Recent advancements in polycystic ovarian syndrome diagnosis and therapy

Svetlana Ten, MDPediatric  Endocrinologist

Brooklyn, NY , USA

PCOS criteria in Adolescence

In adolescence, there is overlap between the features of PCOS and

physiologic findings observed during the normal progression of puberty.

•Oligomenorrhea or amenorrhea at least 2 years postmenarche

• Clinical/biologic hyperandrogenism

•Polycystic ovary using transabdominal US an ovarian volume > than 10 cm 3

PCOS is a heterogeneous group of disorders

• Androgen excess

Ovarian and/or Adrenal in origin

• PCOS Lean and Overweight

with insulin resistance

Underlying insulin resistance and metabolic

syndrome are increasingly recognized to be one

of the causes or highly associated

with Polycystic Ovary Syndrome.

Skin

Acanthosis nigricans

Skin tags

Heart Increased Cancer Risk

Premature Atherosclerosis

Hypertension

Pancreas

DiabetesOvaryHyperandrogenism

Alopecia, Acne

PCOS

Infertility

Muscle

TG accumulation

Features of the Insulin Resistance Syndrome:

Fat

DyslipidemiaCentrally biased obesity

Kidney

Focal IgA type glomerulosclerosis

Liver

Fatty liver

• She has been overweight since 5 years of age

• Acanthosis nigricans was noted from 11 yrs

• AN, Insulin resistance, IGTT

• Fatty liver, Elevated TG 442 mg/dl, low HDL 35 mg/dl

• Elevated Blood pressure from 16 yrs

• Adrenal profile was normal at 12 yrs

• Menarche - from 12 years of age, periods were irregular

• Testosterone became elevated from 15 yrs

2 OGTT revealed impaired glucose tolerance and severe Insulin resistance:

Time Glucose mg/dl Insulin uIU/ml

0 min 78 51.3 30 min 164 537 60 min 176 677 90 min 188 781 120 min 156 834.6

After 10 months of glucophage 500 mg BID

12/12/01 Glucose mg/dl Insulin uIU/ml

0 min 78 35.5 30 min 122 170 60 min 143 387 90 min 118 280 120 min 126 479

Hormones

normal values

9/27/00

LH U/L 2.8 FSH U/L 4.9 SHBG nmol/L 15-123 7 Cholesterol mg/dl 150-200 187

TG mg/dl 35-135 442

HDL mg/dl > 40 35

ALT U/L 1-30 43

13 yrs old girl with

•Obesity BMI 32.3 kg/m2

•AN, Insulin resistance, IGTT

•Fatty liver, Elevated TG

Subhashini Yaturu (2013). Diabetes and Cancer, Type 2 Diabetes, Prof. Kazuko Masuo (Ed.), ISBN: 978-953-51-1171-9, InTech, DOI

SHBG and Insulin resistance

Ovarian steroid biosynthetic pathwaysOvarian steroid biosynthetic pathways

Endocrinol Metab Clin North Am 1999; 28:265. LH stimulates LH stimulates

androgen androgen formation within formation within

theca cellstheca cells..

Insulin

Journal of Clinical Endocrinology & Metabolism.

68(6):1027-32, 1989 Jun.Nestler JE et al.

Suppression of serum insulin by diazoxide reduces serum testosterone levels in obese women with polycystic ovary syndrome.

In despite suppression of insulin release, diazoxide administration did not affect serum total testosterone or sex hormone-binding globulin in nonobese

healthy women.

Modulation by insulin of follicle-stimulating hormone and luteinizing hormone actions in human granulosa

cells of normal and polycystic ovaries.

Willis D - J Clin Endocrinol Metab - 01-Jan-1996; 81(1): 302-9

Insulin preincubation enhances the subsequent response of human

granulosa cells to LH.

Thecal cells were isolated from one woman with PCOS (PCOS) and one healthy woman (non-PCOS) and cultured in the absence or presence of various concentrations of insulin.

Insulin stimulates testosterone biosynthesis in human thecal cells Nestler JE - J Clin Endocrinol Metab - 01-Jun-1998; 83(6): 2001-5

  MetforminTherapy in Obese Adolescents with  Polycystic OvarySyndrome and Impaired Glucose Tolerance:Amelioration of Exaggerated Adrenal Response to

Adrenocorticotropin with Reduction of Insulinemia/Insulin Resistance Silva A.Arslanian et al.JCEM, 2002; 87: 1555 - 1559. 

Correlation between fasting Insulin  and 17-hydroxypregnenelone response to ACTH in adolescents with PCOS.

Early metformin therapy prevents progression from Precocious Pubarche to PCOS

Lourdes Ibáñez MD, PhD, The Journal of PediatricsVolume 144, Issue 1, January 2004, Pages 23-29

Metformin Therapy During Puberty Delays Menarche, Prolongs Pubertal Growth, and Augments Adult Height

Metformin treatment resulted in • a longer duration from stage 2 breast development to

menarche, taller near-adult height • Leaner body composition • Lower insulin resistance, Leptin and IGF-I levels• Higher SHBG and IGFBP-1 levels • Improved lipid profile• Bone mineral density and uterine-ovarian growth were

unaffected

Ibáñez, L. et al., J Clin Endocrinol Metab 2006;91:2068-73.

Effects of Rosiglitazone in Obese Women with Polycystic Ovary Syndrome and Severe Insulin ResistanceJCEM Vol. 90, No. 1 60-65, 2005

Rosiglitazone therapy: •Improves insulin resistance and glucose tolerance in PCOS

• Decreases ovarian androgen, independent of changes in LH

•Restore ovulation with no change in BMI

•Attenuation of insulin levels was associated with decreased testosterone levels

Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a

randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation.

J Clin Endocrinol Metab. 85:139–146, 2000

• In PCOS metformin reduced Insulin and Androgens and normalized ovulation.

Baseline predictors of clinical response to metformin:

•Higher plasma insulin

•Lower serum androstenedione

•less severe menstrual abnormalities

Elevated concentrations of myo-inositol in human follicular fluids appear to play a positive function in follicular maturity are as well mediators of insulin action.

Myo-Inositol was classified as a member of the vitamin B complex (often referred to as vitamin B8), but was found to be synthesized by the human body.

Myo-inositol is naturally present in a variety of foods. According to research, foods containing the highest concentrations of myo-inositol include fruits, beans, grains, and nuts.

Androgen and lipid profiles in adolescents with polycystic ovary syndrome who were treated with two forms of combined oral

contraceptives.Fertil Steril. 2002 May;77(5):919-27

• Treatment of adolescent girls with PCOS was effective in decreasing hirsutism and androgen levels.

• Combined oral contraceptives were associated with an increase of cholesterol, LDL and HDL

Lean Women with Polycystic Ovary Syndrome Respond to Insulin Reduction with Decreases in Ovarian P450c17  Activity and Serum

AndrogensJohn E. Nestler and Daniela J. Jakubowicz

J. Clin. Endocrinol. Metab., Dec 1997; 82: 4075 - 4079. 

Results: •Lean PCOS (NIRPCO) had Insulin sensitivity, Insuln secretion, SBP, IGF-1, IGFBP-3 and C-peptide lower than obese PCOS (IRPCO). •Lean PCOS didn’t have history of type-2 diabetes in first-degree relatives. •LH/FSH ratios were higher in Lean PCOS. •There were no difference in testosterone levels between groups. •The degree of insulin resistance did not correlate with testosterone.•A history of type-2 diabetes in first-degree relatives was present in 81 % cases of Obese PCOS (13 from 16 cases)

Ten S 2003 PAS

After dexamethasone suppression the IRS-PCOS group had significantly higher testosterone levels than did the group without insulin resistance

There were no differences at baseline in testosterone levels between both groups.

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Testosterone levels:

ISR-PCO PCO

at baseline

after aygestin

after dexamethasone

Design/Patients: We enrolled 54 adolescents with PCOS and 18 controls for evaluation of glucocorticoid sensitivity. Number of Glucocrticoid receptors was compared between patients and controls and was found to be the same by flowcytometry.

Impaired glucocorticoid sensitivity clinically present as Polycystic Ovarian Syndrome.

ESPE 2013Divya, Khurana, Aristotle Panayiotopoulos, Josef Michl, Felicitas Lacbawan, Amrit Bhangoo,Svetlana Ten , Steven Ghanny

Functional studies of the glucocorticoid receptor were done by using Fluorinated Dexamethasone (F-Dex) Monocyte binding studies. Glucocorticoid Resistance Index (GCRI) was calculated as AUC from the curve of F-Dex binding results according trapezoid rule

• Twenty nine (54 %) patients with PCOS had decreased F-dex binding and considered glucocorticoid resistant (GCR)

• 4 (7%) had increased F-dex binding and considered glucocorticoid sensitive (GCS)

• 18 (33 %) had GC sensitivity the same as controls.

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GC Index

• GCRI correlated with 17 pregnenalone, Testosterone and Cortisol.

However, the mechanisms of this process that is likely involving glucocorticoid receptor signaling has to be addressed in future studies.

Groups GCI Testosterone ng/dl

DHEA Androstendione Cortisol

Adrenal Androgen PCOSN=26

57% GCR

25.7 ± 11 391 ±262

120 ± 30 27 ± 6

Ovarian and Adrenal PCOSN=21

45% GCR

77 ± 30 731 ±495

247 ± 128 29 ± 7

P < 0.05 P < 0.03

P < 0.01

An oral low- and high-dose dexamethasone (DEX)-suppression test (Liddle’s test) was done in 38 women with PCOS and 20 healthy volunteers (HV) aged 16-29 yrs

•Baseline urinary 17OHS were higher in the women with PCOS vs HV (5.7±1.6 vs 4.4±2.4 mg/gr creatinine/day)

•UFC was higher in the PCOS group (2.0±0.7 mcg/m2/day) than the HV group (1.5±0.5) on day 8 of the Liddle’s test

•17OHS and UFC were negatively correlated with adrenal volumes.

•PCOS patients above the 75th quartile for UFC or 17OHS after high dose dexamethasone had a significantly smaller total adrenal volume when compared to the remaining PCOS patients (6.9±1.9 vs 9.2±1.8 cc).

Conclusion: in a subset of young women with PCOS there is a micronodular adrenocortical hyperplasia: smaller adrenals, with some nodularity, and in association with higher steroid hormone secretion after dexamethasone than controls.

Micronodular Adrenal Hyperplasia: A New Mechanism for Hyperandrogenism in Women with Polycystic Ovarian Syndrome Session: MON 0057-0090-Hyperandrogenic Disorders, June 2014Evgenia Gourgari, Maya Beth Lodish, Margaret Keil, Ninet Sinai, Evrim Turkbey, Charalampos Lyssikatos, Divya Khurana, Chris Crutchfield, Maria V Nesterova, , Maria De La Luz Sierra, Paraskevi Xekouki, Peter Backlund , Al Yergey, Svetlana B Ten, Adrian Sandra Dobs, Constantine A Stratakis.

Expression of 11 -hydroxysteroid dehydrogenase 1 and 2 in subcutaneous adipose tissue of lean and obese women with and without polycystic ovary syndrome P F Svendsen, S Madsbad, L Nilas, S K Paulsen and S B Pedersen

Recent evidence further suggests that high fat-mediated downregulation of adipose 11beta -HSD1