HORMONAL THERAPIES IN DERMATOLOGY James Q. Del Rosso, DO

Adjunct Clinical Professor (Dermatology) Touro University Nevada Henderson, Nevada Lakes Dermatology Del Rosso Dermatology Research Center Las Vegas, Nevada

Disclosures Aclaris*# Allergan*+# Anacor*+ Aqua/Almirall*+ Bayer Dermatology*+# BioPharmX*# Celgene*+ Cutanea# Dermira* Ferndale*+ Foamix# Galderma*+#

Genentech+# LeoPharma*+# Novartis*+ Novan*# Valeant*+# Pharmaderm*+ Promius*+ Sebacia*# SunPharma*+# Unilever*+ Consultant*/ Speaker+ / Researcher# (Updated as of 6-10-16)

Objectives of the Presentation  Provide an overview of the role of hormonal therapies in the management of common dermatologic disorders  Review specific therapies used to treat common disorders such as acne vulgaris and alopecia in men and women  FINASTERIDE / DUTASTERIDE  ORAL CONTRACEPTIVES  SPIRONOLACTONE

 Outline the use of each agent regarding dosing, monitoring of clinical response and potential adverse effects, and adjustments in therapy based on individual response

Acknowledgements  Jason M. Hirshburg MD, PhD, Petra A. Kelsey BS, Chelsea A. Therrien BS, A. Carlo Gavino MD1, Jason S. Reichenberg MD. Adverse Effects and Safety of 5-alpha Reductase Inhibitors (Finasteride, Dutasteride): A Systematic Review. J Clin Aesthet Dermatol. 2016.  Harper JC. The Use of Oral Contraceptives for Management of Acne Vulgaris. Dermatol Clin. 2016;34:159-165  Kim GK, Del Rosso JQ. Oral spironolactone in post-teenage female patients with acne vulgaris: practical considerations for the clinician based on current data and clinical experience. J Clin Aesthet Dermatol. 2012;5(31):37-50

Oral 5-alpha Reductase Inhibitors (5ARIs) Management of Androgenetic Alopecia (AgA)

 Androgenetic alopecia (AgA)1,2  Affects >75% of males and ~50% of females by end of the 7th decade  Pattern differences based on gender

 Finasteride / Dutasteride 2-4  Oral 5-alpha reductase inhibitors (5ARIs) Reduce testosterone formation  Finasteride inhibits Type 2 5AR receptors  Dutasteride inhibits Type 1 and Type 2 5AR receptors (greater potency)

 Finasteride FDA-approved for treatment of AgA in men  Use of 5AR inhibitors increasing in women in selected cases

 Used to prevent progession of hair loss and promote hair regrowth 1 Sperling LC et al, Alopecias. In: Bolognia J, Jorizzo J, Rapini R, editors. Dermatology. 3rd ed. Vol. 1. Philadelphia: Elsevier; 2013.p.1093-114. 2 Harcha WG, Martinez JB, Tsai T, Katsuoka K, Kawashima M, Tsuboi R, et al. A randomized, active- and placebo-controlled study of the efficacy and safety of different doses of dutasteride versus placebo and finasteride in the treatment of male subjects with androgenetic alopecia. J Am Acad Dermatol. 2014;70(3):489-498. 3 Aggarwal S, et al. An overview on 5α-reductase inhibitiors. Steroids. 2010;75:109-153. 4 Clark RV, et al. Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5alpha-reductase inhibitor. J Clin Endocrinol Metab. 2004;89:2179-2184.

Oral 5-alpha Reductase Inhibitors

Emerging Concerns About Adverse Events: Fact or Fiction  Does Use of Finasteride Increase Risk of Prostate Cancer?1-3  Finasteride and dutasteride used to treat benigh prostatic hypertrophy  Assocation of androgen dependency and prostate cancer ??  AAD Task force to address concern with position statement

 Prostate Cancer Prevention Trial (PCPT)2,4  2003: 18,800 subjects ~ Finasteride vs Placebo – followed x 7 years  25% relative risk increase of Prostate Cancer in Placebo arm  27% greater risk of high grade prostate cancer in Finasteride arm

 2013: Initial PCPT group at 18 years follow-up  Prostate Cancer in 10.5% in Finasteride arm vs 14.9% in Placebo arm  High Grade Prostate Cancer in 3.5% Finasteride arm vs 3.0% in Placebo arm 1 Traish AM, et al. Adverse effects of 5α-reductase inhibitors: What do we know, don’t know, and need to know? Rev Endocr Metab Disord. 2015;16:177-198. 2 Thompson IM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003;349:215-224. 3 Feldman BJ, et al. The development of androgen-independent prostate cancer. Nature Rev Cancer. 2001;1:34-45. 4 Thompson IM, et al. Long-term survival of participants in the prostate cancer prevention trial. N Engl J Med. 2013;603-610.

Oral 5-alpha Reductase Inhibitors (5ARIs)

Emerging Concerns About Adverse Events: Fact or Fiction  Does Use of Oral 5ARIs Increase Risk of Prostate Cancer?1,2

 Controversial Topic ~ Some Opposing Data Findings in Literature  Reports showing no statistical difference in prostate cancer grade with use of finasteride  Dustasteride vs Placebo trail (N=6729 males); potential suggestion of risk ?

 Theories On Potential Increase in Higher Prostate Cancer Grade3-7  Direct Induction Theory  Detection Bias Theory

 Summary  (1) No increased incidence (2) Possible increased risk of higher grade (3) No negative impact on overall survival rate 1 Preston MA, et al. 5α-reductase inhibitors and risk of high-grade or lethal prostate cancer. JAMA Int Med. 2014;174:1301-1307. 2 Lacy JM et al. A tale of two trials: the impact of 5α-reductase inhibition on prostate cancer (review). Oncology letters. 2014;8:1391-1396. 3 Andriole GL, et al. Effect of dutasteride on the risk of prostate cancer. N Engl J Med. 2010;362:1192-1202. 4 Kosaka T, et al. Potent increased risk of the initiation of DNA replication in human prostate cancer with the use of 5α-reductase inhibitors. Am J Clin Exp Urol. 2014;12:136-144. 5 Hirano D, et al. Neuroendocrine differentiation in hormone refractory prostate cancer following androgen deprivation therapy. Eur Urol. 2004;45:586-592. 6 Ehdaie B, Touijer KA. 5-alpha reductase inhibitiors in prostate cancer: from clinical trials to clinical practice. Eur Urol. 2013; 63:788-791. 7 Lucia MS, et al. Finasteride and high-grade prostate cancer in the prostate cancer prevention trial. J Natl Cancer Inst. 2007; 99(18):1375-1383.

Oral 5-alpha Reductase Inhibitors

Emerging Concerns About Adverse Events: Fact or Fiction  Does Finasteride Cause Depression/Psychiatric Side Effects?1-3  Depression not initially listed in approved product labeling with Finasteride for AgA (1 mg daily) or for BPH (5 mg daily)  Anecdotal and published reports of depression  subsequently added to product labeling for AgA product (1 mg daily)

 Collection of studies correlating depressive symptoms with use of finasteride in some patients  Potential increase in depressive symptoms in past users of finasteride – possible association with concurrent sexual dysfunction

 Summary  No definitive direct link with depression / Depressive symptoms may occur in some treated with 5ARIs / More data on reversibility of mood-related changes are needed 1 Altomare G, et al. Depression circumstantially related to the administration of finasteride for androgenetic alopecia. J Dermatol. 2002;29:665–669. 2 Rahimi-Ardabili B, et al. Finasteride induced depression: a prospective study. BMC Clinical Pharmacology. 2006;7(6):7. 3 Irwig MS. Depressive symptoms and suicidal thoughts among former users of finasteride with persistent sexual side effects. J Clin Psychiatry. 2012;73(9):1220-1223.

Oral 5-alpha Reductase Inhibitors

Emerging Concerns About Adverse Events: Fact or Fiction  Does Use of Oral Finasteride Cause Sexual Side Effects (SSEs)?  Reported to occur in 0.9% - 38% ~ most common adverse effects1-4     

ERECTILE DYSFUNCTION: Finasteride – 3.4% - 15.8% vs Placebo 1.7% - 6.3% EJACULATORY DISTURBANCE: Finasteride – 0.9% - 5.7% vs Placebo 0.5% - 1.7% LOSS OF LIBIDO: Finasteride – 2.36% - 10.0% vs Placebo 1.2% - 6.3% Incidence of SSEs inceased vs placebo and not dose-dependent (1 mg = 5 mg) Rates similar with dutasteride

 Spontaneous Improvement/Resolution vs Persistence5-6  PLESS* reported 22% initial rate  Improved over 2-4 months  Baseline  Averages: Start after 1.8 years + Last 5.4 months after stopping use *Proscar Long Term Efficacy and Safety Study 1 Traish AM, et al. Adverse effects of 5α-reductase inhibitors: What do we know, don’t know, and need to know? Rev Endocr Metab Disord. 2015;16:177-198. 2 Jason M. Hirshburg MD, et al. Adverse Effects and Safety of 5-alpha Reductase Inhibitors (Finasteride, Dutasteride): A Systematic Review. JCAD. 2016. 3 Gormley GJ, et al. The effect of finasteride in men with benign prostatic hyperplasia. The finasteride study group. N Engl J Med. 1992;327:1185-1191. 4 Roehrborn CG, et al. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology. 2002;60:434-441. 5 Stoner E. Three-year safety and efficacy data on the use of finasteride in the treatment of benign prostatic hyperplasia. Urology. 1994;43:284-292. 6 Ali AK, et al. Persistent sexual dysfunction and suicidal ideation in young men treated with low-dose finasteride: A pharmacovigilance study. Pharmacotherapy. 2015;35:687-695.

Oral 5-alpha Reductase Inhibitors

Use in Androgenetic Alopecia (AgA) in Women  Major concern is exposure of male fetus in pregnant women1-5  Abnormal development of male genitalia  Contraindicated in pregnancy ~ consider exclusion pre-treatment  Limited data on side effects ~ small studies and case reports  Decreased libido, breast tenderness, menstrual changes, and cephalgia reported  Some case reports and small series show lack of side effects  Long term data very limited  137 women (age range 41-60 yrs) ~ Side Effects  Finasteride 1 mg = Placebo 1 McClellan KJ, et al. Finasteride a review of its use in male pattern hair loss. Drugs. 1999;57:111-126. 2 Stout SM et al. Finasteride treatment of hair loss in women. The annals of pharmacotherapy. 2010;44:1097. 3 Falsetti L, et al. Treatment of hirsutism by finasteride and flutamide in women with polycystic ovary syndrome. Gynecol Endocrinol. 1997;11:251-157. 4 Lumachi F et al. Use of cyproterone acetate, finasteride, and spironolactone to treat idiopathic hirsutism. Fertility and Sterility. 2003;79:942-946. 5 Jason M. Hirshburg MD, et al. Adverse Effects and Safety of 5-alpha Reductase Inhibitors (Finasteride, Dutasteride): A Systematic Review. JCAD. 2016.

Combination Oral Contraceptives (COCs) General Overview

 Combination of ethinyl estradiol (EE) and a progestin1,2  EE dose range: 10 ug – 50 ug ~ variation is estrogenic potency  Marked variability among progestins used in different COCs

 First and second generation progestins ~ derived from testosterone  May interact with progesterone, estrogen, and androgen receptors  NORETHINDRONE, NORETHINDRONE ACETATE, LEVONORGESTREL

 Third generation progestins ~ derived from testosterone  Modified to induce LESS androgenic activity  NORGESTIMATE, DESOGESTREL, GESTODENE

 Fourth generation progestins  Bind only to progesterone receptor  NO angrogenic effects  DROSPERINONE ~ derivative of 17-alpha spironolactone

• NET INCREASE IN SEX HORMONE BINDING GLOBULIN (SHBG) • NET DECREASE IN FREE TESTOSTERONE

1 Harper JC. The Use of Oral Contraceptives for Management of Acne Vulgaris. Dermatol Clin. 2016;34:159-165 2 Arowojolu AO, Gallo MF, Lopez LM, et al. Combined oral contraceptive pills for treatment of acne. Cochrane Database Syst Rev. 2012;(7):CD004425.

Combination Oral Contraceptives (COCs) Use for Treatment of Acne Vulgaris (AV)1-4

 Modes of action for Acne Vulgaris (AV)  Suppress ovarian production of androgens and ovulation  EE increases hepatic synthesis of SHBG  decreases free testosterone  Inhibition of 5-AR by some progestins

 Efficacy for treatment of AV  Most COCs not FDA-approved for AV  Can be used with or without hyperandrogenism (clinical and/or lab)  Multiple studies showing efficacy for facial AV ~ allow 3 cycles for onset  Data showing efficacy for moderate truncal AV ~ 24 week study  Comparative data limited among COCs for AV 1 Harper JC. The Use of Oral Contraceptives for Management of Acne Vulgaris. Dermatol Clin. 2016;34:159-165 2 Arowojolu AO, Gallo MF, Lopez LM, et al. Combined oral contraceptive pills for treatment of acne. Cochrane Database Syst Rev. 2012;(7):CD004425. 3 Sitruk-Ware R, et al. Phrmacology of different progestogens: the special case of drosperinone. Climacteric. 2005;8(Suppl 3):4-12. 4 Palli MB, et al. A single center, randomized, double-blind, parallel-group study to examine thec safety and efficacy of 3 mg dosperinone /0.02 mg ethinyl estradiol compared with placebo in the treatment of moderate truncal acne vulgaris. J Drugs Dermatol. 2013;12(6):633-637.

Combination Oral Contraceptives (COCs) Use for Treatment of Acne Vulgaris (AV)1-5

 “Bonus” Noncontraceptive Benefits of COCs  Normalize menstrual cycle, reduce anemia  Reduce risks of endometrial, ovarian, and colorectal cancer  Decrease symptoms of premenstrual dysmorphic disorder

 When to use COCs for treatment of AV  Consideration in women with AV and no contraindications to COCs  Important to review potential risks and contraindications

 Useful especially in women who also desire contraception 1 Harper JC. The Use of Oral Contraceptives for Management of Acne Vulgaris. Dermatol Clin. 2016;34:159-165 2 The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. N Engl J Med. 1987;316:650-655. 3 Burkman R, et al. Safety concerns and health benefits associated with oral contraception. Am J Obstet Gynecol. 2004;190:S5-S22. 4 Lopez LM, et al. Oral contraceptives containing drosperinone for premenstrual syndrome. Cochrane Database Syst Rev. 2012;(2):CD006586. 5 Frangos JE, et al. Acne and oral contraceptives: update on women’s health screening guidelines. J Am Acad Dermatol. 2008;58:781-786.

Combination Oral Contraceptives (COCs) Potential Risks and Contraindications1-5

CARDIOVASCULAR RISKS    

Increased risk of Venous Thromboembolism (VTE) Affected by dose of EE and progestin use Risk may be increased with drosperinone Overall 3-9 vs 1-5 events/10,000 woman years in COC users vs non-users/not pregnant  Increased risk >age 35; phlebitis history; postpartum, immobilization, some GI diseases, others

CANCER RISKS  

Possible slight increase in breast cancer but not if at 10+ years after stopping COC use Cervical cancer increase correlated with duration of COC use - 2-fold higher after 5 years of use + no increased risk if at 10+ years after stopping COC use

BONE RISKS 

Risk of inadequate bone mass if EE 2 years

1 Harper JC. The Use of Oral Contraceptives for Management of Acne Vulgaris. Dermatol Clin. 2016;34:159-165 2 Frangos JE, et al. Acne and oral contraceptives: update on women’s health screening guidelines. J Am Acad Dermatol. 2008;58:781-786.

??? Spironolactone ??? Approach to Monitoring of Serum Potassium Levels • Plovanich M, Weng QY. Mostaghimi A. Low Usefulness of Potassium Monitoring Among Healthy Young Women Taking Spironolactone for Acne. JAMA Dermatol. 2015;151(9):941-944. • 974 healthy adult women with acne • 1165 young healthy women on or off spironolactone • 13 ABNORMAL K+ VALUES / 1802 MEASUREMENTS • 6/13 normalized with repeat testing • The rate of hyperkalemia in healthy young women taking spironolactone (0.72%) for acne is equivalent to the baseline rate of hyperkalemia in this population (0.76%). • Routine potassium monitoring is unecessary for healthy women taking spironolactone for acne.

??? Spironolactone ??? Approach to Monitoring of Serum Potassium Levels • Plovanich M, Weng QY. Mostaghimi A. Low Usefulness of Potassium Monitoring Among Healthy Young Women Taking Spironolactone for Acne. JAMA Dermatol. 2015;151(9):941-944. • 974 healthy adult women with acne • 1165 young healthy women on or off spironolactone • 13 ABNORMAL K+ VALUES / 1802 MEASUREMENTS • 6/13 normalized with repeat testing • The rate of hyperkalemia in healthy young women taking spironolactone (0.72%) for acne is equivalent to the baseline rate of hyperkalemia in this population (0.76%). • Routine potassium monitoring MAY BE unnecessary for healthy women taking spironolactone for acne.

??? Spironolactone ???

Approach to Monitoring of Serum Potassium Levels

POPULATION-BASED DATA

??? Spironolactone ???

Approach to Monitoring of Serum Potassium Levels

NOT LIKELY TO MATTER TO THIRD PARTY PAYOR VERY LIKELY TO MATTER TO THE DOCTOR AND PATIENT