- 1.Polycystic Ovarian Syndrome (PCOS) Pathophysiology & Wider Health Issues Dr. Mariam Al-Saqqa Consultant Obstetrics & Gynecology
- In 1935 Stein & Leventhal described seven women presenting with oligomenorrhea combined with the presence of bilateral polycystic ovaries (PCO) established during surgery.
- Three of these seven women also presented with obesity, while five showed signs of hirsutism.
3. Introduction (cont):
- Only one woman has both obesity & showed hirsutism.
- The polycystic ovarian syndrome, one of the most common causes of infertility due to anovulation affecting 4-10% of women
4. Introduction (cont):
- 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.
- Rotterdam consensus 2003, PCOS is defined as a syndrome of ovulation dysfunction along with the cardinal features of hyperandrogenism & polycystic ovaries morphology.
5. Pathophysiology of PCOS:
- PCOS is a condition that originates possibly at the time of puberty due to interplay of:
- (1) obesity & excess of ovarian androgenproduction, due to hyperinsulinemia
- (2) intrauterine environment.
- (3) genetic factors both X-linked, autosomaldominant modes of inheritance.
- (4) disturbance to hypothalamic-pituitary-ovarianaxis.
6. (1) Impact of obesity in PCOS pathophysiology:
- Obesity is strongly associated with PCOS, it ranges from 30%-75% of cases.
- 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.
7. Impact of obesity in PCOS pathophysiology (cont) :
- 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.
- 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.
8. Obesity & sex hormone binding protein (SHBG):
- Obesity is considered a condition of SHBG imbalance.
- Levels of SHBG tend to decrease with increasing body fat, this lead to an increased fraction of free androgens delivered to target sensitive tissues.
9. Obesity & sex hormone binding protein (SHBG):
- SHBG levels are regulated by a complex of factors including estrogens, iodothyronines & GH as stimulating agents and androgens & insulin as inhibitory factors.
- 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.
10. Role of leptin in the pathophysiology of PCOS:
- Leptin is considered as one of the major peripheral signals that affects food intake & energy balance.
- Obesity is a classic condition of circulating leptin excess.
11. Role of leptin in the pathophysiology of PCOS:
- 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.
- Mitchell m in 2005, there is evidence that leptin acts directly on the ovaries through functional receptors defect.
12. Potential role of the endocannabinoid system:
- 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.
- 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).
13. Potential role of the endocannabinoid system (cont):
- 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.
- 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.
14. Potential role of the endocannabinoid system (cont):
- Endocannabinoids are deeply involved in the dynamic & homeostatic regulation of feeding & energy metabolism.
- Di Marzo et al 2004 showed that antagonists of CB1 receptors may reduce food intake.
- The regulation of metabolic process includes both central at the hypothalamic level & peripheral actions in the adipose tissue & liver.
15. Potential role of the endocannabinoid system (cont):
- The peripheral action of the endocannabinoids has been documented in animal models treated with a selective CB1 antagonist rimonabant by Jbiloo et al 2005.
- Despite JP et al 2005 used rimonabant in patients as a new pharmacological treatment for tackling obesity.
- The endocannabinoid system has been found to regulate multiple endocrine functions including H-P-O axis.
16. Potential role of the endocannabinoid system (cont):
- 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 glucosetransport for recruitment & activation.
- 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.
17. Insulin resistance, hyperinsulinemia & hyperandrogenism:
- The association between increased insulin resistance & PCO is well recognized.
- Acanthosis nigricans in hyperandrogenic women is dependent upon the presence & severity of hyperinsulinemia.
- There are several mechanisms for the state of insulin resistance: peripheral target tissue resistance, decrease hepatic clearance or increased pancreatic sensitivity.
18. 19. Insulin resistance, hyperinsulinemia & hyperandrogenism (cont):
- 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)
- Excess insulin participate in increased ovarian androgen syntheses (androsteindione & testosterone)
20. How does hyperinsulinemia produse hyperandrogenism?
- Android obesity is the result of fat deposition in the abdominal wall & visceral mesenteric locations.
- This fat is more active metabolically, resulting in higher free fatty acid concentrations leading to hyperglycemia.
- At higher concentrations, insulin binds to the IGF-1 receptors & augmenting the thecal androgen production.
21. How does hyperinsulinemia produse hyperandrogenism?
- Hyperinsulinemia leads to inhibition of hepatic syntheses of SHBG & inhibition of hepatic production of IGF-1 binding protein.
- In vitro studies indicate that both insulin & IGF-1 directly inhibit SHBGsecretion by human hepatoma cells.
- Hyperandrogenism, considered biochemically, free androgen index > 4.5 (FAI= total testosterone x 100 /SHBG).
22. Metabolic abnormalities in PCOS:
- Several metabolic abnormalities that are strongly influenced by the presence of obesity.
- Obese women affected by PCOS who present with glucose intolerance ranging from 20- 49%.
- Alterations of both lipid & lipoprotein metabolism, the coexistence of obesity leads to more atherogenic lipoprotein pattern.
23. Metabolic abnormalities in PCOS:
- A great reduction of (HDL) with higher increase of both triglycerides & total cholesterol, may make them prone to hypertension as well.
- Risk of atherosclerosis & premature cardiovascular events increases whether or not the woman is diabetic.
24. (2) Intrauterine environment & PCOS:
- 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.
- The apparent influence of intrauterine milieu in poorly controlled diabetics who end with stillborn fetuses, showed ovarian changes similar to those seen in PCOS.
- Aerts et al have shown that maternal diabetes induces insulin resistance in her offspring, this defect is acquired & not hereditary.
25. (3) Familial studies of PCO