Treating PCOS Acne From the Inside Out

Cause and Effect
Stacey Shillington, ND

According to the principles of naturopathic medicine, the root cause of a condition must be treated as opposed to simply masking the presenting symptoms. Acne is one of the most palliated conditions in our society, and to follow our naturopathic principles, we must first understand its pathogenesis. Studies have found that more than 41% of postadolescent women are affected by acne,1 and its incidence is predominantly in Westernized societies.2 In a time when mainstream media have created abnormal expectations about the outward appearance of women, acne can be seriously detrimental to a woman’s self-esteem. The research that exists on the causes of acne is varied and confusing, but it can be compiled into a model that implicates excess androgens as the precursor to acne pathogenesis. In women, the most common cause of hyperandrogenism is polycystic ovary syndrome (PCOS),3 and acne caused by this condition can be difficult to treat based on our incomplete knowledge of the complex pathogenesis of PCOS.

In addition to acne, many women with PCOS experience hirsutism, android obesity, hair loss, disrupted menstrual cycles, acanthosis nigricans, skin tags, dyslipidemia, and infertility.4 If a patient is seen with acne for which PCOS is the suspected perpetrator, a proper diagnosis can be obtained via blood workup and ultrasonography. Diagnostic blood tests include free testosterone, dehydroepiandrosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), fasting insulin, fasting glucose, sex hormone–binding globulin (SHBG), and lipid levels. Not all patients with PCOS exhibit all the signs and symptoms aforementioned. Although patients with acne may not entirely fit the criteria for PCOS, many of the naturopathic treatments discussed herein may be effective for their condition if the cause of acne is excess androgens.

The Pathogenesis of PCOS Acne

Treating PCOS acne from the inside out requires an understanding of the mechanisms that lead to excess androgen production. The pathogenesis of PCOS acne involves the following 6 conditions:

1. Primary Ovarian Dysregulation

The hallmark of PCOS seems to be ovarian dysregulation, specifically upregulated androgen-producing enzymes in the ovarian theca cells.5 Results of several recent studies suggest that exposure of the ovary and/or adrenals to bisphenol A during fetal development6 or from ongoing environmental exposure7,8 can contribute to polycystic ovaries.9 A strong correlation has been found between serum levels of bisphenol A and androgen concentrations. Although this environmental assault is certainly not the only contributor to PCOS, it seems to be a central component to its pathogenesis. Other suspected contributors to ovarian dysregulation include prenatal exposure to insulinlike growth factor 1 (IGF-1) and testosterone,10 as well as a potential familial disorder, although its genetic basis remains unclear.11

2. Ovarian Inflammation

When the increased androgens produced by the ovarian theca cells are exposed to hormonal imbalances in the body, they start a vicious circle of dysregulation. The stimulatory effects of androgens and glucose on mononuclear cells trigger the release of tumor necrosis factor, a potent inflammatory cytokine that is found in elevated levels in PCOS ovaries.12,13 Ovarian inflammation aggravates the already upregulated androgenic enzymes in PCOS, leading to overproduction of androgens, which causes more inflammation. In addition, because of the high levels of tumor necrosis factor and inflammation, patients with PCOS acne experience high levels of oxidative stress and low levels of glutathione.14,15

3. Insulin Resistance

The link between PCOS and insulin resistance is well documented, although the magnitude varies among patients. Patients with obesity and PCOS tend to have more pronounced insulin resistance than lean patients with PCOS,16 many of whom are not initially seen with any insulin resistance at all.17 Insulin resistance, which is characterized by high levels of serum insulin, not only aggravates ovarian androgen production and inflammation but also leads to low levels of SHBG and high levels of gonadotropin-releasing hormone (GnRH), as well as the development of android obesity, which results in increased aromatization. These hormonal disturbances aggravate the PCOS condition and set the stage for further hormonal imbalance and more acne for the following 2 reasons: (1) low levels of SHBG result in increased free testosterone and (2) high levels of GnRH result in increased LH, which increases ovarian theca cell androgen production.16 Increased aromatization raises estrogen levels, which can cause relative progesterone deficiency and lead to increased LH secretion.

4. High LH Level

Because of anovulation in PCOS, low levels of progesterone stimulate the GnRH in the anterior pituitary gland to produce high levels of LH. High levels of estradiol due to ovarian overproduction and increased aromatization inhibit the release of FSH.18 In patients with PCOS, LH is increased relative to FSH, usually in a 2:1 to 3:1 ratio. Luteinizing hormone levels tend to be higher in lean women with PCOS.13 The abnormal amounts of LH in PCOS invoke the ovarian theca cells to produce androgens, which in turn block the release of the egg follicle, resulting in anovulation. In addition, the androgens block the progesterone signal to the hypothalamus,19 so even if ovulation occurs in the presence of high androgen levels, it is likely that there will still be an abnormal increase in both GnRH and LH. It is a vicious cycle, resulting in increasing amounts of androgens.

5. High IGF-1 Level

Insulinlike growth factor 1 is a hormone that is produced mainly in response to growth hormone levels, which are especially high in lean patients with PCOS,16 perhaps owing to reduced cortisol levels (ie, adrenal fatigue) or dysregulated insulin levels. In addition to the growth hormone effect, dairy product consumption19 and puberty increase IGF-1 levels. Increased IGF-1 is associated with higher 5α-reductase levels, which convert testosterone to dihydrotestosterone, a hormone that stimulates sebum production in patients with acne. Insulinlike growth factor 1 increases the number of sebocytes in the skin.19

6. Increased Stress Response

Patients with PCOS have a heightened stress response,20 and individuals with acne have increased substance P activity,21 which leads to increased sebaceous gland activity. Given that high cortisol levels can affect insulin levels and contribute to insulin resistance, stress is a major contributor to PCOS, androgen production, and the development of acne.

 

Treating PCOS Acne

Considering the upregulated enzymes, inflammation, and hormonal pathways that are involved in the development of PCOS, a multifaceted naturopathic protocol is necessary to reduce the circulating androgens that cause acne. The following are 7 treatment goals and options:

1. Decrease Primary Androgen Production in the Ovaries

Some promising research findings suggest that a combination of Glycyrrhiza glabra and Paeonia lactifloracan reduce testosterone and free testosterone serum levels, increase the ratio of estrogen to testosterone, and decrease the ratio of LH to FSH.22 The investigators postulated that this herbal combination, particularly G glabra, blocks the enzymes 17-hydroxysteroid dehydrogenase and 17α−hydroxyprogesterone aldolase. Results of another study23 suggest that the combination of G glabra and P lactiflora decreases testosterone levels by increasing aromatization, which synthesizes estrogen from testosterone. As such, it is prudent to include indole-3-carbinol in the protocol to ensure that excess estrogens are metabolized properly. Recent findings suggest that acupuncture, especially using manual needle stimulation, may be effective in regulating steroid hormone receptors and lowering circulating androgen levels in PCOS.24 It is essential that the patient with PCOS must avoid bisphenol A as much as possible, and the liver should be supported to facilitate efficient elimination of excess androgens, estrogens, and environmental toxins from the circulation.

2. Decrease Ovarian Inflammation

A recent study25 attributed the following phytochemicals to reducing ovarian inflammation in ovarian cancer: apigenin, baicalein, curcumin, epigallocatechin, genistein, luteolin, oridonin, quercetin, and wogonin via the inhibition of proinflammatory cytokines such as tumor necrosis factor and interleukin 6. It is reasonable to assume that the same phytochemicals would be effective in reducing ovarian inflammation in PCOS. Epigallocatechin, an extract from green tea, is especially effective in reducing acne because, in addition to reducing ovarian inflammation, it inhibits 5α-reductase, the enzyme that converts testosterone to its more active form of dihydrotestosterone and increases levels of SHBG.26

3. Reduce Insulin Resistance

Diet and lifestyle changes are necessary in the naturopathic treatment of PCOS acne. A whole-foods diet designed to balance insulin levels should be implemented, consisting of lean protein, healthy fats, vegetables, fruits, and a small amount of whole grains, along with the elimination of refined grains, sugar, dairy products, and sometimes gluten. The goal is to normalize a patient’s body mass index, while regulating insulin and glucose levels. In addition, research findings have shown that inositol27 and vitamin D328 are important insulin regulators in PCOS. Low levels of vitamin D3 have been implicated in endocrine disturbances in women with PCOS.29

4. Reduce LH Levels

One of the most effective treatments to reduce LH and regulate GnRH is the use of bioidentical progesterone. A recent study30 reported a reduction in LH levels after 7 days of progesterone administration, although no change in androgen levels was reported. It is reasonable to assume that a reduction in androgens could result after several cycles of reduced LH. According to Dr John Lee, a pioneer in the use of bioidentical progesterone, at least 6 months of progesterone use is required to help normalize cycles and decrease androgen levels in PCOS,31 which will lead to reduced acne.

5. Reduce IGF-1 Levels

Avoidance of all dairy products is essential in the treatment of PCOS acne. Patients with PCOS are hormonally sensitive, and additional stimulation of IGF-1 via dairy product consumption will exacerbate androgen production in the body. Adrenal support and insulin balance are critical in lowering growth hormone levels, which in turn will reduce IGF-1 levels.

Reduce 5α-Reductase Levels

5α-reductase type 1 is upregulated by
IGF-1 and can be inhibited by several natural substances, including zinc and epigallocatechin. As previously mentioned, the use of epigallocatechin is especially effective because it decreases ovarian inflammation and increases SHBG.

7. Decrease Stress Levels

Balancing cortisol levels is essential to achieve hormonal balance, especially in patients with PCOS. Adrenal support is helpful, and in addition to reducing ovarian androgen levels, G glabra is an excellent adaptogen. Mindfulness-based stress reduction techniques are beneficial because they improve quality of life, reduce stress symptoms, and enhance the function of the hypothalamus-pituitary-adrenal axis.32

Naturopathic Conclusion

Resolution of PCOS acne with this naturopathic treatment approach takes time. With patience and perseverance, the patient will not only experience clear skin but also alleviate many other PCOS symptoms.


Stacey Shillington, ND graduated from the Canadian College of Naturopathic Medicine (Toronto, Ontario, Canada) in 2006. She has since established a practice in downtown Toronto focusing on naturopathic antiaging and skin care, including mesotherapy and cosmetic acupuncture. For more information, visit her website at www.naturopathicbeauty.com, or follow her on Twitter @dr_shillington.

 

References

Poli F, Dreno B, Verschoore M. An epidemiological study of acne in female adults: results of a survey conducted in France. J Eur Acad Dermatol Venereol. 2001;15(6):541-545.

Cordain L, Lindeberg S, Hurtado M, Hill K, Eaton SB, Brand-Miller J. Acne vulgaris: a disease of Western civilization. Arch Dermatol. 2002;138(12):1584-1590.

Timpatanapong P, Rojanasakul A. Hormonal profiles and prevalence of polycystic ovary syndrome in women with acne. J Dermatol. 1997;24(4):223-229.

Moura HH, Costa DL, Bagatin E, Sodré CT, Manela-Azulay M. Polycystic ovary syndrome: a dermatologic approach [in English and Portuguese]. An Bras Dermatol. 2011;86(1):111-119.

Wickenheisser JK, Nelson-Degrave VL, McAllister JM. Dysregulation of cytochrome P450 17α-hydroxylase messenger ribonucleic acid stability in theca cells isolated from women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90(3):1720-1727.

Fernández M, Bourguignon N, Lux-Lantos V, Libertun C. Neonatal exposure to bisphenol A and reproductive and endocrine alterations resembling the polycystic ovarian syndrome in adult rats. Environ Health Perspect. 2010;118(9):1217-1222.

Kandaraki E, Chatzigeorgiou A, Livadas S, et al. Endocrine disruptors and polycystic ovary syndrome (PCOS): elevated serum levels of bisphenol A in women with PCOS. J Clin Endocrinol Metab. 2011;96(3):E480-E484. http://jcem.endojournals.org/content/96/3/E480.long. Accessed March 19, 2012.

Takeuchi T, Tsutsumi O, Ikezuki Y, Takai Y, Taketani Y. Positive relationship between androgen and the endocrine disruptor, bisphenol A, in normal women and women with ovarian dysfunction. Endocr J. 2004;51(2):165-169.

Diamanti-Kandarakis E, Christakou C, Marinakis E. Phenotypes and environmental factors: their influence in PCOS. Curr Pharm Des. 2012;18(3):270-282.

Veiga-Lopez A, Ye W, Padmanabhan V. Developmental programming: prenatal testosterone excess disrupts anti-Müllerian hormone expression in preantral and antral follicles. Fertil Steril. 2012;97(3):748-756.

Toulis, KA, Goulis DG, Farmakiotis D, et al. Adiponectin levels in women with polycystic ovary syndrome: a systematic review and a meta-analysis. Hum Reprod Update. 2009;15(3):297-307.

González F, Rote NS, Minium J, Kirwan JP. In vitro evidence that hyperglycemia stimulates tumor necrosis factor-α release in obese women with polycystic ovary syndrome. J Endocrinol. 2006;188(3):521-529.

Gonzalez F, Thusu K, Abdel-Rahman E, Prabhala A, Tomani M, Dandona P. Elevated serum levels of tumor necrosis factor α in normal-weight women with polycystic ovary syndrome. Metabolism. 1999;48(4):437-441.

Ikeno H, Tochio T, Tanaka H, Nakata S. Decrease in glutathione may be involved in pathogenesis of acne vulgaris. J Cosmet Dermatol. 2011;10(3):240-244.

Sarici G, Cinar S, Armutcu F, Altinyazar C, Koca R, Tekin NS. Oxidative stress in acne vulgaris. J Eur Acad Dermatol Venereol. 2010;24(7):763-767.

Morales AJ, Laughlin GA, Bützow T, Maheshwari H, Baumann G, Yen SS. Insulin, somatotropic, and luteinizing hormone axes in lean and obese women with polycystic ovary syndrome: common and distinct features. J Clin Endocrinol Metab. 1996;81(8):2854-2864.

Meirow D, Yossepowitch O, Rösler A, et al. Endocrinology: insulin resistant and non-resistant polycystic ovary syndrome represent two clinical and endocrinological subgroups. Hum Reprod. 1995;10(8):1951-1956.

Burt Solorzano CM, Beller JP, Abshire MY, Collins JS, McCartney CR, Marshall JC. Neuroendocrine dysfunction in polycystic ovary syndrome. Steroids. 2012;77(4):332-337.

Melnik BC, Schmitz G. Role of insulin, insulin-like growth factor-1, hyperglycaemic food and milk consumption in the pathogenesis of acne vulgaris. Exp Dermatol. 2009;18(10):833-841.

Benson S, Arck PC, Tan S, et al. Disturbed stress responses in women with polycystic ovary syndrome. Psychoneuroendocrinology. 2009;34(5):727-735.

Lee WJ, Jung HD, Lee HJ, Kim BS, Lee SJ, Kim do W. Influence of substance-P on cultured sebocytes. Arch Dermatol Res. 2008;300(6):311-316.

Armanini D, Mattarello MJ, Fiore C, et al. Licorice reduces serum testosterone in healthy women. Steroids. 2004;69(11-12):763-766.

Takahashi K, Kitao M. Effect of TJ-68 (shakuyaku-kanzo-to) on polycystic ovarian disease. Int J Fertil Menopausal Stud. 1994;39(2):69-76.

Feng Y, Johansson J, Shao R, Mannerås Holm L, Billig H, Stener-Victorin E. Electrical and manual acupuncture stimulation affects estrous cyclicity and neuroendocrine function in a DHT-induced rat polycystic ovary syndrome model [published online ahead of print February 24, 2012]. Exp Physiol. doi:10.1113/expphysiol.2011.063131. Medline:22337865

Chen SS, Michael A, Butler-Manuel SA. Advances in the treatment of ovarian cancer: a potential role of antiinflammatory phytochemicals. Discov Med. 2012;13(68):7-17.

Nagata C, Kabuto M, Shimizu H. Association of coffee, green tea, and caffeine intakes with serum concentrations of estradiol and sex hormone–binding globulin in premenopausal Japanese women. Nutr Cancer. 1998;30(1):21-24.

Donà G, Sabbadin C, Fiore C, et al. Inositol administration reduces oxidative stress in erythrocytes of patients with polycystic ovary syndrome [published online ahead of print January 5, 2012]. Eur J Endocrinol. doi:10.1530/EJE-11-0840. Medline:22223702

Wehr E, Pieber TR, Obermayer-Pietsch B. Effect of vitamin D3 treatment on glucose metabolism and menstrual frequency in polycystic ovary syndrome women: a pilot study. J Endocrinol Invest. 2011;34(10):757-763.

Lerchbaum E, Obermayer-Pietsch BR. Vitamin D and fertility: a systematic review [published online ahead of print January 24, 2012]. Eur J Endocrinol. Medline:22275473.

Livadas S, Boutzios G, Economou F, et al. The effect of oral micronized progesterone on hormonal and metabolic parameters in anovulatory patients with polycystic ovary syndrome. Fertil Steril. 2010;94(1):242-246.

Lee, John R and Hopkins, V. What Your Dr. May Not Tell You about PCOS. http://www.virginiahopkinstestkits.com/aboutpcospf.html”>_tmp_url_0_iahopkinstestkits.com/aboutpcospf.html. Accessed March 19, 2012.

Carlson LE, Speca M, Patel KD, Goodey E. Mindfulness-based stress reduction in relation to quality of life, mood, symptoms of stress and levels of cortisol, dehydroepiandrosterone sulfate (DHEAS) and melatonin in breast and prostate cancer outpatients. Psychoneuroendocrinology. 2004;29(4):448-474.

Poli F, Dreno B, Verschoore M. An epidemiological study of acne in female adults: results of a survey conducted in France. J Eur Acad Dermatol Venereol. 2001;15(6):541-545.

Cordain L, Lindeberg S, Hurtado M, Hill K, Eaton SB, Brand-Miller J. Acne vulgaris: a disease of Western civilization. Arch Dermatol. 2002;138(12):1584-1590.

Timpatanapong P, Rojanasakul A. Hormonal profiles and prevalence of polycystic ovary syndrome in women with acne. J Dermatol. 1997;24(4):223-229.

Moura HH, Costa DL, Bagatin E, Sodré CT, Manela-Azulay M. Polycystic ovary syndrome: a dermatologic approach [in English and Portuguese]. An Bras Dermatol. 2011;86(1):111-119.

Wickenheisser JK, Nelson-Degrave VL, McAllister JM. Dysregulation of cytochrome P450 17α-hydroxylase messenger ribonucleic acid stability in theca cells isolated from women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90(3):1720-1727.

Fernández M, Bourguignon N, Lux-Lantos V, Libertun C. Neonatal exposure to bisphenol A and reproductive and endocrine alterations resembling the polycystic ovarian syndrome in adult rats. Environ Health Perspect. 2010;118(9):1217-1222.

Kandaraki E, Chatzigeorgiou A, Livadas S, et al. Endocrine disruptors and polycystic ovary syndrome (PCOS): elevated serum levels of bisphenol A in women with PCOS. J Clin Endocrinol Metab. 2011;96(3):E480-E484. http://jcem.endojournals.org/content/96/3/E480.long. Accessed March 19, 2012.

Takeuchi T, Tsutsumi O, Ikezuki Y, Takai Y, Taketani Y. Positive relationship between androgen and the endocrine disruptor, bisphenol A, in normal women and women with ovarian dysfunction. Endocr J. 2004;51(2):165-169.

Diamanti-Kandarakis E, Christakou C, Marinakis E. Phenotypes and environmental factors: their influence in PCOS. Curr Pharm Des. 2012;18(3):270-282.

Veiga-Lopez A, Ye W, Padmanabhan V. Developmental programming: prenatal testosterone excess disrupts anti-Müllerian hormone expression in preantral and antral follicles. Fertil Steril. 2012;97(3):748-756.

Toulis, KA, Goulis DG, Farmakiotis D, et al. Adiponectin levels in women with polycystic ovary syndrome: a systematic review and a meta-analysis. Hum Reprod Update. 2009;15(3):297-307.

González F, Rote NS, Minium J, Kirwan JP. In vitro evidence that hyperglycemia stimulates tumor necrosis factor-α release in obese women with polycystic ovary syndrome. J Endocrinol. 2006;188(3):521-529.

Gonzalez F, Thusu K, Abdel-Rahman E, Prabhala A, Tomani M, Dandona P. Elevated serum levels of tumor necrosis factor α in normal-weight women with polycystic ovary syndrome. Metabolism. 1999;48(4):437-441.

Ikeno H, Tochio T, Tanaka H, Nakata S. Decrease in glutathione may be involved in pathogenesis of acne vulgaris. J Cosmet Dermatol. 2011;10(3):240-244.

Sarici G, Cinar S, Armutcu F, Altinyazar C, Koca R, Tekin NS. Oxidative stress in acne vulgaris. J Eur Acad Dermatol Venereol. 2010;24(7):763-767.

Morales AJ, Laughlin GA, Bützow T, Maheshwari H, Baumann G, Yen SS. Insulin, somatotropic, and luteinizing hormone axes in lean and obese women with polycystic ovary syndrome: common and distinct features. J Clin Endocrinol Metab. 1996;81(8):2854-2864.

Meirow D, Yossepowitch O, Rösler A, et al. Endocrinology: insulin resistant and non-resistant polycystic ovary syndrome represent two clinical and endocrinological subgroups. Hum Reprod. 1995;10(8):1951-1956.

Burt Solorzano CM, Beller JP, Abshire MY, Collins JS, McCartney CR, Marshall JC. Neuroendocrine dysfunction in polycystic ovary syndrome. Steroids. 2012;77(4):332-337.

Melnik BC, Schmitz G. Role of insulin, insulin-like growth factor-1, hyperglycaemic food and milk consumption in the pathogenesis of acne vulgaris. Exp Dermatol. 2009;18(10):833-841.

Benson S, Arck PC, Tan S, et al. Disturbed stress responses in women with polycystic ovary syndrome. Psychoneuroendocrinology. 2009;34(5):727-735.

Lee WJ, Jung HD, Lee HJ, Kim BS, Lee SJ, Kim do W. Influence of substance-P on cultured sebocytes. Arch Dermatol Res. 2008;300(6):311-316.

Armanini D, Mattarello MJ, Fiore C, et al. Licorice reduces serum testosterone in healthy women. Steroids. 2004;69(11-12):763-766.

Takahashi K, Kitao M. Effect of TJ-68 (shakuyaku-kanzo-to) on polycystic ovarian disease. Int J Fertil Menopausal Stud. 1994;39(2):69-76.

Feng Y, Johansson J, Shao R, Mannerås Holm L, Billig H, Stener-Victorin E. Electrical and manual acupuncture stimulation affects estrous cyclicity and neuroendocrine function in a DHT-induced rat polycystic ovary syndrome model [published online ahead of print February 24, 2012]. Exp Physiol. doi:10.1113/expphysiol.2011.063131. Medline:22337865

Chen SS, Michael A, Butler-Manuel SA. Advances in the treatment of ovarian cancer: a potential role of antiinflammatory phytochemicals. Discov Med. 2012;13(68):7-17.

Nagata C, Kabuto M, Shimizu H. Association of coffee, green tea, and caffeine intakes with serum concentrations of estradiol and sex hormone–binding globulin in premenopausal Japanese women. Nutr Cancer. 1998;30(1):21-24.

Donà G, Sabbadin C, Fiore C, et al. Inositol administration reduces oxidative stress in erythrocytes of patients with polycystic ovary syndrome [published online ahead of print January 5, 2012]. Eur J Endocrinol. doi:10.1530/EJE-11-0840. Medline:22223702

Wehr E, Pieber TR, Obermayer-Pietsch B. Effect of vitamin D3 treatment on glucose metabolism and menstrual frequency in polycystic ovary syndrome women: a pilot study. J Endocrinol Invest. 2011;34(10):757-763.

Lerchbaum E, Obermayer-Pietsch BR. Vitamin D and fertility: a systematic review [published online ahead of print January 24, 2012]. Eur J Endocrinol. Medline:22275473.

Livadas S, Boutzios G, Economou F, et al. The effect of oral micronized progesterone on hormonal and metabolic parameters in anovulatory patients with polycystic ovary syndrome. Fertil Steril. 2010;94(1):242-246.

Lee, John R and Hopkins, V. What Your Dr. May Not Tell You about PCOS. http://www.virginiahopkinstestkits.com/aboutpcospf.html”>_tmp_url_0_iahopkinstestkits.com/aboutpcospf.html. Accessed March 19, 2012.

Carlson LE, Speca M, Patel KD, Goodey E. Mindfulness-based stress reduction in relation to quality of life, mood, symptoms of stress and levels of cortisol, dehydroepiandrosterone sulfate (DHEAS) and melatonin in breast and prostate cancer outpatients. Psychoneuroendocrinology. 2004;29(4):448-474.

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