sÍndrome de ovario poliquÍstico...

SÍNDROME DE OVARIO POLIQUÍSTICO (SOP)

Ricardo Azziz, M.D., M.P.H., M.B.A.

Georgia Regents University

COI • KinDex Pharmaceuticals - Consultant

OBJETIVOS DE LA CONFERENCIA:

• Evaluar las pruebas endocrinológicas a usar en pacientes sospechadas de tener SOP

• Entender como evaluar la complicaciones metabólicas del SOP

• Entender el manejo durante el embarazo del SOP

• Evaluar la paciente joven o adolescente con posible SOP

EVALUATING PATIENTS WITH POSSIBLE PCOS

• Who should be assessed for possible PCOS?

–Data suggests two major features may be sufficient to identify PCOS

• Signs & complaints consistent with clinical hyperandrogenism (alopecia, persistent acne, and excess male-like terminal hair growth

• History & complaints suggestive of ovulatory dysfunction (polymenorrhea, and oligo-amonerrhea)

EVALUATION OF THE HYPERANDROGENIC/HIRSUTE PATIENT • HISTORY:

Drugs/skin irritants/menses/ onset and progression/ change in weight/ change in head or extremity size/ family

• PHYSICAL:

Hair pattern and type/ galactorrhea/ acanthosis/ cushingoid features/ clitoromegaly or virilization/ regional distribution of obesity

LABORATORY EVALUATION OF THE HIRSUTE OR POTENTIALLY HYPERANDROGENIC PATIENT

• TSH & PRL

– In oligo-ovulatory patients, to R/O other causes of ovulatory dysfunction

• 17-HP

– To R/O 21-OH deficient NCAH

• d. 22-24 P4 level

– In hirsute eumenorrheic women, 40% of which are anovulatory

• Total & free T, and DHS

– Most importantly, in evaluating non-hirsute or minimally hirsute patients to R/O Androgen Excess

– MUST USE HIGH-QUALITY WELL-REFERENCED ASSAY

ANDROGEN LEVELS IN PCOS: LIMITED SENSITIVITY OF MEASURING ONLY TOTAL T

• In NIH 1990 (classic) PCOS patients, using high quality sensitive assays (for TT, FT & DHEAS) 75% demonstrate HA

• Alternatively, in NIH 1990 (classic) PCOS patients if TT alone is measured (using a high quality RIA) then only 33% of demonstrate HA

• ~50% of PCOS phenotype studies assessed only TT, usually using a chemiluminescent platform assay, so one can expect that in these studies detection rates for HA will be well less than 30%

Huang et al. Fertil Steril 93:1938–41, 2010

Total T Free T DHEAS

% patients

with PCOS

Normal Normal Normal 24.7%

Normal 20.4%

Normal Normal 20.0%

Normal Normal 13.8%

8.7%

Normal 8.5%

Normal Normal 2.2%

Normal 1.7%

Prevalence of specific combinations of androgen

levels in NIH 1990 PCOS

SPECIFICITY AND PREDICTIVE VALUE OF CIRCULATING TT & FT, ASSESSED BY LC-MS/MS, FOR THE DIAGNOSIS OF PCOS

Salameh et al, Fertil Steril. 2014;101:1135-1141

SONOGRAPHIC CRITERIA FOR PCOM

• Presence of 12 or more follicles in each ovary measuring 2-9 mm in diameter, and/or

• Increased ovarian volume (> 10 ml)

• Only one ovary fitting this definition is sufficient to define PCOM

• Does not apply to women taking OCPs

• If evidence of a dominant follicle (> 10 mm) or a corpus luteum, scan should be repeated next cycle

The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop

group. Fertil Steril 81:19-25, 2004; & Hum Reprod 19:41-7, 2004

SONOGRAPHIC CRITERIA FOR PCOM

• Presence of 12 or more follicles (should this # be higher?) in each ovary measuring 2-9 mm in diameter, and/or

• Increased ovarian volume (> 10 ml)

• Only one ovary fitting this definition is sufficient to define PCOM

• Does not apply to women taking OCPs

• If evidence of a dominant follicle (> 10 mm) or a corpus luteum, scan should be repeated next cycle

The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop

group. Fertil Steril 81:19-25, 2004; & Hum Reprod 19:41-7, 2004

DIFFERENTIAL DIAGNOSIS AMONG 873 CONSECUTIVE UNTREATED PATIENTS EVALUATED

FOR ANDROGEN EXCESS

Azziz et al. J Clin Endocrinol Metab 89:453-62, 2004

Diagnosis

Total #

% Prevalence

% Unbiased Prevalence

Specific disorders

ASNs 2 0.2%

CAH 6 0.7%

NCAH 18 2.1% 1.6%

HAIRAN 33 3.8% 3.1%

Disorders of exclusion

PCOS 716 82.0%

IH 39 4.5% 4.7%

HA+Hirsutism 59 6.8%

Total 873 100.0%

COMPARING THE PHENOTYPES OF PCOS BY NIH 1990, ROTTERDAM 2003, AND AE-PCOS 2006

Phenotypes

Characteristics A B C D

Hirsutism/HA

Ovulatory Dysfunction

Polycystic ovaries

NIH 1990

Rotterdam 2003

AE-PCOS 2006

Rotterdam, 2003

ROTTERDAM 2003 AND AE-PCOS 2006 ARE EXPANSIONS OF NIH 1990

NIH 1990

AE-PCOS Soc., 2006

CRITERIA VS. PHENOTYPE: USING A PHENOTYPIC APPROACH TO THE DIAGNOSIS OF PCOS

• Rotterdam 2003 presents the broadest criteria

• NIH 1990 and AE-PCOS Society 2006 criteria identify subjects more likely to have metabolic dysfunction

• It is likely that there are various forms of PCOS – Hyperandrogenic vs. non-hyperandrogenic

– Ovulatory vs. non-ovulatory

• Regardless of criteria chosen, it is critical that clinicians & investigators understand/describe the specific phenotypes of PCOS being studied

PREVALENCE OF PCOS BY DIFFERING CRITERIA IN UNSELECTED ADULT WOMEN WORLDWIDE

Reference Location Population

% PCOS in population by

NIH 1990


AE-PCOS 2006


Rotterdam 2003

Mean BMI of

population (kg/M2)

% Obesity in country*

Knochenhauer et al, 1998 Birmingham, AL, USA 269 4.0% 26.9 33.8%

Diamanti-Kandarakis et al, 1999 Lesbos, Greece 192 6.8% 26.7 18.1%

Michelmore et al, 1999 Oxford, UK 224 8.0% 23.0 23.0%

Asuncion et al, 2000 Madrid, Spain 154 6.5% 23.8 16.0%

Lowe et al, 2005 Melbourne, Australia 100 5.5% -- 24.6%

Yildiz et al, 2008 Birmingham, AL, USA 675 9.4% 35.7 33.8%

Chen et al, 2008 Guangzhou, China 915 2.2% 20.9 --

Kumarapeli et al, 2008 Gampaha, Sri Lanka 2,915 6.3% -- --

March et al, 2009 Adelaide, Australia 728 8.7% 12.0% 17.8% 24.6%

Moran et al, 2010 Mexico City, Mexico 150 6.0% 6.6% 27.5 30.0%

Tehrani et al, 2011 Tehran, Iran 1,002 8.5% 24.7** --

Tehrani et al, 2011 Ghazin, Kermanshah, Golestan & Hormozgan, Iran 1,126 7.1% 11.7% 14.6% 26.9** --

Mehrabian et al, 2011 Isfahan, Iran 820 7.0% 8.2% 15.2% 25.7 --

Yildiz et al, 2012 Ankara, Turkey 392 6.1% 15.3% 19.9% 24.2 15.2%

*OECD Factbook 2011-2012: Economic, Environmental and Social Statistics, OED Publishing, 2011

**Personal communication by author

RELATIONSHIP OF PCOS PREVALENCE TO POPULATION BMI

20 25 30 35

4

6

8

10

% PCOS NIH

BMI of the population (kg/m2)

r= - 0.09 p=0.7743

Ezeh et al, unpublished

THE FAMILY HISTORY: A POWERFUL PREDICTOR OF PCOS

Mothers Sisters

Total No. 78 50

PCOS 19 (24%) 16 (32%)

Hirsutism only 5 (6%) 1 (2%)

Oligomenorrhea 8 (10%) 6 (12%)

Kahsar-Miller & Azziz. Fertil Steril 2001;75:53-8

PREDICTORS AT AGE 15 YEARS FOR OLIGO-AMENORRHEA AT AGE 18 YEARS

• Adolescents were followed between ages 15 and 18 y.o.

• The risk of developing oligomenorrhea at 18 y.o. was:

• 2% (2/128) for adolescents with regular menstrual cycles at 15 y.o.

• 12% (17/148) for girls with irregular menstrual cycles* at 15 y.o.

• 51% (34/67) for girls with oligomenorrhea* at 15 y.o.

*Irregular menstrual cycle = average cycle length 22-41 d., and

2 or more cycles <22 or >41 days in length during past year

**Oligomenorrhea = average length of the cycle of 42-180 d.

van Hooff M et al. Hum. Reprod. 2004;19:383-392

The risk of

developing

persistent OLIGO in

girls with irregular

menstrual cycles is

greater if their

initial average

menstrual cycle

length is 35-41

days

van Hooff M et al. Hum. Reprod. 2004;19:383-392

The risk of

persistent OLIGO

in girls is greater if

their initial BMI is

above the median

BMI (p50 = 19.6

kg/m2 in this

study)

PREDICTORS AT AGE 15 YEARS FOR OLIGO-AMENORRHEA AT AGE 18 YEARS

COMPARING PCOS PRESENTATION IN ADOLESCENTS (N=91) VS. YOUNG ADULTS (N=183)

* *

*

*

Lizneva et al, unpublished

Degree of Menstrual

Dysfunction

Degree of

Obesity

PCOS Phenotype % Hyperandrogenemia (HA),

Hirsutism, or acne

COMPARING PCOS PRESENTATION IN EARLY (N=31) VS. LATE (N=60) ADOLESCENTS

Lizneva et al, unpublished

Degree of

Obesity

Degree of Menstrual

Dysfunction

PCOS Phenotype % Hyperandrogenemia (HA),

Hirsutism, or acne

DIAGNOSING PCOS IN ADOLESCENCE

• There are no established criteria for the diagnosis of PCOS in adolescents

• The diagnosis of PCOS has life-long implications and the features of PCOS may be less well established in adolescents

• Thus, the diagnosis of PCOS in adolescents should be made with great caution

• If the diagnosis is unclear then the most prudent course may be:

– Expectant management with regular, but not overzealous, follow-up

– Reassurance and patient (and family) education

– Lifestyle modification

– Treatment of individual symptoms/complaints, if needed/desired

GLUCOSE AND INS LEVELS IN 8 PCOS AND 6 WEIGHT-MATCHED CONTROLS DURING OGTT

Burghen et al, J Clin Endocrinol Metab 50:113, 1980

Time (hrs)

400 -

350 -

300 -

250 -

200 -

150 -

100 -

50 -

0 -

- 400

- 350

- 300

- 250

- 200

- 150

- 100

- 50

- 0 | | | |

0 1 2 3

Pla

sm

a In

su

lin

, (m

U/m

l)

Pla

sm

a G

luco

se (

mg

/dl)

Obese PCOD SEM + NS * p<0.05 ** p<0.01

* *

*

*

*

**

| | | |

0 1 2 3

PREVALENCE OF IR IN PCOS USING THE HOMA-IR

• 271 consecutive PCOS patients,

and 260 controls were studied

• The HOMA-IR was adjusted for age,

BMI & race; with a 95th percentile

of controls (cut-off value) of 3.902

• 64.4% of PCOS patients had

HOMA-IR values above the

cut-off value

DeUgarte et al. Fertil Steril 83:1454-60, 2005

PREDICTORS OF mFG SCORE IN 749 ADULT PATIENTS WITH PCOS

Landay et al, Fertil Steril 2009;92:643–7

p<0.005 after Bonferroni adjustment for multiple comparisons

SEVERITY OF MENSTRUAL DYSFUNCTION PREDICTS DEGREE OF IR IN 494 PCOS

Modified from Brower et al, J Clin Endocrinol Metab 98: E1967–E1971, 2013

POLYCYSTIC OVARIES DO NOT PREDICT METABOLIC OR REPRODUCTIVE PHENOTYPE

Control correlation: 0.19 (–0.32, 0.61)

PCOS correlation: 0.03 (–0.20, 0.25)

Legro et al. J Clin Endocrinol Metab 2005;90:2571-9

INSULIN RESISTANCE

HYPERINSULINEMIA

OVARIAN THECA

STIMULATION

HYPERANDROGENISM

Anti-insulin- receptor

antibodies

Genetic syndromes

OBESITY

Insulin receptor LH

IGF-1 receptor

INSULIN POST-RECEPTOR ABNORMALITIES

HEPATIC SHBG

SUPPRESSION

(-) (+)

(-)

(+) (+) (+)

(+) (+)

ADIPOSE TISSUE DYSFUNCTION

INSULIN STIMULATED GLUCOSE UPTAKE AND GLUT-4 EXPRESSION ARE REDUCED IN ADIPOCYTES FROM PCOS

Chang et al. Fertil Steril 2008; 90:2291-7 Chen et al. Diabetes 62: 2278-86, 2013

INSULIN-MEDIATED GLUCOSE UPTAKE (IMGU) IN PCOS AND

CONTROL WOMEN WHO HAD FREQUENT MUSCLE BIOPSIES

PCOS (n=12)

Controls (n=8)

Dunaif et al. Am J Physiol Endocrinol Metab 2001;281:E392-9

DYSREGULATION OF ADIPOKINE SECRETION BY ADIPOCYTES OF PCOS WOMEN

Chazenbalk et al. JCEM 2010; 95:935-42, and unpublished

RESPONSE OF ADIPOKINE SECRETION TO ADIPOCYTE-RESIDENT MACROPHAGE CO-CULTURE IN PCOS

Chazenbalk et al. JCEM 2010; 95:935-42, and unpublished

Chen et al. Diabetes 62: 2278-86, 2013

NO OBVIOUS DEFECT IN PI3-K/AKT INSULIN-SIGNALING PATHWAY IN ADIPOSE OF PCOS

miR-93 IS OVEREXPRESSED

AND IS NEGATIVELY ASSOCIATED WITH

GLUT-4 EXPRESSION IN ADIPOSE TISSUE

OF PCOS

Chen et al. Diabetes 62: 2278-86, 2013

Normal IGT Type 2 DM 0

10

20

30

40

50

60

70

80

90

100 University of Chicago** 122

Penn State Univ* 144

Mt Sinai* 110

Perc

en

t PREVALENCE OF GLUCOSE

INTOLERANCE & TYPE 2 DM IN PCOS

**Ehrmann et al. Diabetes Care 1999; 22:141

*Legro et al. J Clin Endocrinol Metab 1999; 84:165 ¥Azziz et al. J Clin Endocrinol Metab 2001; 86:1626

Rezulin Collab Grp¥ 408

TOTAL 784

PREVALENCE OF GLUCOSE INTOLERANCE IN PCOS BY AGE AND BMI

0

10

20

30

40

50

60

70

<20 <25 <30 <35 <40

Age (yrs)

Percen

t

0

10

20

30

40

50

60

70

<20 <25 <30 <35 <40 <45 <50

BMI (Kg/M2)

Percen

t

Legro et al. J Clin Endocrinol Metab 1999; 84:165

METABOLIC EVALUATION OF THE PCOS PATIENT

• Fasting Glucose

– To R/O Type 2 DM (1997 ADA criteria)

• Fasting Insulin

– To R/O hyperinsulinemia

• Hgb A1c (or Glycosylated Hgb)

– To R/O Type 2 DM

• 2-3 hr. oGTT for Insulin & Glucose

– To R/O GIT & Type 2 DM (1985 WHO), and hyperinsulinemia

PREDICTIVE VALUE OF A FASTING GLUCOSE VALUE ON OGTT STATUS


110 mg/dL

126 mg/dL

DEGREE OF IR ESTIMATED FROM THE PEAK INSULIN LEVELS DURING A 75 gm oGTT IN

NORMOGLYCEMIC WOMEN WITH PCOS

• Very dependent on quality of insulin assay

• General cut-off values

– Normal-weight normal: <60 mI/mL

– Obese normal: <80 mI/mL

– Mild IR: 80-150 mI/mL

– Moderate IR: 151-300 mI/mL

– Severe IR: >300 mI/mL

Marin & Azziz. Contempo Ob/Gyn, March, 2005, pp. 66-74

HYPERANDROGENISM IN PCOS IS ASSOCIATED WITH RISK OF METABOLIC SYNDROME

Shroff et al. Fertil Steril 2007; 88:1389-1395

Age-adjusted prevalence of MS is higher in all hyperandrogenic phenotypes of PCOS, compared to the non-hyperandrogenic PCOS phenotype and to controls

POSITION STATEMENT OF THE ANDROGEN EXCESS & PCOS SOCIETY

• Recommends that women with PCOS, regardless of weight, be screened for IGT/DM with the use of an oGTT at the initial presentation and every 2 years thereafter

• Notes that the use of metformin to treat or prevent progression to IGT may be considered but should not be mandated until there have been well-designed randomized, controlled trials demonstrating efficacy

Salley et al. J Clin Endocrinol Metab 2007;92:4546-4556

PREVALENCE OF LIPID ABNORMALITIES ACCORDING TO NCEP CRITERIA

All subjects

(n=398)

% High Total cholesterol (mg/dl) 8.8%

% Low HDL-C (mg/dl) 14.6%

% High LDL-C (mg/dl) 8.5%

% High TTG (mg/dl) 2.5%


TREATMENT OF PCOS

• Goals include treatment & prevention of: – Dermatologic disorders (hirsutism, acne, alopecia)

– Ovulatory & menstrual dysfunction (DUB, endometrial hyperplasia or Ca)

– Metabolic abnormalities, incl. dyslipidemia, glucose intolerance & obesity

– Infertility

• Optimum treatment is generally combination therapy

LIFESTYLE MODIFICATION IN PCOS

• Dietary restriction has beneficial effects on ovulation, fertility,

pregnancy outcome, QOL, and various metabolic/inflammatory

markers in overweight PCOS women

• Compliance is difficult with up to a 50% drop-out rate

• No obvious difference in outcome or satiety has been observed

with different dietary regimens long-term, although most

studies are short and limited in size

• However, higher stimulated GLU levels during oGTT have been

observed with the lower protein diets

• In a crossover-diet intervention, 30

women with PCOS consumed a

reduced-CHO diet (41:19:40%

energy from CHO:protein:fat) for 8

weeks and a standard diet (55:18:27)

for 8 weeks

• Change in fat mass, adjusted for

baseline total fat, and change in total

lean mass was greater following

reduced-CHO diet compared to STD

diet in PCOS

EFFECTS OF A EUCALORIC REDUCED-CHO DIET ON BODY COMPOSITION AND FAT DISTRIBUTION IN WOMEN WITH

PCOS

Goss et al. Metabolism 63:1257-1264, 2014

*p<0.05

METFORMIN THERAPY IN PCOS

• Metformin is an agent that acts indirectly and modestly to:

–Improve ovulation

–Reduce long-term metabolic complications

DIABETES PREVENTION TRIAL

Knowler et al. N Engl J Med 2002;346:393-403

• 3234 subjects with IGT randomized to:

– Metformin 1700 mg/d

– Intensive lifestyle intervention

– PBO

• Average follow-up 2.8 years

• Compared with PBO, the incidence of DM was reduced:

– By 58% (95th CI: 48-66%) with lifestyle intervention

– By 31% (95th CI: 17-43%) with metformin

PCOS VS. NON-PCOS FOR LONG-TERM

TREATMENT OF METABOLIC RISK PCOS

• Meta-analysis of pooled results of 31 trials with 4570

participants followed for 8267 patient-years

• No significant differences in response between PCOS

and non-PCOS women

– Except lesser decrease in Fasting INS (-5.7% in PCOS vs.

-16.1% in non-PCOS)

• No PCOS trials to date have evaluated the effect of

treatment on the incidence of DM

Salpeter et al. Am J Med 2008;121:149-157.e2

SELECTING PCOS PATIENTS AT HIGH RISK FOR T2DM

• All PCOS? – Probably not

• Selected PCOS? – IGT or GDM

– Family history of T2DM

– Laboratory evidence of IR, i.e. hyperinsulinemia (oGTT, metabolic syndrome)

– Clinical evidence of hyperinsulinemia (acanthosis nigricans, obesity, android obesity)

Ra

te o

f L

ive

Bir

ths

PPCOS-I TRIAL: PREGNANCY RATES BY TREATMENT

Legro et al. N Engl J Med 2007;356:551-66

CC MET COMBO

All Pregnancy

loss

16/62

(26%) 10/25

(40%) 24/80

(30%)

1st trimester

losses

14/62

(23%) 10/25

(40%) 20/80

(25%)

*No significant differences

PPCOS-I TRIAL: PREGNANCY LOSS BY TREATMENT*

Legro et al. N Engl J Med 2007;356:551-66

THE THESSALONIKI ESHRE/ASRM-SPONSORED

PCOS CONSENSUS WORKSHOP GROUP

• At present, use of metformin in PCOS should be restricted to those

patients with glucose intolerance

• Decisions about continuing insulin sensitizers during pregnancy in

women with glucose intolerance should be left to obstetricians

providing care and based on a careful evaluation of risks and benefits

• Metformin alone is less effective than CC in inducing ovulation in

women with PCOS

• There seems to be no advantage to adding metformin to CC in women

with PCOS…. MAYBE….

Thessaloniki ESHRE/ASRM-Sponsored PCOS Workshop Group.

Hum Reprod. 2008;23:462-77

CC OR LETROZOLE AS FIRST-LINE OVULATION INDUCTION DRUG IN INFERTILE PCOS WOMEN:

A PROSPECTIVE RANDOMIZED TRIAL

Kar. J Hum Reprod Sci. 2012;5:262-5

LETROZOLE VS. CC IN PCOS: LIVE BIRTH RATE

Legro et al. N Engl J Med. 2014;371:119-29

LETROZOLE VS. CC IN PCOS: PREGNANCY OUTCOMES

Legro et al. N Engl J Med. 2014;371:119-29

Outcome

Clomiphene

Group

(N = 376)

Letrozole

Group

(N = 374)

P

Value

Pregnancy loss among women who

conceived — No./total no. (%) 30/103

(29.1)

49/154

(31.8)

0.65

Loss in first trimester —

No./total no. (%)

29/103

(28.2)

45/154

(29.2)

0.85

Congenital anomaly

1/66

(1.5)

4/102

(3.9) 0.65

PCOS: CREATING A TREATMENT PLAN

• Good treatment plans are based on sound and complete evaluations – History of the disorder

– Evaluation history

– Treatment history

– Past medical/surgical history

– Family history

– Physical exam

– TV U/S

– Laboratory

PCOS: CREATING A TREATMENT PLAN

• Rx includes: – OCs or progestins, for endometrial protection/HA

– Antiandrogens, for hirsutism, alopecia

– Metformin for metabolic dysfunction

– Ovulation induction for infertility

– Life-style modification

– Cosmetic care

• PCOS treatment generally requires combination

Rx, and life-long care and counseling

Gracias

sÍndrome de ovario poliquÍstico...

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