ESTROGENS IN ACNE

15 May

Very little is known about the role of estrogens in modulating sebum production. Any estrogen given  systemically in sufficient  amounts will decrease sebum production. The dose  of estrogen required to suppress sebum production, however, is greater than  the dose required to suppress ovulation (27). The major active estrogen is estra- diol,  which  is produced from  testosterone by the  action  of the  enzyme aromatase. Aromatase is active in the ovary, adipose tissue, and other peripheral tissues. Estradiol can be converted to the less potent estrogen, estrone, by the action  of the 17b -HSD enzyme. Both  aromatase and  17b -HSD  are  present in  the  skin  (17,28). Estrogens may act by several mechanisms; they may: (i) directly oppose the effects of androgens locally within the sebaceous gland, (ii) inhibit the production of androgens by gonadal tissue   via  a  negative  feedback loop  on  pituitary gonadotrophin release,  and  (iii) regulate genes that negatively influence sebaceous gland growth or lipid production.

GROWTH HORMONE AND INSULIN-LIKE GROWTH FACTORS  IN ACNE

Growth hormone is secreted by the pituitary gland.  It acts on the liver and  periph- eral tissues to stimulate the production of IGFs, formerly known as somatomedians. There  are two  forms  of IGF, termed IGF-1 and  IGF-2. IGF-1 is the more  prevalent growth factor.  It has been  hypothesized that  growth hormone may  be involved in the  development of  acne  (29). Acne  is  most  prevalent in  adolescents during  a time  when growth hormone is maximally secreted and  serum levels  of IGF-1 are highest. In addition, IGF-1 can be produced locally  within the  skin,  where it can interact with receptors on the sebaceous gland to stimulate its growth. Furthermore, conditions of growth hormone excess such as acromegaly are associated with sebor- rhea  and  the  development of acne.  In some  tissues,  the  actions  of IGF-1 can  be mediated by androgens. It is possible that  androgens may  influence IGF-1 action in the sebaceous gland  as well.

CLINICAL PRESENTATION OF ADULT FEMALE ACNE

For reasons that  are not understood, the distribution of facial acne in many  adult females  differs  from  that  seen  in  adolescents and  in  males.  Many  adult women

note that  acne localizes  to the lateral  face, chin, and  neck (Fig. 2). Oftentimes, acne in  these  women is  not  necessarily widespread  or  severe,  but  rather it  may  be low-grade, persistent, and  consist  of a few isolated deep-seated tender nodules.

Many women note flares of their acne just prior to their menstrual period with reports ranging from 27 – 60% to 70% of women (30 – 32). One study has been pub- lished  that  provides quantitative documentation of acne  lesion  counts  over  the menstrual period (33). In this study of women, who  were  followed over two men- strual cycles, 63% showed a 25% increase in inflammatory acne lesions  prior  to the menstrual period. Some  women may  feel that  intermittent acne  therapy prior  to their  menstrual period may  be beneficial.  There  is no evidence for this  approach. Since most  acne therapy is designed to prevent the formation of lesions  and  since this process  often  takes  several  weeks,  it seems  unlikely that  intermittent therapy would be beneficial.  For this reason, it is important to have patients use their medi- cations  consistently and  to avoid  spot  treatment.

WHEN TO SUSPECT AN ENDOCRINE  DISORDER  IN ACNE PATIENTS

Although hormones influence acne, most  acne patients do not have  an endocrine disorder. Hyperandrogenism should be considered in female  patients whose acne is severe, sudden in its onset, or is associated with hirsutism, or irregular menstrual periods. Additional clinical signs of hyperandrogenism include Cushinoid features, increased libido,  clitoromegaly, deepening  of the  voice,  acanthosis nigricans, or androgenetic  alopecia. Women with   hyperandrogenism may  also  have  insulin resistance. They  are  at  risk  for  the  development of diabetes and  cardiovascular disease. It is therefore important for the long-term health of these patients to ident- ify hyperandrogenism so that  they  can receive  appropriate therapy from an endo- crinologist or gynecologist.

SCREENING  FOR AN ENDOCRINE DISORDER

A medical history and  physical examination should be performed that  is directed toward eliciting any symptoms or signs of hyperandrogenism. Screening laboratory tests for hyperandrogenism include a serum DHEAS, total testosterone, free testos- terone, and   luteinizing  hormone/follicle-stimulating  hormone  (LH/FSH)  ratio. These  tests  should be obtained apart from  the time  of ovulation in order  to avoid the  surge  of hormones associated with  ovulation. From  a practical standpoint, it may  be easiest  to suggest that  women have  these  tests performed either  just prior to or during the  menstrual period. It is important to note  that  if a patient is on oral contraceptives at the time of hormonal testing,  an underlying hyperandrogen- emia may be masked. This does not occur with  antiandrogens such as cyproterone or spironolactone. Therefore, it is best that patients discontinue oral contraceptives four  to six weeks  prior  to the endocrine evaluation.

Excess androgens may  be produced by either  the adrenal gland or the ovary. Serum levels of DHEAS can be used to screen for an adrenal source of excess androgen production. Patients with a serum DHEAS greater than 8000 ng/mL (units may differ depending upon the laboratory) may have an adrenal tumor and should be referred to an endocrinologist for further evaluation. Some adrenal tumors may also produce tes- tosterone. Values of DHEAS in the range of 4000 ng/mL to 8000 ng/mL may be associ- ated  with  congenital adrenal hyperplasia, which  is most commonly due  to a partial deficiency in the 21-hydroxylase  or   11-hydroxylase enzyme in the adrenal gland.

Such an enzyme deficiency results in the shunting of steroids from the cortisol biosyn- thetic pathway into the androgen biosynthetic pathway.

An ovarian source  of excess androgens can be suspected in cases where the serum total  testosterone is  elevated. Serum   total  testosterone  in  the  range   of

150 ng/dL  to 200 ng/dL  or  an  increased LH/FSH  ratio  (greater than  2 to 3) can be found in cases of polycystic ovary  disease. This condition is a spectrum and  is often, but not always, associated with irregular menstrual periods, reduced fertility, obesity,  insulin resistance, or hirsutism. Greater elevations in serum testosterone may  indicate an ovarian tumor and  appropriate referral should be made. In some cases,  there  can be modest elevations in both  DHEAS  and  testosterone. A serum level of 17-hydroxypregneneolone can be obtained to discern between an ovarian or adrenal source of androgens. If 17-hydroxypregneneolone is elevated, it indicates an adrenal source  of excess androgens, most often secondary to late onset congeni- tal adrenal hyperplasia. Of note is that  there  is a significant amount of variation in an  individual’s serum  androgen  levels.   In  cases   where  abnormal  results  are obtained, it is recommended to repeat the test before  proceeding with  therapy or a more  extensive work-up.

Questions arise as to the importance of a pelvic ultrasound in the diagnosis of polycystic ovarian syndrome. This  test  can  be  nonspecific, in  that  women with normal androgens may  have  ovarian cysts and  conversely, women with  hyperan- drogenism  and   other   findings  associated  with   polycystic ovarian                                         syndrome may  not  have  ovarian cysts  at the  time  of pelvic  ultrasound. For this  reason, the diagnosis of polycystic ovarian syndrome is more  heavily  based  upon the  serum hormonal profile  and  associated clinical findings.

In the majority of women with acne, serum androgens are completely normal, yet these women will in fact respond if treated with hormonal therapy. Studies  have shown that, as a group, women with acne may have higher levels of serum DHEAS, testosterone, and  DHT than  those  without acne (7,34). However, although higher, these  laboratory values may  still  be  within the  normal range.   Serum  levels  of DHEAS,  DHT,  and  IGF-1  are  reported to  correlate positively with  acne  lesion counts in  women, whereas androstenedione  and  DHEAS  correlate with  lesion counts in men  (35). Reduction of serum androgens or inhibition of their  action,  as obtained  with   oral   contraceptives  or  antiandrogens,  respectively, can  lead   to improvement in acne in women with  normal serum androgen levels.

OPTIONS  FOR THE HORMONAL THERAPY OF ACNE IN WOMEN

Once the decision has been made to initiate hormonal therapy, the various options to choose from include: (i) androgen receptor blockers,  or antiandrogens (this class of drugs block  the  effect of androgens on the  sebaceous gland);  (ii) inhibitors of androgen production by  the  ovary  or  adrenal gland such  as oral  contraceptives or  glucocorticosteroids, respectively; or  (iii) in  the  future, it may  be  possible to inhibit  the  activity  of androgen metabolizing enzymes in  the  skin  or  sebaceous gland itself.

Agents that Block the  Androgen Receptor

Within the class of androgen receptor blockers, therapeutic options include spirono- lactone,  cyproterone acetate,  and  flutamide. In the United States, spironolactone is the most  commonly used  drug, although flutamide is also available.

Spironolactone

Oral spironolactone decreases sebum excretion rate by 30% to 50%. Recommended doses  are  50 to  100 mg  taken  with  meals  (36,37). However, many  women with sporadic outbreaks of  inflammatory  lesions   or  isolated cysts  respond well  to

25 mg  twice  daily  and  some  even  respond to just  25 mg  a day.  These  low  doses in  healthy young women are  generally well-tolerated. However, if this  drug is used  in older  women who  may  have  other  medical problems, or if higher doses are used  for conditions such  as hirsutism or androgenetic alopecia, serum electro- lytes should be monitored. Side effects of spironolactone include breast  tenderness and   menstrual  irregularities.  Additionally,  it  is  important  that   pregnancy  be avoided during treatment with  spironolactone due  to the potential for abnormal- ities of the male  fetal genitalia such  as hypospadias.

Cyproterone Acetate

Cyproterone acetate  is available in many  parts  of the world, but not in the United States. It possesses dual  activity  in that it serves  as a progestogen in oral contracep- tives in addition to its direct  inhibition of the androgen receptor. It can be given  in doses  of 2 to 100 mg per day as a single agent,  in which  case there  can be improve- ment  in 75% to 90% of women with  acne.  Cyproterone acetate,  however, is most commonly used  in the form of an oral contraceptive combined with  ethinyl estra- diol in varying doses  (38). Numerous clinical  studies support the efficacy of these oral contraceptive preparations in women with  acne.

Flutamide

Flutamide is a potent nonsteroidal antagonist of the androgen receptor. Although most commonly used to treat prostate cancer, flutamide has been reported to be efficacious in the treatment of acne, hirsutism, and  androgenic alopecia (39). It can be given  in doses of 250 mg twice daily in combination with an oral contraceptive. Fatal hepatitis has been reported with this drug. Liver function tests should be monitored and serious consideration should be given to the risk/benefit ratio of its use in acne (40). Addition- ally, because it is an antiandrogen, pregnancy issues are a concern.

Inhibitors of Adrenal Androgen Production

Another option in hormone therapy is to block the production of androgens either by the adrenal gland  or ovary,  which  can be accomplished through the use of low- dose  glucocorticoids or oral contraceptives, respectively.

Glucocorticoids

Low-dose glucocorticoids are most commonly used  to treat patients with late onset congenital adrenal hyperplasia, which  is an  inherent defect  in the  21-hydroxylase or the 11-hydroxylase enzyme. This defect causes a block in the cortisol biosynthetic pathway, which  results in a buildup of steroid precursors that are shunted into the androgen biosynthetic pathway. Low-dose prednisone (2.5 to 5 mg a day, at bedtime) can be used.  Low doses  of dexamethasone can also be used,  but the risk of adrenal suppression is higher. To ascertain if therapy with  glucocorticoids is having the desired effect, serum DHEAS can be monitored for a decrease or normalization  of the  level  of DHEAS.  To check  for  adrenal suppression, an  adrenocorticotrophin hormone (ACTH)  simulation test  can  be  performed. This  consists   of  injecting

ACTH and assessing the plasma cortisol 30 minutes later. If plasma cortisol has risen by an appropriate amount, the adrenal gland  is not suppressed.

Inhibition of Ovarian Androgen Production

Gonadotropin-Releasing Agonists

Androgen production in the  ovary  can also be blocked  by gonadotropin-releasing hormone agonists such  as buserelin, nafarelin, or leuprolide. These  gonadotropin- releasing agonists block ovulation by interrupting the cyclic release  of FSH and  LH from the pituitary. These drugs are efficacious in acne and hirsutism, and are available as injectable drugs or nasal spray. However, in addition to suppressing the production of ovarian androgens, these drugs also suppress the ovarian production of estrogens, thereby eliminating the function of the ovary.  Thus, the patient could develop meno- pausal symptoms and suffer from hypoestrogenism. Headaches can also develop, as well as the occurrence of bone loss, due to the reduction in estrogen.

Oral Contraceptives

Oral  contraceptives generally contain an estrogen (most  commonly ethinyl estra- diol)  and  a progestin. In  their  early  formulations, oral  contraceptives contained over 100 mg of estrogen. In these  and  higher doses,  estrogens themselves can sup- press  sebum production. Estrogens also act on the liver to increase the synthesis of sex hormone-binding globulin that  binds  testosterone and  lowers  the  circulating levels of free testosterone. In addition, oral contraceptives inhibit  the ovarian pro- duction of androgens by  suppressing ovulation. This,  in  turn,  decreases serum androgen levels  and  reduces sebum production. The  concentrations of estrogen in  oral  contraceptives have  decreased over  the  years  from  150 to  35 mg, and  in the  most  recent  forms,  to  20 mg, in  order   to  reduce the  side  effects  associated with   estrogen  (41).  Oral  contraceptives  containing  low  doses   of  estrogen are listed  in Table 1.

Progestins

The  progestins contained in  oral  contraceptives include estranges and  gonanes, which  are derivatives of 19-nortestosterone, cyprotereone acetate,  and  a novel pro- gestin,   drosperinone.  Members of  the  estrane  and   gonane class  of  progestins (Table 2) can cross-react with  the  androgen receptor, which  can lead  to increased androgenic effects  and  could  aggravate acne,  hirsutism, or  androgenic alopecia. These  progestins can  also  cause  changes in  lipid  metabolism and  can  increase serum glucose,  leading to glucose  intolerance, as well as possibly interfering with the  beneficial  effect  of estrogen on  the  sex hormone-binding globulin. However, the  third generation progestins, including norgestimate, desogestrel, and  gesto- dene,  are  more  selective  for the  progesterone receptor rather than  the  androgen receptor. The biological  relevance of these  differences, however, is uncertain. For

years,  it has  been  known that  almost  all oral  contraceptives are  beneficial  in the treatment of acne  (42). It is possible that  some  women are  more  sensitive to the androgenic effects of a progestin, but  it is more  likely  that  the  effect of progestin may be offset by estrogen. All oral contraceptives, regardless of the type of proges- tin, will inhibit  serum androgen levels. Moreover, although some progestins might be more androgenic than others,  there is an increase in sex hormone-binding globu- lin  with  the  use  of any  oral  contraceptives and  an  improvement of the  acne  in women who  are treated with  them.

Drospirenone is a novel progestin that is derived from 17a-spironolactone. It possesses  antiandrogenic  and   antimineralocorticoid  activity,   which   can  be  of benefit  in  androgenic-related conditions such  as  acne  and  hirsutism and  in  the estrogen-related fluid  retention associated with  some  oral contraceptives (43).

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