Polycystic Ovarian Syndrome (PCOS) Pathophysiology & Wider Health Issues Dr. Mariam Al-Saqqa Consultant Obstetrics & Gynec...
Introduction: <ul><li>In 1935 Stein & Leventhal described seven women presenting with oligomenorrhea combined with the pre...
Introduction (cont): <ul><li>Only one woman has both obesity & showed hirsutism. </li></ul><ul><li>The polycystic ovarian ...
Introduction (cont): <ul><li>The presentations of PCOS are heterogeneous & may change through out the lifespan, starting f...
Pathophysiology of PCOS: <ul><li>PCOS is a condition that originates possibly at the time of puberty due to interplay of: ...
(1) Impact of obesity in PCOS pathophysiology: <ul><li>Obesity is strongly associated with PCOS, it ranges from 30%-75% of...
Impact of obesity in PCOS pathophysiology (cont) : <ul><li>Obesity induces, through the path of insulin resistance, high l...
Obesity & sex hormone binding protein (SHBG): <ul><li>Obesity is considered a condition of SHBG imbalance. </li></ul><ul><...
Obesity & sex hormone binding protein (SHBG): <ul><li>SHBG levels are regulated by a complex of factors including estrogen...
Role of leptin in the pathophysiology of PCOS: <ul><li>Leptin is considered as one of the major peripheral signals that af...
Role of leptin in the pathophysiology of PCOS: <ul><li>The discrepancy between increased leptin blood levels & its central...
Potential role of the endocannabinoid system: <ul><li>Endocannabinoids are derivatives of arachidonic acid & they belong t...
Potential role of the endocannabinoid system (cont): <ul><li>An interesting aspect of the endocannabinoid system is its ac...
Potential role of the endocannabinoid system (cont): <ul><li>Endocannabinoids are deeply involved in the dynamic & homeost...
Potential role of the endocannabinoid system (cont): <ul><li>The peripheral action of the endocannabinoids has been docume...
Potential role of the endocannabinoid system (cont): <ul><li>Van et al in Lancet 2005, showed that CB1 antagonist have bee...
Insulin resistance, hyperinsulinemia & hyperandrogenism: <ul><li>The association between increased insulin resistance & PC...
 
Insulin resistance, hyperinsulinemia & hyperandrogenism (cont): <ul><li>Insulin resistance leads to compensatory hyperinsu...
How does hyperinsulinemia produse hyperandrogenism? <ul><li>Android obesity is the result of fat deposition in the abdomin...
How does hyperinsulinemia produse hyperandrogenism? <ul><li>Hyperinsulinemia leads to inhibition of hepatic syntheses of S...
Metabolic abnormalities in PCOS: <ul><li>Several metabolic abnormalities that are strongly influenced by the presence of o...
Metabolic abnormalities in PCOS: <ul><li>A great reduction of (HDL) with higher increase of both triglycerides & total cho...
(2) Intrauterine environment & PCOS: <ul><li>Hague et al 1988 postulated that the intrauterine environment has a role in t...
(3) Familial studies of PCOS: <ul><li>Goind et al 1999 studied 1 st  degree relatives of 29 women affected by PCOS & 10 as...
Familial studies of PCOS (cont): <ul><li>Urbbanek et al 1999, carried out a multicenter study using the same diagnostic cr...
Familial studies of PCOS (cont): <ul><li>Follistatin is a glycosylated polypeptide homologous to epidermal growth factor, ...
(4) The disturbance of the hypothalamic-pituitary-ovarian axis H-P-O: <ul><li>Evidence of dysfunction at the level of both...
Abnormal folliculogenesis: <ul><li>Estradiol levels may not fall low enough to allow sufficient  FSH response for initial ...
Abnormal steroidogenesis: <ul><li>The LH stimulates the theca cells to produce androgens witch are the precursor for estro...
Abnormal LH stimulus <ul><li>Granulosa cells of small antral follicles in anovulatory women with PCOS acquire LH receptors...
Clinical features of PCOS: <ul><li>Menstrual abnormalities 80% </li></ul><ul><li>Infertility “anovulation” </li></ul><ul><...
Clinical features of PCOS: <ul><li>Increased risk of endomentreal cancer & ? Breast cancer </li></ul><ul><li>Hyperlipidemi...
Criteria for classification of PCOS: <ul><li>Major criteria </li></ul><ul><li>Anovulation </li></ul><ul><li>Oligominorrhea...
Diagnosis of PCOS: <ul><li>Tendency  of PCOS; presence of one minor criteria </li></ul><ul><li>Mild form  of PCOS; presenc...
 
 
Differential diagnosis of PCOS: <ul><li>The differential diagnosis of hirsutism & oligomenorrha includes: </li></ul><ul><l...
Investigations: <ul><li>History & physical examination </li></ul><ul><li>CD3: LH:FSH, E2, testosterone, androstendione, SH...
Treatment: <ul><li>The first step is to help the patient understand that this chronic disease process can be controlled by...
Treatment (cont): <ul><li>Metformin may complement the effects of lifestyle modification, it causes marked improvement in ...
 
Treatment (cont): <ul><li>Adrenal suppression by dexamethasone 0.5mg at night facilitate ovulation. </li></ul><ul><li>Anti...
Case presentation of PCOS: <ul><li>Mrs.: S.J. </li></ul><ul><li>Age: 35 years </li></ul><ul><li>Nationality: Indian </li><...
<ul><li>Investigation: </li></ul><ul><li>LH:17 IU/L </li></ul><ul><li>FSH:5 IU/L </li></ul><ul><li>Testosterone: ↑3.05 (0....
Management (cont): <ul><li>Treatment: </li></ul><ul><li>Ovulation was induced by clomiphine-citrate 100mg daily. </li></ul...
Management (cont): <ul><li>Pregnancy achieved after 3 cycles of Rx & it was twin pregnancy. </li></ul><ul><li>Gestational ...
Thank You
Upcoming SlideShare
Loading in...5
×

Polycystic Ovarian Syndrome (PCOS) Pathophysiology

7,935

Published on

0 Comments
11 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
7,935
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
406
Comments
0
Likes
11
Embeds 0
No embeds

No notes for slide

Polycystic Ovarian Syndrome (PCOS) Pathophysiology

  1. 1. Polycystic Ovarian Syndrome (PCOS) Pathophysiology & Wider Health Issues Dr. Mariam Al-Saqqa Consultant Obstetrics & Gynecology
  2. 2. Introduction: <ul><li>In 1935 Stein & Leventhal described seven women presenting with oligomenorrhea combined with the presence of bilateral polycystic ovaries (PCO) established during surgery. </li></ul><ul><li>Three of these seven women also presented with obesity, while five showed signs of hirsutism. </li></ul>
  3. 3. Introduction (cont): <ul><li>Only one woman has both obesity & showed hirsutism. </li></ul><ul><li>The polycystic ovarian syndrome, one of the most common causes of infertility due to anovulation affecting 4-10% of women </li></ul>
  4. 4. Introduction (cont): <ul><li>The presentations of PCOS are heterogeneous & may change through out the lifespan, starting from adolescence to post-menopausal age, & may have health impaction later in life. </li></ul><ul><li>Rotterdam consensus 2003, PCOS is defined as a syndrome of ovulation dysfunction along with the cardinal features of hyperandrogenism & polycystic ovaries morphology. </li></ul>
  5. 5. Pathophysiology of PCOS: <ul><li>PCOS is a condition that originates possibly at the time of puberty due to interplay of: </li></ul><ul><li>(1) obesity & excess of ovarian androgen production, due to hyperinsulinemia </li></ul><ul><li>(2) intrauterine environment. </li></ul><ul><li>(3) genetic factors both X-linked, autosomal dominant modes of inheritance. </li></ul><ul><li>(4) disturbance to hypothalamic-pituitary-ovarian axis. </li></ul>
  6. 6. (1) Impact of obesity in PCOS pathophysiology: <ul><li>Obesity is strongly associated with PCOS, it ranges from 30%-75% of cases. </li></ul><ul><li>Increased body weight in PCOS is often due to increased visceral fat, central obesity which is particularly associated with increased risk of cardiovascular diseases & type 2 diabetes & hypertention. </li></ul>
  7. 7. Impact of obesity in PCOS pathophysiology (cont) : <ul><li>Obesity induces, through the path of insulin resistance, high levels of insulin-related growth factors, these will stimulate theca cells to produce supranormal amounts of androgens & reduce (SHBG) syntheses by liver cells, thereby raising the proportion of free circulating testosterone. </li></ul><ul><li>The resulting androgen excess is considered to contribute to the presence of increased number of follicles in all stages, as well as arrested maturation of (FSH) sensitive follicles. </li></ul>
  8. 8. Obesity & sex hormone binding protein (SHBG): <ul><li>Obesity is considered a condition of SHBG imbalance. </li></ul><ul><li>Levels of SHBG tend to decrease with increasing body fat, this lead to an increased fraction of free androgens delivered to target sensitive tissues. </li></ul>
  9. 9. Obesity & sex hormone binding protein (SHBG): <ul><li>SHBG levels are regulated by a complex of factors including estrogens, iodothyronines & GH as stimulating agents and androgens & insulin as inhibitory factors. </li></ul><ul><li>The net balance , with the dominant role of insulin which inhibits SHBG synthesis in the liver, may be responsible for the decrease of SHBG concentrations observed in obesity. </li></ul>
  10. 10. Role of leptin in the pathophysiology of PCOS: <ul><li>Leptin is considered as one of the major peripheral signals that affects food intake & energy balance. </li></ul><ul><li>Obesity is a classic condition of circulating leptin excess. </li></ul>
  11. 11. Role of leptin in the pathophysiology of PCOS: <ul><li>The discrepancy between increased leptin blood levels & its central effects represents a leptin resistance as shown by study of Moschos et al 2002 in Fertility Sterility Journal. </li></ul><ul><li>Mitchell m in 2005, there is evidence that leptin acts directly on the ovaries through functional receptors defect. </li></ul>
  12. 12. Potential role of the endocannabinoid system: <ul><li>Endocannabinoids are derivatives of arachidonic acid & they belong to a family composed of an increasing numbers of compounds , the most studied so far being arachidonoyl ethanolamide (AEA) named anandamide. </li></ul><ul><li>Pagotto U in Endocrine review 2006, he focused on the emerging role of the endocannabinoid system in endocrine regulation & energy balance, through specific cannabiniod receptors type 1 (CB1) & type 2 (CB2). </li></ul>
  13. 13. Potential role of the endocannabinoid system (cont): <ul><li>An interesting aspect of the endocannabinoid system is its activity “on demand”, meaning that the system can b activated with a closely regulated selectivity: only “when” & “where” it is needed. </li></ul><ul><li>Astonishing amount of data accumulated providing deeper insights regarding the biological notes of the endocannabinoid system, it can be summarizes that it is involved in different physiological functions many of which are related to the stress recovery systems & to the maintenance of homeostatic balance. </li></ul>
  14. 14. Potential role of the endocannabinoid system (cont): <ul><li>Endocannabinoids are deeply involved in the dynamic & homeostatic regulation of feeding & energy metabolism. </li></ul><ul><li>Di Marzo et al 2004 showed that antagonists of CB1 receptors may reduce food intake. </li></ul><ul><li>The regulation of metabolic process includes both central at the hypothalamic level & peripheral actions in the adipose tissue & liver. </li></ul>
  15. 15. Potential role of the endocannabinoid system (cont): <ul><li>The peripheral action of the endocannabinoids has been documented in animal models treated with a selective CB1 antagonist “rimonabant” by Jbiloo et al 2005. </li></ul><ul><li>Despite JP et al 2005 used rimonabant in patients as a new pharmacological treatment for tackling obesity. </li></ul><ul><li>The endocannabinoid system has been found to regulate multiple endocrine functions including H-P-O axis. </li></ul>
  16. 16. Potential role of the endocannabinoid system (cont): <ul><li>Van et al in Lancet 2005, showed that CB1 antagonist have been found to increase energy expenditure through activation of futile cycles, enhance lipolysis & stimulate glucose metabolism increasing glucose transport for recruitment & activation. </li></ul><ul><li>It has been demonstrated that AEA fluctuates during ovarian cycle in both the hypothalamus & pituitary, thus influencing hormonal secretion & sexual behavior through CB1 receptor activation. </li></ul>
  17. 17. Insulin resistance, hyperinsulinemia & hyperandrogenism: <ul><li>The association between increased insulin resistance & PCO is well recognized. </li></ul><ul><li>Acanthosis nigricans in hyperandrogenic women is dependent upon the presence & severity of hyperinsulinemia. </li></ul><ul><li>There are several mechanisms for the state of insulin resistance: peripheral target tissue resistance, decrease hepatic clearance or increased pancreatic sensitivity. </li></ul>
  18. 19. Insulin resistance, hyperinsulinemia & hyperandrogenism (cont): <ul><li>Insulin resistance leads to compensatory hyperinsulinemia to the target tissues of insulin action, that become resistant to insulin, the ovaries remain responsive to insulin throughout the interaction with its own receptors, (fasting glucose/insulin ratio < 0.25 mmol/ mU) </li></ul><ul><li>Excess insulin participate in increased ovarian androgen syntheses (androsteindione & testosterone) </li></ul>
  19. 20. How does hyperinsulinemia produse hyperandrogenism? <ul><li>Android obesity is the result of fat deposition in the abdominal wall & visceral mesenteric locations. </li></ul><ul><li>This fat is more active metabolically, resulting in higher free fatty acid concentrations leading to hyperglycemia. </li></ul><ul><li>At higher concentrations, insulin binds to the IGF-1 receptors & augmenting the thecal androgen production. </li></ul>
  20. 21. How does hyperinsulinemia produse hyperandrogenism? <ul><li>Hyperinsulinemia leads to inhibition of hepatic syntheses of SHBG & inhibition of hepatic production of IGF-1 binding protein. </li></ul><ul><li>In vitro studies indicate that both insulin & IGF-1 directly inhibit SHBG secretion by human hepatoma cells. </li></ul><ul><li>Hyperandrogenism, considered biochemically, free androgen index > 4.5 (FAI= total testosterone x 100 /SHBG). </li></ul>
  21. 22. Metabolic abnormalities in PCOS: <ul><li>Several metabolic abnormalities that are strongly influenced by the presence of obesity. </li></ul><ul><li>Obese women affected by PCOS who present with glucose intolerance ranging from 20- 49%. </li></ul><ul><li>Alterations of both lipid & lipoprotein metabolism, the coexistence of obesity leads to more atherogenic lipoprotein pattern. </li></ul>
  22. 23. Metabolic abnormalities in PCOS: <ul><li>A great reduction of (HDL) with higher increase of both triglycerides & total cholesterol, may make them prone to hypertension as well. </li></ul><ul><li>Risk of atherosclerosis & premature cardiovascular events increases whether or not the woman is diabetic. </li></ul>
  23. 24. (2) Intrauterine environment & PCOS: <ul><li>Hague et al 1988 postulated that the intrauterine environment has a role in the pathogenesis of PCOS, & suggested that hyperandrogenism during fetal life may be the determining factor. </li></ul><ul><li>The apparent influence of intrauterine milieu in poorly controlled diabetics who end with stillborn fetuses, showed ovarian changes similar to those seen in PCOS. </li></ul><ul><li>Aerts et al have shown that maternal diabetes induces insulin resistance in her offspring, this defect is acquired & not hereditary. </li></ul>
  24. 25. (3) Familial studies of PCOS: <ul><li>Goind et al 1999 studied 1 st degree relatives of 29 women affected by PCOS & 10 asymptomatic control volunteers of reproductive age; sibling of the PCOS probands were affected for a segregation ratio of 55% which is considered with autosomal dominant inheritance with nearly complete penetrance in comparison to the control families with segregation ratio of 25% </li></ul>
  25. 26. Familial studies of PCOS (cont): <ul><li>Urbbanek et al 1999, carried out a multicenter study using the same diagnostic criteria for PCOS, tested 37 candidate genes for PCOS from 150 families with at least one affected member, they found follistatin gene with the strongest evidence & remained significant even after correction for multiple testing. </li></ul>
  26. 27. Familial studies of PCOS (cont): <ul><li>Follistatin is a glycosylated polypeptide homologous to epidermal growth factor, it binds to activin thereby reducing serum follicle stimulating hormone levels & increasing ovarian androgen production. </li></ul>
  27. 28. (4) The disturbance of the hypothalamic-pituitary-ovarian axis H-P-O: <ul><li>Evidence of dysfunction at the level of both the pituitary & the ovary in women with PCOS gave rise to the hypothesis of self-perpetual vicious cycles. </li></ul><ul><li>Abnormal gonadotrophin secretion characterized by overproduction of LH relative to FSH induces hyperactivity of ovarian stromal tissue, atresia of antral follicles & disordered ovarian steroidogenesis. </li></ul><ul><li>The resulting imbalance of estrogenic & androgenic steroids in turn accentuates the hypersecretion of LH by anterior pituitary. </li></ul>
  28. 29. Abnormal folliculogenesis: <ul><li>Estradiol levels may not fall low enough to allow sufficient FSH response for initial growth stimulus & levels of estradiol may be inadequate to produce the positive stimulatory effects necessary to induce the ovulatory surge of LH. </li></ul><ul><li>The mechanism of the disturbed folliculogenesis includes relative FSH deficiency & loss of LH stimulation, deficiency of certain local growth factors & abnormal ovarian steroidogenesis. </li></ul>
  29. 30. Abnormal steroidogenesis: <ul><li>The LH stimulates the theca cells to produce androgens witch are the precursor for estrogen synthesis. </li></ul><ul><li>The raising intraovarian estrogen & inhibin B concentration result in a negative feedback on FSH secretion & a positive feedback on LH secretion. </li></ul><ul><li>The resulting increase in LH, together with the rising inhibin B level, leads to further increase of androgen. </li></ul>
  30. 31. Abnormal LH stimulus <ul><li>Granulosa cells of small antral follicles in anovulatory women with PCOS acquire LH receptors prematurely at follicular diameter of 4mm. </li></ul><ul><li>LH receptors acquisition of the granulosa cells seem to switch the follicle from proliferative to differentiation, resulting in a suppression of granulosa cell growth & ultimately inducing an arrest of follicular development & a failure of dominance. </li></ul>
  31. 32. Clinical features of PCOS: <ul><li>Menstrual abnormalities 80% </li></ul><ul><li>Infertility “anovulation” </li></ul><ul><li>Hirsutism 60%, acne 70%, aloplecia </li></ul><ul><li>Increased risk of atherosclerosis & cardiovascular events. </li></ul><ul><li>Increased risk of diabetes mellitus in patients with hyperinsulinemia. </li></ul>
  32. 33. Clinical features of PCOS: <ul><li>Increased risk of endomentreal cancer & ? Breast cancer </li></ul><ul><li>Hyperlipidemia with its impact on atherosclerotic changes. </li></ul><ul><li>Hypertension observed later in life </li></ul><ul><li>Obesity 40% with health risks including saphenous varicosities, hemorrhoids, hernias & osteoarthritis. </li></ul><ul><li>Several mental health problems, depression, anxiety..etc </li></ul>
  33. 34. Criteria for classification of PCOS: <ul><li>Major criteria </li></ul><ul><li>Anovulation </li></ul><ul><li>Oligominorrhea </li></ul><ul><li>Hyperandrogenemia </li></ul><ul><li>Severe hirsutism </li></ul><ul><li>Insulin resistance </li></ul><ul><li>Minor criteria </li></ul><ul><li>Polycystic ovaries on ultrasound </li></ul><ul><li>Elevated LH:FSH </li></ul><ul><li>Acne </li></ul><ul><li>Mild hirsutism </li></ul><ul><li>Obesity </li></ul>
  34. 35. Diagnosis of PCOS: <ul><li>Tendency of PCOS; presence of one minor criteria </li></ul><ul><li>Mild form of PCOS; presence of two minor criteria </li></ul><ul><li>Moderate form of PCOS; presence of one major & one minor criteria </li></ul><ul><li>Severe form of PCOS; presence of one or more major & two or more minor criteria. </li></ul>
  35. 38. Differential diagnosis of PCOS: <ul><li>The differential diagnosis of hirsutism & oligomenorrha includes: </li></ul><ul><li>- congenital adrenal hyperplasia </li></ul><ul><li>- cushing syndrome </li></ul><ul><li>- hyperthecosis ovarii </li></ul><ul><li>- benign & malignant androgen </li></ul><ul><li>secreting tumors or ovaries. </li></ul>
  36. 39. Investigations: <ul><li>History & physical examination </li></ul><ul><li>CD3: LH:FSH, E2, testosterone, androstendione, SHBG, 17-OHp, DHEAS, prolactin, TSH, T3, T4 & fasting insulin level. </li></ul><ul><li>FBS, total cholesterol, LDL & HDL. </li></ul><ul><li>Pelvic ultrasound scan for the ovarian features of PCO </li></ul><ul><li>Specific imaging procedures to exclude adrenal tumors if presentation is rapid. </li></ul>
  37. 40. Treatment: <ul><li>The first step is to help the patient understand that this chronic disease process can be controlled by changes in lifestyle. </li></ul><ul><li>Lifestyle modification must be emphasized to include appropriate diets & exercise program is essential. </li></ul>
  38. 41. Treatment (cont): <ul><li>Metformin may complement the effects of lifestyle modification, it causes marked improvement in menstrual pattern & may improve the response to ovulatory agents. </li></ul><ul><li>Clomifene-citrate is the standard first line method of medical ovulation induction in anovulatory women. </li></ul><ul><li>The second line treatment, laparoscopic ovarian diathermy, gonadotrophin therapy. </li></ul>
  39. 43. Treatment (cont): <ul><li>Adrenal suppression by dexamethasone 0.5mg at night facilitate ovulation. </li></ul><ul><li>Anti-androgens: cyproterone acetate & EE in combination (dianatte) </li></ul><ul><li>Spironolactone: alternative anti-androgen. </li></ul><ul><li>Low dose of oral contraceptives are effective in treating acne & hirsutism, minimum of 2 years & cosmetic measures are needed to achieve good results. </li></ul>
  40. 44. Case presentation of PCOS: <ul><li>Mrs.: S.J. </li></ul><ul><li>Age: 35 years </li></ul><ul><li>Nationality: Indian </li></ul><ul><li>Status: married for 8 years </li></ul><ul><li>Obstetrical Hx: Nulliparous + ? Complete abortion 6 years ago. </li></ul><ul><li>Presented: irregular period & failure to conceive. </li></ul><ul><li>Weight: 50kg, height: 150cm -> BMI:22.2kg/m </li></ul><ul><li>Hirsute lady. </li></ul>
  41. 45. <ul><li>Investigation: </li></ul><ul><li>LH:17 IU/L </li></ul><ul><li>FSH:5 IU/L </li></ul><ul><li>Testosterone: ↑3.05 (0.2-2.9) nmol/L </li></ul><ul><li>Free testosterone: ↑0.04 (0.02-0.3) nmol/L </li></ul><ul><li>Bioavailable testosterone: ↑1.3 (0.1-1.0) nmol/L </li></ul><ul><li>SHBG:40.2 (20-100) nmol/L </li></ul><ul><li>Free androgen index = total testosterone x 100 / SHBG </li></ul><ul><li>= 3.05 x 100 /40.2 </li></ul><ul><li>= ↑7.5 (>4.5) </li></ul><ul><li>Pelvic scan showed cystic ovaries. </li></ul>Management:
  42. 46. Management (cont): <ul><li>Treatment: </li></ul><ul><li>Ovulation was induced by clomiphine-citrate 100mg daily. </li></ul><ul><li>She was put on 0.5mg dexamethasone daily at night for 2 months </li></ul><ul><li>Pregnyl 10000 IU to target ovulation when mature follicle ≈ 18mm. </li></ul>
  43. 47. Management (cont): <ul><li>Pregnancy achieved after 3 cycles of Rx & it was twin pregnancy. </li></ul><ul><li>Gestational diabetes diagnosed at 5 th month of pregnancy & she was managed by diet control. </li></ul><ul><li>Delivered by LSCS at 35 weeks gestation & delivered 2 baby girls 2.2kg & 2.3kg in good condition. </li></ul>
  44. 48. Thank You
  1. A particular slide catching your eye?

    Clipping is a handy way to collect important slides you want to go back to later.

×