Obesity and reproduction Professor Aleksandar Ljubić Medical school University of Belgrade Clinic...

Obesity and reproduction

Professor Aleksandar LjubićMedical school University of BelgradeClinic for Obstetrics and Gynecology

Clinical center of Serbia

Obesity and reproductionObesity and reproduction

EpidemiologEpidemiologyy

PatoPatophysphysiologiologyy

IVFIVF

PregnancyPregnancy

IntergeneraIntergenerational obesitytional obesity

Health Challenges of the Future?

Increasing burden of “lifestyle” diseases1. Obesity

2. Cardiovascular disease (hypertension, atherosclerosis)

3. Type 2 Diabetes

Associated with increasing morbidity and mortality

Appearing at younger and younger ages

WHO, 2005

Obesity – pandemic disease

WHO, 2005

Women of reproductive ageWomen of reproductive age

Martorell, R, et al;Eur J Clin Nutrit, 2000

Obesity and its associated metabolic problems areappearing at younger ages

WHO, 2005

Horgan, Bellizzi and Dietz, 2000. IOTF.

Obesity during childhood in Obesity during childhood in developing countriesdeveloping countries

Cover page of The Economist, December 13-19th, 2003.

Our physiology has not been able to adapt to advances

in technology and food production.

Chrousos GP2009

PCOS and obesity

PCOS the most frequent ovarian disorder in premenopausal

women Azziz et al., 2004

Obesity 20–69% of women with PCOS - BMI > 30 Independent of obesity, women with PCOS have

increased intra-abdominal fat accumulation Asuncion et al., 2000; Azziz et al., 2004; Carmina et al.,

2007.

NIH PCOS groups a more severe phenotype

ESHRE including ovulatory and non-hyperandrogenic PCOS groups

less severe with metabolic features primarily related to excess weight, specifically increased abdominal fat

Moran and Teede, 2009.

PCOS clasification

PCOS and long-term sequelae

IR and subsequent hyperinsulinaemia: Impaired glucose tolerance, Gestational diabetes mellitus - OR 2.94, T2DM Cardiovascular disease

exacerbated by coexistent obesity Boudreaux et al., 2006 Ehrmann et al., 2006

AbdominalAbdominal adiposity and adiposity and PCOS PCOS

Escobar-Morreale H et al. Trends in Endocrinology and Metabolism, 2007; 18(7): 266-272.

PCOS and obesity - patophysiologyPCOS and obesity - patophysiology

Compensatory hyperinsulinaemia - significant contributor to the hyperandrogenism

Increased serum insulin stimulates ovarian androgen production, reduces SHBG increasing serum levels of free bio-available androgens

Apart from reproductive (anovulation) and cosmetic (acne, alopecia, hirsutism) consequences hyperandrogenaemia

increases abdominal obesity, aggravates existing IR

Preadipocytes have androgen receptors and high androgen levels have been shown to induce selective IR in

cultured adipocytes

D. Rachon, H. Teede Molecular and Cellular Endocrinology (2010)

Molecules secreted by the intraabdominal adipose tissue (adipokines)

promote ovarian androgen production. TNF stimulate proliferation and steroidogenesis apoptosis

and anovulation in the rat’s ovary leptin induces anovulation by direct ovarian effects

Duggal et al., 2000 Intraabdominal fat tissue

express enzymes involved in the metabolism of androgens further contribute to the hyperandrogenism in women with

PCOS Gambineri et al., 2002


IR and ovarian hyperandrogenism promote the accumulation of intra-

abdominal fat primary determinants of the

metabolic abnormalities present in women with PCOS

D. Rachon, H. Teede Molecular and Cellular Endocrinology (2010)


Fat distribution and anovulationFat distribution and anovulation

Abdominal fat in anovulatory women - SAF not intraabdominal fat.

Abdominal and trunk SAF accumulation are associated with anovulation.

Kuchenbecker et al, J Clin Endocrinol Metab 2010

PCOS – PCOS – abdominalabdominal adiposity adiposity

Escobar-Morreale H et al. Trends in Endocrinology and Metabolism, 2007;18 (7) : 266-272.

Obesity - sterility Obesity - sterility Multiple steroid and

metabolic disturbances Production and effect of

Insulin, leptin, resistin, ghrelin and adiponectin.

Poretsky et al., 1999; Moschos et al., 2002; Tanbo, 2002; Pasquali et al., 2003),

GGhrelinhrelinreproductive reproductive

functionfunction

Garcia MC et al, Reproduction 2007; 133: 531-540

A putative signal forenergy insufficiency

Follicle growth and maturationEmbryonic

developmentImplantation

Fedorscak et al, Human Reproduction, 2004

No - 5019No - 5019

Obesity and IVFObesity and IVF

Fedorscak et al, Human Reproduction, 2004


BMI BMI – age – age - IVF- IVF

ResponseResponseBMIBMI

UnderwtUnderwt NormalNormal OverwtOverwt ObeseObese

Can. Cy. (%)Can. Cy. (%) 28.628.6 18.818.8 20.620.6 17.617.6

Ret. OocytesRet. Oocytes 15.515.5 14.114.1 13.413.4 14.514.5

Mat. OocytesMat. Oocytes 11.811.8 10.410.4 9.99.9 10.710.7

Fert. OocytesFert. Oocytes 9.39.3 8.68.6 8.48.4 8.58.5

Sneed et al. Sneed et al. Human Reproduction 2008


OutcomeOutcomeBMIBMI

UnderwtUnderwt NormalNormal OverwtOverwt ObeseObese

Pts with ETPts with ET 2020 498498 258258 253253

Em. Trans.Em. Trans. 2.22.2 2.32.3 2.32.3 2.32.3

Imp. Rate (%)Imp. Rate (%) 27.527.5 23.323.3 23.423.4 21.521.5

Preg. Rate (%)Preg. Rate (%) 58.858.8 48.748.7 45.345.3 39.539.5

Misc. Rate (%)Misc. Rate (%) 00 17.717.7 15.115.1 10.010.0

Clin.Preg. (%)Clin.Preg. (%) 58.858.8 38.638.6 36.836.8 35.135.1


0

10

20

30

40

50

60

70

80

90

18 20 22 24 26 28 30 32 34 36 38 40

BMI

Cli

nic

al

Pre

gn

an

cy

Ra

te

20 25 30 35 40


Younger patientsYounger patients

- - BMIBMI reduction reduction


Outcome measures

The primary outcome measure was live birth rate per woman.

Secondary outcome measures included total dose of gonadotrophins, Cancellation rates, number of oocytes retrieved, number of embryos obtained, pregnancy rate, miscarriage rate and ovarian hyperstimulation syndrome (OHSS) rate.

A. Maheshwari, Aberdeen, Human Reproduction Update, 2007, 1843 studies

Live birth rate

In women with BMI of < 25, the odds of live birth per woman were 1.08 (95%: CI 0.92, 1.26), and per cycle were 0.74 (95% CI: 0.27, 2.01) when compared with women with BMI of > 25.

In women with BMI of < 30, the odds of live birth per woman were 1.12 (95% CI: 0.91, 1.37) when compared with women with BMI of > 30.

There was significant statistical heterogeneity in results from the different studies (P = 0.003).

A. Maheshwari, Aberdeen, Human Reproduction Update, 2007

Pregnancy rate BMI of < 25, OR - 1.24 (95% CI: 1.02, 1.50) when

compared with BMI of > 25. Significant statistical heterogeneity (P = 0.03).


Pregnancy rate

BMI 20–25, OR - 1.40 (95% CI: 1.22, 1.60) as compared to a BMI > 25.

Significant statistical heterogeneity (P< 0.00001).


Pregnancy rate

BMI < 30, OR - 1.47 (95% CI: 1.20, 1.80) as compared to women with BMI of > 30.

Significant statistical heterogeneity (P< 0.00001).


The dose of gonadotrophins

The dose of gonadotrophins was higher in women with BMI of > 25 (WMD 210.08, 95% CI: 149.12, 271.05) in comparison with those with BMI of < 25.


The dose of gonadotrophins

The requirement for gonadotrophins was higher (WMD 361.94, 95% CI: 156.47, 567.40) in obese women (BMI > 30 versus BMI < 30)


Number of oocytes retrieved

The WMD of the number of oocytes recovered in women with BMI < 25 was 0.58 (95% CI: 0.22, 0.94) in comparison with women with BMI > 25.


Number of oocytes retrieved

The WMD of the number of oocytes retrieved in women with BMI < 30 was 0.68 (95% CI: 0.11, 1.25) as compared to women with BMI of > 30.


Cancellation rate

BMI of > 25 OR were 1.83 (95% CI: 1.36, 2.45), as compared to BMI < 25.

BMI of > 30, OR were 1.59 (95%CI: 0.53, 4.80), as compared to women with BMI < 30

Significant statistical heterogeneity (P = 0.05).


Ovarian hyperstimulation rate

BMI of > 25, the odds of OHSS were 1.12 (95% CI: 0.74, 1.68), as compared to BMI of < 25.

BMI of > 30, the odds of OHSS were 1.16 (95% CI: 0.69, 1.96), as compared to BMI of < 30.


Miscarriage rate BMI of > 25, the odds were 1.33 (95% CI: 1.06,

1.638), compared to BMI of < 25. The results showed statistical heterogeneity (P = 0.05).


Miscarriage rate

The risk of miscarriage was higher (OR = 1.53, 95% CI: 1.27, 1.84), in women with BMI > 30 versus BMI < 30.

Increased FSH consumption Less oocytes Lower E2 More cancelation Less pregnancies

Crosignani et al., 1994; Homburg et al., 1996; Soderstrom-Anttila et al., 1996; Wang et al., 2000; Wittemer et al., 2000; Carrell et al., 2001; Loveland et al., 2001; Mulders et al., 2003; Nichols et al., 2003


Pregnancy complications - Pregnancy complications - BMIBMI

Adapted from Galtier-Dereure et al. (1995)

Congenital malformations – BMI Congenital malformations – BMI

Watkins ML, et al., Pediatrics 111:1152, 2003)

Why might obesity lead to congenital Why might obesity lead to congenital anomalies?anomalies?

Four potential mechanisms:Four potential mechanisms:- Undiagnosed diabetesUndiagnosed diabetes

HypertensionDyslipidaemia

Glucose intolerance Inflammation

Abdominal Obesity

Why might obesity lead to Why might obesity lead to congenital anomalies?congenital anomalies?

Four potential mechanisms:Four potential mechanisms: Undiagnosed diabetesUndiagnosed diabetes Folate statusFolate status


Four potential mechanisms:Four potential mechanisms: Undiagnosed diabetesUndiagnosed diabetes Folate statusFolate status Nutritional deficienciesNutritional deficiencies


Four potential mechanisms:Four potential mechanisms: Undiagnosed diabetesUndiagnosed diabetes Folate statusFolate status Nutritional deficienciesNutritional deficiencies Difficulties with antenatal detectionDifficulties with antenatal detection

The Developmental Origins of Health and Disease

“A process whereby a stimulus or insult applied at a critical or sensitive period of development results in long term or permanent changes in the structure or function of the organism”

Lucas J. The childhood environment and adult , 1991

Parsons et al, BMJ 2001

Excessive birth weightExcessive birth weight

Fetal Fetal programming programming

Increased weight gain

Glucose intolerance Insulin resistance Diabetes Cardiovascular

problems

Prevention / TreatmentPrevention / Treatment

Influence of maternal and fetal health on Obesity pandemic

When to intervene? Before conception Around conception During pregnancy During childhood

Inter-generational obesity cycleInter-generational obesity cycle

“Maternal obesity

Next preventable risk for reducing perinatal mortality and morbidity”

CNATTINGIUS, S ET AL; NEJM, 1998

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