Hormonal Influences in Acne | Kickoff

Hormonal Influences in Acne

15 May

Diane Thiboutot
Department of Dermatology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, U.S.A.

INTRODUCTION

The effects  of hormones in acne  are  most  notable in women. Androgens such  as dihydrotestosterone (DHT) and  testosterone, the adrenal precursor dehydroepian- drosterone sulfate   (DHEAS),  estrogen, and   other   hormones, including growth hormone or insulin-like growth factors  (IGFs), may  each be important. It is likely that   the  hormones affecting   the  sebaceous  gland   are  both  taken   up  from  the serum in addition to being  made locally within the gland.

Hormonal therapy is an option in women whose acne  is not  responding to conventional treatment or if signs of endocrine abnormalities are present. The great- est  therapeutic benefit  from  hormonal therapy is achieved in  combination with other  effective anti-acne medications. This chapter focuses  on the role of hormones in acne, the clinical presentation of adult female  acne, the work-up of a suspected endocrine abnormality, and  the available options for hormonal therapy.

ANDROGENS  IN ACNE

Both  clinical  observation and  experimental evidence confirm  the  importance  of androgens in the pathophysiology of acne.  The majority of circulating androgens are produced by the gonads and the adrenal gland. Androgens can also be produced locally  within the sebaceous gland  from  the adrenal precursor hormone, DHEAS. The  main  androgens that  interact with  the  androgen receptor are    testosterone and  DHT. Androgen receptors are found in the basal  layer  of the sebaceous gland and the outer root sheath keratinocytes of the hair follicle (1,2). DHT is approximately five to 10 times  more  potent than  testosterone in its interaction with  the androgen receptor.

An essential role for androgens in stimulating sebum production is supported by several  lines of evidence. For example, the development of acne in the prepuber- tal period has been associated with elevated serum levels of DHEAS, a precursor for testosterone  (3,4).  Androgen-insensitive subjects  who  lack  functional androgen receptors do  not  produce sebum and  do  not  develop acne  (5). Tumors of  the ovary   or  the   adrenal  that   produce  androgens  are   often   associated  with   the development of acne. Systemic  administration of testosterone and  dehydroepian- drosterone increases the size and  secretion of sebaceous glands (6), and  we know that  severe  acne is often associated with  elevated serum androgens (7,8).

Androgen Metabolism Within  the  Skin

Acne may be mediated by serum androgens, locally produced androgens, or a com- bination of  both.  Insights have  been  gained regarding the  local  metabolism  of 83

androgens within sebaceous glands (9). Such  insights may  be  of benefit  in  the design  of  new   acne  therapies.  The  skin  and   sebaceous  gland   are  capable  of producing and  metabolizing androgens (9). DHEAS is the major adrenal androgen precursor. It circulates in the blood  stream in relatively high  levels compared with other   hormones  with   the   exception  of  cortisol.   In   fact,   in   for   review,   see Ref. postmenopausal women, all sex steroids made in the  skin  are  from  adrenal steroid precursors,  especially DHEA.  Secretion  of this  precursor steroid by  the adrenals decreases progressively from  age  30 to  less  than  50% of  its  maximal value  at  age  60 (10). The  enzyme 3b -hydroxysteroid   dehydrogenase (3b -HSD) acts on DHEA  to convert it to androstenedione (Fig. 1). This conversion may  take place in the adrenal gland and  tissues  such  as  the  sebaceous gland, where activity of the  3b -HSD enzyme has  been  identified by several  investigators (11 – 13). The reversible conversion of  androstenedione into  testosterone is  then  catalyzed in the human skin by 17b -HSD, a member of the short  chain  alcohol  dehydrogenases that  are  related to retinol    metabolizing  enzymes  (14 – 18).   This  is a reversible enzyme that can oxidize  and reduce both androgens and estrogens. It is responsible for converting the weak  androgen androstenedione into the more  potent androgen testosterone. It can also interconvert weak  and  potent estrogens such   as   estrone and  estradiol. The  17b -HSD  enzyme may  represent a regulatory point  in andro- gen and  estrogen metabolism within the skin.

DHT is produced from testosterone within peripheral tissues such as the skin by the action of the 5a -reductase enzyme. Two isozymes of 5a -reductase have been identified (19). The type 1 isozyme is active within the sebaceous gland (20,21). The type  2 isozyme is most  active  in the  prostate gland, where it can be inhibited by drugs such  as finasteride. Activity  of 5a-reductase and  17b -HSD exhibits  regional differences depending upon the source  of the sebaceous glands (9). In skin that  is prone to acne, such  as facial skin, activity  of the type  1 5a-reductase in sebaceous glands is  greater than   in  sebaceous glands obtained from  nonacne-prone skin (20). This  implies that  more  DHT  is being  produced in  sebaceous glands from facial  skin  compared with  other  areas  of the  body  that  are  not  prone to develop acne. The net effect of the activity  of these  two  enzymes is the greater production of potent androgens such  as  testosterone and  DHT  within  sebaceous glands of facial areas,  which  may in part  account for the development of acne in these  areas.

FIGURE 1    The   steroidogenic  pathway.  Abbreviations:  HSD,   hydroxysteroid dehydrogenase; P450scc, P450  side chain cleavage enzyme; StAR, steroidogenic acute regulatory  protein.

The  Sebaceous Gland Is a Steroidogenic Tissue

The skin and sebaceous glands are capable of synthesizing cholesterol de novo from acetate  (22 – 24). Although this cholesterol is utilized in cell membranes, in the for- mation of the epidermal barrier, and  is secreted in sebum, its use as a substrate for steroid hormone synthesis had  not  been  established until  recently. In  order for steroid synthesis to occur,  cholesterol needs  to be translocated from  the  outer  to the inner  mitochondrial membrane. This process  is regulated by the steroidogenic acute regulatory protein (25). Additional enzymes and  cofactors  needed to convert cholesterol into a steroid include P450 cholesterol side chain cleavage, adrenodoxin reductase, cytochrome P450c17, and  steroidogenic factor-1.  Expression of each  of these  proteins was found in human facial skin, sebocytes, and  in a recently devel- oped  simian   virus  (SV) 40-immortalized human  sebocyte cell  line  (SEB-1) (26). These  data  demonstrate that  the skin  is in fact a steroidogenic tissue.  The clinical significance of this  finding in mediating androgenic skin  disorders such  as acne, hirsutism, or androgenetic alopecia remains to be established.

m and  in  the estrogen-related fluid  retention associated with  some  oral contraceptives (43).

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