Androgen-related disorders and hormone therapy for patients with keloids

Yating Yang,Zongan Chen,Xiaoli Wu,Wei Liu ,Zhen Gao

Department of Plastic and Reconstructive Surgery,Shanghai Tissue Engineering Key Laboratory,Shanghai Research Institute of Plastic and Reconstructive Surgery,Shanghai Ninth People’s Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200011,China

Keywords:Keloids Androgen Sebum Inflammation Systemic treatment

ABSTRACT Keloids are a fibroproliferative disorder of the skin and can cause physical discomfort and psychological burden.Apart from local factors such as skin tension and infection,increasing evidence has suggested that systemic endocrine factors also contribute to the emergence and development of keloids.Hormone disorders have long been suspected to be a risk factor;however,previous studies have mainly focused on the role of female hormones and neglected the critical role of male hormones.As we reviewed the published literature addressing sex steroids in pathological scars,we speculated that androgens(i.e.,male hormones)could become actively involved through sebum-associated hypersensitivity reactions and acne-derived skin lesions,resulting in persistent cutaneous inflammation.This hypothesis was also supported by previous in vitro studies,in which elevated androgen levels and androgenic receptors were detected in keloid tissues.Moreover,relief of pain and pruritus has been observed in patients with keloids who accidently received anti-androgen treatment for other irrelevant indications.Thus,we propose that androgen-related disorders are critical in the pathogenesis of keloids,and systemic treatment targeting sex hormones may provide long-term benefits for predisposed patients with multiple keloids.

1.Introduction

Keloids are a fibroproliferative skin disorder that results from collagen deposition in the extracellular matrix after skin injury.At the proliferation stage,keloids often present with annoying symptoms such as pruritus,pain,and erythema.Unlike hypertrophic scars,keloids can invade normal peripheral tissues,but their tumor-like growth does not regress spontaneously.Steroid injection,surgical removal,radiation,and many types of traditional medicine are frequently used in clinical practice;however,recurrence remains a major challenge because the pathological mechanism of keloids has not yet been fully elucidated.Moreover,repeated iatrogenic lesions could increase the risk for secondary infection,promote keloid initiation,and aggravate disfiguring outcomes.

Asian and African populations are particularly sensitive to the occurrence of keloids.With a prevalence rate of 3.5%,1the risk for keloids among the African population is almost 40 times higher than that among Caucasians(0.09%in England).2Apart from local factors such as skin tension and infection,studies investigating typical cases have identified several systemic risk factors,including genetic predisposition,3,4hypertension,5,6and hormonal abnormalities.The robust growth of keloids during puberty and pregnancy has been documented worldwide;accordingly,a potential relationship between keloids and hormone fluctuation has long been suspected.Unfortunately,the specific role of sex steroids in keloid development remains poorly understood,and hormonal treatment has not yet been introduced.

As derivatives of cholesterol molecules,sex hormones are categorized into androgens,estrogens,and progestins based on their structures and functions.They share a common precursor—pregnenolone,and are systemically regulated by the hypothalamic-pituitary-adrenal axis.7In addition to sexual development and reproduction,sex hormones have multiple tissue-specific functions and actively participate in the regulation of aseptic inflammation.As the major target of sex steroids and the site ofde novoandrogen production,the skin and skin appendages are significantly affected by hormonal fluctuations.8–10Clinically,we have also observed that androgen-associated skin conditions,such as acne and oily skin (overactivated sebaceous glands),are frequently exhibited by patients with keloids.However,previous studies investigating endocrine mechanisms in keloids,especially among female patients,have mainly focused on estrogens (i.e.,female hormones),while the contribution of androgens has been overlooked or neglected.Moreover,extensive studies have demonstrated that sex steroid imbalance and androgen disorders are responsible for cutaneous inflammatory conditions such as acne8and systemic diseases with skin lesions such as polycystic ovary syndrome(PCOS).11,12

A search of the PubMed and Embase databases using subject headings,including“[Keloid] AND [sex hormone]”and“[Keloid] AND[androgen]”,retrieved published studies investigating androgenic hormone metabolism in keloids,and we summarized three plausible mechanisms that may promote keloid pathogenesis.Thus,we propose the following hypothesis:androgen-related disorders are critical for patients predisposed to keloid development,and hormonal treatment targeting androgen or androgenic receptors may be a promising systemic therapeutic strategy that could provide long-term benefits.Herein,we present a literature review and discuss why androgenic hormones are critical in the pathogenesis of keloids.

2.Literature review

In clinical practice,puberty and pregnancy (among females) are annoying for patients with keloids due to the higher risks for recurrence and development.Interestingly,androgen levels also exhibit natural arousal during these periods.Featuring robust development of body odor,pubic hair,and oily skin,adolescents experience adrenarche(awakening of the adrenal gland) due to the activated production of androgens by the adrenal cortex,including dehydroepiandrosterone sulfate (DHEAS),DHEA,and androstenedione.7It should be noted that elevated androgen levels during puberty stimulated by adrenarche occur equally in children of both sexes.Regarding pregnant women,the rise in progesterone and estradiol levels is considered to be responsible for changes in skin conditions and other physiological features,while published studies have reported a significant increase in both testosterone and androstenedione levels from the ovaries initiated within the cycle of normal conception.13Furthermore,elevated androgen levels are prominent in prenatal mothers with PCOS14and/or in those bearing boys.15Acne vulgaris,a skin condition strongly associated with androgen levels,is also a common problem encountered among pregnant and lactating women.16Accumulating evidence indicates that androgen-related disorders may be the major endocrine factor contributing to keloid development during pregnancy and puberty.

The rarity of keloids in childhood was acknowledged as early as 1976,together with its concentrated onset during puberty.17Ogawa et al.18investigated 1 290 Japanese keloid patients and confirmed that keloids were most likely to start at puberty regardless of sex (24 ± 14.4 vs.25.1±15.1,or mode value 16 vs.20 years).A previous study by the same research team also reported that the increased prevalence rate in adolescents was independent of increased traumatic events at approximately 10 years of age.5

Prominent keloid recurrence during pregnancy was first documented in an Egyptian woman who stated that her bilateral ear keloids and concomitant pruritus aggregated rapidly during her pregnancy,and the symptoms diminished shortly after delivery.19Another published investigation also identified pregnancy as a strong risk factor,with 63.2% (12/19) of female patients experiencing recurrence after completing their protocol.20

The effect of sex hormones has been postulated as the reason for activated keloid growth during adolescence and/or pregnancy.5,20However,previous studies have mainly focused on estrogens instead of androgen abnormalities.Nevertheless,sex hormone-binding proteins in keloid tissues,adjacent skin,and normal scars were investigated in 1983,and a higher level of androgen binding (510–1149 Fm/mg of cytosol protein) was observed in keloid tissues.21Comparison of results of the testosterone-binding receptor and DNA amount between active and inactive keloid tissues and normal tissues also demonstrated statistically significant differences at the 0.05 level (0.046,0.038,and 0.012 per mg of tissues;3.356,2.077,and 1.010 fmol per microgram of DNA),suggesting that elevated androgen receptor levels exist in clinically activated keloid tissues and that recurrence is associated with high testosterone-binding activity.22Moreover,it was predicted that androgen antagonists and androgen receptor inhibitors may relieve keloid fibrosis by downregulating procollagen gene expression.22The highertransepidermal water loss rate in males and faster barrier retrieval in hypogonadal mice also implied that androgens may influence skin barrier function,serving as a competitive candidate for keloid pathogenesis.23

3.Evaluations of the hypothesis

3.1.Androgen-driven sebum excess may initiate cutaneous inflammation

First introduced in 1979,the sebum hypothesis proposed that disruption of the pilosebaceous structure initiates the chain,and the leakage of sebum triggers T-lymphocyte recognition and proliferation,leading to a delayed-type hypersensitivity reaction in sensitive individuals.24,25Therefore,androgen-driven sebum excess may initiate keloid-related cutaneous inflammation.

The sebaceous gland has multiple biological functions in hormonal and immune modulation.26Its number remains virtually the same throughout life,while its activity increases,driven by elevated androgen levels during puberty.27As an androgen target tissue,the sebaceous glands possess steroidogenic enzymes that convert adrenal and ovarian precursor androgens into active androgens.28Differentiated sebocytes were found to have the highest androgen receptor density.29In contrast,androgen receptor and androgen signaling could play pivotal roles in cells associated with sebaceous differentiation,suggesting that the androgen receptor is a sensitive marker of the sebaceous gland.28

As reported in 1997,scientists detected elevated androgen receptors in keloid tissues and predicted that the activation and abundance of sebocytes might be involved in the keloid mechanism.22Furthermore,homogenizing sebum tested in 40 keloid patients demonstrated positive outcomes,implying that androgen-driven sebum excess could initiate a chronic cutaneous immune response in the keloid population.25

The sebum hypothesis is also strongly supported by clinical observations.First,many representative patients developed keloids after piercing or tattooing,in which their sebaceous glands were ruptured and enveloped into the deep.In addition,the distribution of“spontaneous keloids”on the back,chest,shoulders,and face is consistent with sebaceous gland-enriched skin.24Finally,the higher prevalence rate of keloids in the African population could also be related to the fact that obstruction of the sebaceous gland is more likely to occur in individuals with thicker skin.

Recently,we observed that several patients with symptoms of pruritus and erythema experienced relief after applying selenium sulfide lotion(reduced sebum production)to the keloid skin,which prompted us to study the internal connection between androgen,sebum,and keloid development.

3.2.Androgen-associated acne may incur traumatic risks for the predisposed population

Acne is a common cause of keloids,and its correlation with androgens has been well defined.Acne pathogenesis primarily comprises three aspects:follicular hyperkeratinization,Propionibacterium acnes(P.acnes)colonization,and increased sebum production.29According to previous studies,androgens significantly promote sebum production.The extra sebum is then degraded by lipase andP.acnesinto pro-inflammatory free fatty acids,which stimulates inflammatory host responses,leading to follicular wall rupture and inflammatory lesion formation.29–31Similar to keloids,acne onset often coincides with puberty.32

Moreover,patients with conditions associated with androgen excesses,such as PCOS,congenital adrenal cortical hyperplasia,11,12and acne-prone areas (jawlines),exhibit higher expression of androgen receptors and elevated 5 α-reductase activity.31Therefore,acne induced by androgen disorders may increase the risk of skin injury.Thus,patients with a history of keloids are more likely to be affected by androgen-associated acne lesions.Future research investigating whether patients with androgen-associated acne are more likely to have keloid recurrence and whether acne patients have a higher prevalence rate of keloids may confirm our hypothesis.

3.3.Altered sex steroid levels may stimulate cutaneous inflammation

Topical immune responses and chronic inflammation are fundamental pathological changes in keloid formation.Researchers have found elevated immunoglobulin (Ig)G,IgA,and IgM levels33,34as well as increased immune cells (T cells,B cells,macrophages,and Langerhans cells) in keloid tissues compared to normal skin.35,36In addition,disproportionated regular T cells and altered macrophage polarization have also been observed,37–39implying that immune dysregulation is actively involved in keloid pathogenesis.Ogawa et al.40argued that inflammatory disorders of the skin,especially in the reticular dermis,are critical for keloid initiation and development because increased inflammatory cell infiltration and elevated pro-inflammatory factors (interleukin (IL)-1,IL-6,and tumor necrosis factor-α) were found in the reticular dermis of keloids and hypertrophic scars,suggesting an increased sensitivity of pro-inflammatory genes to traumatic events.

Extensive studies have revealed the complex roles of sex hormones in immune malfunction.Estrogen exerts both anti-inflammatory and proinflammatory effects depending on the type of immune stimulus,the targeted organ microenvironment,and the relative expression level of estrogen receptor α/β.41It has been reported that estrogens may promote inflammation by regulating inflammatory mediators through the Akt/mTOR pathway42,43and suppressing the immune response by repressing the expression of multiple NF-kB-and c-Jun-driven cytokine genes during pregnancy.44–47DHEA,a moderate androgen related to decreased scalp hair and increased sebum production,29may be involved in many aspects of the immune regulatory effects of sex hormones.48,49

Different sex hormones jointly contribute to the endocrine modulation of inflammation and immune homeostasis.Abnormalities in their proportions are as important as their absolute values.Moreover,the simultaneous action of sex steroids on immune regulation is significantly affected by individual factors,including inflammatory disease,prolonged stress,metabolic changes or injuries,and administration of pharmacological agents.41

4.Anti-androgen treatment may alleviate keloid symptoms and result in long-term benefits

Several studies have confirmed the involvement of sex steroid disorders in specific skin conditions and systemic diseases,and various drugs that target androgenic hormones,enzymes,or receptors have been widely used in clinical practice with verified safety and efficacy.Because androgen-related disorders are speculated to be a critical systemic risk factor among patients predisposed to keloids,we believe that hormonal treatment targeting androgens or androgenic receptors may be a promising therapeutic strategy that could provide long-term benefits.

Finasteride,a 5-α reductase inhibitor widely used to manage benign prostate hyperplasia and male pattern hair loss,50could convert testosterone into dihydrotestosterone,the most potent androgenic hormone.29We have received positive feedback from one patient who reported that the texture and pruritus of his chest keloids were unexpectedly relieved after taking finasteride for other indications.In addition,hidradenitis suppurativa,a pathological follicular disease with manifestations of abscesses,scarring,and keloids,was also reported to respond to finasteride treatment in resistant cases.51

Combined oral contraceptives (COCs,combinations of estrogen and progestin)are effective and convenient choices for female patients.As a well-known hormonal treatment for acne,COCs potently decrease serum androgen levels via two pathways:inhibiting follicle-stimulating hormone and luteinizing hormone secretion(through negative feedback on the pituitary) to decrease ovarian androgen production;and stimulating hepatic sex hormone-binding globulin production to selectively bind free circulating testosterone.52Because hormonal treatment has been used for over 60 years,many COCs have emerged with guaranteed androgen-blocking effects and biosafety.In China,“Diane-35”(ethinyl estradiol and cyproterone acetate) is usually recommended for female patients with androgen-dependent diseases,especially acne and PCOS.Similarly,relief from itchiness and erythema in the keloidal skin has been frequently observed in patients who took COCs for acne or contraception,suggesting that the balance of sex hormones is of significant benefit and should be considered a promising adjuvant treatment.

Anti-androgen medicine is often recommended for keloid patients with hormonal disorder symptoms;however,it has not been officially included in keloid treatment regimens.Therefore,large-scale clinical trials and in-depth biological studies are warranted.

5.Conclusion

With a deeper understanding of the mechanisms of keloid development,the pivotal role of systemic factors has been well appreciated.Previous studies investigating the influence of sex hormones on keloids have primarily focused on female hormones.In contrast,we speculate that male hormone-related sebum overproduction,acne lesions,and prolonged cutaneous inflammation may also contribute to keloid pathogenesis.Furthermore,we propose that androgen or androgenic producttargeted medicine,including COCs,finasteride sulfide,and selenium sulfide lotion,may result in long-term benefits for patients predisposed to the development of keloids.

Alterations to sex hormones,especially female hormones,were reported to be related to keloid development in the past century;however,it remains unclear how they affect keloid development.We propose the following mechanisms and therapeutic strategies.First,androgens received by keloid fibroblasts could be secreted from the distant sexual gonad or producedde novoby the skin,and the cutaneous production of androgens can significantly contribute to circulating levels and affect the systemic state.Thus,it is critical to determine the different effects of circulating androgens andin situproducts in keloid tissues.Aberrant receptors and binding affinities should also be evaluated in future studies.

Moreover,as a multifactorial disease,sex hormones may not be equally important in all types of keloids.Therefore,a qualified classification system able to reliably distinguish keloid patients who are more likely to be affected by sex hormones would be highly valuable to researchers and clinicians.For example,patients with multiple keloids(more than two keloidal lesions at one or different anatomic sites) with typical excess androgen symptoms (e.g.,oily,hairy skin,moderate to severe acne,and menstrual disorder in female patients)may respond well to anti-androgen treatment;as such,it may be studied in predisposed patients(i.e.,with personal or family history of keloids).

Finally,exceptional cases among special groups are noteworthy.Scott et al.53reported linear keloids resulting from the abuse of anabolic-androgenic steroid drugs among athletes.The presence of keloids in transmasculine individuals after sex-reassignment surgery has also been reported,54implying the active involvement of male hormones.Despite their rarity,extensive studies including such patient populations are valuable.

Ethics approval and consent to participate

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Authors’contributions

Yang Y:Investigation,Writing-Original draft.Chen Z:Investigation.Wu X:Conceptualization.Liu W:Writing-Review and Editing,Funding acquisition.Gao Z:Conceptualization,Funding acquisition,Supervision.

Acknowledgments

This study was supported by the National Natural Science Foundation(grant no.81671921) and Shanghai Municipal Key Clinical Specialty(grant no.shslczdzk00901).