2 August 2017

Options for acne in the post-adolescent female

Clinical Dermatology Women

Acne vulgaris affects more than  80% of teenagers and persists well past the age of 25 in 3% of men and 12% of women.1, 2 In our general community acne vulgaris is considered a teenage/adolescent condition.  Presently dermatologists are seeing increasing numbers of pre-teenagers.

Adult female patients, best described as those over 25, are also becoming more prevalent. Like most things in dermatology, good longitudinal studies are lacking.3, 4  Women seek medical care for their acne at twice the rate of men.5  In Western societies, one third of total acne office visits are made by women aged over 25.6

In the adult female group two distinctions are made. Firstly, there is the persistent group, which represent acne vulgaris that first presented in adolescence and continues into adulthood.  New onset acne presents first in adulthood.

There is a further subset described as recurrent disease, that is acne that is present in adolescents, clears for a period of time, then returns in adulthood.7, 8, 9 Of these, persistent acne is the most common presentation seen in 75-85% of cases.9, 10, 11

The late onset acne is much less frequent, being reported for 20-40% of women.9, 12, 13

There is very little research data on recurrent acne, as this has not been screened for. The original view that the adult female acne presentation is of a mild to moderate inflammatory papular process, predominantly affecting the jawline, has now been challenged.14 In this international study it was concluded that adult women commonly have a low level of mixed comedones and inflammatory papules across all facial zones.

The treatments available to this patient group include all of those that are normally prescribed, e.g. topical retinoids, topical antibiotics, systemic antibiotics, hormonal therapies.

There are certain medications that are more frequently chosen for this group.  Mature females prefer not to take oral antibiotics in the long term and the use of hormonal therapy is much more frequent in my patients. In my clinical practice a variety of topical agents have been used by these patients prior to meeting me.

I struggle to find choices they will not reject because of prior unsuccessful use. Tolerability of topical agents is problematic because of the heavy use of cosmetics as well as overuse of cleansers, toners, facial masks and cosmetic procedures.  The ready recurrence of cutaneous irritation, erythema, dryness, peeling, stinging leads to poor uptake of topical therapies. Consequently topical agents are less popular, or less diligently applied.15, 16

Very rarely there is a clinical sign or symptom that leads the practitioner to consider an underlying endocrinopathy. Hyperandrogenism is similarly rare in this group, however the acute presentation or significant clinical presence of the features listed below would raise a red flag indicating investigation of androgens:

• Seborrhoea

• Hirsutism

• Androgenic alopecia

• Cushionoid features

• Increased libido

• Deepening of voice

• Acanthosis Nigricans

• Cliteromegally

Additionally, acne that is particularly therapeutic resistant, rapidly lapsing, very severe and associated with mark seborrhoea, may also need to be investigated.

The most common condition is polycystic ovarian syndrome for which luteinising hormone, follicular stimulating hormone, total testosterone and prolactin are investigations of interest. More rarely, dehydroepiandrosterone (DHEA), 17-hydroxy progesterone, thyroid-stimulating hormone and/or ACTH stimulation tests may be needed if a full hormonal battery is to be conducted.

TOPICALS

There are a variety of topical agents, from over-the-counter benzoyl peroxides, azaleic acids, salicylic acid combinations et cetera, to prescription monotherapy, retinoids, combinational retinoids and antibiotics, which are too numerous to list in this article.

In the next few years, there will be a number of newer topical combinations retinoids/antibiotics released in the Australian market.  These will contain lower concentrations and newer formulations of topical retinoids, hence less irritation.

Topical dapsone has been released in Australia.  In women 18 years and over, topical dapsone 5% gave a mean percent reduction of inflammatory lesions of 46.6%, and for comedonal lesions 39.8%.  This was from a pooled analysis of two phase three studies of 5% gel. The Australian formulation is 7.5% and used as a monotherapy and is best used at night.17

HORMONES

Oral therapies for acne include combined oral contraceptives. Certainly in my practice, I am seeing an increasing number of women for whom such treatments are contraindicated.  Some of these include family or personal history of breast cancer or thrombophilias. A number of patients do not tolerate any oral contraceptive due to side effects.

However, many patients are improved with agents containing cyproterone acetate, desogestrel, diengestrel, drospirenone, gestodene or low dose (100 microgram) Levonorgestrel as the progesterone-only contraceptive pills and implantable contraceptives generally worsen acne.12, 16, 17

Hormonal therapies are very slow in onset, with maximal results in at least four to six months after commencement.  Patients should be counselled that it will take three or more months for a visible improvement to occur. Oral hormonal therapies are frequently combined with more standard and topical systemic therapies at first, and then these agents can be dropped out once control occurs.

SPIRONOLACTONE

Spironolactone is a synthetic steroid and weak diuretic which is often prescribed by dermatologists for seborrhoea and/or hypertrichosis.  It is an agent that can improve acne control as monotherapy, or in addition to other agents.  The usual dose is 50-100mg daily and, like all hormonal therapies, it is extremely slow in onset, needing three to six months for clinical results to be apparent.

Occasionally patients treated with this agent will develop menstrual irregularities and/or heavy periods. If this occurs, therapy should be combined with an oral contraceptive. Ceasing these agents can result in an acute flare or rebound of acne.  It is now considered not necessary to review renal electrolytes.18

A common question in practice is the use of oral contraception and a potential of antibiotic interaction.

A number of studies have found no link between the intermittent or long-term use of oral antibiotics and oral contraceptive efficacy.19, 20

METFORMIN

Polycystic ovarian syndrome and insulin resistance are often associated with the presence of acne and seborrhoea.  Hormonal therapies are more successful in these patients when the issues of insulin resistance and weight loss are addressed.

Metformin is becoming more popular in this treatment group.  The doses of 500mg twice daily for three months, and then 1000mg twice daily, have been helpful.21

PREGNANCY AND BREASTFEEDING

Hormonal acne generally flares during the first trimester.  As the pregnancy continues, acne usually improves significantly and by the last trimester can clear.

Breastfeeding generally slows the return of acne.22

As a rule, acne becomes less severe over subsequent pregnancies.  Therapy while pregnant and/or breastfeeding is always problematic.

Treatments that are safe during this time include:

• Benzyl peroxide

• Erythromycin topical and oral

• Clindamycin topical and oral

• Azelaic acid

• Combinations of the above

Agents that should be avoided include:

• Oral isotretinoin

• Tetracycline antibiotics, doxycycline, minocycline

• Spironolactone

• Retinoid creams/gels

Isotretinoin is the only acne medication with proven teratogenicity and carries an extremely high risk of causing birth defects, particularly in the first trimester.

Another commonly occurring issue in practice is female patients being well established on a therapy who are unexpectedly fall pregnant. The issue with tetracycline antibiotics is staining of teeth in the later trimester of pregnancy.  It is not relevant in the first few weeks of pregnancy. It is quite safe for the patient to stop their oral therapies and carry on with their pregnancy.

Those taking spironolactone should stop the drug immediately. The issue with spironolactone is considered to be feminisation of the male foetus.  Again, in very early pregnancy there is no scientific evidence of any risk or harm. Spironolactone has not been associated with teratogenic defects.

It is well proven that systemic retinoids, particular isotretinoin, is strongly teratogenic. The use of topical retinoids, either as a cream or a gel, is contraindicated as a result of the potential possibility of systemic exposure.  Once again, those using topical retinoids should stop immediately once pregnancy is discovered.

Data from large studies looking at systemic absorption of tretinoin are highly reassuring.23  There is no evidence to suggest that there is an elevation of systemic retinoid levels with limited topical skin application on tretinoin.

Acne in adults is associated with Western diet, defined as a high consumption of milk, high glycaemic load and high calorie intake. This diet can result in a significant increase in insulin/insulin growth factor 1 serum level, and consequently in the molecular interplay of mammalian target of rapamycin complex 1 kinase, mediated nutrient signalling.

This leads to increased proliferation of keratinocytes, increased lipogenesis and sebum production and finally to aggravation of acne.24

Clinical Associate Professor Kurt Gebauer is a recognised authority on dermatological conditions and co-chair of All About Acne

References:

1. Purdy S, Deberker D. BMJ Clin Evid. 2008 May 15; 2008. Pii: 1714

2. Sullivan J, Preda V.  A clinically practical approach to acne Part 2: treatment. Medicine Today 2008; 9(1): 37-48.  

3. Preneau S, Dreno B. Female acne – a different subtype of teenager acne.   J Eur Acad Dermatol Venereol. 2012;26(3):277-282

4. Knaggs HE, Wood EJ, Rizer RL, et al. Post-adolescent acne. Int J Cosmet Sci. 2004;26(3):129-138. 

5. Yentzer BA, Hick J, Reese EL, et al. Acne vulgaris in the United States: a descriptive epidemiology. Cutis. 2010;86:94-99.

6. Zeichner JA. Evaluating and treating the adult female patient with acne. J Drugs Dermatol. 2013;12:1416-1427.

7. Poli F. Dreno B, Verschoore M. An epidermiological study of acne in female adults: results of a survey conducted in France. J Eur Acad Dermatol Venereol.  2001;15:541-545

8. Williams C. Layton AM. Persistent acne in women: implications for the patient and for therapy.  Am J Clin Dermatol. 2006;7:281-290.

9. Dumont-Wallon G, Dreno B. Specificity of acne in women older than 25 years.  Presse Med. 2008;37:585-591.

10.  Perkins AC, Maglione J. Hillebrand GG, et al.  Acne vulgaris in women: prevalence across the life span. J Womens Health. 2012;21:223-230. 

11. Kim GK, Michaels BB. Postadolescent acne in women: more common and more clinical consideration.  J Drugs Dermatol.  2012;11:708-713

12. Trivedi MK, Shinkai K, Murase JE.  A review of hormone-based therapies to treat adult acne vulgaris in women.
Int J Womens Dermatol. 2017 Mar: 3(1): 44-52

13. Holzmann R, Shakery K. Postadolescent acne in females.  Skin Pharmacol Physiol. 2014;27(Suppl.1):3-8.

14. Dreno B, Thiboutot D. Layton AM, et al.  Large-scale international study enhances understanding of an emerging acne population: adult females. J Eur Acad Dermatol Venereol. 2015;29(6): 1096-1106

15. Akomeah FK. Topical dermatological drug delivery: Quo Vardis? Curr Drug Deliv. 2010;7(4):283-296

16. Castro GA, Ferreira LA. Novel vesicular and particulate drug delivery system for topical treatment of acne.  Expert Opin Drug Deliv. 2008;5(6):665-679.

17. Tanghetti E, Harper JC, Oefelein MG. The efficacy and tolerability of Dapsone 5% gel in female vs. male patients with facial acne vulgaris: gender as a clinically relevant outcome variable. J Drugs Dermatol.  2012; 11(12): 1417-1421.  

18. Layton AM, Eady EA, Whitehouse H et al.  Oral Spironolactone for Ace Vulgaris in Adult Females: A Hybrid Systematic Review.  Am J Cin Dermatology. 2017: 18(2) 169-191

19. Archer JS, Archer DF.  Oral contraceptive efficacy and antibiotic interaction:  a myth debunked.
J Am Acad Dermatol. 2002 June; 46(6):917-23

20. Koo EB, Petersen TD, Kimball AB.  Meta-analysis comparing efficacy of antibiotics versus oral contraceptives in acne vulgaris.  J. Am Acad Dermatol. 2014 Sep; 71(3): 450-9.  Doi: 10.1016/j.jaad.2014.03.051.  

21. Norman RJ, Kidson WJ, Cuneo RC, Zacharin MR. Metformin and intervention in polycystic ovarian syndrome.  Med J. Aust 2001; 174: 580-583 

22. Feldman S, Careccia R, Barham KL, Hancox J. Diagnosis and treatment of acne. Am Fam Physician 2004; 69: 2123-2130

23. Kaplan YC, Ozsarfati J, Etwel F, et al.  Pregnancy outcomes following first-trimester exposure to tropical retinoids:  a systemic review and  meta-analysis. Br J Dermatol. 2015 Nov; 173(5): 1132-41       doi:10.1111bjd.14053. 

24. Romanska-Gocka K, Wozniak M, Kaczmarek-Skamira E, Zegarska B.  The possible role of diet in the pathogenesis of adult female acne. Postepy Dermatol Alergol. 2016 Dec; 33(6): 416-420

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