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

7. ETIOLOGY

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

9. • 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

10. Probable Genes Involved

11. • 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

14. PATHO-PHYSIOLOGY

15. • 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

16. 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

17. 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

18. Neuro-endocrine chain
of PCOS

19. 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

20. 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.

21. 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)

22. Effects of IR & Hyper- Insulinemia
• 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

23. Causes & effects of IR

24. Effects of IR in PCOS

25. An overview of effects of
insulin resistance

26. HYPER-ANDROGENEMIA
• There is a positive correlation between the degree
of hyper-androgenemia & clinical features
associated with IR.
• “TWINNING PATHO-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

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

28. 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

29. 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

30. 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

31. Effect of obesity on PCOS

32. The link & the consequence

33. 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

34. • 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

35. Dys-regulated ovarian steroidogeneisis

36. Ovarian Hyper-androgenism A signifiacant link

37. 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.

38. • 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

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

40. MISCELLANEOUS
• Kiss-1 System- Disturbed HPO axis functions
accentuates the gonadotropic abnormalities via
kisspeptin molecules of the Kiss-1 system
• Vit 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
• Immune Dysregulation- 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

41. DE-MYSTIFYING THE
MYSTERY

43. 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

44. 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

45. SUMMARIZING PCOS

46. THANK YOU