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Indian J Dermatol Venereol Leprol | January-February 2009 | Vol 75 | Supplement 1S44
Acne in India: Guidelines for management
Hormonal therapy of acne
Hormonal therapy of acne
Hormonal therapy is an excellent choice for female
patients with acne who have SAHA syndrome [Figure
44–46], polycystic ovarian syndrome (PCOS), HAIR-
AN syndrome (hyperandrogenism, insulin resistance,
acanthosis nigricans) [Figures 50-52], or cutaneous
hyperandrogenism (CH). It is also the logical treatment
for adult/androgenic acne [Figures 12-13] which
is distinguished by its persistence or late onset,
localization to the lower face, and premenstrual flares.
Hormonal therapy is also justified in refractory/difficult
acne and in nodulocystic acne where isotretinoin
is either contraindicated or inadequate. Hormonal
therapy is synergistic with other forms of acne therapy
and may be combined to enhance therapeutic efficacy.
[1] Hormonal therapy alone or in combination represents
a higher step on the therapeutic ladder. Some hormonal
therapies also provide contraception which can be a
bonus. The goal of the hormonal therapy is to oppose
the effects of androgens on the sebaceous glands and
follicular keratinocytes.[1]
CUTANEOUS SIGNS OF HYPERANDROGENISM
CUTANEOUS SIGNS OF HYPERANDROGENISM
• Seborrhea
• Acne – persistent or late onset, lower face,
premenstual flare
• Hirsutism
• Frontal scalp hair thinning (FAGA)
• Coarse, steatotic skin with prominent ostia
• Acanthosis nigricans
• Striae
Hormonal evaluation in acne is indicated when
cutaneous signs of hyperandrogenism are observed.
These include, besides acne (vide supra), hirsutism,
frontal scalp hair thinning, seborrhea, coarse facial
skin with prominent ostia, acanthosis nigricans, and
striae. About 50% of such individuals have underlying
polycystic ovaries (bulky ovaries with loose stroma and
multiple peripherally arranged follicles) and most of
them are clinically identifiable by irregular menstrual
cycle. The full syndrome with obesity, infertility, and
insulin resistance is only occasionally seen in the
dermatology clinics. PCOS is a spectral disease with
mild and incomplete expressions. American College
of Gynecologists (ACOG) criteria for clinical diagnosis
of PCOS include: presence of anovulation (fewer than
nine periods per year or periods >40 days apart) and
signs of hyperandrogenism.[2] CH is a clinical entity
in itself and denotes absence of systemic features of
hyperandrogenism. It is postulated that skin has the
ability to synthesize androgens de novo. CH responds
well to hormonal therapy.
Hormonal evaluation is a prerequisite to hormonal
therapy. A limited and budget-conscious evaluation
should include LH, FSH, prolactin, total and free
testosterone, DHEAS, and an ultrasound of abdomen
and pelvis. While the ultrasound is best done on
the second day of the cycle, blood hormone assays
are recommended to be done in the luteal phase
(last two weeks of the cycle).[1] Some experts prefer
to do the blood hormone assays also on the second
day. A comprehensive hormonal evaluation may
also include cortisol AM and PM, androstenedione,
17--hydroxyprogesterone, 5--dihydrotestosterone,
and sex hormone binding globulin.[1] LH/FSH ratio
in excess of two supports PCOS. Modest elevation
of prolactin and testosterone are likely ovarian in
origin and part of PCOS. High levels of testosterone
are uncommon and suggest ovarian tumor. DHEAS is
derived from the adrenals. Modest increase is seen at
adrenarche and its level correlates with the severity
of comedonal acne in prepubertal girls.[3,4] High levels
of DHEAS indicate congenital adrenal hyperplasia
(4000–8000 ng/ml), or adrenal tumor (over 8000 ng/
ml).[1] Congenital adrenal hyperplasia (CAH) is also
identified by elevated 17--hydroxyprogesterone.
There are partial forms of CAH and the defect is 21
carboxylase and 11 carboxylase deficiencies [Figure
51]. Hormonal assays are expensive to perform and
the cost of comprehensive hormonal evaluation is in
excess of INR ten thousand.
HORMONAL EVALUATION OF CUTANEOUS
HORMONAL EVALUATION OF CUTANEOUS
HYPERANDROGENISM
HYPERANDROGENISM
• FSH/ LH ratio
• Prolactin
• Testosterone free and total
• Androstenedione
• Dehydroepiandrosterone sulfate (DHEAS)
• 5-dihydrotestosterone (5-DHT)
• 17- hydroxyprogesterone (17-OHP)
• Sex hormone binding globulin (SHBG)
• Serum cortisol AM and PM
• Fasting and postprandial Insulin
IAA Consensus
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S45Indian J Dermatol Venereol Leprol | January-February 2009 | Vol 75 | Supplement 1
Acne in India: Guidelines for management
Specific hormonal therapies may be divided into
two groups. One group is agents that block androgen
receptors – also referred to as antiandrogens. This
group includes cyproterone acetate, spironolactone,
drospirenone, and flutamide. The other group is agents
that decrease the androgen production by ovaries and
adrenals. This group includes oral contraceptives and
glucocorticoids.[1]
Combination oral contraceptives are the most widely
used agents in the treatment of acne especially
in our country. The most popular combination is
ethinylestradiol 35 μg plus cyproterone acetate 2 mg
(EE-CPA). Besides decreasing ovarian production of
androgens, EE-CPA also increases SHBG which, in
turn, binds free circulating testosterone. The product
is cost-effective, widely available, and well received
by the patients. EE-CPA comes in a strip of 21 tablets.
It can be started on day 1 (if contraception is a
requirement) or day 5 (if the date of the menstruation is
to be maintained); the therapeutic response is the same
either way. The dose is one tablet a day, best taken after
dinner and the course is repeated after seven tablet-
free days. EE-CPA is typically given for 6–12 months
but may be given for 3 years or longer where well
tolerated and needed. It is contraindicated in patients
with personal or family history of thromboembolism,
and should be used with caution and with greater
justification in cases with family history of breast or
uterine malignancies, in mature adults, in the presence
of depression, hypertension, or other internal medical
problems. It may be used in combination with oral
antibiotics, oral isotretinoin, and other adjunctive
therapy. The combination with oral antibiotics may
compromise the contraceptive function of EE-CPA.
Whether EE-CPA causes weight gain is debatable?
A newer combination oral contraceptive containing
EE 20 μg and drospirenone 3 mg is available and is
indicated in patients intolerant to EE-CPA (including
those who allege weight gain), and in mature adults.
Drospirenone is a derivative of spironolacone. Oral
contraceptives containing third-generation progestins
(norgestimate) and EE have also been used in acne.[5]
Second-generation oral contraceptive ethinylestradiol
plus desogesterel helps regulate menstrual cycle but
does not exert antiandrogenic effect.
Cyproterone acetate 50 mg is an imported drug. It is
available as a tablet and is supplied as a bottle of 50
tablets. Fifty tablets cost approximately INR thirty five
hundred. It can be combined with EE-CPA for a greater
therapeutic effect. It is given as 50–100 mg for first ten
days of the EE-CPA cycle for 5–10 cycles. It is very
effective and well tolerated. Occasionally, it may cause
reversible increase in blood pressure.
Spironolactone functions both as an androgen receptor
blocker and an inhibitor of 5 reductase.[1] In doses of
50–100 mg twice daily, it has been shown to reduce
sebum production and improve acne.[5] It is also
effective in reversing female androgenetic alopecia. It is
indicated in therapy resistant acne and in cases of CH.
It may be combined with other therapies [Figure 64]. It
is widely available, cost effective, and well tolerated.
Adverse effects include menstrual irregularities and
breast tenderness. In young otherwise healthy females,
hyperkalemia and hypotension are nonissues.
Flutamide is an androgen receptor blocker. In a dose
of 250 mg twice daily, in combination with an oral
contraceptive, it is very effective in the treatment of
hirsutism. It is also effective in acne,[7,8] but because
of few case reports of fatal hepatitis, and because
other safer options are available, it is not very popular.
Calutamide is a new introduction and is claimed to
be less hepatotoxic. Finasteride, on the other hand, is
ineffective in acne, because it works by inhibiting 5
reductase type II, which is present in hair follicles but
not in sebaceous glands. Finasteride inhibits 50–60%
of DHT, where as dutasteride, a newer compound,
inhibits 90%. There are yet other agents with marginal
antiandrogenic effect, namely: ketoconazole, cimetidine,
and oral zinc. Zinc reportedly inhibits 5 reductase.[9]
In conclusion, antiandrogens and oral contraceptives
Figure 64: (a and b) Persistent/adult acne with hyperandrogenism
treated with low-dose isotretinoin, spironolactone, and metformin.
Note the change in skin quality
ab
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Indian J Dermatol Venereol Leprol | January-February 2009 | Vol 75 | Supplement 1S46
Acne in India: Guidelines for management
are effective and useful modalities in management of
difficult and complicated acne, but because of their
systemic effects, they should be used by dermatologists
who are familiar with reproductive endocrinology,
or those who elect to work with gynecologists or
endocrinologists.
REFERENCES
REFERENCES
1. Gollnick H, Cunliffe W, Berson D, Dreno B, Finlay A,
Leyden JJ, et al. Management of acne: A report from a global
alliance to improve outcomes in acne. J Am Acad Dermatol
2003;49:S1-38.
2. James WD, Berger TG, Elston DM. Andrews’ diseases of
the skin – Clinical dermatology. 10th ed. Canada: Saunders
Elsevier; 2006. p. 231-50.
3. Lucky AW, Biro FM, Hustar GA, Leach AD, Morrison
JA, Ratterman J. Acne vulgaris in premenarcheal girls:
An early sign of puberty associated with rising levels of
dehydroepiandrosterone Arch Dermatol 1994;130:308-14.
4. Lucky A, Henderson T, Olson W, Robisch DM, Lebwohl
M, Swinyer LJ. Effectiveness of norgestimate and ethinyl
estradiol in treating moderate acne. J Am Acad Dermatol
1997;37:746-54.
5. Redmond GP, Olson WH, Lippman JS, Kafrissen ME, Jones
TM, Jorizzo JL. Norgestimate and ethinylestradiol in the
treatment of acne vulgaris: A randomized, placebo controlled-
trial. Obstet Gynecol 1997;89:615-22.
6. Goodfellow A, Alaghband-Zadeh J, Carter G, Cream JJ,
Holland S, Scully J, et al. Oral spironolactone improves
acne vulgaris and reduces sebum excretion. Br J Dermatol
1984;111:209-14.
7. Cusan L, Dupont A, Belanger A, Tremblay RR, Manhes G,
Labrie F. Treatment of hirsutism with the pure antiandrogen
flutamide. J Am Acad Dermatol 1990;23:462-9.
8. Cusan L, Dupont A, Gomez JL, Tremblay RR, Labrie F.
Comparison of flutamide and spironolactone in the treatment
of hirsutism: A randomized controlled trial. Fertil Steril
1995;61:281-7.
9. Stamatiadis D, Bulteau-Portos MC, Mowszowicz I. Inhibition
of 5 alpha-reductase activity in human skin by zinc and
azelaic acid. Br J Dermatol 1988;119:627-32.
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... Эффективны также комбинированные эстроген-гестагенные препараты. Гормональные методы терапии актуальны не только для пациентов с лабораторно подтвержденной гиперандрогенией, но и в случае тяжелого, резистентного к проводимой терапии течения акне, а также с частыми эпизодами обострения [15]. ...
... Эти компоненты взаимодействуют с рецепторами тестостерона. Производные тестостерона имеют андрогеноподобное действие -способствуют развитию акне, вызывают раздражительность, усталость [15]. ...
... При этом обязательно следует учитывать побочные эффекты преднизолона, в частности остеопороз, повышение уровня глюкозы крови. Применение таких препаратов более 6 мес не рекомендуют в связи с подавлением функции надпочечников [15]. ...
... Evidence shows that high glycemic food consumption triggers acne by inducing compensatory hyperinsulinemia. 29 Prolonged high glycemic index foods consumption will increase blood glucose and insulin level. 11 Prolonged high blood glucose can lower the responsiveness of β-cells to glucose stimulation and causes hyperglycemia and increases blood insulin level, which affects androgen and IGF-1 levels, leading to uncontrolled tissue growth and increased androgen synthesis which worsen acne. ...
... 11 Prolonged high blood glucose can lower the responsiveness of β-cells to glucose stimulation and causes hyperglycemia and increases blood insulin level, which affects androgen and IGF-1 levels, leading to uncontrolled tissue growth and increased androgen synthesis which worsen acne. 29 High insulin concentration can exacerbate acne by increasing basal keratinocyte proliferation inside pilosebaceous unit duct leading to failed terminal differentiation of follicular korneocyte. Insulin also stimulates adrenal and gonadal androgen synthesis, androgen receptor signal transduction, sebocyte proliferation, sebum production, and sebaceous gland lipogenesis, which affect acne development. ...
Article
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Background: Insulin resistance and high carbohydrate diets are currently considered to be influential in acne aetiology. Insulin is a hormone that does not only regulate the concentration of blood glucose but also affects the production of sebum and through the Insulin Growth Factor-1 (IGF-1) receptor stimulates androgen synthesis which will increase the proliferation of keratinocytes duct and the production of sebum in acne of the pilosebaceous. Methods: This is a cross sectional observational analytic study involving 38 acne patients and 38 controls. This study aims to determine whether the increase in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) value is a risk factor for acne. HOMA-IR formula was used to determine insulin activity in basal state. High HOMA-IR values are expressed from cut-off point ≥2. Subject was recruited with consecutive sampling who meets inclusion and exclusion criteria. Fasting insulin and blood glucose levels was derived from venous blood examination. Results: The average age of acne subjects was 23.71 years old in both groups (10 men and 28 women). The mean value of HOMA-IR in the acne group was higher (2.63 ± 0.29) than those in the control group (1.71 ± 0.26) and was statistically significant difference (p value
... There are three isoenzymes of 5 -reductase (5 -R1, 5 -R2, and 5 -R3), which vary in different tissues with age. In adult skin, the 5 -R1 isoform is expressed dominantly, and sebocytes in the sebaceous follicles and epidermal keratinocytes are reported to express the 5 -R1 isoform of the enzyme [4][5][6][7]. ...
... On the other hand, the pathological changes of acne are significantly affected by diet, psychological stress, and hormonal imbalance, as a systemic disease [43,44]. Actually, sebocytes express various types of receptors, especially neural and endocrine sensors [4,5]. That is why acne is recurrent and difficult to cure completely and needs combination therapy with reciprocally different mechanisms and/or features. ...
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Objective. Bokusoku (BK) is an extract from the Quercus cortex used in folk medicine for treatment of skin disorders and convergence, and is present in jumihaidokuto, a traditional Japanese medicine that is prescribed for purulent skin diseases like acne vulgaris. The excess of sebum production induced by androgen is involved in the development of acne. Our aim is to examine whether BK and its constituents inhibit testosterone metabolism and testosterone-induced sebum synthesis. Methods. Measurements of 5α-reductase activity and lipogenesis were performed using rat liver microsomes and hamster sebocytes, respectively. Results. BK dose-dependently reduced the conversion of testosterone to a more active androgen, dihydrotestosterone in a 5α-reductase enzymatic reaction. Twenty polyphenols in BK categorized as gallotannin, ellagitannin, and flavonoid were identified by LC-MS/MS. Nine polyphenols with gallate group, tetragalloyl glucose, pentagalloyl glucose, eugeniin, 1-desgalloyl eugeniin, casuarinin, castalagin, stenophyllanin C, (-)-epicatechin gallate, and (-)-epigallocatechin gallate, inhibited testosterone metabolism. In particular, pentagalloyl glucose showed the strongest activity. BK and pentagalloyl glucose suppressed testosterone-induced lipogenesis, whereas they weakly inhibited the lipogenic action of insulin. Conclusions. BK inhibited androgen-related pathogenesis of acne, testosterone conversion, and sebum synthesis, partially through 5α-reductase inhibition, and has potential to be a useful agent in the therapeutic strategy of acne.
... Para as mulheres o bloqueio hormonal é sempre útil, uma vez que a acne é doença androgênio-dependente. É opção segura, eficaz e que pode ser utilizada quando há distúrbios hormonais, como a síndrome dos ovários policísticos (SOP) e para mulheres normoandrogênicas (Moura, 2011;Lakshmi, 2013;Betolli, 2015). Para as mulheres adultas, acima dos 25 anos é boa opção isolada ou associada aos tratamentos tópicos. ...
... Para as mulheres o bloqueio hormonal é sempre útil, uma vez que a acne é doença androgênio-dependente. É opção segura, eficaz e que pode ser utilizada quando há distúrbios hormonais, como a síndrome dos ovários policísticos (SOP) e para mulheres normoandrogênicas (Moura, 2011;Lakshmi, 2013;Betolli, 2015). Para as mulheres adultas, acima dos 25 anos é boa opção isolada ou associada aos tratamentos tópicos. ...
... They stated that the pathophysiology of acne is a function of inflammatory cells, mediators and responses. Lakshmi noted that acne can be caused by an increase in sebum production from sebocytes lining [17] the sebaceous gland. ...
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Acne is one of the commonest skin diseases in adolescents and young adults.It usually presents as rashes which could be multiple widespread mixed papules, macules and confluent pustules on indurated bases black head comedones with erythematous background. These usually appear on the cheeks, chin, forehead, pre-auricular areas, the nose and the trunk.Acne is a worldwide chronic inflammatory skin disease which affects the pilosebaceous gland. It affects about 95% of the worlds' adolescent population usually between the ages of 12-25 years though it can occur at a younger age. It affects about 9.4% of the worlds' population. Adults, neonates and infants are also affected. Some of the patients reduce extracurricular activities and are ashamed of going out with friends due to disfiguring lesions. There are several myths around the causes of acne including spiritual afflictions. Patients use several medications and seek spiritual treatment. Scar formation, a complication of acne presents in the forms of atrophic, keloidal and hypertrophic scars especially when appropriate treatment is not stated early in the course of the disease. Serial photography is used in monitoring treatment. It is in this light that the authors wish to discuss the pathophysiology of acne with a view to assist in the management and to allay the patients' fear and anxiety.
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The effects of zinc sulphate and azelaic acid on 5α-reductase activity in human skin were studied using an in vitro assay with 1,2[3H]-testosterone as substrate. When added at concentrations of 3 or 9 mmol/1, zinc was a potent inhibitor of 5α-reductase activity. At high concentrations, zinc could completely inhibit the enzyme activity. Azelaic acid was also a potent inhibitor of 5α-reductase; inhibition was detectable at concentrations as low as 0.2 mmol/l and was complete at 3 mmol/l. An additive effect of the two inhibitors was observed. Vitamin B6 potentiated the inhibitory effect of zinc, but not of azelaic acid, suggesting that two different mechanisms are involved. When the three substances were added together at very low concentrations which had been shown to be ineffective alone, 90% inhibition of 5α-reductase activity was obtained. If this inhibition is confirmed in vivo, zinc sulphate combined with azelaic acid could be an effective agent in the treatment of androgen related pathology of human skin.
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The effectiveness of the antiandrogen flutamide in combination with an oral contraceptive was studied in 20 patients with moderate to severe hirsutism. Eight patients had no previous therapy, whereas 12 had failed to respond to oral contraceptives, spironolactone, or dexamethasone therapy. Treatment with the antiandrogen flutamide (250 mg twice daily) and an oral contraceptive (Ortho 1/35) resulted in a particularly rapid and marked decrease in the total hirsutism score, which reached the normal range at 7 months. Seborrhea, acne, and hair loss score were also rapidly corrected. Treatment was associated with a decrease in plasma luteinizing hormone, progesterone, and estradiol levels. Plasma sex hormone-binding globulin levels were initially low in 18 to 20 patients but increased significantly during therapy. No clinically significant side effects were observed.
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In a consecutive series of thirty-six male and female patients referred with severe acne, the effect of 3 months' treatment with placebo or spironolactone (50-200 mg daily) on sebum excretion and clinical and endocrine status was evaluated double-blind. Twenty-six patients completed the study. Abnormal free androgen indices were found in 27% of the original nineteen female subjects. Spironolactone reduced sebum excretion in all female subjects, but there was no correlation between sebum response and androgen status. The clinical response was dose-dependent, with maximum subjective and objective benefit when spironolactone doses of 150-200 mg were used.
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This study examined the relationships of pubertal maturation and sex steroid hormones to the development of acne in young girls. Black (n = 317) and white (n = 306) premenarchal girls with a mean age of 9.97 +/- 0.62 years were evaluated for acne prevalence and severity, pubic hair and areolar maturation, and sex steroid hormone levels. Overall, 77.8% of the girls had some acne; of the whole group, 48.3% had only comedonal acne, 2.2% had only inflammatory acne, and 27.3% had both types. Although black girls matured at an earlier age than white girls, racial differences in acne were minimal when adjusted for pubertal maturation. Acne increased with advancing maturation; at Tanner pubic hair stages 1, 2, and 3, the prevalence of acne rose from 73.1% to 84.0% and to 90.6%, respectively. Acne lesion counts at seven facial locations revealed a predominance of midfacial acne on the middle aspect of the forehead, nose, and chin. Sex steroid hormone levels measured in 365 of the girls were found to increase significantly during maturation from prepuberty to early puberty. Testosterone-estrogen-binding globulin and the ratio of testosterone to estradiol decreased. In 118 prepubertal girls, estradiol, total and free testosterone, progesterone, testosterone to estradiol ratio, and testosterone-estrogen-binding globulin levels were no different whether in subjects with acne or without acne. However, the level of dehydroepiandrosterone sulfate, an androgen of adrenal origin, was significantly higher in prepubertal girls with acne. Acne, especially the comedonal type, can be the first sign of pubertal maturation in girls, even preceding pubic hair and areolar development. Concentration of dehydroepiandrosterone sulfate is significantly and specifically associated with the initiation of acne in young girls.
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An excess of androgen is believed to contribute to development of acne in some patients. Because oral contraceptives (OCs) may reduce the active androgen level, hormonal therapy with OCs has been used successfully to treat patients with acne, although this treatment has previously not been studied in placebo-controlled trials. Our purpose was to evaluate the efficacy of a triphasic, combination OC (ORTHO TRI-CYCLEN [Ortho-McNeil Pharmaceutical, Raritan, N.J.], norgestimate/ethinyl estradiol) compared with placebo in the treatment of moderate acne vulgaris. Two hundred fifty-seven healthy female subjects, 15 to 49 years of age with moderate acne vulgaris, were enrolled in a multicenter, randomized, double-blind, placebo-controlled clinical trial. Each month for 6 months, subjects received either 3 consecutive weeks of the OC (i.e., tablets containing a fixed dose of ethinyl estradiol [0.035 mg] and increasing doses of norgestimate [0.180 mg, 0.215 mg, 0.250 mg]) followed by 7 days of inactive drug or placebo (color-matched tablets). Efficacy was assessed by facial acne lesion counts, an investigator's global assessment, a subject's self-assessment, and an analysis of within-cycle variation (cycle 6) in lesion counts. Of the 160 subjects in whom efficacy could be evaluated, the OC group showed a statistically significantly greater improvement than the placebo group for all primary efficacy measures. The mean decrease in inflammatory lesion count from baseline to cycle 6 was 11.8 (62.0%) versus 7.6 (38.6%) (p = 0.0001), and the mean decrease in total lesion count was 29.1 (53.1%) versus 14.1 (26.8%) (p = 0.0001) in the OC and placebo groups, respectively. In the investigator's global assessment, 93.7% of the active treatment group versus 65.4% of the placebo group were rated as improved at the end of the study (p < 0.001). Six of the seven secondary efficacy measures (total comedones, open comedones, closed comedones, papules, pustules, and the subject's self-assessment of study treatment) were also significantly more favorable in the OC group compared with the placebo group. An OC containing 0.035 mg of ethinyl estradiol combined with the triphasic regimen of norgestimate is a safe and effective treatment of moderate acne vulgaris in women with no known contraindication to OC therapy.
Andrews' diseases of the skin – Clinical dermatology
  • Wd James
  • Tg Berger
  • Dm Elston
James WD, Berger TG, Elston DM. Andrews' diseases of the skin – Clinical dermatology. 10 th ed. Canada: Saunders Elsevier; 2006. p. 231-50.
Andrews' diseases of the skin -Clinical dermatology. 10 th ed. Canada: Saunders Elsevier
  • W D James
  • T G Berger
  • D M Elston
James WD, Berger TG, Elston DM. Andrews' diseases of the skin -Clinical dermatology. 10 th ed. Canada: Saunders Elsevier; 2006. p. 231-50.