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OBESITY & INFERTILITY BY DR SHASHWAT JANI
1. Dr . 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
2. Most prevalent nutritional disorder of affluent
nations, as also of developing countries which
are undergoing rapid nutritional and lifestyle
transition.
Broad and significant impact on many
endocrinologic parameters.
Substantial changes in lifestyle, e.g., greater
consumption of energy dense foods and inactive
lifestyle are the predominant reasons for the
increase in prevalence of obesity and related
disorders.
3. Current guidelines for overweight and obesity
based 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
5. BMI 5
( kg/ m2 ) Class
25.0 -29.9 Overweight
BMI(kg/m2) Class
25.0-29.9 Overweight
30.0 – 34.9 Obesity Class I
30.0-34.9 Obesity class I
35.0-39.9 Obesity class II
35.0 – 39.9 Obesity Class II
40 or more Obesity class III or
40 or more Obesity Class III or
extreme obesity
Extreme Obesity
6. 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.
7. 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.
8. 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.
9. 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)
10. 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.
11. 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.
12. 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.
13. 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.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. 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.
23. 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.
24. 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.
25. 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.
26. 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.
27. 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.
28. 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.
29. Women with PCOS have
lower circulating
concentrations of Ghrelin
than weight matched
controls.
Ghrelin concentration
inversely correlated with
androstenedione
concentration in both
groups
Its concentration
correlated with insulin
sensitivity only among
PCOS group.
J ClinEndocrinol Metab 2002;87:5625
In another study, no
difference was found in
ghreling levels in PCOS
and normal women
No association between
circulating ghreling levels
and concentrayion of
several reproductiove and
metabolic hormones
observed within PCOS
Groups.
J.CLinEndocrinol Metab 2003;88:942
Further research needed…..
30. 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.
31. 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.
32. 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
33. 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.
34. Obesity augments the metabolic disorder
prevalent in PCOS leading to:
- Oligomenorrhoea.
- Chronic anovulation.
- Lower pregnancy rates.
- Higher miscarriage rates.
- Increased obstetric complications.
35. 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
36. 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
37. 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.
38. 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
39. Maternal obesity (BMI> 30 kg/m2) has
significant detrimental impact on fetal
development with an increased risk of
fetal 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 not
completely abolished by folic acid fortification of
food.
40.
41.
42. 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.
43. 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.
44. 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.
45. 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.
46.
47. 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.
48. 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.
49.
50. 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.
51. Reis et al (2012):
20 men; 2-year follow-up
No changes in sperm quality; increase in TT levels
Di 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 arrest
Sermondade 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
53. An emerging are of interest is
“inter-generational tracking” of
high maternal body weight into
second and subsequent
generations.
It is observed that
high maternal weight results in
not only an increased risk of
metabolic disease but also
perturbed reproductive
functional in the offspring…!!!