endocrine update 2014 polycystic ovary syndrome: is it a ...09) pcos and obesity.pdfmetabolic...

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Endocrine Update 2014

Polycystic Ovary Syndrome: Is it a unique form of obesity?

Lekshmi T. Nair, MD, MHSClinical Assistant ProfessorDivision Of Endocrinology Department of Internal MedicineOhio State University Columbus OHOhio State University, Columbus OH

March 29, 2014

Objectives

Introduction Introduce background statistics of PCOS Review the diagnosis of PCOSReview the diagnosis of PCOS Summarize the evaluation of PCOS

PCOS & obesity Explore PCOS related metabolic disturbances Explain the relationship between androgens & obesity

Conclusions & summary

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Background

PCOS is a complex endocrine disorder affecting women of childbearing age characterized by increased androgen production and ovulatoryincreased androgen production and ovulatory dysfunction PCOS is the leading cause of anovulatory

infertility and hirsutism Women with PCOS have an increased risk of

miscarriage, insulin resistance, hyperlipidemia, type 2 diabetes, cardiovascular disease, andtype 2 diabetes, cardiovascular disease, and endometrial cancer.

Background

There is no uniform definition for PCOS.

PCOS describes a diverse and heterogeneous group of womenof women.

PCOS is a syndrome and not a disease.

PCOS is prevalent. 5-10% women in US are affected.

PCOS is not cured but instead requires management of symptoms risk factors & co-morbiditiesof symptoms, risk factors & co morbidities.

Azziz et al. J Clin Endocrinol Metab. 2005; 90(8):4650–4658.

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Background

PCOS imparts a significant health care-related economic burden.

Diagnostic evaluation is only ~ 2% of the cost.

Screening for the disorder appears be a cost-effective strategyg pp gyearlier diagnosis, intervention prevention of serious sequelae

Annual cost in millions of US dollars (% of total)

Initial evaluation 99 (2.3)

Treatment 4271 (97.7)

f / ( ) Menstrual dysfunction/AUB Infertility DM type 2 Hirsutism

1350 (30.9)533 (12.2)1766 (40.4)622 (14.2)

Total cost 4370 (100)

Azziz et al. J Clin Endocrinol Metab. 2005; 90(8):4650–4658.

Diagnosis

PCOS was initially described in1935 by Irvin Stein & Michael Leventhal as syndrome based on a case study of 7 women with: y Obesity Infertility with amenorrhea Hirsutism Polycystic ovaries

These are still in part considered characteristic b t not consistentl fo nd in all omen ithbut not consistently found in all women with PCOS.

Stein et al. Am J Obstet Gynecol 1935;29:181-191.

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Diagnosis

Diagnostic criteria has changed and evolved over time.

Many different professional medical groups have Many different professional medical groups have offered guidelines

PCOS may be managed by many different medical specialties Pediatricians/Internists/Family practice Dermatologistsg OB/GYN, reproductive endocrinologists Endocrinologists

Diagnosis

NIH 1990 Rotterdam 2003

AE-PCOS2006

AE-PCOS2009

Hyperandrogenism(clinical or biochemical)

+ +/ - + +

Ovulatorydysfunction

anovulation oligo- and/or anovulation

+/ - +

Polycystic ovaries by ultrasound(≥ 12 follicles in each

+/ - +/ - +/ - +

2 of 3 Ovarian ovary (2-9mm) or increased ovarian volume >10ml)

Exclusion of other disorders

+ + + +

Wild et al. J Clin Endocrinol Metab. 2010. May;95(5):2038-49.Vilmann et al. Horm Res Paediatr 2012; 78:269-278.

dysfunction

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Evaluation

History Physical LaboratoryPubertal age/sexual development

Vitals (BP, BMI, waist circumference)

Pregnancy test

Menstrual history (menarche, Cutaneous manifestations (acne, Gonadotropins (high LH or menstrual pattern) hirsutism, acanthosis, skin tags) LH:FSH ratio >2-2.5)*Reproductive history General exam Prolactin, Thyroid (TSH)

Androgens (Free and Total T**, DHEA-s)Adrenal steroids (excess cortisol, 17-OHP)

Obesity (onset, progression) May require pelvic exam (GYN) Glycemic evaluation: fasting glucose, Hemoglobin A1c, c-peptide/insulin level, 2 hrglucose toleranceglucose tolerance

Androgen related symptoms (acne, hirsutism, virilization)

Lipids (low HDL, high trigs, high LDL)

Family history Hepatic function (fatty liver)Renal function (for treatment)

*Only present in 1/3 of PCOS women**Assay quality is important. Ensure using female reference range.

Pathology

The pathogenesis of PCOS is not fully understood.

There is evidence of a polygenic component There is evidence of a polygenic component.

Likely genetic and environmental contributions.

Hyperandrogenism & Insulin resistance are important elements in the development of PCOS but there are complex interactions involving many systems.many systems.

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↑LH↓FSH

Insulin i t

↓FSH

↑glucose↑FFA↑Adipose

resistance

Nestler et al. N Eng J Med. 2008;358: 47-54.

↓SHBG

↑Androgens

Pathology – Possible explanations

HPG axis abnormality with GnRH dysregulation resulting in increased LH levels and exaggerated ovarian androgen production.ovarian androgen production.

Unmeasured enzymatic defect (ovarian +/-adrenal) favoring androgen excess.

Insulin resistance as the culprit for both the metabolic and androgen (reproductive) abnormalities vs. vice versa?

Cobin et. al. Endocr Pract. 2005; 11(2):125-134.

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Obesity, Insulin changes & PCOS

Abdominal obesity promotes insulin resistance (IR) and compensatory hyperinsulinemia (HI).

Increased visceral adipose mass increases free fattyIncreased visceral adipose mass increases free fatty acids which in turn affects insulin secretion and metabolism in the periphery.

Insulin resistance has been described in both obese and normal weight PCOS women.

Obesity appears to amplify the IR and HI in PCOS.

Exposure to androgens can increase visceral fat in obeseExposure to androgens can increase visceral fat in obese and normal weight PCOS women.

Gambineri et al. Int J Obes Relat Metab Disord. 2002 Jul;26(7):883-96.

Obesity is present in at least 50% of PCOS women.

Obesity is thought to exacerbate PCOS

PCOS & Obesity

PCOS.

History of weight gain typically precedes the symptoms of PCOS.

Links between androgen excess, insulin resistance and adipose tissue are being exploredtissue are being explored.

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Metabolic consequences of PCOS Metabolic syndrome + reproductive abnormalities

Prenatal Childhood Reproductive years Postmenopausal

• Intrauterine growth restriction

•Premature adrenarche

•Insulin resistance/obesity

•Ovulatory dysfunction, infertility, hirsutism, acne

•IR, obesity, IGT, T2DM, dyslipidemia

•Endometrial hyperplasia cancer

•Hirsutism•IR, obesity, IGT, T2DM, dyslipidemia CVD

•Endometrial cancer?

Sam S et al. Trends in Endocrinology & Metabolism. 14 (8) Oct 2003:365-370.

Insulin resistance in PCOS

Peripheral insulin sensitivity reduced in all PCOS women. Insulin mediated glucose disposal is decreased by 35-Insulin mediated glucose disposal is decreased by 35

40% in PCOS (compared to same weight controls). Defect is worsened by obesity.

Hepatic insulin resistance is demonstrated in obese women with PCOS.

Dunaif A. Endocrinol Metab Clin North Am. 1999 June; 28(2):341-59.

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Insulin compensation to insulin resistance and glucose levels are inappropriately low.

“Disposition Index” Normally changes in insulin Disposition Index Normally changes in insulin sensitivity are compensated by appropriate changes in insulin secretion = normal glucose tolerance.

In PCOS (obese and non-obese) the disposition index is lower compared to weight matched controls.

This perturbation is made worse with weight gain.

Dunaif A. Endocrinol Metab Clin North Am. 1999 June; 28(2):341-59.


PCOS adipocytes may have a post-binding defect in insulin receptor-mediated signal transduction.

Similar suggestion for skeletal muscle the major site Similar suggestion for skeletal muscle, the major site of insulin-mediated glucose uptake.


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Adipocytes in PCOS

Visceral adipocytes appear to have increased responsiveness to catecholamine stimulated lipolysis independent of obesity.p y

The increase in visceral fat lipolysis leads to an increase in FFA release directly into the portal circulation.

Portal FFA levels are major positive modulators of hepatic glucose production.

Another mechanism for the increased risk for Another mechanism for the increased risk for glucose intolerance in PCOS.


Adipocytes in PCOS – Role of Androgens

Androgens inhibit adipocyte differentiation thereby increasing lipolysis & lipogenesis

Testosterone induces IR in adipose tissue Testosterone induces IR in adipose tissue

Insulin stimulates GnRH ↑pituitary gonadotropins ↑ovarian androgen production

Insulin reducing SHBG production ↑free androgen concentration

Vilmann LS. Et al. Horm Res Paediatr. 2012; 78:269-278.

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Schematic representation of a link between obesity and PCOS via adipokines.

Chen X et al. J Mol Endocrinol 2013;50:R21-R37

© 2013 Society for Endocrinology

PCOS hormonal disruption

Leptin’s role Signal of energy

sufficiency

Proportional to adipose mass and increased in obesity.

PCOS subjects had higher leptin levels.

Adiponectincorrelates with insulin sensitivy.

HMW adiponectinwas lower in PCOS regardless of weight

Vilmann LS. Et al. Horm Res Paediatr. 2012; 78:269-278.

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Ghrelin’s role food initiation and

termination

Obese have lower fasting ghrelin levels and post-meal suppression may be impaired. Rises with weight

loss.

PCOS subjects had less ghrelin rise with weight loss.

Moran LJ. J Clin Endocrinol Metab. 2004 Jul; 89(7):3337-44.


PCOS is characterized by abnormalities in GnRHpulsatility (more LH action vs FSH).

Independent of obesityIndependent of obesity Obese reproductively normal women do not have

abnormalities in 24-hour LH and FSH plasma concentrations.

Sam S. Obes Manag. Apr 2007; 3(2): 69–73.

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Androgen excess

Androgen formation in the ovary and adrenal gland is dependent on P450c17 enzyme.

Hyperactivity of the P450c17 enzyme is thought a Hyperactivity of the P450c17 enzyme is thought a key mechanism resulting in hyperandrogenism in PCOS.

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Insulin receptor has been found to be abnormally phosphorylated resulting in inhibition of its action = insulin resistanceinhibition of its action insulin resistance.

P450c17 enzyme has been found to abnormally phosphorylated resulting in increased androgen biosynthesis = hyperandrogenemia.

Block of MEK/ERK pathways that help reduce andorgenesis resulting from insulin stimulation.

Baptiste Cg. J Steroid Biochem Mol Biol. 2010 Oct;122(1-3):42-52.

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Does obesity cause PCOS?

Reproductive disturbances more common in obese women regardless of the diagnosis of PCOS. Risk of anovulatory infertility increases at a BMI > 24 kg/m2

hi hor higher. Weight reduction can restore regular menstrual cycles in

these women.

Yet, the majority of obese women do not develop hyperandrogenemia and do not have PCOS. Non PCOS obese may have increased androgen

production (esp w/upper-body obesity) but clearance is l i d t halso increased = no net change

PCOS bioavailable androgen levels are increased.


Obesity Androgens

Obesity amplifies hyperandrogenism.

Increased adiposity in women results in altered sex steroid balance. Increased androgen production Reduced SHBG More estrogen available (less SHBG)

Possible alterations in the HPA axis Exaggerated ACTH response to CRH? Altered ACTH pulsatile dynamics?

Dietary contributors High lipid load decrease SHBG, increase free

androgens


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Does PCOS cause obesity?

Androgens role in body composition. Android: greater g

distribution of fat in the upper body

Gynoid: accumulating fat in the lower body.

Most critical appears to be the presence of central/visceral adiposity.

Androgens Insulin Resistance

Androgens may induce an insulin resistance state Activation of lipolytic cascade increased FFA from

visceral adipose depot.p p Testosterone may impact muscle insulin sensitivity.

Trials with anti-androgens (flutaminde and spironolactone) led to improvement in insulin resistance.


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Androgens Insulin Resistance

Chronic exposure higher androgen concentrations may modify body fat distribution. Rats exposed to high dose testosterone early in life lead to

IR d l ti f i l di i d lth dIR and accumulation of visceral adipose in adulthood. Androgen treatment in nonobese female to male

transexuals increased visceral fat and reduced insulin sensitivity.

Postmenopuasal women exposed to androgens increased visceral fat independent of weight.

PCOS abdominal tissue revealed larger-sized adipose cells in b th b d bboth obese and nonobese women preferential abdominal accumulation of adipose tissue?


Androgens excess

Alpanes M et al. Expert Rev. Endocrinol. Metab. 7(1), 91-102. 2012.

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Hyperinsulinemia and hyperandrogenism

Insulin stimulates ovarian & adrenal androgen secretion.

Insulin decreases SHBG synthesis in the liver which increases free androgen tissue availability.increases free androgen tissue availability.

Insulin decreases IGFBP-1 in liver and ovary.

Insulin upregulates ovarian IGF receptors resulting in amplification of IGF actions in the ovary.

Insulin increases LH receptors in the ovary & sensitizes LH secreting pituitary cells to GnRH stimulation.

I li i h d f i Insulin promotes ovarian growth and cysts formations.


Alpanes M et al. Expert Rev. Endocrinol. Metab. 7(1), 91-102. 2012.

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PCOS Management

Weight loss improves hormone imbalance through improved insulin levels/sensitivity. Decreased P450c17 enzyme activity, reduced leptin. Reduced androgens, increased SHBG, improved

ovulation/fertility unique finding in PCOS women.

Insulin lowering drugs reduced androgen concentration and improve SHBG levels. Results were positive even without changes in weight. Some data to suggest that obese PCOS women have

favorable weight loss.g

Antiandrogens improve IR/HI in all PCOS women.

OCPs reduce androgen activity and may improve weight/insulin sensitivity in some.


Summary

Most experts agree that androgen excess is critical in describing PCOS.

Evidence suggests that androgen excess may be Evidence suggests that androgen excess may be causally involved in abdominal fat accumulation in women.

In PCOS, those with more HA are described to have more metabolic dysfunction and CV risks.

Correction of HA may improve the abdominal adiposity and related metabolic disorders Thisadiposity and related metabolic disorders. This treatment would still require TLC.

Obese PCOS women appear to have more severe IR/HI as compared to weight matched controls.

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Summary

Increased androgen secretion by ovarian theca cells appears to be key in PCOS.

Androgen excess favors the development of abdominal adiposity, i li i t t h i li i d b tlinsulin resistance, compensatory hyperinsulinism and subsequently further androgen excess.

This cycles predisposes these women to metabolic dysfunction and CV risk.

Increased androgens explain cutaneous manifestations of PCOS, intraovarian androgen excess leads to ovulatory dysfunction and polycystic ovarian morphology.

In mild androgen excess PCOS may only become apparent when In mild androgen excess, PCOS may only become apparent when associated with increased obesity or IR.

Current therapies focus on addressing the androgen excess, IR and adiposity.

Proposed PCOS/Obesity Cycle

Hyperandrogenism • Androgens contribute to IR/HI &Ob it

↑Estrogen

↑LH↑HPA

&Obesity• Obesity and insulin

dysregulation contribute to HA.

Insulin resistance & hyperinsulinemiaObesity

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Thank you.

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