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| REVIEW ARTICLE |
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| Year : 2021 | Volume
: 64
| Issue : 6 | Page : 257-265 |
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Hidradenitis suppurativa: Disease pathophysiology and sex hormones
Chia-Bao Chu1, Chao-Chun Yang2, Shaw-Jenq Tsai3
1 Department of Dermatology, National Cheng Kung University Hospital; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
2 Department of Dermatology, National Cheng Kung University Hospital, College of Medicine; International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan
3 Institute of Basic Medical Sciences, College of Medicine; Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| Date of Submission | 17-Jul-2021 |
| Date of Decision | 29-Sep-2021 |
| Date of Acceptance | 17-Nov-2021 |
| Date of Web Publication | 27-Dec-2021 |
Correspondence Address:
Prof. Shaw-Jenq Tsai
Department of Physiology, College of Medicine, National Cheng Kung University, 1 University Road, Tainan 70101; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, 1 University Road, Tainan 70101
Taiwan
 Source of Support: None, Conflict of Interest: None  | 4 |
DOI: 10.4103/cjp.cjp_67_21
Hidradenitis suppurativa is a cutaneous chronic inflammatory disease that is estimated to affect about 1% of the population and caused pain, malodorous discharge, disfigurement, and poor quality of life with psychosocial problems. The typical features are recurrent painful nodules, abscesses, and sinus tracts on the axillae, groins, gluteal areas, and anogenital regions since postpuberty. Smoking and obesity are two major triggering factors of hidradenitis suppurativa. Women are prone to have hidradenitis suppurativa than men in Western countries, but the male-to-female ratio is reversed in oriental countries. The disease severity can be affected by menstruation, pregnancy, and menopause. Furthermore, the phenotypes are different among men and women with hidradenitis suppurativa. Men are prone to have buttock involvement while women are prone to have axillary, groins, and submammary lesions. This review introduces the skin appendages and pathophysiology of hidradenitis suppurativa and then focuses on the sex difference and the effects of sex hormones on hidradenitis suppurativa and current hormone-associated treatments.
Keywords: Apocrine glands, hair follicle, hidradenitis suppurativa, hormone, sebaceous glands, sex
How to cite this article:
Chu CB, Yang CC, Tsai SJ. Hidradenitis suppurativa: Disease pathophysiology and sex hormones. Chin J Physiol 2021;64:257-65 |
| Introduction | |  |
Hidradenitis suppurativa, also called acne inversa or terminal hair dissecting folliculitis,[1] is a chronic inflammatory disease of the terminal hair follicles. The characteristic lesions are painful deep-seated inflamed nodules, abscesses, fistulae, or scar formation in the axillary, inframammary, inguinal, genital, and gluteal regions. The estimated global prevalence rate is about 1%[2] and the average age at onset is usually in the early 20s. Mutations of γ-secretase-related genes (NCSTN, PSENEN, and PSEN1) were identified in a small number of hidradenitis suppurativa patients from China, Japan, India, Singapore, North America, and Europe.[3] Obesity and tobacco smoking are two major risk factors associated with the development of hidradenitis suppurativa. Involvements of the gluteal areas are common in men while involvements of the axillary and groins are common in women.[4] The female-to-male ratio for hidradenitis suppurativa is approximately 3:1 in North America and Europe, but 1:2 in Asia.[4],[5] There is a strong positive association between the sex ratio in patients with hidradenitis suppurativa and the ratio of sex-specific smoking rates among North American, European, and Asian countries.[6] Tobacco smoking is associated with sex predilection in hidradenitis suppurativa. Disrupted microbiome, overgrowth of anerobic opportunistic bacteria, biofilm formation with aberrant immune reaction contribute to hidradenitis suppurativa. Tumor necrosis factor-α (TNF-α),[7],[8] interleukin 1 (IL-1),[9] and IL-17[10] are the critical cytokines in the pathogenesis of hidradenitis suppurativa.[11] Biological agents targeted for TNF-α, IL-1, and IL-17, antibiotics, systemic retinoids, oral contraceptives, anti-androgen drugs are current treatments for this disease.[12] However, there is no specific medication that can cure hidradenitis suppurativa. The role of smoking, obesity, and inflammatory cytokines in initial pathologic change or developed active lesions is still largely unknown. Based on clinical observation, antiandrogen agents exert beneficial effects for patients with hidradenitis suppurativa.[13] However, the mechanism of these hormone-related therapies still waits for investigation. Pathophysiologically, the pospuberty onset, high prevalence of acne history, sex disparities, premenstrual flare-up, and improvement after menopause suggest that the sex hormones may participate in the development and progression of hidradenitis suppurativa. This review introduces the pathophysiology of hidradenitis suppurativa and summarizes the most recent findings regarding the effect of sex hormones on skin appendages and on the progression of hidradenitis suppurativa.
| The Hair Follicles and Other Skin Appendages | | |
Epidermis, dermis, and subcutaneous tissue are the three main layers of the skin. Epidermal invagination develops into the skin appendages, such as hair follicles, apocrine glands, and eccrine glands.[14] Here, we introduce the structures and location of hair follicles and other skin appendages [Figure 1]. | Figure 1: The structure of the skin. The skin is composed of the epidermis, dermis, and subcutaneous fat tissue. The pilosebaceous-apocrine units are a combination of the hair follicle, sebaceous gland, and apocrine gland. The hair follicles are always associated with sebaceous glands. However, apocrine glands have limited distribution and are mainly located in the axillary area. In the hair follicle, the outer root sheath is an epithelial extension of the interfollicular epidermis. The inner root sheath is located between the outer root sheath and the hair shaft. There is an independent skin appendage, the eccrine gland, which can secrete sweat. The figure was drawn by using the commercial web-based software purchased from BioRender.com.
Click here to view |
The hair follicles
Hair follicles are distributed in most skin surface areas except the lips, palms, and soles. Each hair follicle has three segments: the upper segment (infundibulum), the middle segment (isthmus), and the lower segment (suprabulb and bulb). Around the hair shaft, there are inner root sheath, outer root sheath, and dermal sheath. The outer root sheath is contiguous with the interfollicular epidermis. Hair follicles in humans have various functions, such as social communication, thermoregulation, and wound regeneration.
The sebaceous glands
The sebaceous glands are located in the mid-dermis and connected to the hair follicle. They are unilobular or multilobular holocrine glands that secret an oily and waxy substance, called sebum, to the skin surface. Sebum is one of the essential factors of the skin barrier that can prevent water loss from the skin surface and protect skin from frictional injury. Furthermore, sebum has strong antibacterial activity[15] and transports antioxidants such as Vitamin E to protect against oxidative stress.[16]
The eccrine glands and apocrine glands
Eccrine glands and apocrine glands are two main types of human sweat glands. Eccrine glands consist of the straight eccrine duct and secretory coiled portion. Thermoregulation is the main function of the eccrine gland.
The size of apocrine glands is larger than eccrine glands, but the total number is much less than eccrine glands. The apocrine glands mainly distribute in the axillary area, anogenital area, areolae, and eyelids.
| The Physiology Changes of Skin Appendages During Puberty | | |
The skin appendages are considered as a peripheral endocrine organ.[17] It not only expresses the hormone receptors but also synthesizes various hormones. Androgen is one of the well-studied hormones in the hair follicles and sebaceous glands. The biosynthesis and metabolism of steroid sex hormones can be processed independently in the skin appendages.[17],[18],[19],[20] The sex hormone in puberty is regulated by the hypothalamic-pituitary-gonadal axis. During adolescence, the gonadal cells in the ovary and testis secrete estrogen and testosterone under luteinizing hormone (LH) and follicle-stimulating hormone (FSH) stimulation. Then, the secondary sexual characteristics, including pubic hairs and axillary hairs, are developed. In addition, the cells in sebaceous glands and hair follicles use adrenal circulation precursors to synthesize androgen.[21] Testosterone can be de novo synthesized from cholesterol or circulating dehydroepiandrosterone (DHEA) by sebocytes in sebaceous glands.[18] Androgens regulate hair growth,[22] enlargement of apocrine glands, and sebum secretion.[23]
The sebaceous gland is considered a skin brain.[24] As an endocrine organ, it has the function of secreting hormones and metabolizing hormones with the similar feature of hypothalamic–pituitary–adrenal axis for skin homeostasis.[25] In addition, the sebaceous glands contribute to wound regeneration.[24] Human sebocytes have the androgen receptor and progesterone receptor. During puberty, the size of sebaceous glands gradually enlarged with more sebum production, especially in the face, scalp, upper chest, and upper back.[26] Adult men usually have more sebum production than adult women.[27],[28]
Similar to sebaceous glands, the apocrine glands also increase in size and number during adolescence.[29] The secretory function of apocrine glands develops in the same period. In some animals, the apocrine glands produce pheromones which are chemical attraction signals between members. The function of the apocrine glands in humans is not well known. The body odor is mainly from the axillary apocrine sweat glands, related to the bacterial catabolism of apocrine sweat.
| The Alteration of the Skin Appendages in Hidradenitis Suppurativa | | |
The hair follicles
Morphological changes of the hair follicles in hidradenitis suppurativa
The classical histological patterns of hidradenitis suppurativa are hyperkeratosis of the terminal follicle openings, hyperplasia of follicular epithelium, and perifolliculitis [Figure 2]. The proposed pathogenesis of hidradenitis suppurativa begins with occlusion and dilatation or elongation of the infundibular follicles. The infundibulum then ruptures, followed by dermal suppurative inflammation with subsequent sinus tract formation and dermal fibrosis [Figure 2]. The cause of follicular occlusion is still unclear. The crosstalk of follicular keratinocytes, microbiota, and innate immunity may play roles in the initial pathological change. | Figure 2: Pathogenesis and histopathology of hidradenitis suppurativa (a) The postulated three pathogenetic events in hidradenitis suppurativa. First, epidermal hyperkeratosis in the hair follicles with subsequent occlusion and dilation. Second, the follicular epithelial wall rupture occurs in the dermis and results in inflammatory cells infiltrate. Third, the formation of interconnecting sinus tracts is typical in the advanced stage of hidradenitis suppurativa. (b) The histopathologic change in hidradenitis suppurativa. The hair follicles reveal hyperkeratosis, hyperplasia, occlusion, dilation, or elongation. There is an inflammation around the hair follicles and apocrine glands. Besides, the dermis shows fibrosis. Rupture of the follicular wall can cause dense inflammatory cells aggregate and suppurative change in the dermis. The figure was drawn by using the commercial web-based software purchased from BioRender.com.
Click here to view |
Evidence supports the hair follicles involved in hidradenitis suppurativa
Hyperkeratotic plugging at the opening of terminal hair follicles is a typical characteristic of the early stage of hidradenitis suppurativa [Figure 2]. Epithelial hyperplasia at the interfollicular epithelium and infundibula of follicles are common features in hidradenitis suppurative [Figure 2]b. In lesional skin of hidradenitis suppurativa, keratin 16 expression is increased at the interfollicular epidermis and infundibulum.[30] The transcriptome profiling by microarray revealed dysregulation in genes related to epidermal cell differentiation and innate immunity in hidradenitis suppurativa compared to healthy skin.[31] However, the underlying mechanisms responsible for these changes remain unknown.
It has been reported that keratinocytes from the outer root sheath of hair follicles of the occipital scalp exert intrinsic defect develop hidradenitis suppurativa.[32] The study using IL-1β to stimulate outer root sheath-keratinocytes from the occipital scalp revealed that the keratinocytes produced significantly more IL-6, IL-8, TNF-α, interferon gamma-induced protein 10, and C-C motif chemokine ligand 5 in patients with hidradenitis suppurativa compared to a healthy individual.[32] The hair follicles stem cells of hidradenitis suppurativa patients revealed lost quiescent hair follicle stem cells with a higher number of progenitor cells. In the outer root sheath cells from hidradenitis suppurativa patients, cytoplasmic single-strand DNA and micronuclei, which related to nuclear damage, were detected. They induced type I interferon synthesis through the STING pathway and resulted in follicular inflammation in hidradenitis suppurativa.[33]
The apocrine glands
Morphological changes of the apocrine glands in hidradenitis suppurativa
Hidradenitis suppurativa was originally recognized as an apocrine gland disorder, but the inflammation of the apocrine glands is not a constant finding in hidradenitis suppurativa.[34],[35] In the lesions of hidradenitis suppurativa, some secretory cell-like materials are found in the canal of apocrine glands. In addition, there is a ground glass-like appearance of secretory cells in apocrine glands with a thick basement membrane zone in inflamed apocrine glands. Ruptured epithelium with secondary bacterial colonization causes diffuse dense inflammatory aggregated in the dermis with dilated vessels, fibrotic changes and diminished or disappeared appendageal structures, including apocrine glands.
Evidence supports the apocrine glands involved in hidradenitis suppurativa
In some investigators' opinion, the involvement of the apocrine gland in hidradenitis suppurativa [Figure 2]b was incidental or secondary.[34],[35] One study investigating the gene expression of apocrine glands using lesional and perilesional specimens of inflammatory lesions in patients with hidradenitis suppurativa suggests that apocrine was the bystander in hidradenitis suppurativa.[36] In contrast, another study demonstrated the increased expression of IL-17 and TNF-α in the apocrine-rich region of hidradenitis suppurativa compared to that in healthy controls.[37] Hence, it is still controversial whether the apocrine glands initiate or participate in the development of hidradenitis suppurativa.
The eccrine glands
Jemec et al. found that 25% of the hidradenitis suppurativa specimens had inflammation of the eccrine glands.[38] Dermcidin is an antimicrobial peptide that is mainly produced by the eccrine sweat gland.[39] In hidradenitis suppurativa lesional skin, there was a significant decrease in the level of dermcidin.[40],[41] Furthermore, the number of eccrine sweat glands was reduced in hidradenitis suppurativa lesion, which can be identified by keratin 77. A comparison of the level of dermcidin in the eccrine sweat from the back of hidradenitis suppurativa patient and healthy individual showed no apparent difference between the two groups.[42] Taken together, reduced dermcidin is possibly caused by damage of eccrine sweat glands in suppurative inflammation of hidradenitis suppurativa.
The sebaceous glands
Morphological changes of the sebaceous glands in hidradenitis suppurativa
Hidradenitis suppurativa patients have reduced volume and number of sebaceous glands in the axilla or groin.[43] The mean volume of sebaceous glands in healthy control was seven times more than that in hidradenitis suppurativa patients. The surgical specimens of hidradenitis suppurativa sometimes lack sebaceous glands (58.8% in hidradenitis suppurativa and 25% in control).[44]
Evidence supports the sebaceous glands involved in hidradenitis suppurativa
The effect of decreased sebaceous glands causes a decrease in antimicrobial peptides and impaired innate immunity. There was an increased expression of integrin α6β4 in patients' sebaceous glands, which may be associated with a bacterial infection in the hidradenitis suppurativa lesion.[44] Systemic retinoid (isotretinoin, acitretin, and etretinate) is one of the treatment options for hidradenitis suppurativa patients. It decreases sebaceous glands' size, inhibits abnormal keratinization, reduces the follicular plugs, and suppresses the inflammatory response. However, Gallagher et al. reported eight patients developed hidradenitis suppurativa after oral isotretinoin for the treatment of severe acne.[45] In a systemic review of oral isotretinoin use in 174 patients with hidradenitis suppurativa,[46] there are 18% of patients with significant improvement, 17% with moderate improvement, and 64% without response. Acitretin used in hidradenitis suppurativa was recorded in six papers and a total of 22 patients. Sixteen patients with hidradenitis suppurativa revealed significant improvement after systemic acitretin use. The response rate of acitretin is higher than isotretinoin in hidradenitis suppurativa.[46] The mechanism of the different retinoid acids targets on hidradenitis suppurativa is still unclear and needs further investigation.
| The Sex Difference of the Involved Regions in Hidradenitis Suppurativa | | |
There is a sex-specific difference in the clinical features of hidradenitis suppurativa. [Table 1] reveals 11 countries with information of sex-specific involving areas in hidradenitis suppurativa. Axillary involvement was more common in women, especially in the United States,[56] Korea,[53] Japan,[54] and Taiwan.[4] Men were prone to have gluteal lesions in most countries except the United States.[56] Women had a higher percentage of groin lesions than men in all 11 countries, and more than half showed a statistical difference. Inframammary involvement occurs more often in women. In addition, men with hidradenitis suppurativa tend to have severe acne than women.[51] The cause of sex difference is still unknown, and a possible reason is that the response to sex hormones in the skin is different among men and women. | Table 1: Sex-specific affected site of hidradenitis suppurativa in different countries
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| Hidradenitis Suppurativa and Sex Hormone | | |
Peri-menstruation flare-up in hidradenitis suppurativa
Peri-menstruation flare-up was reported in 44%–63% of women with hidradenitis suppurativa [Figure 3].[57],[58],[59],[60],[61],[62] Among them, approximately three quarters got flare-up in the week before menstruation.[63] After ovulation, the progesterone elevation reaches the highest level in the midluteal phase. The mechanism of premenstruation flare-up still awaits further investigation. The cells of the hair bulge strongly expressed estrogen receptor β, whereas no androgen receptor was detected in the bulge area.[64] The pilosebaceous unit is an endocrine organ that can synthesize hormones such as adrenocorticotropic hormone, androgen, corticotropin-releasing hormone, LH, estrogen, and growth hormone-releasing hormone.[17] The hormone may influence skin homeostasis and contribute to infundibular hyperkeratinization. | Figure 3: Sex difference in hidradenitis suppurativa. In hidradenitis suppurativa, men are prone to have lesions on the buttocks, while women are common to have lesions on the regions of axillae, groins, and breasts. Men with hidradenitis suppurativa usually have an acne history suggesting that androgen may play a role in the pathogenesis of hidradenitis suppurativa and acne. The expression of androgen receptors in the sinus tracts of hidradenitis suppurativa is higher in men. Women with hidradenitis suppurativa have premenstrual and postpartum flares. The possible hormones associated with the flare-up of premenstrual and postpartum are progesterone and prolactin, respectively. After menopause, the level of progesterone is decreased, and the symptoms of hidradenitis suppurativa are usually improving. The figure was drawn by using the commercial web-based software purchased from BioRender.com.
Click here to view |
Pregnancy and hidradenitis suppurativa
The disease activity of hidradenitis suppurativa can be modified by pregnancy [Figure 3].[65] Hidradenitis suppurativa is ameliorated by 20% and 30.2% during pregnancy and worsened in 8% and 16.7% of two studies in the Netherlands and Denmark, respectively.[66],[67] In the United States, a higher percentage (61.9%) of hidradenitis suppurativa patients deteriorated in pregnancy.[65] About 40%–66% of patients experienced postpartum exacerbation.[57],[65] These all indicate that the hormone may play a role in the pathogenesis of hidradenitis suppurativa. However, the change is not consistent among all patients, and the reason is still unclear. In a cross-section study, near half of postmenopausal women get remission.[67] A quarter of women with implantation of an intrauterine device or taking medroxyprogesterone acetate suffered from deterioration of hidradenitis suppurativa.[68] In contrast, a third of hidradenitis suppurativa patients with irregular menstruation cycle respond to spironolactone, a diuretic with antiandrogenic effects.[68] The influence of pregnancy on hidradenitis suppurativa has great diversity, and the cause is still uncertain. The levels of sex hormones are different in every trimester. One study measured the medium concentration of estradiol as 2.2, 9.7, and 20.4 ng/ml in the first, second, and third trimester of uncomplicated pregnant women, respectively. The medium level of progesterone was 25.6, 48.1, and 130 ng/ml in the first, second, and third trimesters, respectively.[69] The peak of human chorionic gonadotropin is in the first trimester. Besides, the concentration of prolactin is also gradually elevated during pregnancy. The effect of pregnancy in hidradenitis suppurativa may not be the same in different trimesters, which may be one of the reasons for the discrepancies. The correlation of circulating sex hormones and symptoms during hidradenitis suppurativa needs further research.
Acne and hidradenitis suppurativa
One meta-analysis found the hidradenitis suppurativa patients had a greater than threefold increased adjusted odds of acne vulgaris or acne conglobata than the control.[70] The histology of acne and hidradenitis suppurativa reveals a similar pattern in abnormal follicular keratinization with plugging and dilatation. Both of the diseases commonly occur during or after adolescence when androgen levels are elevated. Besides acne conglobata (a severe form of acne), dissecting cellulitis of the scalp and hidradenitis suppurativa has been called a follicular occlusion triad.[71] They have similar pathophysiologic changes of hair follicles and can occur in the same patient, suggesting that they may share the same underlying pathophysiological mechanism.
Systemic hormone changes in hidradenitis suppurativa
Several studies compared the hormone changes in blood from hidradenitis suppurativa patients and healthy controls.[58],[62],[72],[73],[74] Most reports showed no obvious difference between the two groups. The blood levels of DHEA sulfate (DHEAS), testosterone, and sex hormone-binding globulin were similar in two groups with matched age, body mass index, and hirsutism. Under the stimulation of GnRH or thyrotropin-releasing hormone in the luteal phase, the level of LH, FSH, 17β-estradiol, progesterone, testosterone, DHEAS revealed no apparent difference in the baseline and after 10–60 min in the two groups. Hidradenitis suppurativa patients had a significant increase in prolactin and thyroid-stimulating hormone under treatment of thyrotropin-releasing hormone.[72] Hidradenitis suppurativa patients with premenstrual flare showed similar levels of androstenedione and testosterone compared to control. In contrast, hidradenitis suppurativa patients without premenstrual flare revealed a higher level of androstenedione and testosterone.[58] The contribution of the sex hormone in the circulation system seems to be small in hidradenitis suppurativa.
Sex hormone receptors of the appendages in hidradenitis suppurativa
There is no significant difference in the expression of estrogen receptors and androgen receptors between hidradenitis suppurativa patients and healthy controls in apocrine glands.[75] The enzyme activity of 5α-reductase, which converts testosterone to dihydrotestosterone, was similar in the apocrine glands of both groups.[76] In recent studies, an increase in androgen receptor transcriptional activity was detected in lesional skin than non-lesional skin of hidradenitis suppurativa patients.[77] The expression of androgen receptors was higher in hidradenitis suppurativa lesions, especially in the sinus tract. Cells positive for androgen receptors in the epidermis and infundibulum were 5.4% of hidradenitis suppurativa lesions and 2.6% of healthy donor skin. The percentage of androgen receptor-positive cells was higher in the sinus tracts of hidradenitis suppurativa lesions, averaging 22.6% in males and 7.8% in females [Figure 3]. In contrast, the estrogen receptors were not expressed in the epidermis and sinus tracts of hidradenitis suppurativa lesions and healthy control.[78]
Sex hormones in the pathogenesis of hidradenitis suppurativa
Based on the clinical findings, at least three hormones may participate in the pathogenesis of hidradenitis suppurativa: androgen, progesterone, and prolactin. During and after puberty, the level of androgen and progesterone is elevated and may involve the occlusion of hair follicles.[79] In the premenstrual period, the serum progesterone level is higher and linked to a premenstrual flare-up [Figure 3]. The use of a progestogen-only pill worsened the symptoms of hidradenitis suppurativa.[68] On the other hand, postpartum exacerbation is possibly associated with a high level of prolactin [Figure 3], which is also a higher level under stimulation of thyrotropin-releasing hormone in patients with hidradenitis suppurativa. The symptoms of hidradenitis suppurativa usually improve after menopause [Figure 3]. To put it all together, androgen, progesterone, and prolactin may take parts in infundibular hyperkeratosis, follicular occlusion, and hidradenitis suppurativa disease progression.
| Hormonal Treatment of Hidradenitis Suppurativa | | |
The current treatments of hidradenitis suppurativa include antibiotics, retinoic acid, cyclosporine, systemic corticosteroids, TNF-α inhibitors, sex hormone-related therapy, hair removal laser, and surgery. [Table 2] summarizes current medication in hidradenitis suppurativa. Here, we review the treatment associated with sex hormones.[57],[85]
Finasteride is an inhibitor of type II 5α-reductase and is widely used for benign prostatic hyperplasia and androgenetic alopecia.[80] In 1999, finasteride was first reported to be effective in a 56-year-old male and a postmenopausal 55-year-old female with hidradenitis suppurativa.[86] Five children (four females and one male) who received finasteride 1–5 mg/day as monotherapy revealed improvement without side effects.[87] Another study, including three children with hidradenitis suppurativa, also reported successful treatment of hidradenitis suppurativa with finasteride.[88] Hidradenitis suppurativa in adults also benefited from the use of finasteride.[89] Finasteride has antiandrogenic effects and is efficacious for the treatment of hidradenitis suppurativa in children and adults.
Metformin is a diabetic drug that can inhibit gluconeogenesis, increase insulin sensitivity, and reduce androgen production.[57] In a prospective study that recruited 25 hidradenitis suppurativa patients (22 females and three males) with the metformin therapy for 24 weeks, 64% of cases revealed significant improvement of the disease and 72% with better life quality.[81] A retrospective chart review of 53 hidradenitis suppurativa patients with metformin use showed 68% subjective clinical response.[90] Metformin is an inexpensive and effective choice for the treatment of hidradenitis suppurativa, especially for female patients with overweight or obesity.
Spironolactone is a potassium-sparing diuretic with an antiandrogen effect.[44],[45],[46] It also suppresses the inflammation caused by TNF-α.[91] Daily 75 mg of spironolactone achieved disease improvement and reduced pain sensation in hidradenitis suppurativa.[82] An retrospective case series highlighted more than half of female hidradenitis suppurativa patients have had a positive response to 100–150 mg spironolactone for 3 months.[83] In this study, 17 of 20 patients have improved hidradenitis suppurativa symptoms, including seven patients with spironolactone monotherapy, five patients with spironolactone and antibiotic use, and five patients with contraceptives simultaneously. Management of hidradenitis with spironolactone relieves pain, reduces the active lesions, and decreases the severity of hidradenitis suppurativa.[82]
The use of oral contraceptive pills has different effects on hidradenitis suppurativa. Pills with a lower estrogen-to-progesterone ratio or progesterone-only may worsen the symptoms of hidradenitis suppurativa. A randomized controlled trial of cyproterone acetate with estrogen for hidradenitis suppurativa patients displayed improvement in more than half of patients, with seven patients completely recovered during the trial.[84] Nonetheless, the use of progesterone-only pills should be avoided to prevent the flare of hidradenitis suppurativa.
| Conclusion | | |
The initial key triggering factor in the pathogenesis of hidradenitis suppurativa is the occlusion of the hair follicles. There is hyperkeratosis or proliferation of follicular and interfollicular epidermis. Some of the hereditary cases with hidradenitis suppurativa have a deficiency in notch signaling which can lead to follicular occlusion.[92] Subsequently, cyst and fistula may be generated in hidradenitis suppurativa lesions, accompanied by cyst ruptured, inflammation, interconnection of fistula, and bacterial colonization. Suppurativa change is a neutrophil-mediated inflammation with a mixture of bacteria, damaged tissues, and abundant neutrophils which undergo autolysis. It is a critical finding in the lesions of the hidradenitis suppurativa and also links to the origin of the naming, hidradenitis “suppurativa.” The alterations of microbiota, innate, and adaptive immunity are the molecular pillar in hidradenitis suppurativa.[31],[92],[93] The change in the sebaceous glands and sweat glands may also be directly or indirectly involved in the pathogenesis of hidradenitis suppurativa. The sex difference of the affected site, premenstruation flare-up, postmenopause improvement, and hormone-related therapy as a treatment choice suggest that sex hormones participate in the pathophysiology of hidradenitis suppurativa. The increased number of androgen receptors in the sinus tracts of hidradenitis suppurativa lesions may provide a new direction for studies. The crosstalk of sex hormone and pilosebaceous-apocrine units in hidradenitis suppurativa is a critical issue waiting for further investigation. Unraveling the underlying mechanism related to sex hormones and inflammation may offer new avenues for developing effective therapies for hidradenitis suppurativa.
Financial support and sponsorship
This study is funded by a grant from the Clinical Research Fund of National Cheng Kung University Medical Center (NCKUH-11004023) and in part by the Ministry of Science and Technology, Taiwan (MOST 108-2321-B-006-006).
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]
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