Obesity and reproduction

1
Obesity and reproduction

• Professor Aleksandar Ljubic
• Medical school University of Belgrade
• Clinic for Obstetrics and Gynecology
• Clinical center of Serbia

2
Obesity and reproduction

• Epidemiology
• Patophysiology
• IVF
• Pregnancy
• Intergenerational obesity

3
Health Challenges of the Future?

• Increasing burden of lifestyle diseases
• 1. Obesity
• 2. Cardiovascular disease (hypertension,
  atherosclerosis)
• 3. Type 2 Diabetes
• Associated with increasing morbidity and
  mortality
• Appearing at younger and younger ages

WHO, 2005
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Obesity pandemic disease
WHO, 2005
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Women of reproductive age
Martorell, R, et al Eur J Clin Nutrit, 2000
6
Obesity and its associated metabolic problems
areappearing at younger ages
WHO, 2005
7
Obesity during childhood in developing countries
Horgan, Bellizzi and Dietz, 2000. IOTF.
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Our physiology has not been able to adapt to
advances in technology and food production.
Cover page of The Economist, December 13-19th,
2003.
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Chrousos GP 2009
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PCOS and obesity

• PCOS
• the most frequent ovarian disorder in
  premenopausal women
• Azziz et al., 2004
• Obesity
• 2069 of women with PCOS - BMI gt 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.

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PCOS clasification

• 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.

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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

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Abdominal adiposity and PCOS
Escobar-Morreale H et al. Trends
in Endocrinology and Metabolism, 2007 18(7)
266-272.
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PCOS 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)
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PCOS and obesity - patophysiology

• Molecules secreted by the intraabdominal adipose
  tissue (adipokines)
• promote ovarian androgen production.
• TNF stimulate proliferation and steroidogenesis
  apoptosis and anovulation in the rats 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

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PCOS and obesity - patophysiology

• 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)
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Fat 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
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PCOS abdominal adiposity
Escobar-Morreale H et al. Trends in
Endocrinology and Metabolism, 200718 (7)
266-272.
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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),
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Ghrelinreproductive function
Follicle growth and maturation Embryonic
development Implantation
A putative signal for energy insufficiency
Garcia MC et al, Reproduction 2007 133 531-540
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Obesity and IVF
No - 5019
Fedorscak et al, Human Reproduction, 2004
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Obesity and IVF
Fedorscak et al, Human Reproduction, 2004
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BMI age - IVF
Response BMI BMI BMI BMI
Response Underwt Normal Overwt Obese
Can. Cy. () 28.6 18.8 20.6 17.6
Ret. Oocytes 15.5 14.1 13.4 14.5
Mat. Oocytes 11.8 10.4 9.9 10.7
Fert. Oocytes 9.3 8.6 8.4 8.5
Sneed et al. Human Reproduction 2008
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BMI age - IVF
Outcome BMI BMI BMI BMI
Outcome Underwt Normal Overwt Obese
Pts with ET 20 498 258 253
Em. Trans. 2.2 2.3 2.3 2.3
Imp. Rate () 27.5 23.3 23.4 21.5
Preg. Rate () 58.8 48.7 45.3 39.5
Misc. Rate () 0 17.7 15.1 10.0
Clin.Preg. () 58.8 38.6 36.8 35.1
Sneed et al. Human Reproduction 2008
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BMI age - IVF
Younger patients - BMI reduction
Sneed et al. Human Reproduction 2008
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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
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Live birth rate

• In women with BMI of lt 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 gt 25.
• In women with BMI of lt 30, the odds of live birth
  per woman were 1.12 (95 CI 0.91, 1.37) when
  compared with women with BMI of gt 30.
• There was significant statistical heterogeneity
  in results from the different studies (P 0.003).

A. Maheshwari, Aberdeen, Human Reproduction
Update, 2007
28
Pregnancy rate

• BMI of lt 25, OR - 1.24 (95 CI 1.02, 1.50) when
  compared with BMI of gt 25.
• Significant statistical heterogeneity (P 0.03).

A. Maheshwari, Aberdeen, Human Reproduction
Update, 2007
29
Pregnancy rate

• BMI 2025, OR - 1.40 (95 CI 1.22, 1.60) as
  compared to a BMI gt 25.
• Significant statistical heterogeneity (Plt
  0.00001).

A. Maheshwari, Aberdeen, Human Reproduction
Update, 2007
30
Pregnancy rate

• BMI lt 30, OR - 1.47 (95 CI 1.20, 1.80) as
  compared to women with BMI of gt 30.
• Significant statistical heterogeneity (Plt
  0.00001).

A. Maheshwari, Aberdeen, Human Reproduction
Update, 2007
31
The dose of gonadotrophins

• The dose of gonadotrophins was higher in women
  with BMI of gt 25 (WMD 210.08, 95 CI 149.12,
  271.05) in comparison with those with BMI of lt
  25.

A. Maheshwari, Aberdeen, Human Reproduction
Update, 2007
32
The dose of gonadotrophins

• The requirement for gonadotrophins was higher
  (WMD 361.94, 95 CI 156.47, 567.40) in obese
  women (BMI gt 30 versus BMI lt 30)

A. Maheshwari, Aberdeen, Human Reproduction
Update, 2007
33
Number of oocytes retrieved

• The WMD of the number of oocytes recovered in
  women with BMI lt 25 was 0.58 (95 CI 0.22, 0.94)
  in comparison with women with BMI gt 25.

A. Maheshwari, Aberdeen, Human Reproduction
Update, 2007
34
Number of oocytes retrieved

• The WMD of the number of oocytes retrieved in
  women with BMI lt 30 was 0.68 (95 CI 0.11, 1.25)
  as compared to women with BMI of gt 30.

A. Maheshwari, Aberdeen, Human Reproduction
Update, 2007
35
Cancellation rate

• BMI of gt 25 OR were 1.83 (95 CI 1.36, 2.45), as
  compared to BMI lt 25.
• BMI of gt 30, OR were 1.59 (95CI 0.53, 4.80), as
  compared to women with BMI lt 30
• Significant statistical heterogeneity (P 0.05).
  

A. Maheshwari, Aberdeen, Human Reproduction
Update, 2007
36
Ovarian hyperstimulation rate

• BMI of gt 25, the odds of OHSS were 1.12 (95 CI
  0.74, 1.68), as compared to BMI of lt 25.
• BMI of gt 30, the odds of OHSS were 1.16 (95 CI
  0.69, 1.96), as compared to BMI of lt 30.

A. Maheshwari, Aberdeen, Human Reproduction
Update, 2007
37
Miscarriage rate

• BMI of gt 25, the odds were 1.33 (95 CI 1.06,
  1.638), compared to BMI of lt 25.
• The results showed statistical heterogeneity (P
  0.05).

A. Maheshwari, Aberdeen, Human Reproduction
Update, 2007
38
Miscarriage rate

• The risk of miscarriage was higher (OR 1.53,
  95 CI 1.27, 1.84), in women with BMI gt 30
  versus BMI lt 30.

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Obesity and IVF

• 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
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Pregnancy complications - BMI
Adapted from Galtier-Dereure et al. (1995)
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Congenital malformations BMI
Watkins ML, et al., Pediatrics 1111152, 2003)
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Why might obesity lead to congenital anomalies?

• Four potential mechanisms
• Undiagnosed diabetes

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Why might obesity lead to congenital anomalies?

• Four potential mechanisms
• Undiagnosed diabetes
• Folate status

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Why might obesity lead to congenital anomalies?

• Four potential mechanisms
• Undiagnosed diabetes
• Folate status
• Nutritional deficiencies

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Why might obesity lead to congenital anomalies?

• Four potential mechanisms
• Undiagnosed diabetes
• Folate status
• Nutritional deficiencies
• Difficulties with antenatal detection

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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
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Excessive birth weight
Parsons et al, BMJ 2001
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Fetal programming

• Increased weight gain
• Glucose intolerance
• Insulin resistance
• Diabetes
• Cardiovascular problems

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Prevention / Treatment

• Influence of maternal and fetal health on Obesity
  pandemic
• When to intervene?
• Before conception
• Around conception
• During pregnancy
• During childhood

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Inter-generational obesity cycle
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Maternal obesity Next preventable risk for
reducing perinatal mortality and morbidity
CNATTINGIUS, S ET AL NEJM, 1998