OBESITY&

INFERTILITYDr . SHASHWAT JANI.

M.S. ( GYNEC ) DIPLOMA IN ADVANCED ENDOSCOPY ( FRANCE )

Asst. Prof. , Smt. N.H.L. MUN. MED. COLLEGE, AHMEDABAD.

MOBILE : +91 99099 44160.E – mail : drshashwatjani@gmail.com

OBESITY: A MAJOR HEALTH PROBLEM

Most prevalent nutritional disorder of affluent nations, as also of developing countries which

are undergoing rapid nutritional and lifestyletransition.

Broad and significant impact on manyendocrinologic parameters.

Substantial changes in lifestyle, e.g., greaterconsumption of energy dense foods and inactivelifestyle are the predominant reasons for theincrease in prevalence of obesity and relateddisorders.

DEFINITION OF OBESITY

Current guidelines for overweight and obesitybased on Body mass index(BMI)

BMI = Weight in kgs / Height in m2

WHO & CDC definition for adults: BMI of 25 or more - OVERWEIGHT BMI of 30 or more - OBESE

OVERWEIGHT & OBESEACCORDING TO WHO & CDC

OVERWEIGHT OBESE

DEFINITION OF OBESITY

5

BMI(kg/m2) Class 25.0-29.9 Overweight 30.0-34.9 Obesity class I 35.0-39.9 Obesity class II 40 or more Obesity class III or extreme obesity

BMI ( kg/ m2 ) Class

25.0 -29.9 Overweight

30.0 – 34.9 Obesity Class I

35.0 – 39.9 Obesity Class II

40 or more Obesity Class III or Extreme Obesity

PREVELANCE OFOBESITY

In UK : 18.3% of female population in reproductive age group In USA : overweight – 64.5% obese – 30.5% extremely obese – 4.7% In INDIA : urban prelevance of

obesity has increased alarmingly. Almost 50% of adult urban Indians

and 29% of children fulfill

criteria for either overweight or obese.

Obesity is rarely the result of endocrinologic disorders. The presence of obesity is associated with a number of disturbances in androgens, estrogen, binding globulins, insulin/glucose, gonadotrophin, prolactin and growth hormone / growth factor metabolism. The hormone leptin (produced in and secreted by adipose tissue) affects the

neuroendocrinereproductiveaxis, both centrally and

peripherally. Some or all of these alterations play a role in the genesis of obesity related ovulatory dysfunction.

OBESITY AND INFERTILITY

Complex relationship between female obesity and reproductive success. Obese women have more infertility and are less successful at conceiving than women of normal weight. The outcome of pregnancy in obese women in also highly complex. Soaring levels of obesity in affluent and fast developing societies are expected to trigger a major new infertility crisis among women.

BODY FAT DISTRIBUTION SEVERAL TOPOGRAPHIC PATTERNS: - Upper body or central or android

obesity - Lower body or gynoid obesity - Intra-abdominal or visceral obesity Upper Body Obesity More Closely

Associated With: - Metabolic disturbances - Reproductive anomalies - Lower frequency of ovulatory

cycles (17.5% v/s 35.2%) Best measure of upper body obesity: - Waist: hip ratio - Waist circumference ( > 100 cm :

risk of metabolic disorder)

OBESITY AND INFERTILITY An increased BMI may alter fertility via several established biochemical mechanisms:

Increased volume of distribution contributed by adipose tissue with respect to either endogenous or exogenous steroidal hormones and storage of lipid soluble steroids, leading to increased free hormone levels. Changes in metabolism and excretion of hormones or altered production of steroids hormone binding proteins, e.g., SHBG.

OBESITY AND INFERTILITY

Alterations/ polymorphisms of estrogen and /of insulin receptors, such as those involved in the pathophysiology of PCOS. Enhanced peripheral conversion of adrenal androgens to additional

estrogens, via adipose tissue aromatse, 3-β dehydrogenase and 17‐ β dehydrogenase.

OBESITY AND INFERTILITY

Obese women are reported to have a higher prevalence of amenorrhea and infertility.

Underlying biological mechanisms remain unexplained. Obesity represents a state of hormone

imbalance as levels of SHBG decrease linearly with percentage of body fat, leading to increased free androgen levels.

OBESITY AND INFERTILITY

Most steroid hormones preferentially get concentrated within human adipocytes

rather than in the plasma Volume of fat in obese subjects is much Larger than their intra-vascular space. Tissue steroid concentrations are 2 – 13 times higher than those in plasma. Thus steroid pool of severely obese subjects is far greater than that of

normal weight individuals.

ENDOCRINOLOGICAL

CHANGES

IN OBESITY LEADING

TO

INFERTILITY ARE…

ANDROGEN METABOLISM & CIRCULATINGANDROGEN LEVELS IN OBESITY

In adults or adolescents with eumenorrhoeic obesity, circulating levels of plasma total androgens don't vary significantly with weight (testosterone, androstenedione and 24hours urinary cortisol concentrations) In fact, may be lower in overweight subjects. However, percentage of free testosterone elevated sue to obesity related decrease in circulating level of SHBG, particularly in

women with upper body fat distribution.

ANDROGEN METABOLISM Contd…

In obese eumenorrhic women, higher Metabolic clearance rate and production rate of testosterone, dihydro-testosterone and 3α-androstenediol is seen. Fat tissue is also the site of steroid metabolism. Androgens are irreversibly aromatized to estrogens resulting in overproduction of estrogens and functional hyperestrogenism. Excess estrogens may affect hypothalamic pituitary axis and lead to ovulatory dysfunction, menstrual irregularity and increased risk of breast and endometrial carcinoma.

ESTROGEN METABOLISM IN OBESITY

Excess body fat leads to alteration in estrogen metabolism which in turn may affect the HPO axis and lead to ovulatory dysfunction.

Eumenorrhoic obese women demonstrate lower circulating SHBG levels.

Free fraction of circulating E2 higher in obesity, although no significant difference between serum levels of E1 and E2 in obese and normal weight women.

The catabolism of estrogen may also be altered in obesity. Higher E3-catechol estrogen ratio, further contributing to functional hyperestrogenism in obesity.

SHBG IN OBESITY OBESITY LOWERS PLASMA concentration of SHBG

secondary to elevated insulin. Alteration in SHBG levels have a profound impact

on metabolism and action of bound steroids. SHBG ↓ - Increase in unbound fraction of free

E2, testosterone and other sex

steroids - Increase in MCR for both E2 and testosterone - Increased conversion of

testosterone.

GROWTH HORMONE ANDIGF AXIS IN OBESITY

Decreased secretion and increased clearance of GH resulting in depressed serum concentrations of GH.

Low GH : a consequence rather than a cause of obesity.

Mechanism in through obesity associated elevation in insulin.

GROWTH HORMONE ANDIGF AXIS IN OBESITY

GH promotes hepatic production of IGF-1. IGF-1 stimulates aromatase activity and E2

secretion in response to FSH..

IGF -1 also stimulates expression of LH receptors, LH induced progesterone and

androgen synthesis. OBESITY INDUCED CHANGES IN GH AND IGF’S AFFECT OVARIAN STEROIDOGENESIS ANS OVULATION.

INSULIN/GLUCOSE HOMEOSTASISIN SIMPLE OBESITY

Simple obesity is associated with hyperinsulinemeia and insulin resistance.

Both fasting and post-challenge insulin concentrations are higher among obese women.

Abdominal obesity is associated with both insulin resistance and elevated circulating androgens.

Hyperinsulinemia, insulin resistance and elevated free circulating androgens cause ovulatory and menstrual disturbances.

OBESITY RELATEDHORMONES

ANDTHEIR ROLE INREPRODUCTION

LEPTIN AND REPRODUCTION Leptin is a 167 – amino acid peptide

secreted in adipose tissue, circulates in blood bound form to a family of proteins and acts on CNS neurons that regulate eating behavior and energy balance.

Circulating leptin concentrations are proportionate to adiposity, with more obese individuals having higher concentrations.

It serves as an endocrine signal of caloric status.

LEPTIN AND REPRODUCTION

Leptin’s ability to reflect energy balance suggests that it may serve as the link between nutritional status and reproduction.

Leptin may participate in the timing of puberty and in mediating the pathological responses of the reproductive system to both under and over nutrition.

Leptin administration accelerates the onset if puberty in rodents. A 1 ng/ml increment in S.Leptin is associated with a 1 month advance in menarche.

LEPTIN AND REPRODUCTION

Isoform of leptin identified in ovary. Exerts specific action on steroidogenesis

as studied in vitro. Inhibits synergistric action of IGF-1 on

FSH stimulated estradiol production (but not pregesterone) in rat granulosa cells.

Also inhibits FSH stimulation of IGF-1 production.

LEPTIN AND REPRODUCTION

Leptin is expressed in human granulosa cells and cumulus cells and is present in mature human oocytes and follicular fluid, thus it appears to be secreted by ovarian follicle.

A rise in maternal serum leptin levels after the administration of hCG and before ovum retrieval was correlated with a higher pregnancy rate *

Thus, excessive leptin associated with obesity may impair reproductive function at the level of

ovary.

ADIPONECTIN,OBESITY ANDINSULIN RESISTANCE

Adiponectin is a 222 amino acid protein, almost exclusively produced in adipose tissue.

Has anti-atherogenic effect and potent insulin sensitizing action.

High Adiponectin levels are independently associated with increased insulin sensitivity and reduced risk of type II diabetes.

Insulin resistance and obesity are associated with lower plasma adiponectin concentrations and also Adiponectin is found to be lower in PCOS.

Relationship between obesity and adiponectin is due in part to the metabolic changes frequently associated with obesity.

Although, adiponectin might not be actively involved in the pathogenesis of PCOS, it might play a role in the complicated metabolic abnormalities of the syndrome.

GHRELIN AND REPRODUCTION Complex hormone name for its ability to

stimulate the release of growth hormone. A 28 amino acid peptide secreted mainly in the

upper portion of the stomach , and also in other tissues including ovary, testis and placenta

Ghrelin and leptin have opposing actions. Ghrelin is a signal to conserve energy by

increasing appetite; leptin is a signal to expend energy.

The connection between reproduction and the body’s state of energy metabolism is now well established centering around the complex leptin ghrelin system.

ROLE OF GHRELIN INPATHOGENESIS OF PCOS

Women with PCOS havelower circulatingconcentrations of Ghrelinthan weight matchedcontrols. Ghrelin concentrationinversely correlated withandrostenedioneconcentration in bothgroups Its concentrationcorrelated with insulinsensitivity only amongPCOS group.

J ClinEndocrinol Metab 2002;87:5625

In another study, nodifference was found inghreling levels in PCOSand normal women No association betweencirculating ghreling levelsand concentrayion ofseveral reproductiove andmetabolic hormonesobserved within PCOSGroups.

J.CLinEndocrinol Metab 2003;88:942

Further research needed…..

CYTOKINES

Circulating concentration of cytokines- Interleukins : IL-6, IL-18, C-reactive protein and TNF–α are elevated in obese individuals. IL–6 and TNF–α synthesized by adipose tissue Increased TNF–α promotes insulin resistance

and impairs follicular development. Circulating CRP is positively and independently

associated with insulin resistance / hyperinsulinemia.

Thus, elevated cytokine levels may contribute to infertility in this group.

OBESITY AND PUBERTALOVULATORY DYSFUNCTION

Juvenile obesity associated with earlier age at menarche.

Peri-pubertal and pre-pubertal onset of obesity associated with higher risk of oligo-ovulation and menstrual irregularities.

Hyperinsulinemia with childhood obesity plays a role in hyperandrogenism and peri-pubertal ovulatory dysfunction.

Androgen status tracks from childhood to adulthood and is directly related to fertility.

OBESITY AND PUBERTALOVULATORY DYSFUNCTION

Aberrations in androgen production during puberty

due to obesity or related metabolic complications may have

long lasting effects on reproductive function.

Elevated BMI at age 18 is a risk for subsequent

ovulatory infertility with or without a diagnosis of PCOS.** Am J Obst Gynaecol 1994;171:171-177

OBESITY,PCOS ANDOVULATORY INFERTILITY

Obesity has substantial effects on manifestations of PCOS.

35-50% of women with PCOS are obese. 50% of overweight women have PCOS. Obesity plays a significant role in

determining the severity of clinical manifestations and metabolic disorder.

Significant increase in infertility and menstrual irregularities with BMI > 30 kg/m2.

OBESITY,PCOS ANDOVULATORY INFERTILITY…

Obesity augments the metabolic disorder prevalent in PCOS leading to:

- Oligomenorrhoea. - Chronic anovulation. - Lower pregnancy rates. - Higher miscarriage rates. - Increased obstetric

complications.

OBESITY,PCOS ANDOVULATORY INFERTILITY…

Obese PCOS women have : - More marked hyperinsulinemia - Insulin resistance - Relative hyperglycemia - Lower SHBG levels - Higher levels of total and free testosterone and DHEAS - Decreased GH pulse amplitude - Increased LH pulse frequency - Attenuated LH pulse amplitude

ALL THESE LEAD TO ANOVULATION AND INFERTILITY

OBESITY AND IVF SUCCESS RATES

IVF pregnancy rates lower in obese women compare to those of normal weight.

This may be because obese women don't respond to fertility medications and have higher percentage of immature eggs.

Obesity also is an independent risk factor for early pregnancy loss after \IVF or ICSI, partly due to lower number of collected oocytes in obese women.*

*Acta Obstet Gynaecol Scand 2005;vol19;issue1:43-48

OBESITY AND RISK OFSPONTANEOUS ABORTION

Positive relationship between BMI and the risk of spontaneous abortion in infertile women who became pregnant after infertility treatment.

Progressive increase in risk in overweight, obese and very obese women (p<o.o5, p< 0.01, p<0.001 respectively)*

Endocrinological and/or metabolic mileu associated with obesity operating through a functional state such as insulin resistance, can create hostile intra-ovarian or intra-uterine environment for the oocytes or embryos.

OBESITY AND ADVERSEPREGNANCY OUTCOMES

Obesity is a significant risk factor for adverse pregnancy outcome: - Early miscarriage - Recurrent miscarriage - Still birth - Early neonatal death - Preterm birth - Shoulder dystocia - Increased operative morbidity - Ectopic pregnancy

OBESITY AND FETAL RISKS Maternal obesity (BMI> 30 kg/m2) has significant detrimental impact on fetal development with an increased risk offetal anomalies: - Anencephaly - Spine bifida - Exomphalos - Cardiac defects (ASD or VSD) - Orofacial clefts - Multiple anomalies

~7% increase in risk for fetal anomaly for each 1 unit increment in BMI above 25 kg/m2.

Association of obesity with NTD’s is notcompletely abolished by folic acid fortification of food.

OBESITY AND OTHER HEALTH RISKS

OBESITY & MALE INFERTILITY

OBESITY AND MALE INFERTILITY

Fertility is lower among men with BMI of 26 or more and further decreases as BMI rises.

For every three point increase in BMI, the risk of infertility rises by 12%.

Every excess 10 kgs or 20 pounds might reduce a man’s fertility by 10%.

Obesity is associated with altered spermatogenesis and erectile dysfunction.

Overweight men have less sexual intercourse and this can also indirectly influence fertility.

Obesity also reduces fecundity.

Direct correlation between BMI and semen volume and sperm quality.

Obese males express a characteristic hormonal profile described as “ Hyperestrogenic Hypogonadotropic Hypogonadism”.

Both total and free blood testosterone levels decreased in obese men.

Primarily attributable to an increase in circulating estrogens from peripheral aromatization of C19- androgens (testosterone and androstenedione) that result in relative hypogonadotropism.

OBESITY AND MALEINFERTILITY Contd…

The origin of hypoandrogenism in males is multifactorial .

Estrogens act hypothalamus to affect GnRH pulses and at the pituitary level to regulate gonadotropin secretion.

In severe obesity, pituitary gonadotropin secretion appears suppressed with normal or decreased levels of LH in the presence of decreased levels of testosterone.

Insulin resistance, a predisposition for obesity, also reported to be associated with low testosterone levels.

Patients with obstructive sleep apnea also have lower mean testosterone values.

Obese males also have decreased intra-testicular testosterone levels.

OBESITY AND MALE INFERTILITY Contd…

It is hypothesized that alterations of sperm parameters associated with obesity can be attributed to inappropriate suppression of the

hypothalamic - pituitary-gonadal axis by elevated estrogens derived from peripheral aromatization and resulting in decreased testosterone production, reflected in the low levels of circulating and intra-testicular testosterone.

INFERTILITY MANAGEMENTIN OBESE

Obesity has a profound impact on infertility management.

Women should be encouraged to loose weight prior to infertility treatment to improve outcome.

Decrease in free testosteron levels and increase in SHBG levels reported with a weight loss as small as 5% of initial weight.

A 7-10% reduction in body weight effective in restoring fertility resulting in spontaneous ovulation or increased sensitivity to ovulation inducing drugs.

MANAGEMENT OF OBESITY:KEY STRATEGIES

Behavioral Strategies : Self monitoring, social support, Stress management etc..

Dietary Intake : Reducing calori intake by 500 – 1000 kcal per day to reduce weight loss.

Physical activity : Moderate activity ( brisk walking or jogging ), 30 – 45 mins, 4-5 days a week.

Adjunctive Pharmacotherapy : Drug treatment for patients with BMI > 27 with other medical co-morbidities.

Surgery : As last choice when other modalities fail, BMI > 40 or between 35 – 40 with co – morbidities.

MANAGEMENT RECOMMENDATIONSACCORDING TO BMI

BMI 27 ≤ with or without co – morbidities :

Lifestyle management with diet , physical activity, behavioral modification.

Pharmacology not used.

BMI > 27 and ≤ 30 without co- morbidities :

Same as above . Pharmacology therapy can be given.

BMI > 27 and ≤ 30 with co – morbidities :

Pharmacology and life style changes.

Bariatric SurgeryReis et al (2012): 20 men; 2-year follow-up No changes in sperm quality; increase in TT

levelsDi Frega et al (2005): Six fertile men BMI > 40 kg/m2 (mean age 38) Resulted in persistent azoospermia ~16 mo.

later Normal hormone levels; Biopsy: Maturation

arrestSermondade et al (2012): Three men BMI > 40 kg/m2 (mean age 38) Resulted in severe oligoasthenozoospermia ~2

mo. later ICSI with success in 2 cases

OVULATION INDUCTION

Weight reduction followed by:

Clomiphene citrate Aromatase inhibitors :letrozole

etc Gonadotropins GnRH agonists / antagonists.

An emerging are of interest is“inter-generational tracking” ofhigh maternal body weight

intosecond and subsequentgenerations.

It is observed thathigh maternal weight results innot only an increased risk ofmetabolic disease but alsoperturbed reproductivefunctional in the offspring…!!!

THANK YOU