sÍndrome de ovario poliquÍstico...
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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
% PCOS in population by
AE-PCOS 2006
% PCOS in population by
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
Legro et al. J Clin Endocrinol Metab 1999;84:165-9
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%
Legro et al. J Clin Endocrinol Metab 2003;88:5137-5144
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