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From the Townsend Letter
February / March 2019

Non-Pharmaceutical Androgen-Lowering Agents in the Treatment of Hormonal Acne, Hirsute, and Male-Pattern Balding
by Corina Dunlap, ND, MS
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Hirsutism, acne, and male-pattern balding are all common signs of hyper-androgenism. Many suffering from these symptoms are increasingly seeking non-pharmaceutical options. Conventional care guidelines recommend combined oral contraceptives (COCs) as monotherapy, or COCs with an antiandrogen, such as spironolactone or finasteride, as combination therapy.1 Natural alternatives are becoming increasingly in demand due to the potential side effects of these options, which include weight fluctuation, emotional lability, depression, and lowered libido (for COCs), and potential reproductive harm, gastrointestinal discomfort, and irregular menstrual bleeding (for spironolactone and finasteride). There is also increasing awareness that effective natural treatment options exist without complications of these undesirable side effects. This article serves as a resource for non-pharmaceutical, androgen-lowering, evidence-based updates for the effective management of hormonal acne, hirsute, and male-pattern balding.
     
BDNF EssentialsAndrogen-excess leads to an increased rate of terminal (i.e. course) hair growth in androgen-sensitive tissues such as the upper lip, chin, mid-sternum, upper abdomen, back, and buttocks, and hair loss on the scalp, particularly along the temporal region.2 Although acne is in many cases multi-factorial, hyperandrogenism can contribute to the development of acne through its impact on increased production of sebum in the sebaceous glands.3
     
Clinical history goes a long way in determining if someone has hyperandrogenism, but it is also important to test biomarkers in order to 1) confirm clinical suspicion, and 2) identify cause. Based on the 2018 Endocrine Society Clinical Guidelines on hirsutism, serum total testosterone is a mainstay for workup.4 Additional testing may be added if the patient has additional menstrual irregularities (i.e. oligomenorrhea or amenorrhea).

  • First line (for all women with signs of hyperandrogenism): serum total testosterone with liquid chromatography-tandem mass spectroscopy (LC-MS/MS) for accuracy.
    o Upper limit of normal is 45 to 60 ng/dL range (1.6 to 2.1 nmol/L).
    o If elevated, but <150 ng/dL (5.2 nmol/L), most likely PCOS, however, may consider testing 17-hydroxyprogesterone to rule-out nonclassic congenital adrenal hyperplasia (NCCAH) due to 21-hydroxylase deficiency (see below).
    o If >150 ng/dL (5.2 nmol/L), consider possible androgen-secreting tumor and refer to endocrinology specialty.

  • Second line (for women with hyper-androgenism + menstrual irregularities (i.e. oligomenorrhea or amenorrhea), add:
    o 17-hydroxyprogesterone (at 8 am early in follicular phase). A value of 200 ng/dL is a strong indicator for NCCAH.
    o Human chorionic gonadotropin [hCG] to rule out pregnancy or hCG producing adenoma.
    o Prolactin to rule out hyperprolactinemia.
    o Follicle-stimulating hormone [FSH] to rule out primary ovarian insufficiency.
    o Thyroid-stimulating hormone [TSH]), fT4, fT3, and Thyroid Abs to rule out thyroid disease.

The following summaries highlight the natural medicine modalities (e.g. techniques, botanicals, and nutrients) that have been explored in recent human research to lower hyperandrogenism as an alternative, or in addition to pharmaceuticals such as COC and anti-androgenics.

Acupuncture and PCOS
In a meta-analysis of 31 articles and N = 2,321 with PCOS:5

  • Results (significant; all for acupuncture group)
    o Total testosterone decreased.
    o Reduction in Day 3 FSH, insulin resistance, and BMI.

Resveratrol and PCOS
In an RCT, N = 34 with PCOS; randomized to 12 weeks of 1) resveratrol (1.5 g/day) or 2) placebo:6

  • Results (significant; all for resveratrol group)
    o Total testosterone decreased (by 23.1%).
    o DHEAS decreased (by 22.2%).
    o Fasting insulin decreased in the resveratrol group (by 31.8%).

Myo-Inositol (MI) plus Combined Oral Contraceptive Pill (OCP) vs OCP alone in PCOS
In an RCT, N = 155 with PCOS; randomized to 1) MI 4 g/day used alongside OCP (estradiol 30 mg/gestodene 75 mg) or 2) OCP alone for 12 months:7

  • Results (significant; for Myo-Inositol group)
    o Fasting insulin decreased.
    o Androgens decreased.
    o Lipid profile improved.

Myo-Inositol (MI) alone in PCOS
In a prospective cohort trial, N= 46 with PCOS and hirsute received myo-inositol 2 g/2x daily for six months:8

  • Results (significant)
    o Hirsutism decreased.
    o Androgens decreased.
    o Lipid profile improved (specifically, HDL increased and LDL decreased).

Myo-Inositol (MI) plus Folic Acid in PCOS
In a prospective cohort trial, N= 50 with PCOS received myo-inositol 2 g/2x daily plus folic acid 200 mcg/2x daily for six months:9

  • Results (significant)
    o Hirsutism and acne decreased after six months.

Myo-Inositol (MI) plus Alpha Lipoic Acid (ALA) in PCOS
In a prospective cohort trial, N= 50 with PCOS received myo-inositol 2 g/daily plus ALA 800 mg/daily for six months:10

  • Results (significant)
    o Free androgen index (FAI), mean androstenedione, and DHEAS levels decreased.
    o Mean SHBG levels raised.
    o Improvement in mean Ferriman–Gallwey score.
    o Reduction of BMI.
    o Reduction of AMH levels, ovarian volume and total antral follicular.

Melatonin alone in PCOS
In a prospective cohort trial, N= 40 with PCOS received melatonin 2 g/daily at night for six months:11

  • Results (significant)
    o Total testosterone decreased.
    o Free androgen index decreased.
    o AMH decreased.

Omega 3s
In a double-blind, randomized, controlled trial, N=78 overweight and obese women with PCOS, randomized to eight weeks of 1) omega 3s (3gr/day total) or 2) placebo:12

  • Results (significant; for omega 3s group)
    o Reduction in serum concentrations of total testosterone.
    o Regulation of cycles.

BioDisruptAlthough this article is focused on human research, there are many animal studies investigating natural modalities to lower hyperandrogenism, including use of ashwaganda, chrysin, berberine, green tea, and Moringa oleifera. Keep an eye out for follow-up human trials examining these agents.
     
As always, it is extremely important to figure out etiology of hyperandrogenism in order to treat effectively. Many factors such as blood sugar, weight, blood pressure, smoking, alcohol, diet, exercise, and sleep can all play into endocrine dysfunction. There may also be structural endogenous and/or exogenous causes such as an androgen-producing adenoma, or a partner's use of testosterone cream. The importance of addressing these factors is not to be underestimated in order to identify and remove route of potential cause and support the whole person.
     
As an added note to the treatment of acne, a multi-modal approach may be a more efficient treatment approach vs targeted anti-androgenic therapies alone, especially since most patients with acne have normal androgen levels.13 There are effective research implications for use of diet, microbiome optimization, stress and insulin-resistance lowering lifestyle recommendations, and hypoallergenic topical treatments.

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References
1.     Legro RS, et al. Diagnosis and treatment of polycystic ovary syndrome: an endocrine society clinical practice guideline. Reproductive Endocrinology. 2014;20:22-35.
2.     Rosenfield RL. Hirsutism.
NEJM. 2005; 353( 24):2578-2588.
3.     Jeremy AHT, et al. Inflammatory events are involved in acne lesion initiation.
Journal of Investigative Dermatology. 2003;121(1):20-27.
4.     Martin, KA, et al. Evaluation and Treatment of Hirsutism in Premenopausal Women: An Endocrine Society Clinical Practice Guideline.
J Clin Endocrin & Metabolism. 2018;103(4):1233-1257.
5.     Ren LN, et al. A meta-analysis on acupuncture treatment of polycystic ovary syndrome. Zhen ci yan jiu = Acupuncture research / [Zhongguo yi xue ke xue yuan Yi xue qing bao yan jiu suo bian ji]. 2014;39(3): 238–246.
6.     Duleba A, Spaczynski RZ, Pawelczyk L. Effects of resveratrol on polycystic ovary syndrome.
Fertility and Sterility. 2016;106(3):e36–e37. http://doi.org/10.1016/j.fertnstert.2016.07.117
7.     Minozzi M, et al. The effect of a combination therapy with myo-inositol and a combined oral contraceptive pill versus a combined oral contraceptive pill alone on metabolic, endocrine, and clinical parameters in polycystic ovary syndrome.
Gynecological Endocrinology. 2011;27(11):920-924.
8.     Minozzi M, D'Andrea G, Unfer V. Treatment of hirsutism with myo-inositol: a prospective clinical study.
Reprod Biomed Online. 2008;17(4):579–582.
9.     Zacchè MM, et al. Efficacy of myo-inositol in the treatment of cutaneous disorders in young women with polycystic ovary syndrome.
Gynecological Endocrinology. 2009;(25)8:508-513.
10.   De Cicco S, et al. Myoinositol combined with alpha-lipoic acid may improve the clinical and endocrine features of polycystic ovary syndrome through an insulin-independent action.
Gynecological Endocrinology. 2017;33(9):698-701.
11.   Tagliaferri V, Romualdi D, Scarinci E. Melatonin treatment may be able to restore menstrual cyclicity in women with PCOS: a pilot study.
Reproductive Sciences. 2018;25(2):269-275.
12.   Nadjarzadeh A, et al. The effect of omega-3 supplementation on androgen profile and menstrual status in women with polycystic ovary syndrome: A randomized clinical trial.
Iranian J Reproductive Medicine. 2013;11(8):665.
13.   UpToDate. Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris. Accessed November 2018.

Dr. Corina Dunlap graduated with a Doctorate in Naturopathic Medicine and Master of Science in Integrative Medicine Research from the National University of Natural Medicine (NUNM).  Dr. Dunlap sees patients privately at A Woman's Time and is also research and adjunct faculty at the School of Research & Graduate Studies at Helfgott Research Institute and NUNM. She teaches courses such as: Gynecology & Infertility; Women's Health Research: Fertility and Beyond; Medical Anthropology; and Women's Health Journal Club. Before NUNM, she received her B.A. from Smith College with an emphasis in medical anthropology and international relations.

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