Causes of acne

Acne develops as a result of blockages in follicles. Hyperkeratinization and formation of a plug of keratin and sebum (a microcomedo) is the earliest change. Enlargement of sebaceous glands and an increase in sebum production occur with increased androgen (DHEA-S) production at adrenarche. The microcomedo may enlarge to form an open comedone (blackhead) or closed comedone (whitehead). Whiteheads are the direct result of skin pores becoming clogged with sebum, a naturally occurring oil, and dead skin cells. In these conditions the naturally occurring largely commensal bacteria Propionibacterium acnes can cause inflammation, leading to inflammatory lesions (papules, infected pustules, or nodules) in the dermis around the microcomedo or comedone, which results in redness and may result in scarring or hyperpigmentation.

Primary causes

The root causes of why some people get acne and some do not are not fully known.^{[citation needed]} It is known to be partly hereditary. Several factors are known to be linked to acne:

• Family/Genetic history. The tendency to develop acne runs in families. For example, school-age boys with acne often have other members in their family with acne as well. A family history of acne is associated with an earlier occurrence of acne and an increased number of retentional acne lesions.^[11]
• Hormonal activity, such as menstrual cycles and puberty. During puberty, an increase in male sex hormones called androgens cause the follicular glands to get larger and make more sebum.^[12]
• Inflammation, skin irritation or scratching of any sort will activate inflammation. Anti-inflammatories are known to improve acne.^{[citation needed]}
• Stress, through increased output of hormones from the adrenal (stress) glands.^{[citation needed]} While the connection between acne and stress has been debated, scientific research indicates that "increased acne severity" is "significantly associated with increased stress levels."^[13] The National Institutes of Health list stress as a factor that "can cause an acne flare."^[14] A study of adolescents in Singapore "observed a statistically significant positive correlation […] between stress levels and severity of acne."^[15]
• Hyperactive sebaceous glands, secondary to the three hormone sources above.
• Accumulation of dead skin cells that block or cover pores.^{[citation needed]}
• Bacteria in the pores. Propionibacterium acnes (P. acnes) is the anaerobic bacterium that causes acne. In-vitro resistance of P. acnes to commonly used antibiotics has been increasing.^[16]
• Use of anabolic steroids.^[17]
• Any medication containing lithium, barbiturates or androgens.^{[citation needed]}
• Exposure to certain chemical compounds. Chloracne is particularly linked to toxic exposure to dioxins, namely Chlorinated dioxins.^{[citation needed]}
• Exposure to halogens. Halogen acne is linked to exposure to halogens (e.g. iodides, chlorides, bromides, fluorides).^{[citation needed]}
• Chronic use of amphetamines or other similar drugs.^[18]

Several hormones have been linked to acne: the androgens testosterone, dihydrotestosterone (DHT) and dehydroepiandrosterone sulfate (DHEAS), as well as insulin-like growth factor 1 (IGF-I). In addition, acne-prone skin has been shown to be insulin resistant.^{[citation needed]}

Development of acne vulgaris in later years is uncommon, although this is the age group for Rosacea which may have similar appearances. True acne vulgaris in adult women may be a feature of an underlying condition such as pregnancy and disorders such as polycystic ovary syndrome or the rare Cushing's syndrome. Menopause-associated acne occurs as production of the natural anti-acne ovarian hormone estradiol fails at menopause. The lack of estradiol also causes thinning hair, hot flashes, thin skin, wrinkles, vaginal dryness, and predisposes to osteopenia and osteoporosis as well as triggering acne (known as acne climacterica in this situation)

Diet

Chocolate

The popular belief that consumption of chocolate can cause acne is not supported by scientific studies.^[19][20] As discussed below, various studies point not to chocolate, but to the high glycemic nature of certain foods containing simple carbohydrates as a cause of acne. Chocolate itself has a low glycemic index.^[21]

Milk

Recently, three epidemiological studies from the same group of scientists found an association between acne and consumption of partially skimmed milk, instant breakfast drink, sherbet, cottage cheese, and cream cheese.^[22][23][24] The researchers hypothesize that the association may be caused by hormones (such as several sex hormones and bovine insulin-like growth factor 1 (IGF-1)) or even iodine^[25] present in cow milk.

Carbohydrates

The long-held belief that there is no link between diets high in refined sugars and processed foods, and acne, has recently been challenged.^[26] The previous belief was based on earlier studies (some using chocolate and Coca Cola) that were methodologically flawed.^[26][27][28] The recent low glycemic-load hypothesis postulates that rapidly digested carbohydrate foods (such as soft drinks, sweets, white bread) produce an overload in blood glucose (hyperglycemia) that stimulates the secretion of insulin, which in turn triggers the release of IGF-1.^[26] IGF-1 has direct effects on the pilosebaceous unit (and insulin at high concentrations can also bind to the IGF-1 receptor)^[29] and has been shown to stimulate hyperkeratosis and epidermal hyperplasia.^[30] These events facilitate acne formation. Sugar consumption might also influence the activity of androgens via a decrease in sex hormone-binding globulin concentration.^[31][32]

In support of this hypothesis, a randomized controlled trial of a low glycemic-load diet improved acne and reduced weight, androgen activity and levels of insulin-like growth factor binding protein-1.^[33] High IGF-1 levels and mild insulin resistance (which causes higher levels of insulin) had previously been observed in patients with acne.^[34][35][36] High levels of insulin and acne are also both features of polycystic ovarian syndrome.^[26]

According to this hypothesis, the absence of acne in some non-Westernized societies could be explained by the low glycemic index of these cultures' diets.^[37] It is possible that genetic reasons account for there being no acne in these populations, although similar populations (such as South American Indians or Pacific Islanders) do develop acne.^[38][39] Note also that the populations studied consumed no milk or other dairy products.^[40]

Further research is necessary to establish whether a reduced consumption of high-glycemic foods, or treatment that results in increased insulin sensitivity (like metformin) can significantly alleviate acne, though consumption of high-glycemic foods should in any case be kept to a minimum, for general health reasons.^[41] Avoidance of "junk food" with its high fat and sugar content is also recommended.^[42]

Vitamins A and E

Studies have shown that newly diagnosed acne patients tend to have lower levels of vitamin A circulating in their bloodstream than those who are acne free.^[43] In addition people with severe acne also tend to have lower blood levels of vitamin E.^[44]

Hygiene

Acne is not caused by dirt. This misconception probably comes from the fact that blackheads look like dirt stuck in the openings of pores. The black color is not dirt but simply oxidised keratin. In fact, the blockages of keratin that cause acne occur deep within the narrow follicle channel, where it is impossible to wash them away. These plugs are formed by the failure of the cells lining the duct to separate and flow to the surface in the sebum created there by the body. Built-up oil of the skin can block the passages of these pores, so standard washing of the face could wash off old oil and help unblock the pores.

Treatments

Available treatments

There are many products available for the treatment of acne, many of which are without any scientifically proven effects. Generally speaking, successful treatments show little improvement within the first two weeks, instead taking a period of approximately three months to improve and start flattening out.^{[citation needed]} Many treatments that promise big improvements within two weeks are likely to be largely disappointing.^{[citation needed]} However, short bursts of cortisone can give very quick results, and other treatments can rapidly improve some active spots, but usually not all active spots.^{[citation needed]}

Modes of improvement are not necessarily fully understood but in general treatments are believed to work in at least 4 different ways (with many of the best treatments providing multiple simultaneous effects):

• normalising shedding into the pore to prevent blockage
• killing Propionibacterium acnes
• anti-inflammatory effects
• hormonal manipulation

A combination of treatments can greatly reduce the amount and severity of acne in many cases. Those treatments that are most effective tend to have greater potential for side effects and need a greater degree of monitoring, so a step-wise approach is often taken. Many people consult with doctors when deciding which treatments to use, especially when considering using any treatments in combination. There are a number of treatments that have been proven effective

Topical bactericidals

Widely available OTC bactericidal products containing benzoyl peroxide may be used in mild to moderate acne. The gel or cream containing benzoyl peroxide is rubbed, twice daily, into the pores over the affected region. Bar soaps or washes may also be used and vary from 2 to 10% in strength. In addition to its therapeutic effect as a keratolytic (a chemical that dissolves the keratin plugging the pores) benzoyl peroxide also prevents new lesions by killing P. acnes. In one study, roughly 70% of participants using a 10% benzoyl peroxide solution experienced a reduction in acne lesions after six weeks.^[45] Unlike antibiotics, benzoyl peroxide has the advantage of being a strong oxidizer and thus does not appear to generate bacterial resistance. However, it routinely causes dryness, local irritation and redness. A sensible regimen may include the daily use of low-concentration (2.5%) benzoyl peroxide preparations, combined with suitable non-comedogenic moisturisers to help avoid overdrying the skin.

Care must be taken when using benzoyl peroxide, as it can very easily bleach any fabric or hair it comes in contact with.

Other antibacterials that have been used include triclosan, or chlorhexidine gluconate. Though these treatments are often less effective, they also have fewer side-effects.

Prescription-strength benzoyl peroxide preparations do not necessarily differ with regard to the maximum concentration of the active ingredient (10%), but the drug is made available dissolved in a vehicle that more deeply penetrates the pores of the skin.

Topical antibiotics

Externally applied antibiotics such as erythromycin, clindamycin, azelaic acid or tetracycline kill the bacteria that are harbored in the blocked follicles. While topical use of antibiotics is equally as effective as oral use, this method avoids possible side effects including upset stomach and drug interactions (e.g. it will not affect use of the oral contraceptive pill), but may prove awkward to apply over larger areas than just the face alone.

Oral antibiotics

Oral antibiotics used to treat acne include erythromycin or one of the tetracycline antibiotics (tetracycline, the better absorbed oxytetracycline, or one of the once daily doxycycline, minocycline, or lymecycline). Trimethoprim is also sometimes used (off-label use in UK). However, reducing the P. acnes bacteria will not, in itself, do anything to reduce the oil secretion and abnormal cell behaviour that is the initial cause of the blocked follicles. Additionally the antibiotics are becoming less and less useful as resistant P. acnes are becoming more common. Acne may return soon after the end of treatment—days later in the case of topical applications, and weeks later in the case of oral antibiotics. Furthermore, side effects of tetracycline antibiotics can include yellowing of the teeth and an imbalance of gut flora, so are only recommended after topical products have been ruled out.

It has been found that sub-antimicrobial doses of antibiotics such as minocycline also improve acne. It is believed that minocycline's anti-inflammatory effect also prevents acne.

Hormonal treatments

In females, acne can be improved with hormonal treatments. The common combined oestrogen/progestogen methods of hormonal contraception have some effect, but the antiandrogen, Cyproterone, in combination with an oestrogen (Diane 35) is particularly effective at reducing androgenic hormone levels. Diane-35 is not available in the USA, but a newer oral contraceptive containing the progestin drospirenone is now available with fewer side effects than Diane 35 / Dianette. Both can be used where blood tests show abnormally high levels of androgens, but are effective even when this is not the case. Along with this, treatment with low dose spironolactone can have anti-androgenetic properties, especially in patients with polycystic ovarian syndrome.

If a pimple is large and/or does not seem to be affected by other treatments, a dermatologist may administer an injection of cortisone directly into it, which will usually reduce redness and inflammation almost immediately. This has the effect of flattening the pimple, thereby making it easier to cover up with makeup, and can also aid in the healing process. Side effects are minimal, but may include a temporary whitening of the skin around the injection point; and occasionally a small depression forms, which may persist, although often fills eventually. This method also carries a much smaller risk of scarring than surgical removal.

Topical retinoids

A group of medications for normalizing the follicle cell lifecycle are topical retinoids such as tretinoin (brand name Retin-A), adapalene (brand name Differin), and tazarotene (brand name Tazorac). Like isotretinoin, they are related to vitamin A, but they are administered as topicals and generally have much milder side effects. They can, however, cause significant irritation of the skin. The retinoids appear to influence the cell creation and death lifecycle of cells in the follicle lining. This helps prevent the hyperkeratinization of these cells that can create a blockage. Retinol, a form of vitamin A, has similar but milder effects and is used in many over-the-counter moisturizers and other topical products. Effective topical retinoids have been in use over 30 years but are available only on prescription so are not as widely used as the other topical treatments. Topical retinoids often cause an initial flare up of acne and facial flushing.

Oral retinoids

Main article: isotretinoin

A daily oral intake of vitamin A derivative isotretinoin (marketed as Accutane, Amnesteem, Sotret, Claravis, Clarus) over a period of 4–6 months can cause long-term resolution or reduction of acne. It is believed that isotretinoin works primarily by reducing the secretion of oils from the glands, however some studies suggest that it affects other acne-related factors as well. Isotretinoin has been shown to be very effective in treating severe acne and can either improve or clear well over 80% of patients. The drug has a much longer effect than anti-bacterial treatments and will often cure acne for good. The treatment requires close medical supervision by a dermatologist because the drug has many known side effects (many of which can be severe). About 25% of patients may relapse after one treatment. In those cases, a second treatment for another 4–6 months may be indicated to obtain desired results. It is often recommended that one lets a few months pass between the two treatments, because the condition can actually improve somewhat in the time after stopping the treatment and waiting a few months also gives the body a chance to recover. Occasionally a third or even a fourth course is used, but the benefits are often less substantial. The most common side effects are dry skin and occasional nosebleeds (secondary to dry nasal mucosa). Oral retinoids also often cause an initial flare up of acne within a month or so, which can be severe. There are reports that the drug has damaged the liver of patients. For this reason, it is recommended that patients have blood samples taken and examined before and during treatment. In some cases, treatment is terminated or reduced due to elevated liver enzymes in the blood, which might be related to liver damage. Others claim that the reports of permanent damage to the liver are unsubstantiated, and routine testing is considered unnecessary by some dermatologists. Blood triglycerides also need to be monitored. However, routine testing are part of the official guidelines for the use of the drug in many countries. Some press reports suggest that isotretinoin may cause depression but as of September 2005 there is no agreement in the medical literature as to the risk. The drug also causes birth defects if women become pregnant while taking it or take it while pregnant. For this reason, female patients are required to use two separate forms of birth control or vow abstinence while on the drug. Because of this, the drug is supposed to be given to females as a last resort after milder treatments have proven insufficient. Restrictive rules (see iPledge program) for use were put into force in the USA beginning in March 2006 to prevent misuse, causing occasioned widespread editorial comment.^[46]

Phototherapy

'Blue' and red light

Light exposure has long been used as a short term treatment for acne. Recently, visible light has been successfully employed to treat mild to moderate acne (phototherapy or deep penetrating light therapy) - in particular intense violet light (405-420 nm) generated by purpose-built fluorescent lighting, dichroic bulbs, LEDs or lasers. Used twice weekly, this has been shown to reduce the number of acne lesions by about 64%^[47] and is even more effective when applied daily. The mechanism appears to be that a porphyrin (Coproporphyrin III) produced within P. acnes generates free radicals when irradiated by 420 nm and shorter wavelengths of light.^[48] Particularly when applied over several days, these free radicals ultimately kill the bacteria.^[49] Since porphyrins are not otherwise present in skin, and no UV light is employed, it appears to be safe, and has been licensed by the U.S. FDA.^[50][51]

The treatment apparently works even better if used with a mixture of the violet light and red visible light (660 nanometer) resulting in a 76% reduction of lesions after three months of daily treatment for 80% of the patients;^[52] and overall clearance was similar or better than benzoyl peroxide. Unlike most of the other treatments few if any negative side effects are typically experienced, and the development of bacterial resistance to the treatment seems very unlikely. After treatment, clearance can be longer lived than is typical with topical or oral antibiotic treatments; several months is not uncommon. The equipment or treatment, however, is relatively new and reasonably expensive to buy initially, although the total cost of ownership can be similar to many other treatment methods (such as the total cost of benzoyl peroxide, moisturizer, washes) over a couple of years of use.

Photodynamic therapy

In addition, basic science and clinical work by dermatologists Yoram Harth and Alan Shalita and others has produced evidence that intense blue/violet light (405-425 nanometer) can decrease the number of inflammatory acne lesion by 60-70% in four weeks of therapy, particularly when the P. acnes is pretreated with delta-aminolevulinic acid (ALA), which increases the production of porphyrins. However this photodynamic therapy is controversial and apparently not published in a peer reviewed journal. A phase II trial, while it showed improvement occurred, failed to show improved response compared to the blue/violet light alone.^[53]

Laser treatment

Laser surgery has been in use for some time to reduce the scars left behind by acne, but research has been done on lasers for prevention of acne formation itself. The laser is used to produce one of the following effects:

• to burn away the follicle sac from which the hair grows
• to burn away the sebaceous gland which produces the oil
• to induce formation of oxygen in the bacteria, killing them

Since lasers and intense pulsed light sources cause thermal damage to the skin, there are concerns that laser or intense pulsed light treatments for acne will induce hyperpigmented macules (spots) or cause long-term dryness of the skin.

In the United States, the FDA has approved several companies, such as Candela Corp., to use a cosmetic laser for the treatment of acne. However, efficacy studies have used very small sample sizes (fewer than 100 subjects) for periods of six months or less, and have shown contradictory results.^[54] Also, laser treatment being relatively new, protocols remain subject to experimentation and revision,^[55] and treatment can be quite expensive. Also, some Smoothbeam laser devices had to be recalled due to coolant failure, which resulted in painful burn injuries to patients.^[56]

Less widely used treatments

• Aloe vera: there are treatments for acne mentioned in Ayurveda using herbs such as Aloe vera, Neem, Haldi (Turmeric) and Papaya. There is limited evidence from medical studies on these products.^[57] Products from Rubia cordifolia, Curcuma longa (commonly known as Turmeric), Hemidesmus indicus (known as ananthamoola or anantmula), and Azadirachta indica (Neem) have been shown to have anti-inflammatory effects, but not aloe vera.^[58]
• Azelaic acid (brand names Azelex, Finevin and Skinoren) is suitable for mild, comedonal acne.^[59]
• Calendula used in suspension is used as an anti-inflammatory agent.^[60]
• Cortisone injection into spots, also cortisone pills are sometimes used.
• Heat: local heating may be used to kill the bacteria in a developing pimple and so speed healing.^[61]
• Naproxen or ibuprofen^[62] are used for some moderate acne for their anti-inflammatory effect.
• Nicotinamide, (Vitamin B3) used topically in the form of a gel, has been shown in a 1995 study to be of comparable efficacy to topical clindamycin topical antibiotic used for comparison.^[63] Topical nicotinamide is available both on prescription and over-the-counter. The property of topical nicotinamide's benefit in treating acne seems to be its anti-inflammatory nature. It is also purported to result in increased synthesis of collagen, keratin, involucrin and flaggrin and may also according to a cosmetic company be useful for reducing skin hyperpigmentation (acne scars), increased skin moisture and reducing fine wrinkles.^[64]
• Tea tree oil (melaleuca oil) dissolved in a carrier (5% strength) has been used with some success, where it is comparable to benzoyl peroxide but without excessive drying, kills P. acnes, and has been shown to be an effective anti-inflammatory in skin infections.^[57][65][66]
• Rofecoxib was shown to improve premenstrual acne vulgaris in a placebo controlled study.^[67]
• Zinc: Orally administered zinc gluconate has been shown to be effective in the treatment of inflammatory acne, although less so than tetracyclines.^[68][69]
• Comedo extraction
• Pantothenic acid, (high dosage Vitamin B5)^[70]
• Detoxification is a common method used by alternative medicine practitioners for the treatment of acne, although there have been no studies to prove its success. Detoxification is the process of cleansing the body of toxins purportedly caused by the environment, pharmaceutical drugs, food, and cosmetics.