Hidradenitis suppurativa (HS) is a chronic and debilitating inflammatory follicular occlusive skin disease [50]^[1] possessing a broad and heterogenous phenotypic spectrum. HS cases are generally characterized by clinical manifestations, including deep-seated and painful suppurating lesions, nodules, abscesses, tunnels, sinus tracts, fistulas and scars occurring in intertriginous body sites such as the axillae, the anogenital and inguinal regions, the perineum and the infra-mammary folds [7]^[2]. The onset of the disease generally occurs in adolescence or early adulthood and affects 1–2% of the population worldwide [7]^[2].

Current evidence suggests that the pathogenesis of HS is complex and multifactorial hence showing a strict interplay between different etiologic factors, including genetic background (mutations in NCSTN, PSENEN and PSEN1 genes), aberrant immune responses, environmental agents and hormonal imbalance [7]^[2]. The major pathogenic feature in HS is shown by the hyperplasia and hyperkeratosis of keratinocytes found in the infundibular region of terminal hair follicles that lead to follicular occlusion and cyst development followed by the subsequent cyst rupture and scattering of its content in the surrounding dermis. These events progressively elicit a deregulated immune activation and a gradual progression towards a chronic inflammatory state [7]^[2]. Specifically, these responses seem to exhibit the classical features of a neutrophilic dermatosis characterized by a strong anti-inflammatory response dominated by IL-10 and elicit a clear contribution of TH-17 and TH-1 lymphocytes [7]^[2].

Of note, growing attention was recently given to the potential role of hormonal imbalance in the aetiology of HS, specifically of sex hormones, therefore strongly suggesting that this aspect needs to be further examined [51]^[3]. Indeed, female predominance (3:1 female to male ratio), the post-pubertal onset of the phenotypic manifestations with a peak between 30 and 39 years of age [52]^[4], aggravation of clinical symptoms during the premenstrual period and a general improvement of flares during pregnancy and post-menopause, strongly endorse the crucial role played by hormones in the onset, progression and severity of HS [53,54]^[5][6].

During the premenstrual period, when the levels of progesterone and estradiol are high, a 44–63% occurrence rate of premenstrual flares is registered in HS women [55]^[7]. In addition, females affected by HS are more prone to develop androgen-related sequelae such as hirsutism, acne and irregular menstruation cycles. Moreover, the prevalence of a hyper-androgenic disorder, namely polycystic ovary syndrome (PCOS), amongst HS cases is 9% against the 2.9% registered in non-affected female subjects [56]^[8]. While considering therapeutic interventions, different case reports underlined that the administration of progestogen-based oral contraceptives in female cases leads to the onset of exacerbated HS clinical manifestations [51]^[3].

Pregnancy seems to significantly impact the phenotype of HS. Although with different final outcomes, many studies indicate an overall improvement of HS flares during pregnancy, when progesterone and oestrogen levels increase, and a progressive worsening after delivery [51]^[3].

HS rarely manifests after menopause, and the remission of symptoms generally occurs with increasing age when the production of estrogen and progesterone decreases [51]^[3].

Furthermore, the identification of similar phenotypic features occurring between HS and acne vulgaris, the latter is a well known androgen-dependent disorder, strongly suggest that pathogenic patterns involving androgen dysfunction might also exist in HS. Specifically, the principal events considered to support this possible association include the development of premenstrual exacerbations, the onset of most severe forms of the disease in males, and androgen-driven hyperplasia, hyperkeratosis and keratinization of the skin [51,53]^[3][5].

Moreover, HS is often associated with obesity, a condition in which enlarged fat cells actively produce hormones [57]^[9].

Further confirming the importance of hormones in the pathogenesis of HS, Buonomo et al. observed the development or exacerbations of clinical manifestations in two transgender men following the administration of testosterone therapy [58]^[10].

Apart from clinical observational studies, some functional assays addressing the possible role of hormones in HS were also conducted. In vivo experiments performed in mouse models showed that androgens induce an incremented pro-inflammatory response driven by augmented levels of TLR-mediated monocyte expression of TNF-α, thus also strongly suggesting a possible correlation between androgenic imbalance and inflammatory phenotypes [59]^[11].

In a very recent work, the percentage of AR-positive keratinocytes resulted higher in the epidermis, infundibulum and tunnels of HS lesions when compared to healthy skin. These findings strongly suggest a possible role of AR in follicular occlusion and keratinocyte proliferation [60]^[12].

Further corroborating these results are microarray analyses that showed enrichment for genes regulated by the activation of AR in lesional areas with respect to nonlesional HS skin partitions. Transcription factors correlated to epidermal stem cells activity were also enriched, and it is known that these cells are localized in the hair bulge that is strongly sensitive to androgens [61]^[13]. In another microarray transcriptome study, a gender-specific gene expression profile was observed. Indeed, in apocrine glands derived from lesional skin of HS patients, the upregulation of gene signatures involved in testis differentiation regulated by androgens was detected in female individuals, while the downregulation of genes correlated to lipid metabolism was highlighted in male HS subjects [62]^[14].

On the contrary, in an immunohistochemistry study, the levels of expression of ERs and ARs in apocrine glands of HS cases were no different from the controls [63]^[15].

A functional study conducted on ARs showed a reduced activity of 3 β-hydroxysteroid dehydrogenases and 17 β-hydroxysteroids in apocrine glands obtained from the axilla of HS patients when compared to controls thus indicating a reduced conversion of DHEA and androstenedione [64]^[16].

When considering serum levels of circulating sex hormones, testosterone and androgen levels showed an increment in HS subjects when compared to controls, although 78% of analyzed cases fell within the normal range [61]^[13].

An increment in androgen levels was also reported in HS women [65]^[17]. Indeed, when individuals in the premenstrual phase were analyzed, patients with HS flares and controls displayed no differences, while HS patients with no flares presented an increment of testosterone, androstenedione and androgen index and a decrement of progesterone levels, though the mechanisms underlining these association still needs to be clarified [52]^[4].

Further complicating this already intricate picture is another study that failed in detecting differences in the levels of testosterone, sex hormone-binding globulin and DHEA-sulfate in HS patients and controls matched per age, body mass index and hirsutism. These results suggest possible biases in the previous studies due to confounding factors such as BMI and hirsutism, events that are more predominant in individuals affected by HS [66]^[18].

Acne vulgaris (AV) is a common chronic inflammatory skin disease affecting approximately 9.4% of the world’s population, exhibiting the highest prevalence in adolescents. AV primarily affects the pilosebaceous unit, hair shaft and sebaceous glands and is characterized by the development of comedones and inflammatory lesions such as papules, nodules and pustules on the face, neck, trunk, or in the proximal upper extremities of the body [67,68]^[19][20].

The pathogenesis of AV is complex and involves different processes, including alterations in sebaceous gland function correlated to increased sebum production (hyperseborrhea) and abnormal sebum composition, hormonal imbalances, follicular hyperproliferation and hyperkeratinization resulting in follicular plugging and rupture and cutaneous dysbiosis associated with the proliferation of Propionibacterium acnes in the pilosebaceous unit [8,68,69]^[21][20][22]. The combination of these events progressively leads to an enhanced cutaneous inflammatory response, mainly driven by an augmented IL-1 production that promotes the development of AV lesions.

To date, the role exploited by androgens in the pathogenesis of AV is well established; indeed, AV is commonly defined as a hyper-androgenic disorder in which DHT, DHEA-sulfate and testosterone levels are found to be higher in patients when compared to healthy controls [69]^[22].

Sebaceous glands constitute the principal site of the skin compartment involved in steroidogenesis. Sebocytes are known to express the central enzymes required for the conversion of inactive or less active circulating androgens to potent hormone-derivates that, upon binding to intracellular receptors, trigger the transcriptional activation of downstream target genes [70]^[23]. Enhanced activation of androgens in AV promotes the proliferation and differentiation of sebocytes and induces lipid synthesis resulting in hyperseborrhea. Lipogenesis is promoted by the AR-dependent activation of mTOR, while the proliferation and differentiation of sebocytes are induced by the suppression of Wnt/Beta-catenin signalling pathway. The combination of these two effects driven by androgens on sebocytes promotes an increment in lipid synthesis and an augmented release of sebum in the sebaceous duct [71]^[24]. In addition, androgens, together with an altered composition of sebum and high levels of IL-1 pro-inflammatory cytokine, dramatically impact keratinocyte functions by excessively stimulating cellular proliferation and by impairing both differentiation programs and the desquamation of follicular keratinocytes that result in hyperkeratosis and the plugging of the gland’s duct [71]^[24].

In a study conducted by Kumtornrut et al., a correlation between androgens, keratinocytes and dermal fibroblast in AV emerged. Dermal fibroblasts express significant levels of ARs, and in vitro analysis showed that growth factors released by these cells upon hormone stimulation could suppress keratinocyte differentiation, thus demonstrating a possible indirect effect of androgens on keratinocytes [72]^[25].

Atopic dermatitis (AD) is a chronic, relapsing and remitting inflammatory skin disease. In its acute phase, AD is clinically characterized by cutaneous pruritic and erythematous lesions, while red or brown flares with cracked or squamous skin appear during the chronic state that is also associated with the development of lichenification and prurigo nodules [73]^[26]. AD affects 1–10% of adults and 15–25% of children, bearing an onset below 5 years of age in 80–90% of reported cases [73]^[26].

AD presents a multifactorial aetiology accounting for genetic variations, immune dysregulation and environmental factors. AD patients encompass epidermal barrier dysfunctions linked to altered epidermal differentiation processes that are commonly associated with mutations in filaggrin (FLG) gene encoding for a structural protein of the skin [74]^[27] or correlated to alterations in lipid metabolism that collectively leads to transepidermal water loss and the penetration of external factors through the skin [75]^[28]. Immune alterations also play an important role in the pathogenesis of AD and include an excessive activation and massive infiltration of TH2 cells and TH22 lymphocytes in acute lesions, while the TH1 population prevail in the chronic status [76]^[29].

The possible role of sex hormones in the development of AD is poorly explored, though some possible associations have been recently unveiled. Evidence suggests that sex hormones might have an impact on the onset and progression of AD by altering cutaneous immune responses and skin permeability functions.

AD is more frequent in males with respect to females during childhood, but after puberty, this trend is inverted. While considering all ages, intrinsic AD (characterized by normal IgE levels, lack of IgE antibodies against allergens, no epithelial barrier disruption and no FLG mutations) is generally more common in females [77]^[30]. The high prevalence of AD in young boys might be correlated to lower levels of production of steroid sulfatase, an enzyme responsible for the metabolism of DHEA [78]^[31]. During the development phase, the levels of sex hormones rise, and the influence of DHEA should therefore be minor, hence favoring the predominant effect of androgens in suppressing the activity of TH2 cells [78]^[31]. Indeed, DHEA and testosterone serum concentrations are lower in male AD individuals when compared to controls, leading to reduced hormonal suppressive effects on immunity and therefore to an aggravation of AD phenotype [79]^[32]. Conversely, the levels of DHEA, dihydrotestosterone, testosterone, and follicle-stimulating hormone (FSH) in AD females show no differences when compared to healthy female controls [79]^[32].

On the other hand, an impairment in skin barrier function is more pronounced in males, a condition that is worsened by androgens, when compared to females in which higher levels of estrogens are able to promote the reconstitution of the skin barrier [78]^[31].

Nevertheless, females experience a worsening in the clinical manifestations of AD immediately before menstruation [80]^[33]. During the luteal phase of the menstrual cycle, a negative perturbative effect driven by a low estrogen/progesterone ratio predominates in the skin and negatively impacts cutaneous barrier functions by increasing skin permeability, therefore, enhancing the susceptibility towards allergens and irritants. Moreover, increased progesterone and estrogen levels during the premenstrual phase alter the activity of TH2 cells that exacerbate AD conditions by promoting inflammation and IgE production [81]^[34]. It was also observed that AD symptoms worsen during pregnancy in 50–60% of analyzed cases, the effect probably due to the relevant increment of estradiol and progesterone that directly impacts the activity of the TH2 cells and the functionality of the skin [82]^[35].

Intriguingly, the expression of two major regulators of steroidogenesis, namely the steroidogenic acute regulatory protein (StAR) that is a rate-determining protein for steroid synthesis and the metastatic lymph node 64 (MLN64) that is a cholesterol transport protein, were found to be altered in skin biopsies derived from AD patients when compared to healthy controls. Specifically, in AD cases, the StaR protein that is normally expressed in the basal layer was found to be completely absent. Similarly, the production of MLN64 in the suprabasal layer was found to be reduced [83]^[36].

Progesterone hypersensitivity (PH), also known as autoimmune progesterone dermatitis, is a very rare inflammatory skin disease that occurs periodically in correspondence with the peak of progesterone production during the menstrual period. PH is characterized by acute symptoms including urticaria erythema, rash and vesiculobullous lesions, as well as by delayed hypersensitivity signs leading to chronic dermatitis [84]^[37]. In most cases, symptoms arise concomitantly with the peak of endogenous progesterone during the luteal phase and disappear after the menstruation flow; both features are considered as diagnostic markers for the pathology [85]^[38]. Elevated levels of basophils and high levels of mast cell activation associated with IgE production are registered in PH cases [86]^[39].

In this context, it is speculated that women develop sensitization to progesterone following its release at a systemic level (e.g., oral contraceptives or hormonal stimulation during in vitro fertilization) [87]^[40]. On the other hand, a cross-sensitization with molecules structurally similar to progesterone is hypothesized [88]^[41]. Alterations in enzymes involved in the cutaneous metabolism of steroid hormones could also account for the development of PH [89]^[42]. In addition, some women experienced an exacerbation of the condition during pregnancy, but PH can also arise intrapartum or in the postpartum period, thus suggesting a sensitization due to the high level of progesterone during pregnancy [84]^[37].

Psoriasis (PSO) is a chronic inflammatory skin disease given by recurrent inflammatory episodes that lead to an impairment in the proliferation and differentiation of keratinocytes. PSO exhibit primary cutaneous manifestations together with a relevant genetic predisposition and possess a worldwide prevalence of about 2% [90]^[43].

PSO is characterized by lesions called plaques and papules, displaying epidermal hyperplasia and infiltration of immune cells such as dendritic cells, T-cells, neutrophils and macrophages. The initial phase in the development of the psoriatic lesion involves the keratinocytes of the outermost skin layer that, upon activation triggered by pathogens or mechanical damages, start to interact with other cell types of the deeper layers resulting in the activation of innate immunity mechanisms followed by the onset of the adaptive immune response. Subsequently, the perpetuation of an inflammatory environment promotes the chronicity of the disease [90]^[43].

In women affected by PSO, menstruation, pregnancy and menopause influence the progress of the disorder, hence suggesting a possible role of sexual hormones on the pathogenesis of the disease. It was observed that estrogens, mainly E2, affect the severity of the disorder by directly impacting inflammation and keratinocyte function as well as angiogenesis and oxidative stress responses [91]^[44]. In the pathogenesis of PSO, oxidative stress is found to support inflammatory responses. It was observed that estrogens present anti-oxidative effects and that they positively regulate the expression of the vascular endothelial growth factor (VEGF), collectively resulting in increased survival, proliferation and migration rates of endothelial cells, all of which are histological features typical of psoriatic lesions [91]^[44].

TH1 and TH17 cells are upregulated in psoriatic plaques, sites in which they release inflammatory cytokines that stimulate inflammatory responses mediated by keratinocytes. Estrogens can suppress the activity of pro-inflammatory cytokines, as well as stimulate TH2 cells to produce anti-inflammatory molecules. Moreover, estrogens promote T-cell conversion into T-regulatory cells, a population actively involved in the modulation of immune responses. In this context, estrogens attenuate PSO, as observed in women during pregnancy [91]^[44].

Moreover, in PSO, estrogens tightly affect keratinocyte functions. Indeed, several studies demonstrated that E2 promotes keratinocyte proliferation and migration by inducing the expression of cyclin D2 [92,93]^[45][46]. These findings suggest that estrogens may increase epidermal hyperplasia and consequently worsen the manifestation of the psoriatic lesion. On the other hand, estrogens induce a reduction in cytokine production by keratinocytes, with consequent mitigation of the inflammatory environment, thus improving the symptoms of the disease. These factors favor the emergence of an intriguing aspect, highlighting that estrogens may have a double effect on keratinocytes either by supporting PSO or by suppressing its development [91]^[44].