Acne Controversies: Hormonal therapies

Transcription

1 A major teaching hospital of Harvard Medical School Acne Controversies: Hormonal therapies Rachel Reynolds, MD Assistant Professor Harvard Medical school Beth Israel Deaconess Medical Center

2 I have no relevant conflicts of interest I will discuss off- label use of medicadon

3 Hormonal Therapies Combined oral contracepdve pills (OCPs) Combined oral contracepdve pills with andandrogenic progesdns: Drospirenone (DRSP) Cyproterone Acetate (CPA) AnDandrogens Spironolactone

4 Why use hormonal therapies?

5 RetrospecDve analysis claims database, 56 million padents, % increase in spironolactone courses prescribed by dermatologists Greatest increase in adults vs. adolescents Decrease in OCPs Increase in oral andbiodcs mean duradon 126 days- - unchanged

6 Oral ContracepDves

7 Oral Contraceptive Pills (OCPs) Combination of ethinyl estradiol (EE) and a progestin Reduce androgens via: 1. Inhibition of LH release è suppression of ovarian androgen production 2. Increasing hepatic SHBG production Androgenicity varies by progestin Due to estrogen content net effect of OCPS is antiandrogenic overall

8 Androgenicity 1 st Genera*on (Estranes) 2 nd Genera*on (Gonanes) 3rd Genera*on (Gonanes) Norethindrone Levonorgestrel Desogestrel Ethynodiol diacetate NorgesDmate Gestodene 19- nortestosterone derived

9 Androgenicity 1 st Genera*on (Estranes) 2 nd Genera*on (Gonanes) 3rd Genera*on (Gonanes) 4 th Genera*on (an*androgenic) Norethindrone Levonorgestrel Desogestrel Cyproterone Acetate (17- hydroxyprogesterone derived) *Not available in U.S.A. Ethynodiol diacetate NorgesDmate Gestodene Drospirenone (17- alpha spironolactone derived) 19- nortestosterone derived

10 Standard OCPs Effective and Equivalent in Acne Treatment 31 randomized placebo-controlled and comparison trials OCPs containing a variety of progestins demonstrate similar efficacy in the treatment of acne 30-60% reduction in inflammatory lesions Lack of standardization in severity scales limits comparison Arowojolu et al.cochrane Database Syst Rev 2012

11 Controversy #1: Do oral contracepdves work as well as systemic andbiodcs in treadng acne?

12 Meta- analysis of 32 RCTs Oral andbiodcs and OCPS superior to placebo at 3,6, months Oral andbiodcs superior to OCPs at 3 months Oral andbiodcs and OCPs equivalent at 6 months Koo et al., J Am Acad Dermatol 2014;71:450-9

13 FDA- approved OCPs for acne Avoid within first two years afer menarche or age <14 PotenDal impairment of bone mass accrual? FDA Approved age > 14 EE 20ug/Drospirenone 24 day EE 20ug/Drospirenone/levomefolate FDA Approved age > 15 EE/NorgesDmate EE/Norethindrone /ferrous fumarate *FDA Approval specifies treatment of acne in women who also desire contraception

14 Controversy #2: Who should and should not get oral contracepdves and what are the long term risks?

15 OCP Contraindications Pregnancy, early breastfeeding Smokers, obesity, hypertension >35 h/o DVT, PE h/o stroke, CAD, CHF, immobilization Family history of thrombosis Hypertriglycerididemia Liver disease Diabetes advanced or >20 yrs Migraine with aura, or without aura >35 SLE with vascular disease ACOG pracdce bulledn; no. 73; 2006 Arrington et al., CuDs 2012

16 DRSP not worse than 3 rd generadon OCPs 26 studies included in analysis Overall 4- fold increase in thrombosis among users compared to non- users Third generadon OCPS higher risk than second υg EE/ DRSP, gestodene, desogestrel and CPA similar risk, and 50-80% higher than levonorgestrel debastos et al., Cochrane Database Syst Rev 2014 Mar 3;3

17 MulDcenter prospecdve comparadve cohort study 85,109 women 206,296 woman years Similar rates of VTE and ATE among users of DRSP24, DRSP21, LNG and other OCPs Greatest risk in first 6 months

18 VTE risk in perspecdve Non- pregnant non- users 1-5 events/10,000 woman- years Overall OCPs 3-9 events/10,000 woman- years Pregnant women 5-20/10,000 woman- years Postpartum women 40-65/10,000 woman- years ACOG website 2016 FDA drug safety website 2016

19 Other OCP Adverse effects Low absolute risk of MI and stroke MI: smokers, DM, HTN Stroke: smokers, HTN, EE dose, age >35 Breast Cancer RR Greatest reladve risk while using, early age No risk 10 years afer discondnuadon Risk NOT associated with duradon or family hx Cervical Cancer Data conflicts Zaenglein AL et al., JAAD 2016 Acne Guidelines

20 OCP Benefits Menstrual regularity Benign ovarian tumors Decreased risk colorectal, ovarian and endometrial cancer Maguire K and Westhoff C. Am J Obstet Gynecol., 2011

21 OCPs How to Prescribe Pap smear not required prior to inidadon Complete history Check blood pressure Pregnancy test Frangos JE et al J Am Acad Dermatol 2008

22 Controversy #3: Is spironolactone effecdve for acne?

23 Spironolactone Mechanism Aldosterone receptor antagonist Weak diuredc Potent andandrogen 1. Blocks androgen receptor 2. Inhibits 5α- reductase 3. Decreases androgen producdon Not FDA- approved for use as andandrogen

24 Spironolactone Adverse Effects Side effects dose related Diuresis 29% Menstrual IrregulariDes 22% Breast tenderness 17% Breast enlargement FaDgue/headache/dizziness GynecomasDa (men) Pregnancy Category C Rare Hyperkalemia Shaw JC and White LE, J Cut Med Surg 2002

25 Study N Dose Results Sato et. al. Aesthetic Plast Surg Nov-Dec;30(6): M &F Yemisci et al. JEADV Shaw JC. JAAD 2000 Mansurul et al. Bangladesh J Dermatol Venereol 2000 Lubbos et al. Arch Dermatol mg taper 50mg BID, 16d/ mo mg QD mg QD 50mg BID, 16d/ mo 65 pts completed trial 53% excellent 47% good 85.7% clinically significant response 93% clinical response from partial to clear 70% of treated pts. clear vs. 6% placebo (p<0.001) 97% pts showed improvement Azizlerli et al. T Arch Dermatol Syphilol mg/d 89% mean clinical improvement Muhlemann et al. Br J Dermatol 1986 Burke & Cunliffe. Br J Dermatol 1985 Goodfellow et al. Br J Dermatol mg/d 8 200mg/d F mg/d 75% of treated pts. improved vs. 20% placebo (p<0.001) 52% mean clinical improvement at 6 mo 80% reduction in sebum May be useful for acne

26 110 pts. RetrospecDve chart review mg spironolactone daily 85% showed improvement 55% clear 46% side effects (menstrual irregularity, diureses, pruritus) 5% discondnued Limited by retrospecdve design, concurrent treatment

27 RetrospecDve chart review Doses less <150mg daily Remission- - <5 comedones, <2 inflammatory lesions 52 women completed study 71% treated successfully

28 Spironolactone: effecdveness for acne Small trials have demonstrated a trend towards improvement in acne AAD Guidelines recommendadon: B EffecDveness indeterminate given level of available evidence Brown et al. Cochrane SystemaDc Review 2009 Zaenglein AL et al. Acne Guidelines. JAAD 2016

29 Controversy #4: Who do I need to check K+ levels in?

30 RetrospecDve database review 967 women taking spironolactone mg daily for acne Excluded ACEI, ARBs, Renal, CV disease 1723 potassium measurements 0.75% above 5.0mmol/L (0.76% baseline populadon) 6/13 underwent repeat tesdng=normal Suggests tesdng is unnecessary

31 Potassium PrecauDons Avoid coconut water, salt subsdtutes Consider tesdng in: Older padents High dose (200mg daily) ACEI ARBs NSAIDS (Indomethacin) Digoxin Trimethoprim sulfamethoxazole esp. elderly Zaeglein A et al. JAAD 2016 CMAJ 2015 Mar 3;187(4):E138-43

32 Controversy #5: What is the real teratogenicity and carcinogenesis of spironolactone?

33 Teratogenicity of Spironolactone Equivalent human dose: Reduced number live births in rabbits 200mg/kg/day in pregnant rats at embryogenesis femininizadon of male fetus mg/kg/day in rats in later pregnancy decreased size of prostate, seminal vesicles, enlarged ovaries and uteri No human studies Pregancy category C Half life 3-4 hours Aldactone FDA package insert

34 The black box Rats given X human doses of spironolactone Benign adenomas and carcinoma of thyroid Adenomas of liver TesDcular intersddal cell tumors and adenomas Rats given X human dose of potassium canrenoate (spironolactone metabolite) MyelocyDc leukemia HepaDc, thyroid, tesdcular, mammary tumors hrp://

35 RetrospecDve matched cohort study 1.3 million padents >55 28 K exposed spironolactone 29 K cases of breast cancer Incidence 0.39%/yr vs. 0.38%/yr (control), over 4.1 years Concluded no increased risk for breast cancer

36 Danish RetrospecDve cohort 28.8 million person- years Estrogen sensidve and insensidve malignancies Compared spironolactone and furosemide Both diuredcs correlated with slight increase in malignancies within 1 yr of diagnosis Suggests reverse causality No increased risk of cancer with spironolactone and furosemide

37 Spironolactone Guidelines for Use Baseline BUN/CR, K+ Review cardiac history, HTN meds Start 50mg daily to BID Revisit afer 3 months, dose adjust as needed up to 100mg BID Drospirenone 3mg=25mg spironolactone

38 Controversies 1. Do oral contracepdves work as well as systemic andbiodcs in treadng acne? YES! 2. Who should and should not get oral contracepdves and what are long term risks? Those at risk for blood clots. 3. Does spironolactone work? Strong trend for efficacy, RCTs lacking. 4. Who do I need to check K+ levels in? Older padents, those on medicadons that increase K+, and high dose. 5. What is the real teratogenicity and carcinogenesis of spironolactone? No human studies support teratogenesis, but avoid in pregnancy. No established cancer risk in humans.

39 Thank you!!!