Hormonal treatment of acne vulgaris in women
Acne is a common skin condition affecting most people in their lifetime and in most in a mild to moderate degree. Although traditionally thought of as a disease of teenagers and a “rite of passage,” we know acne can affect from infancy well into the adult years. Studies show 79% to 95% of teenagers are affected (1). In addition, acne may begin in the twenties and thirties, with persistence into adulthood. In one review, up to 12% of female patients had symptoms of acne until the age of 44 (1). This percentage appears to be less for men, around 3% in the same study had acne until the age of 44. In a more recent study, surveyed patients reported an increased prevalence of acne into adulthood (2). In this study, over 1013 patients were divided into four age groups: 20 to 29 years, 30 to 39 years, 40 to 49 years, and over 50 years.
In each adult age group, women reported more acne than men and the percentages were striking. In the 20- to 29-year-olds, 50.9% of women versus 42.5% of men reported acne. This trend continued in each age group, with the 35.2%, 26.3%, and 15.3% of women aged 30 to 39, 40 to 49, and over 50 years, respectively, reporting acne. The per-centages for men with acne in the same age groups of increasing years were 20.1%, 12%, and 7.3%. It is these female patients whom we most often refer to when discussing hormonal treatment of acne.
However, when discussing the hormonal treatment of acne, it is important to remember age groups other than teenagers/young adults, and these will be discussed below.
REVIEW OF PATHOGENESIS OF ACNE
For acne to occur, basically four steps are required: (i) follicular plugging and excessive sebum production, (ii) enlargement of sebaceous glands and development of microcomedones, (iii) inflammatory processes triggered by Propionibacterium acnes in microcomedones, and (iv) release of cytotoxic and chemotactic agents that leads to further inflammation. The purpose of this post is to review the hormonal influences in the development of acne and evaluate therapy.
In general, it can be thought that acne begins with the action of androgens. Androgens act at the level of the pilosebaceous unit by increasing the size and secretion of the sebaceous gland and possibly affecting follicular hyper-keratinization. The androgens can come from the adrenal glands, the gonads, and also can be converted at the level of the sebaceous gland from steroid precursors (3). When evaluating a patient, it is helpful to think of the sources of their androgens. In the following section, a guide for initial evaluation of these patients will help define the source of androgens.
HORMONAL EVALUATION OF THE ACNE PATIENT
Infantile acne, in children beyond the neonatal period, can present with come-dones, papules, and pustules. It can persist through early childhood and be associated with scarring. Boys tend to be affected more commonly than girls. This is thought to be because females have a rapid drop-off in testosterone by 2 weeks of age (4), whereas boys persist with testosterone and luteinizing hormone (LH) until around 6 to 12 months (5).
During the first year of life, conditions not to be missed include congenital adrenal hyperplasia (CAH), virilizing tumors, and endocrinopathies. A good evaluation of these patients would include the screening tests of dehydroepiandrosterone sulfate (DHEAS), follicle-stimulating hormone (FSH), LH, prolactin, 17-hydroxyprogesterone, free and total testosterone (6) (Krakowski), and androstenedione (Table 1). In addition, assessing for accelerated bone age as a sign of androgen excess can be done by performing a wrist radiograph.
Early Childhood Acne
Acne from the ages of one to seven years, after the infantile androgen abates, should be viewed with caution, and a source of hyperandrogenism should be considered, again with similar laboratory examinations as those listed above (7). Diagnoses that should be excluded include Cushing’s syndrome; CAH; prema-ture adrenarche; true precocious puberty; polycystic ovarian syndrome (PCOS); and gonadal, adrenal, and ovarian tumors (6).
|Table 1 Recommeded Laboratory Evaluations for Patients with Acne and Possible Hormonal Abnormalities|
|Labs to be considered when evaluating a patient with androgen excessDehydroepiandrosterone sulfate (DHEAS)Follicle stimulating hormone (FSH)
Luteinizing hormone (LH)
Free and total testosterone
Sex hormone binding globulin
In a patient where polycystic ovarian syndrome (PCOS) is a consideration, add
In a patient where Cushing’s syndrome is considered, add
Midnight salivary cortisol level (new test approved by FDA)
Acne in the prepubertal phase, meaning after approximately age 7 in girls and around age 7 to 8 in boys, is considered normal and is correlated with an increase in DHEAS by the adrenal cortex in both sexes (8). However, if severe acne or other concerning physical characteristics such as increased amounts of pubic hair, early breast development, or clitoral enlargement are present, then labo-ratory screening for androgen excess should be performed.
As we enter the teenage years, acne becomes commonplace and the concern for rare diagnoses decreases. However, the role of the hormonal abnormalities in acne pathogenesis should always be considered.
Most frequently, androgen excess is considered in female acne patients. However, we must remember that androgen secreting tumors can occur in all ages, including older patients with sudden onset acne. In addition, young men with resistant acne may have CAH or Cushing’s syndrome. This can be eval-uated in such patients with the same labs listed above and a midnight salivary cortisol.
The largest group to benefit from hormonal therapy in the treatment of acne will be young women. As noted above, the percentage of young adult women with acne appears to be rising or at the minimum, becoming more reported. Therefore, hormonal treatment is a valuable adjuvant in an acne regimen.
History and Physical Examination of Female Acne Patients
Upon initial patient examination, it is wise to look for the acne distribution, not only facial but also truncal. Androgen excess in female patients is often char-acterized by large nodulocystic papules along the jawline and a multitude of small comedones over the forehead. Inspection for other signs of hyper-androgenism is a must. This would include hirsutism, with evaluation not only of the face and neck but also of the lower back and abdomen. Examination of the breasts may also reveal signs of hirsutism, but may be an uncomfortable examination for unsuspecting young women in the dermatologists’ office. Seborrhea and alopecia are also signs of possible hyperandrogenism. During the examination, the patient can be questioned about menses regularity. This question should be asked in an open ended manner, namely, how often do you get your periods/menses? If the clinician asks whether menses/periods are regular, many will say yes because it may be regular for them. It is important to note that many women with androgen excess can still have normal menstrual periods.
It is important to question patients regarding medications that may exac-erbate acne. Contraceptives that contain progestins only such as intramuscular progesterone or intrauterine devices that release progestins can exacerbate acne. For example, recently in a letter to the editor, five patients with new-onset acne after using levonorgestrel-releasing intrauterine system were reported (9). The authors suggest this finding is underreported and suggest dermatologists be aware of the association, although it had been reported in a large open study in the past (10).
Laboratory Examination of Female Acne Patients
If signs, on examination, point to hyperandrogenism, it is best to draw some baseline labs while the patient is free of external hormonal influences, namely, that they are not on oral contraceptive pills (OCPs). It is important to avoid drawing the labs during the middle of the patient’s menstrual cycle when estrogen surges with ovulation. Labs can be drawn within the one to two weeks prior to the menstrual period or within the first few days of the menstrual period. Difficulty in the timing of such blood draws occurs in young women with very irregular periods, and in such a setting, labs drawn on day 3 of menses will suffice. Patients currently on OCP should discontinue them for four to six weeks prior to hormonal laboratory examination as hyperandrogenism may be masked by the OCP (11). When evaluating the labs, look for elevations of DHEAS, which can be associated with CAH, PCOS, or Cushing’s syndrome. Very large elevations (>7000 8000 ng/mL) in DHEAS can mean an adrenal tumor. To differentiate between the diseases, also compare the LH/FSH ratio, and if this is greater than 2:1, then consider a diagnosis of PCOS and refer to an endo-crinologist or gynecologist for medical management of PCOS including drugs such as insulin sensitizers: metformin or thiazolidinediones, nutrition counseling, and lifestyle modification. To exclude CAH, review the 17-hydroxyprogesterone and the dehydroepiandrostenedione levels, where increases in both represent deficiencies in 11- or 21-hydroxylase.
Referral to Endocrinologist Is Appropriate When Such Abnormalities Are Uncovered
PCOS is the most common endocrinologic abnormality that occurs in the acne patient. In the United States, the incidence of PCOS can range from 5% to 10% of women. PCOS is a defined syndrome with significant morbidity. PCOS patients can have other important abnormalities including insulin resistance, diabetes, cardiovascular disease, and infertility. Thus, their identification is essential for the general well being of the patient. Sex hormone binding globulin (SHBG), fasting insulin, and fasting lipid levels are required in addition to the hormonal labs listed above.
Specifically, SHBG levels are getting more attention. SHBG is known to be increased with the use of OCPs. Previously, SHBG has been shown to be decreased in some patients with acne. In postpubertal acne, there appears to be a negative relationship between acne severity and serum SHBG (12). Interestingly, SHBG may be more important than once thought. Recently, it was found to be inversely related to the development of diabetes in women over 45 years of age, so a higher plasma level of SHBG was associated with a lower risk of type 2 diabetes (13). Thus, identifying such women at younger ages can have an impact on their future health.
Most young women do not have true laboratory abnormalities or physical symptoms associated with PCOS or other endocrinopathy. However, many more will have acne that is responsive to an OCP.
HORMONAL THERAPY OF ACNE
Oral Contraceptive Pills
In the United States, there are currently three Food and Drug Administration (FDA)-approved oral contraceptives for acne: (i) ethinyl estradiol and norges-timate (Ortho Tri-Cyclen), (ii) ethinyl estradiol and norethindrone (Estrostep), and (iii) ethinyl estradiol and drospirenone (Yaz); although many others have been reported to be beneficial in acne.
When asked which oral contraceptive will work better, it is sometimes dif-ficult for the clinician to make a choice. Patients have multiple concerns from weight gain to medicine cost, thus starting points are necessary as a reference point.
A Cochrane database review was done in 2009 (14). The search yielded 25 trials. There were 7 placebo controlled trials that made 4 different compar-isons; 17 trials that made 13 comparisons between 2 different combination oral contraceptives; and 1 trial that compared an oral contraceptive versus an anti-biotic. The conclusions reached were that combined OCPs worked better than placebo at controlling acne. Differences between pills containing various progestins and dosages were less clear. However, limited data suggested chlormadinone and cyproterone acetate (neither of which is available in the United States) resulted in greater improvement in acne than levonorgestrel. In addition, levonorgestrel was a little better in reducing acne than desogestrel in one trial, but a second trial found them the same (14).
Recently, the safety of the newer contraceptives containing drospirenone has been called into question. A large study to evaluate the safety of the lower estrogen containing 24 active day pill has been launched to study patients over a five-year period. It will engage over 2000 gynecologists and take place in the United States and five European countries (Austria, Germany, Italy, Poland, and Sweden). The main goal of this study is to provide data to assess the concern of increased risks for the patient, including deep vein thrombosis, pulmonary embolism, acute myocardial infarction, and cerebrovascular accidents (15).
Thus, the initial choice of OCPs may include those approved by FDA. Other OCPs may be helpful, and if choosing outside of these three, it is best to use medications that have been studied and shown some success (16). These include combination pills with levonorgestrel, desogestrel, norgestimate, and desogestrel. In general, these later generation progestins have lower androgenic activity, although in practice all OCPs reduce serum androgens and have the potential to improve acne. In conclusion, we know that such combination OCPs work better than placebo, but there is little data to compare these pills to other acne treatments and limited data evaluating them head to head.
Antiandrogens for the use in treating acne come into play in the adult acne patient more commonly than the younger female and can be utilized with great success in the patient with PCOS.
Spironolactone is an aldosterone antagonist and an antiandrogen that works both by blocking the androgen receptor and by inhibiting androgen biosynthesis. It also influences the ratio of LH to FSH by decreasing the response of LH to gonadotropin-releasing hormone (GnRH) (17). It is a pregnancy category C drug due to its risk of feminization effects on male fetuses, thus it is a good agent to be used in combination with OCP. Spironolactone absorption is increased with food (18). The main concern with its use is the risk of hyperkalemia. Patients with a history of adrenal, renal, or cardiac disease should avoid this drug. In addition to medications such as angiotensin-converting enzyme inhibitors, which decrease aldosterone production and increase the likely hood of hyperkalemia, chronic nonsteroidal anti-inflammatory use can lead to hyperkalemia in patients taking spironolactone. Younger healthy women patients taking this medication do not appear to have the consequence of hyperkalemia.
However, in older women or those with cardiac disease or renal insufficiency, it is prudent to advise the patient of signs/symptoms of hyperkalemia (paresthesia, muscle weakness, fatigue, flaccid paralysis of the extremities, and bradycardia). A potassium level should be taken during the first month and after increasing the dose. Some practitioners recommend taking blood pressure measurements and caution young women on the possibility of orthostatic hypotension. Finally, patients should be advised of the potassium connection and avoid potassium supplements and foods/salt substitutes high in potassium. In addition to the above adverse effects, another long-debated concern is the development of hormonally sensitive can-cers in patients on spironolactone. Although there is no conclusive evidence in humans and no documented cases of breast carcinomas related to spironolactone, some recommend avoidance in patients with a genetic predisposition to breast cancer (19). Other side effects include gynecomastia, menstrual irregularities, lethargy, headache, and reduced libido. A Cochrane database review of spi-ronolactone showed there was evidence that it worked for hirsutism but not for acne, although the data was limited (20).
Flutamide is a nonsteroidal antiandrogen devoid of other hormonal activity. As a drug, it acts after conversion to 2-hydroxyflutamide, a potent competitive inhibitor of dihydrotestosterone (DHT) binding to the androgen receptor. It is indicated for use in prostate cancer. It has also been used in the treatment of acne and hirsutism. It cannot be given to pregnant females as it crosses the placenta and can produce a pseudohermaphrodite condition of a male fetus. It can also cause breast tenderness, decreased libido, diarrhea, nausea, and hot flashes. Serious adverse events include hepatotoxicity and the hematologic conditions of anemia, leucopenia and thrombocytopenia. The most severe adverse is a drug-induced hepatitis. Flutamide has been used alone and in combination with metformin and OCP in patients with PCOS to improve the hyperandrogenic findings in these patients (21).
Cyproterone acetate (not available in the United States) is a progestin with antiandrogen properties. The primary action is competition with DHT for the androgen receptor, and like other antiandrogens will induce pseudohermaph-rodism in a male fetus exposed to this medication. Cyproterone has been used to treat prostate cancer, benign prostatic hypertrophy, virilizing syndromes, androgenetic alopecia, hirsutism, and acne. The most concerning side effect is hepatotoxicity, which appears to be related to other hepatic disease and also to be dose dependent (22). Other adverse events appear to be similar to other anti-androgens. In Europe and Latin America, great success has occurred in the treatment of acne when combined with ethinyl estradiol as a contraceptive (Diane-35 and Dianette).
Other Hormonal Therapies
Low-dose glucocorticoids, generally dexamethasone and prednisone, can be used to treat patients with CAH. This condition can be divided into early onset or late onset. Most of the time in dermatology practices, we see late-onset CAH. These patients lack the enzymes 21-hydroxylase or 11-hydroxylase and get a buildup of androgen precursors. Laboratory evidence for this includes elevated levels of androstenedione, 17-hydroxyprogesterone, and DHEAS. In such patients, monitoring for adrenal suppression is necessary given the use of possible long-term use of glucocorticoids. Doses to treat the condition and the acne associated with it are usually low, from 2.5 to 5 mg of prednisone daily are standard.
Other Androgen Blockers
Other androgen blockers include buserelin (23), nafarelin, and leuprolide, which can be used to block ovarian androgen production but are associated with various side effects that often preclude their use in the acne patient.
To conclude, it is important for physicians to recognize, diagnose, and treat acne in patients with hormonal abnormalities and to assure that patients are appropriately referred and followed for management of the underlying problem and its comorbidities. In the case of PCOS, the most common cause of androgen-induced acne, a holistic approach that often involves medical management and counseling regarding nutrition and lifestyle changes may be most effective. It is also important to recognize that hormonal therapy, when added to an acne regimen, cannot only improve the patient’s acne but in many cases can also obviate the need for chronic antibiotic therapy or repeat courses of isotretinoin.
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