Green Tea and Other Tea Polyphenols: Effects on Sebum Production and Acne Vulgaris

Polyphenols are antioxidant molecules found in many foods including nuts, fruits, vegetables, chocolate, wine, and tea. Polyphenols have antimicrobial, anti-inflammatory, and antineoplastic properties. Recent studies suggest that tea polyphenols may be used for reducing sebum production in the skin and for treatment of acne vulgaris. This review examines the evidence for use of topically and orally ingested tea polyphenols against sebum production and for acne treatment and prevention. The PubMed database was searched for studies on tea polyphenols, sebum secretion, and acne vulgaris. Of the 59 studies found, eight met the inclusion criteria. Two studies evaluated tea polyphenol effects on sebum production; six studies examined tea polyphenol effects on acne vulgaris. Seven studies evaluated topical tea polyphenols; one study examined systemic tea polyphenols. None of the studies evaluated both topical and systemic tea polyphenols. Tea polyphenol sources included green tea (six studies) and tea, type not specified (two studies). Overall, there is some evidence that tea polyphenols in topical formulation may be beneficial in reducing sebum secretion and in treatment of acne. Research studies of high quality and with large sample sizes are needed to assess the efficacy of tea polyphenols in topical and oral prevention of acne vulgaris and lipid synthesis by the sebaceous glands.


Introduction
Polyphenols are naturally occurring compounds found in plants and common foods such as nuts, fruits, vegetables, chocolate, wine, and tea. After ingestion, polyphenols are absorbed in the intestinal epithelium [1] and have been shown to reach systemic circulation [2][3][4][5]. Polyphenols are antioxidants and play a role in preventing oxidative damage caused by the reactive oxygen species (ROS) [6]. They possess anti-inflammatory [7] and anti-carcinogenic properties and may aid in the prevention of cardiovascular disease [8], as well as protect skin from ultraviolet radiation (UVR) [9][10][11].
Tea is the second most consumed beverage worldwide and an important source of plant polyphenols in the human diet [12]. Camellia sinensis is the plant that gives rise to a variety of teas depending on specific processing of the plant [13]. Green tea is produced from fresh leaves in such a way that prevents oxidation of polyphenolic components (mainly catechins), oolong tea polyphenols are partially oxidized, while polyphenols in black tea undergo a high degree of oxidation [13]. Components of green tea beverage measured as weight percentage of extract solids include 30%-42% catechins, 5%-10% flavonols, and 2%-4% other flavonoids [13]. Catechins are divided into catechin (C), (−)-epicatechin (EC), (−)-epicatechin gallate (ECG), (−)-epigallocatechin (EGC), and (−)-epigallocatechin-3-gallate (EGCG) (Figures 1 and 2). EGCG is the most abundant catechin and has been shown to have beneficial health effects on skin [12].   Sebaceous glands are found throughout the human body, especially on the face and scalp, and they produce sebum-a mixture of lipids [14]. Lipids are produced by other glands in the body but the two most specific lipids to sebaceous glands are squalene and wax esters [14]. Sebum secretion is associated with hormonal activity in the human body [15] and excess sebum production is implicated in the development of skin disorders, such as acne vulgaris. Acne is not a life threatening condition but it can leave permanent scaring on the face and cause physical and psychological morbidities [16]. Acne may be caused by multiple mechanisms including (a) increased sebum production by the sebaceous glands; (b) altered keratinization within pilosebaceous follicles; (c) proliferation of bacteria Propionibacterium acnes (P. acnes); and (d) inflammation around pilosebaceous follicles [16,17].
Recent evidence suggests that there is increased phosphoinositide 3-kinase-Akt-mammalian target of rapamycin complex 1 (PI3K-Akt-mTORC1) signaling in the skin of patients with acne vulgaris [18][19][20] and that increased PI3K-Akt-mTORC1 signaling induces sebum production [21]. The green tea-derived plant sterols have shown a therapeutic role in the treatment of acne vulgaris [22]. Im et al., 2012 provided experimental evidence that EGCG treatment of insulin growth factor (IGF-1) stimulated SZ95 sebocytes decreased mTOR phosphorylation and thus mTORC1 activity [23]. Additionally, Van Aller et al., 2011 [24] provided evidence that EGCG is an ATP-competitive inhibitor of both PI3K and mTOR. Molecular docking studies showed that EGCG binds well to the PI3K domain active site, agreeing with the findings that EGCG competes for ATP binding. The mTOR kinase also belongs to the family of PI3K related kinases. Increased insulin-IGF-1 signaling in acne vulgaris activates PI3K-Akt-mTORC1 signaling cascade and plays a key role in the Western-diet induced acne [25]. Natural mTORC1 inhibitors, such as green tea polyphenols, attenuate enhanced mTORC1 signaling [26]. When compared with other types of tea, green tea has the highest polyphenolic content, with EGCG and EGC components being the most abundant [27].
There are multiple acne grading systems but there is no gold standard [28] that is consistently used in clinical practice or research trials. Lesion counting has been validated as a reliable measure for acne [29] and requires counting the number of comedones, papules, pustules, and nodules on the face [30]. The global assessment scale classifies acne into one of five categories based on acne severity (very mild, mild, moderate, severe, and very severe) [30]. In the Leeds technique, a subject's acne is compared to a photographic manual and a score from 1 (mild) to 10 (very severe) is assigned [30]. The Global Acne Grading System (GAGS) was developed in 1997 in an effort to improve accuracy, minimize inter-and intra-rater variability, and allow for quicker assessments [30].
Due to the complex nature of acne vulgaris, most treatments have only modest efficacy [31]. Systemic therapies that influence sebum production include estrogens, anti-androgens (i.e., spironolactone), retinoid (isotretinoin), and oral contraceptives [32]. All these medications predispose individuals to potentially serious side effects, thus there is a need for more natural therapies with minimal side effects. Research suggests that tea polyphenols may be promising in the management of acne vulgaris by reducing sebum production in the skin and acting as an anti-inflammatory [7] and antimicrobial agents [33]. In an in vitro study, Yoon et al., 2013 [31] showed that EGCG decreases lipogenisis in sebocytes, inhibits growth of P. acnes and reduces inflammation caused by P. acnes. The aim of this review is to examine recent clinical trials on tea polyphenols and their effects on sebum production and acne vulgaris management.

Search Strategy
On 4 August 2016 the PubMed database was searched for studies that investigated tea polyphenols, sebum production, and acne. No limits were placed on the publication date. The search combined keywords "tea", "green tea", "EGCG", "polyphenol", "catechin", "sebum" and "acne". No filters were selected.

Selection of Studies
Records were screened by title and/or abstract to exclude studies that did not contribute to answering the question in this review. Inclusion criteria: (1) published in English; (2) intervention included a tea polyphenol; (3) human study. Exclusion criteria: (1) in vitro studies; (2) animal studies; (3) review articles.

Results
Our search yielded a total of 59 studies. Titles and/or abstracts were screened for inclusion and exclusion criteria. Eight articles met the criteria and were subsequently analyzed. Two studies examined the effects of tea polyphenols on sebum production, while six studies investigated the effects of tea polyphenols on acne vulgaris. Seven studies examined the application of topical tea polyphenols and one study examined systemic tea polyphenols. None of the studies examined both topical and systemic tea polyphenols. Tea polyphenol sources included green tea in six studies, while in two studies the tea type was not specified.

Sebum Production Studies
In a single-blinded, placebo controlled monocentric study by Mahmood et al., 2013 [15] conducted in Pakistan, 22 non-smoker, healthy men aged 22-28 years-old were enrolled to investigate the effects of green tea and lotus extract topicals on facial sebum production. This was a split body comparative study in which one group used green tea (GT) topical on one cheek and placebo control on the other (n = 11). The second group used topical green tea and lotus (GT-L) on one cheek and placebo control on the other (n = 11). The GT topical consisted of 5% green tea and the GT-L formulation contained 2.5% green tea and 2.5% lotus extract. Both groups were instructed to apply their respective topicals at bedtime for 60 days. Sebumeter was used to measure sebum secretion on both cheeks at baseline and days 15, 30, 45, and 60. After 60 days, the GT topical group had a significant reduction in sebum secretion from baseline, compared to placebo control (27% reduction, p = 0.006). The GT-L group also had a significant reduction in sebum secretion from baseline to day 60 compared to placebo control (25% reduction, p = 0.002). There were no adverse events reported in either GT or GT-L group. This study showed that GT and GT-L topicals were both effective in significantly reducing sebum secretion. Additionally, even though the GT-L combination topical had a smaller percentage of GT extract (2.5% vs. 5% in GT group), GT-L reduced sebum secretion to a higher degree than GT topical alone; this could indicate an additive effect of GT and L extracts. These findings suggest that GT and GT-L combination topicals could be used to treat skin diseases that are associated with increased sebum secretion, such as acne vulgaris. Limitations of this study include a small sample size and that it only included healthy men. Future studies should focus on studying the effects of the two formulations in patients with acne vulgaris.
In a study by Mahmood et al., 2010 [34], ten healthy men age 24-40 years-old applied 3% GT topical to their cheeks for eight weeks. A sebumeter was used to measure the amount of sebum secretion at 1, 2, 3, 4, and 8 weeks which was used to calculate the percent change in sebum production from week 1 to week 8. The results showed that the 3% GT topical led to a significant reduction in sebum production during the 8 week study period (p < 0.05). Specifically, sebum production decreased by nearly 10% in the first week and as much as 60% by week 8. No side effects were noted.
Limitations of this study include small sample size, no comparison treatment or placebo control, and it did not test individuals with skin diseases known to have high sebum production.

Topical Tea Polyphenols
Sharquie et al., 2008 [35] conducted a single-blind randomized clinical trial examining 2% tea lotion and 5% zinc sulphate solution in treatment of acne vulgaris. The tea type was not specified. Forty-seven subjects (33 women, 14 men) aged 13-27 years-old were enrolled between June 2006 and December 2007 in Iraq. Subjects were randomly assigned one of two groups: 2% tea lotion (n = 24) or 5% zinc sulphate solution (n = 23); both groups applied their respective topical twice daily for 2 months. Inflammatory lesion counting was performed every 2 weeks and graded as follows: mild acne (<20 pustules and <10 papules) and moderate acne (20-40 pustules and >30 papules). It was considered that subjects had a "good response" to treatment if the inflammatory lesion count decreased by >50%; "moderate response" when decrease was 10%-50%; and "no response" when lesion count decreased by <10%. The 2% tea lotion group experienced a significant reduction in inflammatory lesion count (papule count decrease with treatment, p = 0.0001; pustule count decrease with treatment, p = 0.003). Eighty-five percent of subjects had a good or moderate response and 15% had no response to treatment. There was no significant difference in inflammatory lesion count (papule or pustule) in the group treated with 5% zinc sulphate compared to baseline. Adverse event reported by the 2% tea lotion group was mild itching (5 subjects) at the beginning of the treatment period. The 5% zinc sulphate group also reported itching (2 subjects), as well as burning sensation (5 subjects). No serious side effects were reported in either group. One limitation of this study is the small sample size (n = 20 in each group that completed the study). Nevertheless, 2% tea lotion is promising for its effect of decreasing inflammatory lesion count. Future studies could be done to compare it to other known topical treatments for acne to further assess its efficacy and safety profile.
A randomly-assigned split body (face) trial was conducted by Yoon et al., 2013 [31] to examine the effectiveness of 1% EGCG and 5% EGCG topicals compared to vehicle containing 3% ethanol in decreasing acne lesion count. Each group applied the assigned topical to one side of the face (1% EGCG or 5% EGCG); both groups applied the vehicle topical to the other side of face. Non-inflammatory and inflammatory lesions were counted. A revised Leeds score, which represents inflammatory and non-inflammatory acne counts, was used as a global assessment of acne severity. The mean Leeds score at baseline was 5.1 ± 0.4. At eight weeks, the mean Leeds score for the 1% EGCG group was 1.2 ± 0.4 and for the 5% EGCG group it was 1.7 ± 0.6. The reduction in Leeds score was significant in both 1% EGCG and 5% EGCG groups (p < 0.05). Specifically, non-inflammatory lesions reduced by 79% and inflammatory lesions by 89% after eight weeks of 1% EGCG use compared to baseline (p < 0.05). The non-inflammatory and inflammatory lesion reduction was similar in 5% EGCG group (p < 0.05), however, the specific lesion counts and percentage improvement were not provided. Overall, this study showed that 1% and 5% EGCG were both effective in improving acne vulgaris without major side effects.
A single-blind randomized controlled study by Sharquie et al., 2006 [36] investigated the effects of 2% tea lotion compared to placebo lotion in its ability to decrease acne lesion count. Sixty subjects, aged 14-22 years-old (35 women, 25 men) participated in the study for a duration of 2 months between October 2002 and October 2004 in Iraq. The treatment group applied 2% tea lotion twice a day for 2 months and inflammatory lesion count (papules and pustules) was done at weeks 4 and 8. The control group underwent the same procedure but used a control lotion, which consisted of distilled water. The 2% tea lotion group had a significant decrease in inflammatory lesion count at 8 weeks post-treatment (baseline papules 12 ± 3.3, week 8 papules 8.1 ± 19, p < 0.001; baseline pustules 20.7 ± 5.8, week 8 pustules 8.9 ± 2.3, p < 0.001). Eighty-eight percent of subjects in the treatment group reported being fully or partially satisfied with the treatment outcome and 12% were not satisfied.
The control group did not have a significant reduction in lesion count at 8 weeks compared to baseline. In this group, 83.3% of subjects were not satisfied with the outcome and 16.7% were partially or fully satisfied. There were no adverse events reported. This study suggests that 2% tea lotion is an effective topical alternative in acne management. Elsaie et al., 2009 [37] studied the effectiveness of 2% green tea lotion in reducing acne severity. The study had 20 subjects, aged 15-36 years-old (14 women, 6 men) and was conducted in Egypt between May 2007 and February 2008. Acne severity was assessed at baseline via total lesion count (TLC) for pustules and papules and severity index (SI). The TLC at baseline was considered 100% and any decrease during treatment was considered an improvement. Baseline images were taken and subjects were instructed to apply the 2% green tea lotion twice daily for 6 weeks with follow up every 2 weeks. The results showed a mean TLC decrease from 24 (baseline) to 10 after 6 weeks of treatment (58.33% reduction, p < 0.0001, 95% confidence interval (CI) = 8.58-19.42). The mean SI also decreased from 2.05 (baseline) to 1.25 after 6 weeks of treatment (39.02% reduction, p < 0.0001, 95% CI = 0.54-1.26). Five subjects reported stinging sensation or itching, but these resolved within 2-3 days of treatment. Small sample size and lack of comparison, or control group, were limitations in this study. The true effect of the topical green tea lotion was not clear with the lack of a control treatment. Nevertheless, it showed that 2% green tea lotion could be beneficial in acne treatment by reducing acne lesion count and warrants future controlled studies.
In a study by Jung et al., 2012 [38] conducted in Korea, a green tea extract compound called polyphenon-60 was used to examine its potential therapeutic effects on acne vulgaris. Sixty subjects with mild to moderate acne applied 20 mg/mL polyphenon-60 twice daily for 8 weeks; their acne lesion count was assessed at baseline and week 8. Eight weeks post-treatment with polyphenon-60, there was a 61% decrease in open comedones (p < 0.05) and 28% decrease in the number of pustules (p < 0.05) compared to baseline. There was no significant decrease in the number of closed comedones at week 8 compared to baseline. No major adverse events were noted. This study did not have a control group or control treatment.

Systemic Tea Polyphenols
Lu et al., 2016 [39] conducted a randomized, double-blind, placebo controlled trial to investigate whether systemic green tea supplementation could improve acne in post-adolescent women. The study enrolled 80 women aged 25-45 years-old with moderate to severe acne, as determined by the Investigators Global Assessment score of 3 or 4 (scale 0-5). The study was conducted in Taiwan between May 2012 and October 2013. One group (n = 40) received 1500 mg decaffeinated green tea daily (1 capsule 500 mg GT 30 min after meal, 3 times daily) for four weeks. The second group received cellulose capsules (placebo), which looked identical to GT capsules for blinding purposes. A blinded dermatologist recorded inflammatory and non-inflammatory lesion counts on the forehead, cheeks, nose, perioral area, chin, and entire face at baseline and at four weeks post-treatment. There was a significant decrease in the inflammatory lesion counts on the nose (p = 0.03), perioral area (p = 0.04), and chin (p = 0.03) in the green tea group compared to placebo group. There was no significant difference in lesion counts on forehead, cheek, or in the total lesion count between GT and placebo groups. Within the GT group, subjects had significantly lower inflammatory lesion counts on the forehead (p = 0.04) and cheeks (p = 0.04), as well as lower total lesion count (p = 0.03) at the end of treatment compared to baseline. Within the placebo group, there was significant decrease in inflammatory lesion count on cheeks (p = 0.01) and chin (p = 0.01), as well as total lesion count (p = 0.02). Adverse events included mild constipation and abdominal discomfort (three subjects). Placebo group adverse events included thirst and difficulty falling asleep (two subjects). However, no major side effects were reported. Even though decaffeinated GT treatment resulted in decreased lesion counts on nose, perioral area, and chin compared to placebo, the placebo group itself had significant within group difference in lesion counts before and after treatment. Additional studies with more subjects and longer duration are needed to assess the effectiveness of systemic green tea in treatment of acne.

Discussion
Polyphenols are naturally occurring compounds found in many common foods and plants, including Camellia sinensis [13], the plant that gives rise to a variety of teas. Their natural-based ingredients, cost effectiveness and non-invasive attributes have made them increasingly attractive to patients, compared to prescription drugs [40], and this has led to an increase in polyphenol studies examining their effects on the skin. In this review, we include eight studies focusing on tea polyphenols and their effects on sebum production and acne. All eight studies reported that tea polyphenols were effective at either reducing sebum production or improving acne severity in at least one outcome measure.

Tea Polyphenol Bioavailability
Bioavailability of polyphenols varies depending on the polyphenol forms within the dietary source [41]. EGCG, the most abundant catechin found in tea, is primarily absorbed in the small intestine and metabolized by colonic flora in the large intestine [42]. Studies show that bioavailability varies among catechins where EGCG is readily present in plasma after intake, indicating high bioavailability, whereas galloylated catechins have never been recovered in urine samples [41]. Fasting, fish oils, albumin, soft water, piperine, Vitamin C and storage in cool and dry conditions can increase the oral bioavailability of EGCG [42]. Oral bioavailability is reduced by oxidation with air, metal ions, catechol-O-methyl transferase (COMT) polymorphisms, and gastrointestinal inactivation [43]. Yang et al., 1998 [44] showed that maximal EGCG, EGC, and EC plasma concentration was reached between 1.5 and 2.5 h after consumption of green tea, and they became undetectable in plasma after 24 h. Studies have found extensive variance in bioavailability across polyphenols, including tea polyphenols, which may be driven by the nature of study subject diets and their levels of metabolizing enzymes [41]. Therefore, future studies are needed to further investigate bioavailability of tea polyphenols.

Skin Penetration
The partition coefficients of tea polyphenols are shown in Table 1 [45]. EGC is the most hydrophilic molecule, while ECG is the least polar [45]. A study by dal Belo et al., 2009 [46] investigated application of 6% green tea extract on the human skin obtained from abdominal surgery. The results showed that EGCG was retained within the skin, with higher levels of EGCG detected in the stratum corneum, followed by the epidermis and dermis. This suggests that EGCG is more non-polar as non-polar compounds tend to stay in the stratum corneum rather than get into the epidermis and dermis. Additionally, a study by Zillich et al., 2013 [47] used ex vivo pig skin and showed that both size of the molecule and hydrophobicity of the molecule impact skin permeation of green tea compounds. However, studies on human skin penetration by tea polyphenols are limited in number and further research in this area is warranted.

Tolerability
Overall, studies show that topical and systemic tea polyphenols tend to be well tolerated. A study by Elsaie et al. [37] showed minimal side effects to 2% green tea topical. Ten percent of subjects experienced stinging, which resolved within 48 h, and 15% of subjects experienced local pruritus, which resolved by day three. In a study by Lu et al., 2016 [39], systemic green tea was given to subjects three times daily for four weeks and this regimen was well tolerated. One subject experienced mild constipation and two others experienced mild abdominal pain. Of the eight studies included in this review, none reported major adverse events and the tea polyphenols were generally well tolerated in topical and systemic formulations. Further studies investigating the impact of various dosages should be considered.

Mechanisms of Action
Acne is thought to be due to the activity of bacteria called Propionibacterium acnes (P. acnes), sebum production by the sebaceous gland, keratinization of the follicular keratinocytes, and inflammation [17]. Various mechanisms of action for the clinical efficacy of tea polyphenols in reducing acne severity have been suggested. P. acnes [48], Propionibacterium granulosum [49], Staphylococcus aureus [49] and Staphylococcus epidermidis [49] are bacteria present on the skin of acne patients. A recent study by Li et al., 2015 [50] suggests that the clinical efficacy of green tea polyphenols may be due to their anti-microbial properties against these bacteria. The study compared topical green tea extract (EGCG content of 0.081%), pomegranate juice, and pomegranate extract in terms of their anti-microbial properties. The results showed that 98% of P. acnes, P. granulosum, S. aureus, and S. epidermidis was inhibited at concentrations of 400 µg gallic acid equivalents (GAE)/mL GT or less.
In addition to the anti-microbial properties of tea polyphenols, other mechanisms have been proposed to explain the improvement in acne from topical green tea administration. Yoon et al., 2013 [31] postulated that this improvement was due to the modulation of the M locus protein kinase-Sterol regulatory element-binding protein 1 (MLPK-SREBP-1) signaling pathway, which leads to reduction in lipogenesis. Additionally, EGCG increased apoptosis of the SEB-1 cell line of sebocytes and led to a reduction in the mean colony forming units of P. acnes. Altogether, these findings further support the notion that EGCG has anti-microbial activity against P. acnes. EGCG was also found to reduce transcription of the nuclear factor-κB (NF-kB) pathway and reduce inflammation. Overall, studies suggest that tea polyphenols exert their effect on sebum production and acne via several mechanisms, including acting as anti-microbial, anti-lipogenic, anti-inflammatory molecules.

Limitations
Interpretation of this review should be considered in light of the limited number of studies that were available. Many of the studies had small sample sizes and some studies had poor research design, including a lack of control group. More studies of high quality are needed to establish the efficacy of tea polyphenols for controlling sebum production, as well as preventing or managing acne vulgaris.

Conclusions
Our search produced a limited number of results for how tea polyphenols may be used in reducing sebum secretion and acne pathology. While all the studies used some form of tea polyphenols, the exposures were not uniform. Some studies included unknown types of tea and with unspecified amounts of tea polyphenols as exposure. However, based on this review there is some evidence that tea polyphenols used orally and topically may be beneficial for skin health and more specifically, for reducing sebum production by the sebaceous glands and for the prevention and treatment of acne vulgaris. Physicians and other health care professionals should be aware of the studies examining the beneficial effects of tea polyphenols as they could potentially be used as alternatives in skin care. Research studies of high quality and with large sample sizes are needed to assess the efficacy of tea polyphenols in topical and oral prevention of acne vulgaris and lipid synthesis by the sebaceous glands.
Author Contributions: Suzana Saric and Raja K. Sivamani conceived and designed the review; Suzana Saric, Manisha Notay, and Raja K. Sivamani critically evaluated the articles for inclusion in this review; Suzana Saric and Manisha Notay wrote the first draft of this manuscript; Raja K. Sivamani performed critical editing and provided overall oversight for the review.