PCOS-Treatment: When and which€¦ · Roma, 7-10 novembre 2019 MetabolicImpact of...

PCOS-Treatment: When and which

Alessandra GambineriEndocrinology Unit,

University of Bologna, Italy

Roma, 7-10 novembre 2019

Conflitti di interesse

Ai sensi dell’art. 4.5 su “Docenti e moderatori dell’evento”, pag. 8 delManuale Nazionale di Accreditamento per l’erogazione di eventi ECMdel 06/12/2018, dichiaro che negli ultimi 2 anni non ho avuto rapportidiretti di finanziamento con soggetti portatori di interessi commercialiin campo sanitario.


PCOS: a Multifaced Disease

Anovulationand

InfertilityHyperandrogenism

Clinical and/or Biochemical

PCOS (4-10%)

ObesityMetabolic abnormalities(IR/IGT-T2DM/Dyslipidemia/

NAFLD-NASH)

Menstrualirregularities

Others CV Risk FactorsMood disorders

Endometrial cancerSleep disorders

CV events (?) VTE events (?)

ESE PCOS Special Interest Group. Eur J Endocrinol 2014

ÞHyperandrogenic or Not hyperandrogenic phenotype

ÞMetabolic abnormalities

ÞSecondary form of PCOS

ÞMain compliant

ÞOverweight-Obese or Lean phenotype


The concept of ʺsecondary PCOSʺ

Pasquali R et al. Eur J Endocrinol 2016

SecondaryPCOS

Obesity NCAH

Androgen secreting tumors

Exogenous sources

Severe IR

HyperprolactinemiaThyroid disorders

Cushing’s SdAcromegaly

They frequently benefit from

tailored therapies


Hirsutism: When?

Among the hyperandrogenic disorders, hirsutism is the worse in terms of psychological distress and quality of life; it is associated with anxiety,

depression, and impaired well-being and quality of lifeControls(n=240)

Mens. Irregularity

(n=40)

High T (n=26)

Hirsutism(n=71)

PCOS (n=17)

Anxiety 7.48 (4.47) NS NS 9.01(4.93) NS

Depression 5.26 (3.82) NS NS 6.83 (4.52) NS

Hostility/Irritability 6.13 (4.75) NS NS NS 8.94 (6.79)

Well-being 7.39 (1.50) NS NS 6.42 (1.60) NS

Quality of life 2.82 (0.67) NS NS 2.54 (0.77) NS

Autonomy 13.8 (2.94) NS NS 12.2 (3.14) NS

Personal growth 13.3 (2.79) NS NS 12.1 (2.97) NS

Positive relations with others

14.0 (2.96) NS NS 12.7 (3.73) NS

Guidi et al. Clin Endocrinol 2015


Hirsutism: When?

Whenever hirsutism creates distress in the patient (that is not correlatedwith the severity of hirsutism)

Physicians should decide whether hirsutism is to be treated or not by evaluating not only the severity of the phenomenon but also the

subjective perception of the patient that does not necessarily correspondto the true extent of hair growth (use questionnaries!)

Hyperandrogenemia must not be considered to guide the decision for treating or not the patient but, eventually, can guide the choice of the

type of treatment


Pathophysiology of hirsutism: the role of androgens

AR

CIRCULATION- Via shortcut pathway

from circulating DHEA- De novo synthesized

from cholesterol

5aR

T

DHT

Ovary

Adrenal

LOCALLY SYNTHETIZED

25%

25%

50%

From otherandrogens

Escobar-Morreale et al. Hum Reprod Update 2012

The presence or severity of hirsutism

is always notcorrelated with

circulating androgenconcentrations


Ø The treatment of the underlying cause (secondary forms: NCAH,hyperprolactinemia, Cushing’s syndrome, acromegaly,hypothyroidism, exogenous sources)

Ø Treatment targeted at ameliorating hirsutism directly:

Ø Cosmetic methods (Electrolysis and photoepilation)

Ø Topical therapy (Eflornithine) for facial hirsutism

Ø Systemic therapy (OCPs and Antiandrogens)

Endocrine Society Clinical Practice Guideline, J Clin Endocrinol Metab 2018

Hirsutism: Which?


van Zuuren et al. JAMA 2015

ÞOCPsÞAntiandrogens

Systemic pharmacological interventionsfor hirsutism


HIRSUTISM

Mild and localized Moderate to severe or widespread

Seeking fertility?

NO YES

OCPs

Delay drug treatment until delivery

AddAntiandrogen* Unsatisfactory

result

Cosmetic proceduresand/or Eflornitine cream (if

localized on the face)

Proposed algorithm for the treatment of hirsutism

Contraindication for OCPs?

YES

Antiandrogen with secure contraception*

NO

* * Eventually associated to cosmetic proceduresand/or Eflornitine cream

Hyperandrogenemia


Progestin Ethinyl estradiol-EE

ß LH

Ovary

ß Androgens (T, A)

Ý SHBG

ß Bioav. Androgens

Testosterone

DHT

(-) 5a-Reductase

DNA

(-) (-)Cyproterone (I) Drospirenone (IV) Dienogest (IV)

0%

20%

40%

60%

80%

100%

CMADRSPDNGCPA

Antiandrogenic activity

Cyproterone (I) Drospirenone (IV) Dienogest (IV) Clormadinone (IV) Desogestrel (III) Gestodene (III) Norgestimate (III)

Liver

Systemic treatment of hirsutism:combined oral EE-progestin contraceptives

Ovarian androgen suppressionseems to be similar with OCPscontaining different doses of EE


Modified from Odlind, Acta Obstet Gynecol Scand 2002

CPA+EE 35

DNG+EE 30

DRS+EE 30

DSG +EE 30

DSG+EE 20

Lng+EEOC

-E2

GSD+EE 30

The more is the Antiandrogenic propertyof the Progestin and thehigher is the dose of EE, the higher is the Risk of

Venous Tromboembolism

LngNORG

DSG/GSD

CPA

0

50

100

150

200

250

300

mea

n ch

ange

vs

basa

l of S

HBG

(%)

Estimated incidence of VTE (100.000/person years)

Mean change vs. basal of SHBG (%)

OCPs with antiandrogenic property has slightlymore efficacy in treating hirsutism; the efficacy

seems not modified by the dose of EE

All combined oral EE-progestin contraceptives are efficacious in reducing hirsutism

DSP


Metabolic Impact of Different combined EE-progestin contraceptives in PCOS

Durat. GLUOGTT

HOMA-IR HDL TG LDL

EE35+CPA vs. EE30 +DSGBhattacharya, 2012Mastorakos, 2002

12mo12mo

«CPA=DSG « CPA=DSG

EE30+DRSP vs. EE30+DSGBhattacharya, 2012Kriplani, 2010

12mo6mo

«« DRSP>DSG DRSP=DSG ¯DRSPDSG

EE30+DRSP vs. EE30+CMAYildizhan, 2015 24mo ¯DRSP>CMA DRSP>CMA « «

EE35+CPA vs. EE30+DRSPBhattacharya, 2012Kahraman, 2014Panidis, 2011*

12mo12mo6mo

««««

« « «

EE30+DRSP vs. EE20+DRSPRomualdi, 2013 12mo EE30=EE20 EE30=EE20 EE30=EE20

* NonOB PCOS; Others: NonOB and OB PCOS

The more is the Antiandrogenicproperty of the

Progestin and the lower is the dose of EE, the lower isthe Metabolic RiskProfile of the OCP


COMPLIANT RISK FACTORS$ NEUTRAL PROG. (NORG/GSD/DSG)

ANTIANDROGENIC PROG.

Hirsutism BMI ≥25 <30 kg/m2

BMI ≥30 kg/m2

Age ≥35 yrsSmoking (<15 sig/die)Non complicated DMDyslipidemiaImmobilityFirst Degr. Relat. with TVE

XXX

XX

X

X X

$ In the presence of more than one Risk Factors the use of OCPs is contraindicated in PCOS.* Represent contraidications for the use of OCPs in PCOS as well as the general population: knowntrombophilia, hypertension, TVE acute or history of, CV events acute or history of, post partum <21d,migrain with aura, SLE, major surgery with prolonged immobilization, smokes ≥15 sig/die, hepatocellularadenoma, some drugs (certain anticonvulsant, antiretroviral Fosamprenavir).

Hirsutism: Choose the type of oral EE-progestin contraceptiveby considering the phenotype of the patient with PCOS

EE: ≤30 µg; no different effectiveness on hirsutism, but lower metabolic and TEV risks


Testosterone

¯ Adrenal and Ovarian Steroidogenesis

DHT

5a-Reductase Inhibition

AR antagonist

DNA

FlutamideSpironolactone

FinasterideSpironolactone

FlutamideSpironolactone

Bicalutamide

Systemic treatment of hirsutism:Antiandrogens

Antiandrogens Dosing Side effects

Spironolactone 100-200 mg/d (given in divided doses-twicedaily)

Menstrual irregularityHyperkaliemiaHypotensionDizziness

Finasteride 2.5-5 mg/d (7.5 mg/d) ===Flutamide 250-500 mg/d Hepatotoxicity

There is not enough informationto establish a scale of efficacyfor antiandrogens on hirsutism,but … Flut > Spir > Fin


Ø Treatment of the underlying cause (secondary forms: NCAH,hyperprolactinemia, Cushing’s syndrome, acromegaly,hypothyroidism, exogenous sources)

Ø Treatment of Overweight-Obesity

Ø Treatment of insulin-resistance

Ø Ovulation inductors (Letrozole, Clomiphene citrate)

Endocrine Society Clinical Practice Guideline, J Clin Endocrinol Metab 2018

Menstrual irregularities and anovulation: Which?


Recommendations for female with NCAH who wish to conceive

• For those women with NCAH with reported anovulatory infertility butwho wish to conceive, GC therapy is highly recommended (itincreases ovulation and pregnancy rates and decreasesmiscarriages)

• Only use prednisone or hydrocortisone (hydrocortisone is theglucocorticoid of choice during pregnancy because it is efficientlymetabolized by placental 11β-HSD type 2)

Livadas S & Bothou C. Front Endocrinol 2019Reisch N. Endocrinol Metab Clin N Am 2019


Lifestyle intervention aimed at reducing body weight are the first-line therapy in overweight-obese PCOS

Successful WL No successful WLAmenorrhea - 42 (%) NSOligomenorrhea - 19 (%) NSInsulin - 6 (mU/l) NSHOMA - 1.2 NSTriglycerides - 26 (mg/dl) NSHDL-cholesterol + 8 (mg/dl) NSTestosterone - 0.3 (nmol/l) NSSHBG + 8 (nmol/l) NSLH - 4.3 (mU/ml) NS

Lass et al. J Clin Endocrinol Metab 2011


Lifestyle treatment may favour a complete recoveryfrom PCOS (24/65 obese-PCOS pts: 37%)

0

2

4

6

8

10

Baseline Follow-up0

2

4

6

8

10

12

Baseline Follow-up

N° of ovarian folliclesOvarian volume (mL)

PCOm NormalFully Recovered (n) vs. Still PCOS (n)

Pasquali R et al. Eur J Endocrinol 2010

○ Normal-weight at the end of the treatment ● Still overweight or obese at the end of the treatment

Hirsutism (Ferriman-Gallwey score)

024681012141618

Menses (no. previous 6 months)

01234

5678

Total testosterone (ng/mL)

0,00,10,20,30,40,50,60,70,80,91,01,11,2

No more of 10% weight loss


ÞAnti-obesity pharmacological agents or bariatric surgery could be considered as per general population

ÞLifestyle intervention (preferably multicomponent including diet, exercise and behavioural intervention) should be recommended asfirst line treatment for menstrual irregularities and anovulation

In PCOS with excess weight …

ÞAchievable goals are 5% to 10% weight loss

ÞThere is no or limited evidence that any specific energy equivalentdiet type is better than another

ÞThere is any differential response to weight management intervention compared to women without PCOS


Insulin sensitizer: when?

IR identified by the M-clamp value affects most women with PCOS

Surrogate Indexes of IR have a Good Specificity but a LowSensitivity particularly in NW PCOS women

Surrogate Indexes of IR have a Similar Performance as well as the Cut-off values

Classic Ovulatory Normoandrogenic

80%* 64% 38%

Prevalence of IR by M-clamp in different phenotypes of PCOS

* Higher if also PCOm

IR affects 75% of PCOS59% NW; 77% OW; 94% OB

Tosi F et al. Hum Reprod 2017


Clinical predictors of response to metformin in PCOS

Tang T et al. Cochrane Rev 2012

BMI <30 vs. BMI ≥30kg/m2

Pregnancy rate >

WHR >

Testosterone >

Fasting insulin >

Menstrual frequency =

Ovulation rate =

Systolic BP =

Distribution of milligramsmetformin/kg body weight

Higher BMI at baselineHigher T reduction at 6mo

Fulghesu AM et al. Hum Reprod 2012 Metformin efficacy in PCOS seems not to be dose related

Menstrual frequency


In PCOS with menstrual irregularities and anovulation …

ÞMetformin, in addition to lifestyle in case of overweight/obesity, should be recommended as first line approach for the treatment of menses abnormalities and anovulation

ÞMetformin efficay seems not to be dose-related, but gastrointestinalside-effects are generally dose-dependent

ÞThe addition of pioglitazone to metformin can be considered for PCOS resistant to metformin (notwhen pregnancy is the outcome)

Glueck CJ et al. Hum Reprod 2003


First-line pharmacological treatment of anovulatory infertility

Þ Letrozole should be considered firstlyÞ Letrozole is superior to Clomiphene Citrate (CC) in terms of ovulation rate,

pregnancy rate and live birth rateÞ The risk of multiple pregnancy appears to be less with letrozole compared to CCÞ The starting dose is 2.5 mg/day for 5 days up to a maximum dose of 7.5 mg/day for 5

days

Þ Where letrozole is not available or use is not permitted, CC could be used aloneÞ The starting dose is 50 mg/day for 5 days up to a maximum dose of 150 mg/day for 5

days

Þ Metformin could be combined with CC in women with PCOS CC resistant to improveovulation, pregnancy and live birth rates (particularly useful in obese PCOS)

Þ Treatment effects of letrozole and of CC plus metformin in terms of live birth rate are influenced by baseline serum levels of T and of insulin, respectively (directcorrelation)

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