogens that surge during adolescence are important to both sebaceous gland growth and sebum production. 1

In a series of multiple publications on the pathogenesis of acne dating from the early 2000s to 2020, Christos Zouboulis, MD,a long-time proponent of theories suggesting a concordance of multiple etiologies in its pathogenesis, stated that “hyperproliferation, excess sebum, inflammation, and the presence of P acnes all contribute to the development of acne vulgaris.6 It is only recently that the underlying cascade events prompting these mechanisms are becoming clear.4

A cardinal feature of the sebaceous gland, according to Dr Zouboulis, is that, “It is structured—from its periphery to the centre—of undifferentiated, differentiating and mature sebocytes, which burst and die releasing their content to the sebaceous duct and subsequently to the associated follicular canal.” The process of terminal differentiation and death in this case involving holocrine secretions, differs from apoptosis, the programmed death of most mature body cells that is a discrete event. The explosive nature of sebaceous cell death causes interactions with nearby healthy skin cells resulting in acne. 4 These reactions are most prevalent in the regions of the body with the highest concentration of sebaceous follicles, such as the face, chest, and back, and therefore have the greatest severity of acne (92%, 45% and 61%, respectively).1

The Composition of Sebum

Several researchers have noted that the composition of sebum lipids plays a significant role in the development of acne. A 2017 review observed that the presence of lipoperoxides in sebum (as a result of vitamin E deficiency) and reduced levels of linoleic acid contributed to oxidative stress that produced acne in certain individuals, compared with those who had normal levels of these lipids.1 “Both lipoperoxides and monounsaturated fatty acids (MUFA) are capable of inducing alteration in keratinocyte proliferation and differentiation, whereas peroxides are capable of inducing production of pro-inflammatory cytokines and activation of peroxisome proliferator-activated receptors (PPAR),” the investigators wrote. At the same time, histamines and retinoids have also demonstrated effects on sebum production, as receptors have been found in the sebaceous glands.1

Genetic Factors

Despite the high prevalence of acne, there are variations in its severity and duration that suggest strong predispositions associated with genetic immune factors. Results of 5 genome-wide association studies across North America, Northern Europe, China and Australia implicated genetic susceptibilities to TGF-b, TP63, WNT, FGF and phosphoinositol-3-kinase pathways in acne pathogenesis, that were also found in familial studies.7 These patterns suggested predispositions toward acne variants in different ethnic groups that are likely to respond to different genetically targeted therapies in the future. 7

The Effect of Diet

In addition to genetic factors, the high sugar and fat content of the Western Diet packs an added punch that contributes to a higher prevalence of acne in many countries where dairy and high-gluten products are widely consumed. Foods with high glycemic load and animal proteins are often consumed in higher levels during puberty, when the influence on insulin/insulin-like growth factor-1 (IGF-1) enhances the already elevated IGF-1 levels, setting the stage for cascade reactions that lead to sebaceous overload and acne.1


The complexity and interplay of these many mechanisms are being explored, opening new therapeutic avenues for various novel treatments for acne that will focus on immune function and anti-inflammatory activity.4


1. Bhat YJ, Latief I, Hassan I. Update on etiopathogenesis and treatment of Acne. Indian J Dermatol Venereol Leprol. 2017;83:298-306. doi: 10.4103/0378-6323.199581. PMID: 28195079.

2. Zouboulis CC. Acne as a chronic systemic disease. Clin Dermatol. 2014;32:389-96. doi: 10.1016/j.clindermatol.2013.11.005. Epub 2013 Nov 23. PMID: 24767186.

3. Liu PF, Hsieh YD, Lin YC, Two A, Shu CW, Huang CM. Propionibacterium acnes in the pathogenesis and immunotherapy of acne vulgaris. Curr Drug Metab. 2015;16:245-54. doi: 10.2174/1389200216666150812124801. PMID: 26264195. Abstract.

4. Zouboulis CC. Endocrinology and immunology of acne: Two sides of the same coin. Exp Dermatol. 2020 Sep;29(9):840-859. doi: 10.1111/exd.14172. PMID: 32779248.

5. Moradi Tuchayi S, Makrantonaki E, Ganceviciene R, Dessinioti C, Feldman SR, Zouboulis CC. Acne vulgaris. Nat Rev Dis Primers. 2015;1:15029. doi: 10.1038/nrdp.2015.29. PMID: 27189872. Abstract.

6. Zouboulis CC, Eady A, Philpott M, Goldsmith LA, Orfanos C, Cunliffe WC, Rosenfield R. What is the pathogenesis of acne? Exp Dermatol. 2005;14:143-52. doi: 10.1111/j.0906-6705.2005.0285a.x. PMID: 15679586.

7. Common JEA, Barker JN, van Steensel MAM. What does acne genetics teach us about disease pathogenesis? Br J Dermatol. 2019;181:665-676. doi: 10.1111/bjd.17721. Epub 2019 Mar 10. PMID: 30854635.