polycystic ovary syndrome
TRANSCRIPT
METFORMIN IN PCOS
• PROTECTS AGAINST 1ST TRIMESTER MISCARRIAGE
• PROMOTES OVULATION• REDUCES GESTATIONAL DIABETES AND
FETAL MACROSOMIA• PROBABLY REDUCES PRE-ECLAMPSIA-
ECLAMPSIA-HELLP• IS NOT TERATOGENIC• IS ASSOCIATED WITH NORMAL INFANT
GROWTH AND DEVELOPMENT
Pregnancy Outcomes in 125 Women with PCOS
Previously without metformin301 pregnancies
With metformin148 pregnancies, 155 fetuses
McNemar S=148.4, p<0.0001
SAB 68%
Livebirths 32% SAB
14%
Livebirths 86%
SAB 24%
Livebirths 76%SAB 60%
Livebirths 35%
Other 5%
Pregnancy Outcomes in 178 Women with PCOS
Previously without metformin197 pregnancies
With metformin88 pregnancies, 91 fetuses
McNemar S=64.1, p<0.0001
Metformin reduces miscarriage in PCOS by reducing hypofibrinolytic plasminogen activator inhibitor activity, an independent determinant of miscarriage, which is closely correlated with insulin, insulin resistance, and triglycerides. This is particularly important in PCOS where 4G4G PAI-1 homozygosity is much more common than in normal women
Pregnancy Outcomes on Metformin in 144 Women with PCOS
SAB 13%
Livebirths 87%
Pregnancy Outcomes on Metformin in 300 Women with PCOS
SAB 15%
Livebirths 85%
Prevalence of GDM
• GDM PREVALENCE DOUBLED IN KAISER COLORADO FROM 1994-2002 (2.1%4.1%), NATIONALLY 3-8%.
• >50% OF WOMEN WITH GDM DEVELOP TYPE II DM WITHIN 5 YRS
• ASSOCIATED WITH BIRTH DEFECTS AND ABNORMALITIES IN CHILDHOOD GROWTH AND GLUCOSE REGULATION
CROSS-GENERATIONAL CYCLE OF GDM
• MATERNAL GDM BEGETS OFFSPRING’S TYPE II DM AND OBESITY.
Recognized risk factors for GD include body mass index
>25 kg/m 2, first degree family history of type 2 DM, age
25 years, multiparity, previous GD, and previous
macrosomic infants (>9 lbs. or 4000 grams). Additional
risk factors for GD include pre-conception impaired
fasting glucose levels (110-125 mg/dL), pre-conception
impaired glucose tolerance (2 hour post oral glucose
load glucose levels 140-199 mg/dL), polycystic ovary
syndrome (PCOS), and ethnic group (American Indian or
Alaska Native; African American; Asian; Hispanic;
Pacific Islander).
Gestational Diabetes in 40 Women with PCOS
Previously without metforminIn 52 livebirth pregnancies
With metforminIn 40 livebirth pregnancies
GD 13%GD
31%
X2 =4.3, p=0.039
McNemar S=8.3, p=0.039
GD in 121 Women with PCOS140 Livebirth Pregnancies
on Metformin
GD in 251 Livebirth Pregnancies From Community Controls
GD 7%
GD 16%
X2 =6.2, p=0.013
GD IN PCOS ON METFORMIN VS COMMUNITY CONTROLS
GD in 251 Livebirth Pregnancies From Community Controls
GD 16%
GD 17%
GD in 203 Women with PCOS211 Livebirth Pregnancies
on Metformin
X2 =0.11, p=0.75
GD IN WOMEN WITH PCOS ON METFORMIN VS COMMUNITY CONTROLS
Pregnancy increases requirements for insulin secretion, increasing
insulin resistance and demands on pancreatic β-cells, promoting
development of gestational diabetes (GD), particularly in women
with pre-existing insulin resistance, commonly in women with
polycystic ovary syndrome (PCOS).
Preliminary studies suggest that metformin may have unique
potential to prevent development of GD. We postulate that
interventions which reduce insulin resistance and lower
requirements for endogenous insulin secretion can preserve beta
cell function and prevent development of type 2 DM.
Pre-conception Insulin Resistance
Physical inactivity PCOS
Obesity Race
Increased demand on beta cells for insulin secretion
Hyperinsulinemia
Maternal weight gain Neonatal macrosomia 1st trimester miscarriage Pregnancy induced HTN Pre-eclampsia High PAI-Fx
Insulin resistance of pregnancy
Pregnancy increases requirements for insulin secretion
Reduction in beta cell reserve
Glucose intolerance Gestational diabetes Type 2 diabetes
Insulin sensitizing drugs (Metformin)
Reduces demand on beta cells for insulin secretion
Protects beta cell reserve
Overcomes insulin resistance
Euglycemia maintained
• Decreases gestational diabetes• Primary prevention of type 2 diabetes
Pre-eclampsia and pregnancy outcome in 123 women with polycystic ovary syndrome (PCOS) and in 252 healthy controls from a community practice of obstetrics
PCOS (123 women,142 pregnancies, 148 babies)
Community (252 women, 252pregnancies 262 babies)
p
N 123 252
Age 30±5 29±6 . 021
Race94% Caucasian(116 W, 7 other)
90% Caucasian(227 W, 25 B)
NS
Pre-conception weight (kg) 93 ±23 72 ±18 <. 0001
Pre-conception BMI (kg/m2) 33.7 ±7.9 25.6 ±5.9 <. 0001
Pre-conceptionType 2 diabetes mellitus
2/123(1.6%) 1/252 (0.4%) NS
Conception at age > 35 years 22/142(19%) 33/252 (13%) NS
Pre-eclampsia 7/142(4.9%) 9/252 (3.6%) .NS
Pre-eclampsia in primigravidas
5/101(5.0%) 4/92 (4.4%) NS
Gestational diabetes 10/140(7.1%) 40/251 (15.9%) .013
Pre-eclampsia and pregnancy outcome in 123 women with polycystic ovary syndrome (PCOS) and in 252 healthy controls from a community practice of obstetrics
Pre-eclampsia and pregnancy outcome in 123 women with polycystic ovary syndrome (PCOS) and in 252 healthy controls from a community practice of obstetrics
Percent of pregnancies as twins
3/97 (3.1%) 10/252 (4.0%) 1.0
Birth at gestational week ≥37Birth at gestational week <37
120/148(81%)28/148 (19%)
222/249 (89%) 27/249 (11%)
.024
Pre-eclampsia and pregnancy outcome in 123 women with polycystic ovary syndrome (PCOS) and in 252 healthy controls from a community practice of obstetrics
Birth weight for births at ≥37 weeks gestation (gram)
3363 ± 500 3481 ± 555 NS
Birth weight ≥4000g for neonates ≥37 weeks gestation
10.8% (13/120) 17.5% (36/206) NS
Birth weight ≥4500g for neonates ≥37 weeks gestation
0.8% (1/120) 2.9% (6/206) NS
Major and minor birth defects, 142 live births to 125 women with PCOS: 1 tethered spinal cord, 1 hamstring tendon contracture. Birth defects in 1.4%, national average ~4.5%
METFORMIN IN PCOS
• PROMOTES OVULATION• PROTECTS AGAINST 1ST TRIMESTER
MISCARRIAGE• REDUCES GESTATIONAL DIABETES AND
MACROSOMIA• PROBABLY REDUCES PRE-ECLAMPSIA-
ECLAMPSIA-HELLP• IS NOT TERATOGENIC• IS ASSOCIATED WITH NORMAL INFANT
GROWTH AND DEVELOPMENT