Patho physiology of pcos

very important topic

1. PATHO-PHYSIOLOGY OF PCOS DR. LIPIKA MOHARANA CHIEF CONSULTANT INFERTILITY, PCOS, SEXUAL MEDICINE AAROGYAM CLINICS CUTTACK, ODISHA

2. Polycystic Ovaries Insulin Resistance Hyper- Androgenemia Obesity Oligo /An-Ovulation & Sub-Fertility NAVIGATING THE PATHO-PHYSIOLOGIC LABYRINTH

3. OUTLINES INTRODUCTION ETIOLOGY PATHO-PHYSIOLOGY DE-MYSTIFYING THE MYSTERY CONCLUSION

4. INTRODUCTION PCOS affects 6-10% of women of reproductive age The heterogeneity of ovarian morphology & clinical findings in women with PCOS is characteristic Despite being one of the most common endocrino-pathies , a clear comprehensive explanation of patho -physiology is still lacking It’s rational to consider the syndrome as a result of a “vicious cycle” which can be initiated at any one of the many entry points Altered function at any point in the cycle leads to the same end result: ovarian androgen excess & anovulation

5. Suggested Theories A unique defect in insulin action & secretion that leads to hyper- insulinemia & insulin resistance A primary neuro -endocrine defect leading to an exaggerated LH pulse frequency and amplitude A defect of androgen synthesis that results in enhanced ovarian androgen production An alteration in cortisol metabolism resulting in enhanced adrenal androgen production All of these circuits are closely inter-related

6. ETIOLOGY

7. PRE-NATAL/INTRA-UTERINE EXPOSURE GENETIC PRE-DISPOSITION EPIGENETIC MODIFICATIONS ENVIRONMENT DIET & LIFE-STYLE

8. Pre-natal exposure to raised androgen levels & abnormal maternal metabolic parameters increases susceptibility to PCOS .( Barker's Hypothesis ) Genes related to androgen biosynthesis , action & regulation (CYP17,CYP11A,CYP19,LH-1), genes involved in insulin resistance & metabolic functions (INSR) & genes encoding inflammatory cytokines (PON1) play a major role in genetic predisposition to PCOS. GWAS revealed a strong association at 2p16.3,2p21 & 9q33.3 for PCOS. Familial clustering of cases suggest an autosomal dominant inheritance with variable penetrance Epigenetic changes like leukocyte telomere length , DNA methylation , non-coding RNAs have a significant role in origin of PCOS. Telomere length is inversely proportional to serum DHEAS levels

9. Probable Genes Involved

10. Environmental factors , like advanced glycation end products (AGEs) , bis -phenol A (BPA ) exacerbate the symptoms & signs of PCOS, by acting as endocrine disruptors Diet - excessive dietary calorie intake , intake of diet rich in saturated fats , refined sugars leads to increased production of AGEs & hence worsens symptoms of PCOS. Lifestyle patterns- Sedentary lifestyle & lack of exercise play a significant role in initiation & exacerbation of symptoms of PCOS Epilepsy patients have an increased predisposition to PCOS

11. PATHO-PHYSIOLOGY

12. DISRUPTION OF THE HYPO-THALAMO-PITUITARY AXIS INSULIN-RESISTANCE(IR) & HYPER-INSULINEMIA HYPER-ANDROGENEMIA(HA) OBESITY DYSREGULATION OF OVARIAN STEROIDOGENESIS ABNORMALITIES OF ADRENAL STEROIDOGENESIS MISCELLANEOUS

13. DISRUPTION OF HPO AXIS LH hyper-secretion , both basal & in response to GnRH stimulation is a characteristic hallmark of PCOS Highest LH values occur in the afternoon . Bio-active LH is elevated in many patients who have normal immuno -active LH The possible reasons for the LH hyper-secretion may be: The increased activity of neurons occurs at both the hypothalamic & pituitary levels . LH & GnRH pulses are persistently rapid, thereby favor LH synthesis, hyperandrogenemia and impaired follicular maturation There is an underlying insensitivity of the hypothalamic GnRH pulse generator to estrogen & progesterone feedback inhibition - Increased sensitivity of the pituitary to gonadotropin stimulation ( possibly due to hyper- insulinemia ) - Increased pulse frequency of GnRH secretion, with preferential LH release - Diminished thalamic opioid inhibition of hypothalamus , due to reduced progesterone levels

14. Ovarian-pituitary feedback of LH secretion The pulsatile secretion of GnRH is an essential pre-requisite for normal pituitary function. At low concentrations of estrogen, it inhibits both FSH & LH, FSH more than LH. High levels of estrogen exhibit a positive feedback on LH, causing the mid-cycle LH surge, whereas a high steady level of estrogen , as in PCOS leads to a sustained elevated LH level , instead of a pulsatile release. Raised androgen levels at the periphery as well as the ovary lead to diminished negative feedback of sex steroids on hypothalamus & pituitary. The lack of FSH rise is also due to increased inhibin production by ovaries & raised AMH levels, secreted by pre- antral follicles. Increased levels of growth factors, especially IGF-1, TGF-alpha & beta & EGF inhibit FSH action on follicles leading to follicular arrest

15. Neuro -endocrine chain of PCOS

16. Accessory neuropeptides in PCOS The GABAergic system, neuropepetide -Y, dynorphin , kisspeptin , melatonin, KND gamma cells play a significant role in neuro-modulatory roles in PCOS These accessory neuro -modulators have an important effect on hunger, appetite, satiety & sleep patterns in PCOS

17. IR & HYPER-INSULINEMIA The earliest recognized symptoms of PCOS were linked to insulin resistance Was earlier called “the diabetes of bearded women” Both obese & non-obese women with the syndrome are insulin resistant compared to age & weight matched controls There are several mechanisms contributing, major ones including peripheral target tissue resistance, decreased hepatic clearance & increased pancreatic sensitivity.

18. Probable mechanisms Genetic susceptibility Life-style patterns ( diet, lack of exercise, stress, lack of quality sleep) Obesity, esp. abdominal ( both a cause & consequence ) Inherent pancreatic beta cell dysfunction Decreased hepatic clearance of insulin, due to raised free fatty acid levels, especially in obese & dys - lipidemic patients A factor extrinsic to insulin receptor, a serine/threonine kinase causes serine phosphorylation (instead of tyrosine auto-phosphorylation) of the insulin receptor, leading to defective signaling (a post receptor defect)

19. Effects of IR & Hyper- I nsulinemia Increased pituitary sensitivity to GnRH & hence, raised LH levels Decreased hepatic production of SHBG , resulting in raised androgen levels & it’s consequences Decreased production of IGF-1BP from liver, resulting in raised levels of IGF-1 , causing increased ovarian stromal thecosis & decreased response to FSH. “Insulin paradox”- despite peripheral tissue resistance, ovaries remain sensitive to actions of insulin. It mediates LH induced androgen synthesis from theca cells, acting as a co-gonadotropin . It also up-regulates LH & IGF-1 receptors & increases P450c17 Raised insulin & IGF-1 levels increase ACTH levels & adrenal steroid production Has significant effect on lipid & carbohydrate metabolism as well as hunger, thereby potentiating obesity & its potentiating effects on PCOS

20. Causes & effects of IR

21. Effects of IR in PCOS

22. An overview of effects of insulin resistance

23. HYPER-ANDROGENEMIA There is a positive correlation between the degree of hyper- androgenemia & clinical features associated with IR. “ TWINNING PATH O -PHYSIOLOGIC FACTORS” Serine auto-phosphorylation produces both insulin resistance & hyper- androgenemia Most of the clinical features of the syndromes have IR & HA as the major patho -physiology Management of the syndrome is targeted towards lowering both insulin & androgen levels

24. IR & HA Twinning in Patho -Physiology& Management

25. Probable Causes Hyper-secretion of LH, up-regulation of LH receptors on theca cells & increased androgen production Insulin(co-gonadotropin) & IGF-1 mediated exaggerated P450c17 activity in theca cells, leading to increased androgen production Intrinsic theca cell dysfunction & ovarian enzyme over-activity ACTH, insulin & IGF-1 mediated adrenal steroid synthesis

26. Effects of Hyper- Androgenemia Cosmetic features including acne, hirsutism , hyper-pigmentation, acanthosis nigricans , alopecia & unwanted hair growth Oligo /amenorrhea Chronic oligo /anovulation Follicular growth arrest Sub-fertility

27. OBESITY 40-60% PCOS patients are over weight or obese Adipose tissue dysfunction may play a central role in PCOS, by contributing to IR with consequent increase in androgens and leptin Increased levels of FFA from adipose tissue metabolism reduces insulin clearance in liver Obese patients have higher levels of ghrelin , a gastric peptide, which is orexigenic & adipogenic Obese patients have lower levels of adiponectin , which is protective against IR Decreased levels of SHBG , thereby increasing free androgen levels There’s reduced menstrual cyclicity & increased prevalence of oligo / anovulation Attenuated response to gonadotropins & lower ART success rates

28. Effect of obesity on PCOS

29. The link & the consequence

30. DYS-REGULATION OF OVARIAN STEROIDOGENESIS PCOS is a form of gonadotropin-dependant ovarian hyper- androgenism in which the central abnormality is an elevated intra-ovarian androgen concentration. Increased androgen production is a stable phenotype of PCOS theca cells propagated in long term culture, suggesting an intrinsic theca cell abnormality, as well . Women with PCOS have an increased formation of 17-alpha OHP & ASD in response to LH, because of abnormal enzymatic (P450c17 ) regulation, i.e. ( co- ordinately increased activity of 17-alpha hydroxylase & C17,20-lyase) There is a significant increase in both basal & LH-stimulated ASD production per theca cell in polycystic ovaries

31. Dysregulation of steroid biosynthesis & metabolism prominently involves P450c17 enzyme in theca cells, as a response to LH & insulin This enzyme performs both 17-alpha hydroxylation & 17,20-lyase functions in both ovaries & adrenals This enzymatic dys -regulation may be evident in ovaries alone, only adrenals or both. In most of the cases ovaries form the major contributor(mainly ASD) to excess androgen secretion P450c17 & 3-betaHSD enzyme activities were increased by more than 500-1000% in theca cells of polycystic ovaries

32. Dys -regulated ovarian steroidogeneisis

33. Ovarian Hyper- androgenism A signifiacant link

34. ABNORMAL ADRENAL STEROIDOGENESIS Increased adrenal androgen production in 25-30% of PCOS women May be a result of a genetic trait or secondary ovarian hormonal secretion or disturbed HPO axis or IR. A recently studied mechanism is an altered cortisol metabolism , i.e. increased inactivation of cortisol by exaggerated 5-alpha reductase activity or impaired regeneration by defective 11-beta hydroxy steroid dehydrogenase Increased excretion of cortisol metabolites in urine in PCOS patients There is a compensatory rise in ACTH levels , resulting in increased adrenal androgen levels(DHEAS) & normalizing cortisol levels.

35. Increased 5-alpha to 5-beta reductase activity seen in PCOS patients Increased 5-alpha reductase activity in skin produces 5-alpha dihydro testosterone from testosterone , which leads to cutaneous manifestations Enhanced activity of 5-alpha reductase & diminished activity of 11-beta hydroxy steroid dehydrogenase is due to raised androgen levels itself, thereby forming a “vicious cycle” The hyperactivity of 5-alpha reductase is mediated through IGF-1 , which is raised in PCOS Raised PRL levels down-regulate the enzyme activity, hence is a protective mechanism against unwanted hair growth

36. Altered peripheral cortisol metabolism is a proposed mechanism in development of PCOS

37. MISCELLANEOUS K iss -1 S ystem - Disturbed HPO axis functions accentuates the gonadotropic abnormalities via kisspeptin molecules of the Kiss-1 system V it D - Decreased Vit D has been correlated with IR, incr. BMI, raised testosterone & DHEAS in women with PCOS. Vit D also exerts a protective effect against the inflamatory action of AGEs by increasing sRAGE I mmune D ysregulation - Endometrial deficienct expression of GAB-1 protein & mRNA, hyperactivity of growth factors & over expression of fibrillin-3 gene leads to ovarian stroma expansion & matrix deposition characteristic of PCOS

38. DE-MYSTIFYING THE MYSTERY

39. CONCLUSION A combination of genetic & environmental factors predispose to PCOS A complex interplay of genetic tendency, hyper- androgenism , insulin resistance, dietary intake & obesity Genes related to sex steroid synthesis, insulin receptors, metabolism & inflammatory cytokines are likely to be involved Inheritance of PCOS shows autosomal dominance with variable penetrance Environmental factors starting from pre-natal exposure & life-style as well as dietary patterns play a significant role

40. CONCLUSION More than one organ is involved such as ovaries, liver, pancreas, CVS & the HPOA axis PCOS leads to disordered ovarian functions & anovulation characterized by abnormal steroidogenesis & disordered folliculogenesis , along with increased androgen levels & abnormal HPOA axis leading to changes in follicular microenvironment, follicular maturation arrest & infertility The management of infertility would be successful only, if the disturbed pathophysiology & all affected areas are taken care of by a multi-disciplinary approach

41. SUMMARIZING PCOS

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