pcos update 2019: common, subtle, and more serious than ever · diagnosis of pcos • clinical...
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PCOS Update 2019:
Common, Subtle, and More
Serious Than Ever
R. Mimi Secor, DNP, FNP-BC, FAANP
Onset, Massachusetts
Mimi Secor, DNP, FNP-BC, FAANP• FNP for 41 years specializing in Women’s Health
• National Speaker, Educator, Author, Entrepreneur, Athlete
• 2013 Lifetime Achievement Award, (Mass Coalition of NPs)
• DNP-2015, Rocky Mountain University, Provo, Utah
• Also graduated w/ 30 lb weight loss, 12 inches off waist
• 2016 First Bodybuilding Competition, 5th Place trophy
• 2018 (July 28) Fourth Competition, 2nd Place in over 55 !!!
• #1 International Best-Selling Author of NEW Book,
• “Debut a New You: Transforming Your Life at Any Age"
• Passion for Helping NPs/PAs become Healthy and Fit
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Mimi Secor, DNP, FNP-BC, FAANP
Disclosure
Consultant:
• Hologic, Medical Devices, ThinPrep,
Mammograms, Novasure for AUB
Speaker:
• Duchesney, Osphena for VVA
PCOS Objectives for Session
Upon completion of this session attendees will be able to:
• Discuss epidemiology, pathophysiology,
associated risks and complications
15 minutes
• List symptoms, signs & explain diagnostic
work-up
15 minutes
• Describe “best practice” management
approaches including pharmacologic
treatments
15 minutesSecor 2019 copyright
Case Study
30 year old for Annual Exam
• OC in past, side effects
• 3, 4 menses year
• Irregular menses since
Menarche age 12
• Married in 1 year
• Pregnancy NOT desired yet
• Both Parents w Diabetes
and Overweight
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PCOS: Introduction
• Most common reproductive endocrine disorder
• 5 + million women in US
• 1 in 15 women (6-10%)
• Familial tendency
• Exposure in-utero, Environmental, Diet, Lifestyle, Stress
• Obesity (independent risk factor)
• Lean: ~10% (less well understood)
• Associated with serious sequelae:
– MS, Diabetes, CVD, Infertility, Cancer, Mental Health Problems, etc.
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PCOS: Symptoms, Signs & Risks
• Oligomenorrhea: Highly predictive!
• Hyperandrogenism: Hirsutism, acne, (a-reductase)
• Obesity: esp. central obesity
• Infertility (25-37%) & Anovulation
• Abnormal Uterine Bleeding/AUB (new term)
• Uterine Cancer- 3 fold incr. risk (hyperplasia)
• Insulin Resistance, MS, Diabetes Type 2 (3-7x risk)
• Heart Disease, Hypertension; Dyslipidemia (70%)
• Mental Health Problems (Low allopregnanolone)
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PCOS: Menstrual Irregularities
Classic Clinical Profile!Oligomenorrhea to amenorrhea
• History since menarche (CLASSIC)
• 6 or fewer “menses” per year
• BUT may have regular cycles
Stein Leventhal 1935- singular
entity/OVARY
• Persistant Anovulation
• PCOS is a sign, not a disease
• Pathogenesis still unclear! Secor 2019 copyright
PCOS: Definition and
Central Pathogenic Mechanism
2006 Androgen Excess and PCOS Society:
• PCOS is an Androgen Excess Disorder
• Of androgen biosynthesis, utilization, metabolism
• in ovaries & adrenal glands
• associated with Insulin Resistance
• and other Health Risks
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NEW PCOS:
Pathogenesis & Assoc. Risks
• Insulin Resistance (IR) and Hyperinsulinemia
• IR induces ovarian androgen production;
Raising LH, incr. menstrual abnormalities
• Hyperandrogenism increases IR! (CYCLE)
• IR plays critical role in pathogenesis of Hyperandrogenism, Chronic Anovulation
And Cardiometabolic risks!!!Secor 2019 copyright
Pathophysiology of PCOS: Hirsutism
• Hyperinsulinemia (45-65% of PCOS pts)
• Lowers SHBG =Sex Hormone Binding Globulins
• Higher Androgen production (Free T)
leading to
• Increased Alpha-reductase in skin cells
• Testosterone to dihydrotestosterone: > potent T
• Causing acne, hirsutism, etc.
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PCOS and the “Gut” 2018
NEW Research! • Androgens- affect Gut Microbiome
• > T = Less diverse GI microbiota !!!
• These changes may influence how the
pathophysiology of PCOS develops!
• More research needed to determine
effects of androgens on the gut
microbiome
• Total N=163, PCOS N=73Torres PJ et al. J Clin Endocrinol Metab. 2018 Jan 23.doi:
10.1210/jc.2017-02153.Secor 2019 copyright
Pathophysiology of PCOS: Ovary
Hyperinsulinemia,
Hyperandrogenism
• Causes the Pituitary to hyper secrete LH (not All)
TONIC levels of LH, FSH, Estrogen, Testosterone
• Estrogen/estrone, testosterone slightly elevated
• Estrogen/estrone blocks pituitary FSH, LH
• New follicles continuously stimulated,
but don’t fully mature= RARE ovulation
• LH and Testosterone -thickens ovarian tissue (theca)
• Insulin suppresses apoptosis: programmed cell death
• Hence PCOS develops, vicious cycle!!!!
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PCOS Pathophysiology
Normal Cycle versus PCOS
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Pathophysiological Characteristics of the Polycystic Ovary Syndrome (PCOS)
Nestler J. N Engl J Med 2008;358:47-54
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PCOS Case Study
30 year old for Annual Exam
• OC in past, side
effects
• 3, 4 menses year
• Irregular menses since
• Menarche age 12
• Married in 1 year
• Pregnancy NOT
desired yet
• Both Parents w
Diabetes
Diagnostic
Workup/Labs?
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Diagnosis of PCOS• Clinical presentation is sufficient!
– If NO virilizing symptoms
BUT
• Rule out associated conditions!
AND
• Variable presentation is common
• Rapid Hirsutism Onset: Full Work-up!!!
Genazzani. PCOS. Archives of perinatal medicine; 2012: 18 (1): 27-36.
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Rotterdam Criteria 2004
2 of 3 required• Oligomenorrhea (esp. >3 months) or anovulation
• Hyperandrogenism:
Acne, hirsutism, central obesity
• NEW - Ultrasound: Polycystic Ovaries
12 follicles 2-9 mm
or increased volume >10ml in >1 ovary
25% of NORMAL women have ovarian cysts!
Rotterdam consensus group. Revised 2004 consensus criteria.
Fertil Steril 2004 Jan;81:19-25.
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PCOS Ovary
Classic “string of pearls”
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PCOS Diagnostic Work-up? • Body weight, BMI (>30), Waist (>35 inches), BP
• Pelvic ultrasound: Ovaries & hyperplasia>10mm
• Pregnancy test
• CBC, CMP incl, Lipids, CRP-hs, LFTs, TSH
• Random/Fasting Glucose, OGTT (best test)– Hgb-a1C: DM= >6.4, At risk = >5.6-6.4 !!!!
• Estradiol
• Total Testosterone: PCOS = > 60, Tumor > 200– Free T: PCOS= 2- 3%
• Prolactin 3-27ng/ml, FSH >30, DHEA-sulfate
• LH/FSH Ratio >3, but may be normal in PCOSNing, N et al. How to recognize PCOS: results of a web-based survey at IVF-worldwide.com.
Reproductive, BioMedicine Online (2013), http://dx.doi.org/10.1016/j.rbmo.2013.01.009
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PCOS Differential: Cushing’s?• Cushing’s Disease (Pituitary)
• Cushing’s Syndrome (Adrenal)
• Symptoms/Signs: Slow-insidious onset similar to PCOS
– Central adiposity or obesity in general, hirsutism, absent
menses, acne, male pattern hair loss.
– Hypertension, hyperglycemia, dyslipidemia
– Differences: Wide purple striae, easy bruisability,
posterior cervical fat pad (buffalo hump), red round/puffy
face, muscle wasting of extremities
• Labs: May Order or Refer (based on your expertise)
1. Overnight Dexamethasone (1 mg) Suppression test
2. Late night Salivary Cortisol
3. (24 hour urine) for free cortisol and creatinine Secor 2019 copyright
Diagnosis of Metabolic Syndrome
Requires 3 Criteria
• B/P >130/85
• Abdominal obesity >35 inches
• Triglycerides >150 mg/dl
• HDL Cholesterol < 50 mg/dl
• Fasting Glucose 100-125 mg/dl = nl
• 2 hr GTT (75 gm load) 140-199 mg/dl
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Glucose Testing
OGTT for ALL abnormal values
• Random elevations suggest a trend
• Fasting & Oral GTT required
• Fast 8 hours: 65-99 mg/dl = normal
• 100-125 = Impaired fasting glucose
• > 95 suspicious
• > 126, suspect DM, retest different day
• >140 mg/dl x 2 = Probable diabetes
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PCOS Diagnostic Work-up
Preferred for PCOS:
• 2- hour Glucose Response GTT (75 gm load)
>140, < 200 mg/dl = Impaired Glucose
Tolerance
> 200 mg/dl = Non-insulin-dependent DM
• GTT abnormal: 2-8 years before DM
develops !
– Better than FBS
Speroff. PCOS. Dialogues in Contraception 2007;11(1): 5-7.
Diabetes Care 2004;27: S11-14.Secor 2019 copyright
Hgb A1C Guidelines per ADA
for Diabetes Diagnosis:
• Predictive screening tool !
• 5.6-6.4 = “At risk”
• > 6.5 = Diabetes
ADA. (2010 Jan). Diagnosis and classification of DM. 33(1), S62-S69.
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Abnormal Uterine Bleeding (AUB)
• Comprehensive, focused history
• Many causes: PALM-COEIN classification
• Consider DIFFERENTIAL by AGE and HISTORY
• Post-menopause AUB:
- Any bleeding beyond 12 months since LMP
- Even “1 drop of blood” is concerning
- Must REFER to OBGYN to R/o cancer 9% risk!Secor 2019 copyright
Abnormal Uterine Bleeding (AUB)
Classification/Differential: PALM-COEIN
DIAGNOSIS: CAUSE: Consider by AGE:
Structural
P Polyps: > 30 years
A Adenomyosis: > 30
L Leiomyoma/ Fibroids: > 30
M Malignancy/Hyperplasia: > 40 (Obesity, DM, PCOS, >50 yr)
Non Structural
C Coagulopathy: Any age
O Ovulatory Dysfunction: Any age
E Endometrial Disorders: Any age
I Iatrogenic, Medications: Any age
N Not ClassifiedSecor 2019 copyright
EMB: When to Perform?
NOT Based on Age
• Duration of exposure to unopposed
estrogen? EXPLAIN
• If long standing anovulation then…
Risk of hyperplasia, atypia, cancer
When in doubt:
• Transvaginal US & endometrial biopsy!
– “Low threshold” regardless of age
– Do NOT trust JUST an ultrasound
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Ovulatory vs Anovulatory Bleeding:
KEY
Ovulatory
• Premenstrual
symptoms
• Pattern for each
patient
• Bleeding pattern
• From episode to
episode
Anovulatory
• No premenstrual
symptoms
• No pattern
• Each bleeding
event differs
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Ultrasound: If Endometrial Stripe > 10 mm
Must do EMB: Not Based on Age!
Menopause: Endom. stripe >5 mm - abnormal
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Abnormal Uterine Bleeding:
• Amenorrhea (>6 months)
– Progestin challenge
– Medroxyprogesterone acetate 10 mg orally x 10-
12 days
– Withdrawal bleed, then OK
– No withdrawal bleed
– Give Combination OC (COC) x 1 month,
if bleed, OK
– If no bleed, REFER to Endocrinologist
(reproductive)
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Case Study
30 year old for Annual Exam
• OC in past, side
effects
• 3, 4 menses year
• Irregular menses
since
• Menarche age 12
• Married in 1 year
• Pregnancy NOT
desired
• Both Parents w
Diabetes
Work-up/ Labs:
• BMI 32
• Waist 38 inches
• COC withdrawal bleed
• HDL 35 mg/dl
• LDL 130
• Triglycerides 210
mg/dl
• Fasting glucose 102
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Team Approach to PCOS and
Individualized Management
• Primary care
• ObGyn
• Infertility
• Cardiovascular
• Diabetes/Endocrine
• Mental health
• Nutritionist
• Wellness coach?
• Contraception vs
Conception?
• Revisit regularly
• Fast track
fertility!!!
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Case Study
30 year old for Annual Exam
• OC in past, side
effects
• 3, 4 menses year
• Irregular menses since
• Menarche age 12
• Married in 1 year
• Pregnancy NOT
desired
• Both Parents w
Diabetes
Work-up/Labs:
Management plan:
• More labs/tests?
• Metformin ?
• Contraceptive ?
• Pregnancy?
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Before PCOS Management:
Contraception or Conception?
• Discuss plans for future pregnancy
• Shouldn’t wait until age 35 to have 1st
baby
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PCOS and Pregnancy Risks:Obesity is a “Ticking Time Bomb”
for Reproductive Health
• Infertility: 40% female/PCOS
• Spontaneous Abortion /SAB, (25-73%)
• Gestational Diabetes (3 x increased risk)
• Preeclampsia/Hypertension
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Infertility in Obese pts with PCOS:
Lifestyle Approaches 1st Line
• Exercise:
• Weight loss: (>10%)
• Increases insulin sensitivity
• Improves ovulation & fertility
• This addresses role of hyperinsulinemia
in pathogenesis of anovulation
Genazzani. (2012). PCOS. Archives of perinatal medicine. 18 (1), 27-36.
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Potential Uses for Metformin
• Adjunct to Clomiphene for CC-resistant patients
• First line agent for ovulation
• Reduction of miscarriage in patients with PCOS
May not help reduce SABs (spontaneous ab)
• May not reduce risk of Gestational Diabetes
(NEW)
• Alternative to OC for cycle regulation in PCOS
• Treatment of PCOS associated hirsutism
• Weight loss
• Reversing IR, hyperinsulinemia, etc.Secor 2019 copyright
Treatment Options: Metformin
• Biguanide 4+ decades worldwide
• Not FDA approved for PCOS
• BUT widely used for PCOS, and well studied
• Side effects & toxicity well studied
• Must check liver, renal function before use
• Insulin sensitizing effect
• Menses induction: 90% in 6 months
• Increases ovulation esp. w/ clomiphene/ letrozole
75% w Combo Rx
• NOT- Teratogenic: Cat B in pregnancy & lactation
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Infertility and PCOS
Ovulation Doesn’t Equal Pregnancy!
• Easy to stimulate ovulation with
various meds
• Referral to Reproductive Endocrinology
is KEY
Early esp. with PCOS
And if “Older”
30-35 and esp. if >40 years old
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PCOS: Cochrane Review 2010
Metformin Fertility Effects
Mixed:
• Benefits pregnancy & ovulation rates
• But NO evidence of improves live birth rates, used
alone or in combination with clomiphene, or when
compared with clomiphene
• Use of metformin to improve reproductive
outcomes in women with PCOS appears limited
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PCOS and Pregnancy Risks
• Infertility
– Metformin helps
• Spontaneous Abortion
– Metformin may NOT help (new research)
• Gestational Diabetes
– Metformin may NOT help (Diabetic Care 6/2013)
• Preeclampsia
– Metformin helps
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PCOS Pathophysiology
Normal Cycle versus PCOS
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Aromatase Inhibitors: Preferred
Alternative to Clomiphene
• Letrozole (Fumera) OFF LABEL
• BUT preferred by infertility experts (1st line)
• Because:
• Well tolerated, few side effects
• Letrozole produces 1 follicle !!
• PCOS highly responsive to fertility meds
– Have “many eggs”
• Dosing; 5-7.5 mg oral daily, Day 2-6, x 5 days
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NOT Desiring Pregnancy:
PCOS Treatment Approaches
• Life Style Changes: Weight loss, Diet, Exercise!
50% reduction in IR (WOW!)
• Combination Hormonal Contraceptives (CHC)
NEW; Low-androgen safer progestins;
Levonorgestrel (LNG), Norethindrone (NE),
Norgestimate (NGM)Vinodagrova et al. (2015, May 26). BMJ, 350:h2135
(http://dx.doi.org/10.1136/bmj.h2135)
• Insulin sensitizers: Metformin
30% reduction in IR
• Combination therapy: Metformin and CHC?Secor 2019 copyright
Weight Loss: KEY
• 5% loss: improves insulin sensitivity!
• Reduces Testosterone levels
• Improving Acne, Hirsutism, etc.
• Lowers BP, improves labs
• Enhances fertility!
• Return of regular menses (withdrawal bleed)
• Reduces Uterine Cancer risk!
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Hirsutism and PCOS
• Combined hormonal contraceptives (CHC)
• Insulin sensitizers!
• Spironolactone: (Cat C): 25-100 mg orally bid ($)
Inhibits 5a-reductase, preventing T to DHT*
Incr. SHBG, decreasing free T
• Finasteride: (Cat D), 1mg oral daily (same as above)
• Eflornithine HCL: (Cat C): topically ($$$)
• Various hair removal techniques
*DHT = Dihydrotestosterone
Lindheim, PCOS, OBGYN Management, 2012;24 (12)
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Hirsutism and PCOS: Cont’d
• Eflornithine HCL (Vaniqa) topical cream: $$$– “Hair growth retardant”
– Cat C
– Apply thin film BID, rub in thoroughly
– Do NOT wash area for 4 hours
• Finasteride (Propecia, Proscar): Effective, Off-label– Anti-androgenic, inhibits 5a-reductase, T to DHT
– Cat D
– Side effects: Depression, anxiety
– 1 mg oral daily: Reduces side effects (2.5-5 mg daily)
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NOT Desiring Pregnancy:
Combination Therapy for PCOS• Contraceptives: First line
– Combination hormonal contraceptives (CHC)
– Progestin only: Caution w DMPA (insulin resistance?)
– Intrauterine Contraceptives (IUC)
Plus:
• Insulin Sensitizers:
– Metformin XR 500-2250 mg oral daily @ hs (start low, go
slow)
Nestler, J. (2009 Jan). PCOS. NEJM, 358 (1).
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NOT Desiring Pregnancy:
Combination Hormonal Methods• To induce withdrawal bleed (pt thinks is menses)
• Prevent uterine cancer
• Suppress ovarian androgen production (T.)
• Provides symptom relief
• For oligomenorrhea, acne & hirsutism
• Improved BMI, glucose tolerance & basal insulin
• NEW: Possible increased risk of CV events
Lower E2, safer progestins: LNG, NE, NGM*
*LNG= Levonorgestrel, NE= Norethindrone, NGM= Norgestimate
Vinogradova et al (2015, May 26) BMJ, 350:h2135. (http://dx.doi.org/10.1136/bmj.h2135).
• If BMI > 30, VTE risk increased by x 3.5 fold !!!Secor 2019 copyright
PCOS: Metformin vs CHC*?• NEW 2016: Systematic review and meta-analysis
• 172 studies, 4 studies w 231 participants met criteria
• Based on very-low to low quality data
Findings:
• OC: Superior for regulation of Menses, and Acne
• Metformin: greater reduction in BMI, decreased
dysglycemia, lower LDL
• Neither superior for Hirsutism, lowering TG, incr HDL
• CHC = combination hormonal contraceptive
Al Khalifah, et al. PCOS, Teens. Pediatrics 2016 May; 137:e20154089
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Progestin Only Methods and
PCOS • Medroxyprogesterone Acetate (MPA):
– An option esp. if estrogen is contraindicated
– May be associated with weight gain
– Possible impact of high-dose progestin on IR?
• Levonorgestrel IUC:
– Local endometrial effects- so probably OK
– Minimal systemic levels
• Etonogestrel Implant:
– Low systemic levels, so probably OK
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Treatment Options: Metformin• Metformin = Biguanide
• Worldwide use commonly for 4+ decades
• Not FDA approved for PCOS BUT widely used
• Insulin sensitizing effect
– Decreases risk of progression from IGG to DM
– Metformin XR 500-2250 mg oral daily @ hs (slow
increase)
• Side effects & toxicity well studied
• Must check liver and renal function before use
• Category B in pregnancy; NO teratogenic risk
• Increases ovulation esp. w/ clomiphene/letrozole
• Consensus: Safe in pregnancy – Cat B
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Metformin XR: Preferred
• Less side effects
• Improved lipid profile: Triglycerides, HDL, LDL
• Weight loss especially with higher doses !
• Easy dosing at HS/ bedtime
• Start low, go slow…
• Start 500 mg orally at HS
• Increase 500 mg weekly
• 2000-2250 mg daily maximum dose
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PCOS: Menopause (NAMs)
• Systemic estrogen for hot flashes?
• Caution: subclinical cardiovascular disease!
– Transdermal estrogen may be safer than oral
– OR avoid systemic E2, use alternatives (NAMS)
– Progesterone 100 mg orally at hs helps sleep, hot
flashes, etc, fewer side effects than MPA*, may be safer
too *medroxyprogesterone acetate
• Vaginal symptoms: Pelvic PT (APTA.org)
– Vaginal estrogen: cream, tablets, ring (Estring)
– Non-estrogens: SERM Ospemifene (Osphena), DHEA PV
suppositories,
• Mona Lisa Touch laser (NEW FDA Warning, NEED RESEARCH)
– Pelvic PT (APTA.org)
– if superficial or deep dyspareunia doesn't resolve w meds aboveSecor 2019 copyright
PCOS: Prevention is KEY
• Early diagnosis
• Symptom relief
• Normalizing labs
• Obesity control
• Exercise
• Healthy diet (protein)
• Mental health
• Prevention of sequelae!!!Secor 2019 copyright
PCOS Objectives for Session Upon completion of this session attendees will be
able to:
• Discuss epidemiology, pathophysiology,
associated risks and complications
15 minutes
• List symptoms, signs & explain diagnostic work-
up
15 minutes
• Describe “best practice” management approaches
including pharmacologic treatments
15 minutes
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Thank you
Thanks to Carol Lesser NP, Boston IVF
Patty Duprey NP, Tom Bartol NP
R. Mimi Secor, DNP, FNP-BC, FAANP
MimiSecor.Com
My App: text “DrMimi” to 36260
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Resources
• www.PCOSsupport.org
• www.Soulcysters.org
• www.pcosstrategies.org
Patient Education:
• WWW.nih.gov
• www.acog.org
Weight Loss Ap:
• MyFitnessPalSecor 2019 copyright
References: Updated
• Guidi, J, Gambineri, A, Zanotti, L. Psychological aspects of
hyperandrogenic states in late adolescent and young
women. Clin Endocrinol 2015; 83: 872–878.
• Mcluskie,I. PCOS. BMJ 2017; 357:
doi: https://doi.org/10.1136/bmj.i6456
• Moran, LJ, Hutchison, SK, Norman, RJ. Lifestyle changes
in women with polycystic ovary syndrome. Cochrane
Database Syst Rev 2011; (7): CD007506.
• Pasquali, R. Contemporary approaches to the
management of PCOS. Therap Adv Endo/Metab
2018;9(4):123-134. https://doi.org/10.1177/2042018818756790
• Pasquali, R, Zanotti, L, Fanelli, F. Defining
hyperandrogenism in women with polycystic ovary
syndrome: a challenging perspective. J Clin Endocrinol
Metab. 2016; 101: 2013–2022.Secor 2019 copyright
References:-Barry, J.A., Kuczmierczyk, A. R., Hardiman, P. J. (2011). Anxiety and
depression in polycystic ovary: a systematic review and meta-analysis.
Human Reproduction, 26(9): 2442-2451.doi:10.109/humrep/deq197
-Bates, G. W. (2012). Long term management of Polycystic Ovarian
Syndrome. Molecular and Cellular Endocrinology, 373(1-2):91-97. doi:
10.10101/j.mce.2012.10.029.
-Duleba, A. J. (2012). Medical management of metabolic dysfunction in
PCOS. Steroids, 77(4): 306.
-Veltman-Verhulst, S. M., Boivin, J. E., Eijkemans, M.J.C. & Fauser,
B.J.C.M. (2012). Emotional distress as a common risk in women with
polycystic ovary syndrome: a systematic review and meta-analysis of 28
studies. Human Reproduction Update, 18(6): 638-651.doi:
10.109/humupd/dms029.
-Yawn, V. (2012). Polycystic Ovarian Syndrome. Advance for NPs &
PAs, 3(12): 11-15.
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References Bates G, Legro R. Longterm management of PCOS. Molecular and
Cellular Endocrinology. 2012.
http://dx.doi.org/10.1016/j.mce.2012.10.029,
Genazzani. PCOS. Archives of perinatal medicine; 2012: 18 (1): 27-36.
Harborne et al. PCOS. JClin Endocrinol Metab 2005; 90:4593
Nestler, J. PCOS. NEJM 2008; 358:47-54.
Ning, N et al. How to recognize PCOS: results of a web-based survey at
IVF-worldwide.com. Reproductive BioMedicine Online (2013),
http://dx.doi.org/10.1016/j.rbmo.2013.01.009
Romualdi D, et al. How Metformin Acts in PCOS Pregnant Women.
Diabetes Care. Jan 13, 2013;1-5.
Rotterdam consensus group. Revised 2004 consensus criteria.
Fertil Steril 2004 Jan; 81:19-25.
Speroff, L. and Mishell, D. PCOS: Management and contraception.
Dialogues in Contraception, Spring 2007; 11(1):5-7.
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