Prof Shashank R. Joshi MD, DM, FACP, FACE, FRCP Endocrinologist, Lilavati & Bhatia Hospital
President,Endocrine Society of India,President,Indian Academy of DiabetesProf, Dept. of Endocrinology, Grant Medical College& Sir JJ Group of Hospitals
Past President, Research Society for Study of Diabetes in India(RSSDI)Past President, All India Association for Advancement of Research in Obesity
President 2014 , Association of Physicians of India, Emeritus Editor, JAPIIndian Chapter Chair,American Association of Clinical Endocrinology
Understanding the science of
Hyperandrogenaemia & Insulin Resistance
Conflict of Interest and Duality
• Duality and Conflict for current talk :None
• Grants, Research Support,Adboard,Consultant or Speaker support:
• AbbottLtd,MSD,Novartis,BI,PHFI,NovoNordisk,Sanofi,USV,Sun,USV,
Marico,Uptodate(WK),Intas,Serdia,,Pfizer,Johnson and
Johnson,DRL,Cipla,Zydus Cadila,BayerZydus,Takeda.
Scope
• Basics and Phenotypes
• Twins :HA and IR
• Hyperandrogemia and Androgen Excess
• Insulin Resistance
• Some Asian Indian Data on IR
• PCOS:Terminology and Criteria
• Take Home Message
PCOS
• The polycystic ovary syndrome (PCOS) is recognized as one of the
most common endocrine abnormalities of humans, with global
prevalences 5%-15%.
• The disorder appears to be an ancient complex genetic trait
• It is a heterogeneous disorder linked with disturbances of
reproductive, endocrine and metabolic function.
• It is characterized by hyperandrogenism, gonadotropin secretory
changes, polycystic ovarian morphology, and insulin resistance
• Multifactorial and Polygenic
Phenotype of PCOS can be subdivided
into four different types
• Phenotype A and B (hyperandrogenism + ovulatory
dysfunction, with [A] and without [B] polycystic ovarian
morphology [PCOM], respectively) can be considered to
represent the "classic" form of the disorder.
• Phenotype C is the so-called
"ovulatory" PCOS (hyperandrogenism + PCOM only).
• And phenotype D is often referred to as
"nonhyperandrogenic" PCOS(ovulatory dysfunction + PCOM
only).
Phenotype Expression
• The different phenotypes vary in the degree to which they are
associated with an increased risk for metabolic dysfunction and
reproductive complications.
• There are a number of determinants of the epidemiology (prevalence)
and presentation (phenotype) of PCOS, including environmental (e.g.,
socioeconomic, geographic, toxicologic, life-style, and dietary) and
genetic (e.g., gene variants, epigenetic, and race/ethnicity) factors.
• Finally a better understanding of the evolutionary determinants
of PCOS has the potential for providing additional insight into those
factors determining the etiology, prevalence, and persistence of a
disorder that appears to be, superficially at least, an evolutionary
paradox.
Twins
Insulin
Resistance
Hyper
androgenemia
Irregular
bleeding
Infertility
HirsutismPregnancy
complications
Off-spring
Long-term
health
Twin Manifestations :IR and HA
• Insulin resistance and hyperandrogenism are the twin manifestations
of a metabolic genotype that slows apoptosis and aging, thereby
promoting mitosis and (1) increased oocyte endowment and/or
slowed atresia, that manifests as polycystic ovarian morphology; (2)
increased thecal cell endowment, which manifests as stromal
echogenicity on ultrasound imaging and hyperandrogemia; (3) more
GnRH neurons and/or greater GnRH neuronal connectivity leading to
increased GnRH drive that manifests as increased LH pulse
frequency and amplitude as well as decreased FSH with resultant
anovulation; and (4) increased number of adipocytes that amplify
insulin resistance and hyperandrogenism.
Twins:IR and HA
Pathogenesis of HA and IR
Hypothalamic-pituitary, ovarian and adrenal
contributions to polycystic ovary syndrome
• The pathophysiology of PCOS encompasses inherent ovarian dysfunction that is strongly
influenced by external factors including the hypothalamic-pituitary axis and hyperinsulinaemia.
• Neuroendocrine abnormalities including increased gonadotrophin-releasing hormone (GnRH)
pulse frequency with consequent hypersecretion of luteinising hormone (LH) affects ovarian
androgen synthesis, folliculogenesis and oocyte development.
• Disturbed ovarian-pituitary and hypothalamic feedback accentuates the gonadotrophin
abnormalities, and there is emerging evidence putatively implicating dysfunction of the Kiss 1
system.
• Within the follicle subunit itself, there are intra-ovarian paracrine modulators, cytokines and
growth factors, which appear to play a role.
• Adrenally derived androgens may also contribute to the pathogenesis of PCOS, but their role
is less defined.
PCOS Pathophysiology: Through a Scanner
PATHOGENESIS OF HYPERANDROGENAEMIA
IN PCOS
NORMAL OVARIAN PHYSIOLOGY
HYPOTHALAMUS Gn RH
PITUITARY LH FSH
OVARY Cholesterol
Pregnenolone
Progesterone
17-OH Progesterone
AROMATASE
Androstendione OESTRONE
Testesterone OESTRADIOL
THECA CELL GRANULOSA CELL
12 Episodes of secretion in
24 hours
ALTERED OVARIAN PHYSIOLOGY IN PCOS
HYPOTHALAMUS Gn RH
PITUITARY LH FSH
OVARY Cholesterol
Pregnenolone
Progesterone
17-OH Progesterone
AROMATASE
Androstendione OESTRONE
Testesterone OESTRADIOL
24 Episodes of secretion in
24 hours
INSULIN RESISTANCE
“ A subnormal biologic response to a given
concentration of insulin”
- Flier and Moller
INSULIN RESISTANCE & PCOS• INSULIN RESISTANCE IS INTRINSIC TO PCOS
• IT IS INDEPENDENT OF OBESITY (30% OF PCOS WOMEN
ARE NOT OBESE)
• IT PLAYS A CENTRAL ROLE IN THE PATHOGENESIS OF
PCOS AS INSULIN-INDUCED HYPERANDROGENAEMIA IS
THE UNDERLYING BIOCHEMICAL ABNORMALITY IN PCOS
• OBESITY WHEN PRESENT (de novo OR AS A RESULT OF
INTRINSIC IR) IS AN EXTRINSIC CAUSE OF IR IN PCOS.
• INSULIN RESISTANCE IN PCOS INTRINSIC
EXTRINSIC
TISSUE SPECIFIC EFFECTS OF INSULIN
RESISTANCE IN PCOS
INSULIN RESISTANT INSULIN SENSITIVE
MUSCLE ADIPOSE OVARY ADRENAL LIVER PILO –
SEBACEOUS UNIT
Glucose Uptake Lipolysis ANDROGEN PRODUCTION SHBG PROLI -
PRODUCTION FERATION
IGT DYSLIPIDAEMIA
DM
INSULIN RESISTANCE
COMPENSATORY HYPERINSULINAEMIA
OVARY ADRENAL LIVER HYPOTHALAMUS – PITUITARY AXIS
OVARIAN ANDROGEN ADRENAL ANDROGEN SEX HORMONE LH to FSH Secretion
BIOSYNTHESIS BIOSYNTHESIS BINDING GLOBULIN
(SHBG)
OVARIAN ANDROGEN
BIOSYNTHESIS
SERUM ANDROGEN
SERUM ANDROGEN
FREE ANDROGEN POOL
HYPERANDROGENISM
HYPERINSULINAEMIA - HYPERANDROGENAEMIA LINK
GENES LIFE STYLE VISCERAL OBESITY
INSULIN RESISTANCE MENSTRUAL DISTURBANCE
OVARIAN CYSTS
HIRSUTISM
HYPERTENSION
DYSLIPIDAEMIAHYPERINSULINAEMIA
HYPERANDROGENAEMIA
CV RISK
LIVER
IGF – BP1 Free IGF -1
SHBG Free Testesterone
PITUITARY
LH Pulse LH
Frequency
Decreased insulin
receptor
expression
TWO CORE Defects in PCOS IR
Decreased/
Dephosphorylated
AMPK activity
Insulin Resistance in PCOS
Endocrine Rev. 2009;30(1):1–50
WHICH CAME FIRST: HYPERINSULINAEMIA OR
HYPERANDROGENAEMIA?
HYPERINSULINAEMIA IS PRIMARY CONTRIBUTING TO OVARIAN
HYPERANDROGENAEMIA
EVIDENCES
1. Pharmacologic reduction of insulin levels in PCOS
women improves
2. Reduction of androgen levels by Bilateral Oophorectomy or
administration of Gn RH agonist or antiandrogenic
compounds in PCOS women has No effect on Insulin
Resistance or Hyperinsulinaemia
ASSESSMENT OF INSULIN SENSITIVITY
I. GOLD STANDARD
Hyperinsulinaemic – Euglycaemic Clamp Thechnique
Disadvantages: Expensive, time-consuming,
labour-intensive, intravenous,
unsuitable for office practice
II. ALTERNTIVE TESTS:
A. INTRAVENOUS: I.V. G.T.T., I.S.T., CIGMA
B. ORAL : OGTT
Fasting Insulin Level
Fasting Glucose: Insulin Ratio
HOMA (Homeostatic Model Assessment)
QUICKI (Quantitative Insulin Sensitivity Check
Index)
INSULIN SENSITIVITY INDICES• \
TESTS IR CUTOFF IN PCOS
1. OGTT: Glucose: Insulin at 120 min < 1.0
2. Fasting Insulin > 20 µu/ml
3. Fasting Glucose: Insulin ratio > 23
4. HOMA: Fasting Insulin X FBS < 7.2
405
5. QUICKI 1 NONE
(log Fasting Insulin + log FBS)
Hunter - Gatherer
Energy
Expending
Sedentary
Energy
Conserving
Evolution of Epidemic !! ...
Joshi SR. Type 2 diabetes in Asian Indians.Clin Lab Med. 2012 Jun;32(2):207-16.
Insulin Sensitivity in Caucasians and
Asian Indian Subjects at Identical Insulin Levels
Raji et al JCEM Aug 2004;89_3965-72
GD
R m
g/k
g/m
in
7.5
4.
5
Caucasians Asian Indians0
2
4
6
8
10
Asian Indians are More Insulin Resistant
than White Caucasians
0
2
4
6
8
10
A.Indians Caucasians
Mg/kg.m
in
Raji et al., J Clin Endocrinol Metab, 2001
*
0
2
4
6
8
10
12
14
16
18
5 10 15 20 25 30 35
Total BFM (% of body mass)
Ins
uli
n s
en
sit
ivit
y i
nd
ex
Asian Indians (r=-0 .49; p<0 .03)
Caucas ians (r=0 .67; p<0 .01)
Abate et al., J Clin Endocrinol Metab, 1999
At comparable values of BMIAt comparable values of BF
WHY ARE INDIANS MORE PRONE IR ?
Mohan V et al, Diabetologia 1986; Ramachandran A et al, Diabetes Res Clin Pract. 2004; Joshi SR, J Assoc Physicians India.
2003; Yajnik CS et al, J Nutr. 2004; Banerji et al, J Clin. Endocrinol. Metab., 1999; Chandalia M et al, J Clin Endocrinol Metab, 1999;
Chambers JC et al, Circulation. 2001; Misra A et al, Current Sci, 2003; Abate N et al, J Clin Endocrinol Metab. 2004
Greater ethnic susceptibility and genetic familial
aggregation of type 2 diabetes
Lower threshold for
BMI for diabetes
Abdominal
obesity and
visceral fatCharacteristic
dyslipidemia:
HDL cholesterol
triglycerides &
small dense LDL Levels of adiponectin
Inflammatory markers;
CRP
Increased prevalence of type 2 diabetes / premature CVD
Serum insulin levels/
insulin resistanceASIAN INDIAN
PHENOTYPE
Low birth weight – thin fat Indian
Lower age at onset of
Type 2 diabetes
Environmental
factors ?
Is the Asian Indian Phenotype due to
Genetic ?OR
Joshi SR AACE Nashville 2015
Are Asian Indians Differrent?
• Thin Fat Indians –More Fat
• Thin Fat Indians –Less Muscle
• Sarcopenic and Abdominal Obesity
Is it Genetic???
Is it Environmental???
2 key words:Sedentarnism and AffluenzaJoshi SR
AACE Nashville 2015
INSULIN ACTION PATHWAY GENES
Insulin receptorPC-1
PPRE
Regulates genes [adiponectin, and UCPs] involved in fatty acid
uptake and lipogenesis
Insulin resistance
Type 2 diabetes
InsulinPlasma cell glycoprotein
IRS-2Coactivator of PPAR-
Insulin responsive
GLUT 4 vesicles
Glucose
uptakeInsulin Receptor
Substrate
IRS-1
Akt
PDK-1
PI-3 Kinase
GENETICS OF TYPE 2 DIABETES IN ASIAN INDIANS
Abate N, Chandalia M, Satija P, Adams-Huet B, Grundy SM, Sandeep S, Radha
V, Deepa R, Mohan V, Diabetes, 2005, 54: 1207 - 1213
PC1-K121Q POLYMORPHISM
0
10
20
30
40
50
60
PR
OP
OR
TIO
N O
F K
121Q
PO
LY
MO
RP
HIS
M[%
]
Non-diabeticsDiabetics
South Indians
in Chennai
South Asians
in DallasCaucasians
in Dallas
p < 0.05
p < 0.05
p < 0.05
n=456
n=223
n=121
n=962
n=141
n=717
PPAR- GENE: PRO12ALA POLYMORPHISM
0
5
10
15
20
25
PR
OP
OR
TIO
N O
F P
RO
12
AL
A
PO
LY
MO
RP
HIS
M[%
]Non-diabetic subjects
Diabetic subjects
South Indians
in Chennai
South Asians
in DallasCaucasians
in Dallas
p=0.006
n=820n=799
n=616n=81
n=334
n=123
GENETICS OF TYPE 2 DIABETES IN ASIAN INDIANS
Radha V, Vimaleswaran KS, Babu HN, Abate N, Chandalia M, Satija P, Grundy SM, Ghosh S,
Majumder PP, Deepa R, Rao SM, Mohan V. , Diabetes Care, 2006; 29:1046 - 1051
Are Asian Indians Differrent?
• Thin Fat Indians –More Fat
• Thin Fat Indians –Less Muscle
• Sarcopenic and Abdominal Obesity
Is it Genetic???
Is it Environmental???
2 key words:Sedentarnism and AffluenzaJoshi SR
AACE Nashville 2015
Body Composition of Non-obese Asian
Indians:Comparisons with African Americans
18 20 22 24 26 28 30 32
50
40
30
20
10
0
African-Americans
Asian Indians
% BF
Body Mass Index
Banerji et al., J Clin Endocrinol Metab, 1999
TODAY INDIA IS SUFFERING FROM
A DISEASE CALLEDYESTERDAY
TODAY
THREE MAIN RISK FACTORS
1. Increased calories (glycemic load)
2. Physical activity
3. Urbanization
Macronutrient Intake in Non-Diabetics
38
66.8 % energy is provided by CHO in non-diabetic population
Joshi SR, Bhansali A, Bajaj S, Banzal SS, Dharmalingam M, et al .Results from a dietary survey in an Indian T2DM population: a STARCH study.BMJ Open. 2014 Oct 31;4(10):e005138. doi: 10.1136/bmjopen-2014-005138.
67%
13%
20%
North Region-wise macronutrient Intake in Non-Diabetics
Joshi SR, Bhansali A, Bajaj S, Banzal SS, Dharmalingam M, et al .Results from a dietary survey in an Indian T2DM population: a STARCH study.BMJ Open. 2014 Oct 31;4(10):e005138. doi: 10.1136/bmjopen-2014-005138.
Macronutrient In Diabetics
40
64.1 % energy is provided by CHO in diabetic population
Joshi SR, Bhansali A, Bajaj S, Banzal SS, Dharmalingam M, et al .Results from a dietary survey in an Indian T2DM population: a STARCH study.BMJ Open. 2014 Oct 31;4(10):e005138. doi: 10.1136/bmjopen-2014-005138.
Region-wise macronutrient Intake in Diabetics
67%
14%
19%
Central
66%
15%
19%
East
61%14%
25%
West
63%15%
22%
North
64%14%
22%
South
Joshi SR, Bhansali A, Bajaj S, Banzal SS, Dharmalingam M, et al .Results from a dietary survey in an Indian T2DM population: a STARCH study.BMJ Open. 2014 Oct 31;4(10):e005138. doi: 10.1136/bmjopen-2014-005138.
5.6%
9.7%
17.0%
0
5
10
15
20
Heavy Moderate Light
Physical activity grades
Pre
va
len
ce
of
dia
be
tes
[%
]PREVALENCE OF DIABETES IN RELATION
TO PHYSICAL ACTIVITY
Mohan V, Gokulakrishnan K, Deepa R, Shanthirani CS, Manjula Datta.
Diabet Med. 2005;22:1206-11
Major Culprit:TV
Joshi SR AACE Nashville 2015
Sedentarnism
• Key Risk factor for Diabetes
• Lack of Activity as well as NEAT
• NEAT-Non Exercise Activity Thermogenesis
Joshi SR AACE Nashville 2015
Basal metabolic rate
Activity
thermogenesis
Thermic effect of food
Kcal/day
0
1000
2000
3000
Non-exercise
Activity
Thermogenesis
(NEAT)
Exercise
Joshi SR AACE Nashville 2015
Sit
tin
g
Sta
nd
ing
Gu
m
Ch
ew
ing
Sta
ir
Clim
bin
g 1 mph 2 mph 3 mph
Walking
200
70
220
150
15520
Kcal/hour
Joshi SR AACE Nashville 2015
Occupation-type NEAT
(kcal/day)
Chair-bound 300
Seated work: no option of moving 700
Seated work: discretion & requirement to move 1000
Standing work; e.g. homemaker, shop assistant 1400
Strenuous work; e.g. agriculture 2300
Black, Eur J Clin Nutr 50:72
Data assuming BMR = 1600 kcal/day
NEAT = 2000kcal/day
NEAT = 700kcal/day
Joshi SR AACE Nashville 2015
Asian Indians are Sarcopenic
• More Fat,Less Muscle
• Less Muscle Mass
• Mitochondrial defects and IR
• Indians and Mitochondria ?
Joshi SR AACE Nashville 2015
Imbalanced/Improper Dietary Profile
in Asian Indians
55-65
15-30
<10
30-40
10-15
5:10
Reduced Recommended Excess
RangeNutrients
Carbohydrates (% en)
Total fat (% en)
Saturated fat (% en)
Dietary fibre (gm)
MUFA (% en)
-6/-3 ratio
Diet Therapy
• Eat Less
• Calorie Dense Foods
• Foods –Taste and Habits
• Natural,Veg
• Food Fads
• Food cooked in every household differs
• Eating out, not on time
Physical Inactivity
• TV,Internet
• Smart Phones
• AC;Cushion Couch
• Walk
• Yoga
• Stress
Prevention Mantra
•“Eat Less ,Eat on Time,
Eat Right,Walk More,
Sleep well &on time and
Smile”
PCOS:Misnomer ?
• PCOS is a misnomer as ovaries do not contain
epithelial cysts, but they are actually antral follicles.
Moreover, the name PCOS neither reflects
the hyperandrogenism which is essential for diagnosis
nor the metabolic derangements.
• The name "Hyperandrogenic Persistent Ovulatory
Dysfunction Syndrome or HA-PODS" is proposed
here to overcome diagnostic pitfalls of previous
nomenclature
Role of AMH in polycystic ovarian
syndrome.
• AMH is increased and correlated with the various reproductive and
metabolic/endocrine alterations in PCOS. AMH plays an inhibitory role
in follicular development and recruitment, contributing to follicular
arrest.
• AMH inhibitory action on FSH-induced aromatase production likely
contributes tohyperandrogenism in PCOS, which further enhances
insulin resistance in these women.
• Elevated serum AMH concentrations are predictive of poor response to
various treatments of PCOS including weight loss, ovulation induction
and laparoscopic ovarian drilling, while improvement in various clinical
parameters following treatment is associated with serum AMH decline,
further supporting an important role for AMH in the pathophysiology of
this syndrome
Diagnostic criteria for PCOS: Is there a
need for a rethink?• The diagnostic criteria for polycystic ovarian syndrome (PCOS) have been grouped in
different classifications that have been conflicting for many years.
• At present, the classification of Rotterdam is the most used, but with varying frequency
depending on the country and medical specialties. This classification is now >10 years
old.
• Although its fundamental principle (two criteria required out of three) is still valid, each
of its three items (oligo-anovulation (OA), hyperandrogenism (HA), and polycystic
ovarian morphology (PCOM)) needs to be updated.
• The definition of biological HA is still unresolved. The criteria used to define OA are
insufficient. The definition of PCOM proposed in 2003 is now obsolete when using
the latest generation of ultrasound machines.
• The serum anti-Müllerian hormone (AMH) assay seems increasingly to be an excellent
substitute for follicular count and is likely to emerge as the official PCOM marker.
• A new consensus conference is urgently needed.
Lifestyle Impact on IR and PCOS
Insulin receptor
expression
Intracellular
AMPK activity
Increased binding
of insulin to insulin
receptors
Increased
translocation of
GLUT-4
Insulin sensitivity Glucose Uptake
Improves Fertility
outcomes and
HyperandrogenemiaExercise
SUMMARY & CONCLUSION
1. PCOs is an IR Syndrome, a gender-specific form of
Metabolic Syndrome, hence also called “Syndrome XX”
2. There is ONE defect that is IR with consequent
hyperinsulinaemia
3. There are TWO underlying hormonal factors:
Hyperinsulinaemia and Hyperandrogenaemia
4. Its THREE key features are: 1. Oligo - / Anovulation
2. Hyperandrogenism
3. PCO morphology
5. There are FOUR possible phenotypes