1. FRONTAL FIBROSING ALOPECIA: IATROGENIC ENDOCRINE DISRUPTION Vidhi Shah, Colleen Reisz MD FRONTAL FIBROSING ALOPECIA: IATROGENIC ENDOCRINE DISRUPTION Vidhi Shah, Colleen Reisz MD Frontal fibrosing alopecia results from an inflammatory attack on the hair follicle in the frontal hairline in women at menopause[1]. It occurs in women of Northern European ancestry and appears to be increasing in incidence [2]. Fitzpatrick phototyping is a clinical tool for objectively assessing skin pigmentation and may function a potential biomarker of vitamin D status and genotypic variation in the human aromatase complex. The frontal hair line in women has a gender related gradient in aromatase activity. There are physiologic changes in aromatase behavior that accompany age and menopause [6]. Steroid pathways are protected by nuclear receptors that have dual function in bile and drug metabolism. These nuclear receptors are altered by medications and supplements, particularly drugs that target cholesterol and gut defense mechanisms [8]. Physicians caring for women with FFA should include drug histories and drug stratification as part of their treatment plans. The prolific use of vitamins and supplements found in this series supports further investigation into the risks and benefits of this largely unregulated industry. References [1] Ladizinski B, et al. "Frontal Fibrosing Alopecia: A Retrospective Review of 19 Patients Seen at Duke University.” Journal of the American Academy of Dermatology. 2013; 68(5):749-755. [2] Otani C, et al. “Frontal fibrosing alopecia associated with lichen planus pigmentosum.” Journal of the American Academy of Dermatology. 2013; 68 (4): AB51 [3] Cutolo M, et al. "Estrogen Metabolism and Autoimmunity.” Autoimmunity Reviews. 2012; 11:A460-A464. [4] Inoue T, et al. "The Role of Estrogen-metabolizing Enzymes and Estrogen Receptors in Human Epidermis." Molecular and Cellular Immunology. 2011; 344: 34-40. [5] Cutolo M, et al "Oestrogens in Rheumatic Diseases: Friend or Foe?” Rheumatology (Oxford) 2008; 47: (Suppl, 3): iii 2-5 [6] Yip L, et al. "Gene-wide Association Study between the Aromatase Gene (CYP19A1) and Female Pattern Hair Loss." British Journal Dermatology.2009; 289-94. [7] Marino JS, Xu Y, Hll JW. Central Insulin and leptin-mediated autonomic control of glucose homeostasis. Trends Endocrinol Metab. 200;22:275-285. [8] Morris P, et al. "Inflammation and Increased Aromatase Expression Occur in the Breast Tissue of Obese Women with Breast Cancer." Cancer Prevention Research. 2011; 4(7):1021-1029. [9] Tamir S, et al. “The Effect of Oxidative Stress on ER alpha and ER beta Expression.” Journal of Steroid Biochemistry & Molecular Biology. 2002; 327-332. Introduction We collected biometric and drug data in 23 women with FFA from 2011-2014. We noted use of vitamins and supplements, Fitzpatrick phototyping and comorbid states. Fitzpatrick phototyping was included as a potential biomarker of vitamin D status and genomic variation in aromatase. Drugs known to increase insulin resistance were discontinued or modified to improve the insulin resistance profile. Specific note was made of drugs that target cholesterol and the gut microbiome. Patients were categorized as responders or non-responders. Response to therapy was defined as reduction in redness and scale at the follicular os and no further progression of alopecia. Table 1: Patient demographic, clinical, and response characteristics 23 patients presented with FFA during the study interval. 2 patients did not follow up. The remaining patients are summarized in Table 1. 20/23 patients were Fitzpatrick level I and II, consistent with other studies showing a predominance in women of Northern European ancestry. 14/23 patients had a BMI greater than 25. 6 had large babies, gestational diabetes or preeclampsia 12/23 patients were taking drugs known to negatively impact insulin resistance. 8 were on statins, 3 on statins and beta blockers. 6 on SSRI’s, 3 on PPI’s. 11/23 were on 3 or more supplements, with 7/11 on more than 5. 9/23 patients adjusted medications and had reduction in redness; 11 more have agreed to our suggestions on reduction 1/2 patients who were not on medications known to affect insulin resistance or on vitamins/supplements improved with increase in vitamin D (pt 7) Pt 2 with relentless progression, no response to any treatment, history of premature ovarian failure. Pt No. Age/age at onset of hair loss, y BMIFitzpatrickCo-morbid conditions XenobioticResponse/Reduction 1.6232.001-Simvastatin, MetoprololLost to follow up 2.62/5928.301Premature ovarian failure at 42 y -No response 3.58/5722.901-V/S IIIReduction in progress 4.75/7334.902DM IISimvastatin+ 5.71/6933.302-V/S II+ 6.68/6524.802Morgellens disease see noteV/S III+ 7.60/5825.601Multiple squamous cell carcinoma of the skin starting at menopause -+ 8.41/4137.442Preeclampsia II, Multiple Sclerosis Prednisone, Betaseron+ 9.--1Pharmacokinetic/photosensi tivity issues see note V/S III+ 10.73/7326.072-Atorvastatin, Metoprolol, Omeprazole, Losartan, Tramadol, Sertraline + 11.65/5625.091-V/S II Simvastatin + 12.39/3921.484Triathlete with special diet, creatine, whey, amino acids V/S III (10) Orsythia, Spironolactone + 13.58/5522.923-V/S II Pravastatin, Lisinopril, Flax, Glucosamine Reduction in progress 14.60/5820.503Raynauds,livedo, unclassified autoimmune disorder V/S II Switch from oral to patch estrogen Reduction in progress 15.72/6433.991Hair loss temporally within one month of sertraline V/S III Atorvastatin, Sertraline, Mobic, Triamterene, Trazodone, Hydrocodone Reduction in progress 16.56/5518.562-V/S III Sertraline, Evista, Triamterene Refused 17.54/5326.291Gestational diabetesPrevacidReduction in progress 18.61/5830.471-V/S III Tamoxifen for 5 years, Resveretrol, Garcinia, Ubiquinol, Niacin, Coconut oil, Vitamin E, Fish oil, Reduction in progress 19.80/7928.321Had lymphoma and chemotherapy at 78, fluox added around the time of hair loss Triflex, Hydrochlorothiazide, Lisinopril, Amlodipine, Omeprazole, Fluoxetine, Levothyroxine Reduction in progress 20.62/6120.361Very mild disease. Left side>right side Lexapro, c, Valium, AmbienReduction in progress 21.58/5838.442Also has androgenic hair los since 55 y/o. G4p4 with 2 at 8’10’’ B complex, off OCP at 55 y/o Reduction in progress 22.73/7021.561G3p3; 7; 6’15, 8’12’’ R>L ; RA 2006; POF 44 Synthroid, Methotrexate, Crestor, Sertraline, Bystolic Reduction in progress 23.61/5425.822G3P3 11’’14’’V/S II Synthroid, Glucosamine Reduction in progress *V/S I – 1-2 supplements, V/S II – 3-4 supplements, V/S III – Exuberant use of nutraceuticals. >5 supplements or more in order of frequency: MVI, ca and D, fish oil, glucosamine, flax, CoQ10, lutein, black cohosh, gingko, garlic, Stl John’s Wort Image 1: Pt 4, Baseline and one year after changing the statin from simvastatin to atorvastatin as well as starting metformin. Objectives & Methods Results Discussion Frontal Fibrosing Alopecia (FFA) is a form of scarring hair loss that affects the frontal hairline in white women at menopause. The incidence appears to be increasing [1]. The rate limiting step in estrogen formation is aromatase, which is governed locally by at least 11 different exons. Age, obesity, insulin resistance up regulate aromatase [4,6,7]. Aromatase exhibits regional and gender differences in the scalp with women having a 6 fold increase in the frontal scalp [5,6]. The nuclear receptors that regulate bile salt metabolism have overlapping roles in drug metabolism and protection of the endocrine system. The gut microbiome also impacts secondary bile salt metabolism. The introduction of pharmaceuticals and supplements, especially those that target cholesterol and the gut microbiome, alter the nuclear receptors that protect endocrine signaling pathways. We hypothesized that the introduction of drugs and supplements that alter cholesterol and bile salt metabolism may have off target effects in sex steroid dependent tissues. Menopause may represent a ‘critical window’ in which changing physiology is compromised by drugs that alter mechanisms designed to protect the endocrine system. We hypothesized that drugs and supplements that target cholesterol and the gut microbiome may compromise the nuclear receptors designed to protect the endocrine system. We hypothesized further that these off target effects may present in sex steroid dependent tissues, such as the frontal hairline. BEFORE AFTER Image 1: Pt 16, Baseline and 3 months after stopping Boniva, Evista, B complex, lutein, and fish oil. Pt had been on Evista for several years but did not notice the hairloss until the Boniva was introduced.