understanding the science of hyperandrogenaemia & insulin … · 17.0% 0 5 10 15 20 heavy...

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

http://www.hotoku.co.jp/r10.JPG

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


Macronutrient In Diabetics

40

64.1 % energy is provided by CHO in diabetic population


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


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


Sedentarnism

• Key Risk factor for Diabetes

• Lack of Activity as well as NEAT

• NEAT-Non Exercise Activity Thermogenesis


Basal metabolic rate

Activity

thermogenesis

Thermic effect of food

Kcal/day

0

1000

2000

3000

Non-exercise

Activity

Thermogenesis

(NEAT)

Exercise


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


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


Asian Indians are Sarcopenic

• More Fat,Less Muscle

• Less Muscle Mass

• Mitochondrial defects and IR

• Indians and Mitochondria ?


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

understanding the science of hyperandrogenaemia & insulin … · 17.0% 0 5 10 15 20 heavy...

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