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POLYCYSTIC OVARY SYNDROME
(PCOS) :
From the Ovary to the Pancreas
Division of Reproductive Endocrinology and Fertility
Dep...
POLYCYSTIC OVARIES
Abnormal ovarian morphology
Peripherally distributed follicles, like a necklace and completely
encircli...
PATHOPHYSIOLOGY
While the basic dysfunction seems to lie within the
ovary, however the clinical expression and severity
of...
Diagnosing PCOS
There is a lack of consensus between
endocrinologist and gynecologist in the definition,
diagnosis, and tr...
The optimal management of (POCS) is uncertain,
however, treatment is focused on amelioration of
the reproductive clinical ...
SURGIGAL
TREATMENT OF PCOS
Destroying the androgen-producing ovarian stroma.
Destruction of ovarian stroma has an indirect...
(Yarak et al: Hyperandrogenism and skin: Polycystic ovary syndrome
and peripheral insuline resistance, review articel, an ...
The Rotterdam ESHRE/ASRM-sponsored PCOS
consensus workshop group
1. Chronic anovulation
2. Clinical and/or biochemical sig...
Current option in pharmacology
Apart from oligo-ovulation and
hyperandrogenism, other common findings in
women with PCOS i...
PCOS is a hormonal imbalance linked to the
way the body processes insulin after it has been
produced by the pancreas to re...
4. F cells 
Pancreatic
polypeptide
1. α cells ( 20%) 
Glucagon
2. β cells ( 75%) 
Insulin and
Amylin
3. D cells 
Somat...
Insulin receptors & Insulin action
Fat (adipose), liver, and muscle cells,
the three major tissues specialized for energy
...
In the absence of insuline,In the absence of insuline,
glucose cannot enter the cell.glucose cannot enter the cell.
promoter Coding reg
transcription
mRNA
Modified from Howard L. Foyt et al.
Synthesis GLUT 4
translocation
PPARγ
PPRE
Insul...
PPARγ
promoter Coding reg
+RXR
Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental an...
Insulin resistance  PCOS
Insulin resistance vastly reduces the number of insulin
receptor sites or doorways on the walls ...
Insulin resistance  PCOS
GeneticGenetic
predispositionpredisposition
Stress andStress and
UnhealthyUnhealthy livelive
sty...
INSULIN RESISTANCE
….a ratio of less than 4.5 of fasting
glucose to insulin levels correlates
significantly with insulin r...
(This slide is addopted from Muharam presentation, PIT Batam)(This slide is addopted from Muharam presentation, PIT Batam)
Worsening glucose intolerance
PCOS with insulin intolerance
Beta cells dysfunction
Impaired glucose tolerance
Beta cells e...
Main disturbances in PCOS
Insulin resistance
80% of80% of
obeseobese
PCOSPCOS
30%-40%30%-40%
of leanof lean
PCOSPCOS
Genet...
Metabolic syndrome
(Any 3 out of 5 )
• Abdominal obesity (waist > 88 cm)
• Triglycerides (> 150 mg/dl).
• HDL cholesterol ...
GLUCOSE TRANSPORTGLUCOSE TRANSPORT
INTO LIVERINTO LIVER
Glucose transport into lever cells (hepatocytes)
is not directly i...
In fed state, liver cell takes upIn fed state, liver cell takes up
glucoseglucose
In fasted state, liver cell makes glucoseIn fasted state, liver cell makes glucose
and transports it out into the blood to...
Glucose transport in skeletal
muscle
1.1. Exercising skeletal muscle is not dependentExercising skeletal muscle is not dep...
ββ cells ofcells of
PancreasPancreas
InsulinInsulin
LiverLiver
GlucolysisGlucolysis
GlycogenesisGlycogenesis
LipogenesisLi...
αα CCells ofells of
PancreasPancreas
GlucagonGlucagon
LiverLiver MuscleMuscle andand
adiposeadipose tissuetissue
Plasma gl...
Insulin disorder
Central obesity
Infertility
Menstrual disturbances
Hersutism
Endocrine
Manifestation
Long term squelae
In...
(This slide is addopted from Muharam presentation, PIT Batam)(This slide is addopted from Muharam presentation, PIT Batam)
The choice of treatment of PCOS depends on the
patient’s age and the presence of infertility factors
and must be individua...
Obese PCOS women
Ideally , for obese PCOS women, a combination of dietary
restriction and exercise remains the best form o...
INSULIN RESISTANCEINSULIN RESISTANCE
Metformin and homocysteine
• Homocysteine levels higher in PCOS, associated
with insulin resistance.
• Increased risk of C...
Metformin
• Metformin improves insulin resistance and
associated dyslipidemia which may result in
a decrease in cardiovasc...
Lifestyle intervention
“Significantly more effective than metformin in
reducing the incidence of diabetes.”
Diabetes Preve...
Conclusions
• While the basic dysfunction of PCOS seems to lie
within the ovary, the clinical expression and
severity of t...
PCOS and Hyperinsulinemia
PCOS +PCOS +
HyperinsulinemiaHyperinsulinemia
PCOS + Non-PCOS + Non-
HyperinsulinemiaHyperinsuli...
LH ↑
FSH ↓
Androst ↑
Estrone ↑
SHBG ↓
Free
Estradiol ↑
Testost ↑
Endometrial
cancer
Pilosebaceous
unit
Atresia
Granulosa
c...
promoter Coding reg
transcription
mRNA
Modified from Howard L. Foyt et al.
Synthesis GLUT 4
translocation
PPARγ
PPRE
Muscl...
Fed stateFed state
Insulin dominatesInsulin dominates
Screening for insulin resistance in
PCOS
• Insulin resistance is not a diagnostic
• Does not influence treatment.
• Clinic...
1. High of ovulation and pregnancy rate
2. May decrease abortion rate
3. More cost-effective than gonadotropin therapy
4. ...
SUGGESTED STEPWISE TREATMENT SCHEME FOR INFERTILITY ASSOCIATEDSUGGESTED STEPWISE TREATMENT SCHEME FOR INFERTILITY ASSOCIAT...
Metabolism is controlledMetabolism is controlled
by insulin and glucagonby insulin and glucagon
Glucose transport in
fat cells
Pcos medan
Pcos medan
Pcos medan
Pcos medan
Pcos medan
Pcos medan
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Pcos medan

  1. 1. POLYCYSTIC OVARY SYNDROME (PCOS) : From the Ovary to the Pancreas Division of Reproductive Endocrinology and Fertility Department of Obstetrics and Gynecology Faculty of Medicine, Gadjah Mada University Yogyakarta Mochamad Anwar
  2. 2. POLYCYSTIC OVARIES Abnormal ovarian morphology Peripherally distributed follicles, like a necklace and completely encircling the cortical surface of the ovary (10 or more follicles of 2 to 8 mm in diameter). Increased stroma and increased ovarian volume (>10 ml) (Polston et al, 1988)
  3. 3. PATHOPHYSIOLOGY While the basic dysfunction seems to lie within the ovary, however the clinical expression and severity of the symptoms of PCOS dependent on extra- ovarian factors Single defect inSingle defect in action and secretionaction and secretion of insulineof insuline PrimaryPrimary neuroendocrineneuroendocrine defectdefect Defect ofDefect of androgenandrogen sysynnthesisthesis Alteration inAlteration in cortisolcortisol metabolismmetabolism HyperinsulinemiaHyperinsulinemia and insulinand insulin resistanceresistance Increased pulseIncreased pulse frequency andfrequency and amplitudo of LHamplitudo of LH increasedincreased production ofproduction of ovarian androgenovarian androgen IncreasedIncreased production ofproduction of adrenal androgenadrenal androgen
  4. 4. Diagnosing PCOS There is a lack of consensus between endocrinologist and gynecologist in the definition, diagnosis, and treatment of PCOS, and as consequence, women may receive a different diagnosis or treatment depending on the type of specialist consulted ( Cusson et al., 2005)
  5. 5. The optimal management of (POCS) is uncertain, however, treatment is focused on amelioration of the reproductive clinical features For the most part, in reproductive endocrinology fields, treatment aims to restore ovulatory cycles so that the pregnancy can be achieved Reproductive EndocrinologyReproductive Endocrinology
  6. 6. SURGIGAL TREATMENT OF PCOS Destroying the androgen-producing ovarian stroma. Destruction of ovarian stroma has an indirect modulating effect on the pituitary-ovarian axis. LH concentrations decrease after LOD, and appear to be the best determinant of response to treatment.  LAPAROSCOPIC OVARIAN DRILLING (LOD)
  7. 7. (Yarak et al: Hyperandrogenism and skin: Polycystic ovary syndrome and peripheral insuline resistance, review articel, an Bras Dermatol, 2005) The most frequent clinical characteristics of polycystic ovarian syndrome are associated with with the pilosebaceous unit, such as hirsutism, acne, seborrhea and alopecia. DermatologyDermatology Thus, the Dermatologist may be responsible for making an early diagnosis of the syndrome.
  8. 8. The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group 1. Chronic anovulation 2. Clinical and/or biochemical signs of hyperandrogenism, and exclusion of other aetiologies Note : Polycystic-appearing ovaries observed either through ultrasound or gross examination are not necessary for diagnosis. Revised 2003 criteria (2 out of 3) 1. Oligo- and/or anovulation 2. Clinical and/or biochemiocal signs of hyperandrogenism 3. Polycystic ovaries And exclusion of other aetiologis (congenital adrenal hyperplasia, androgen-secreting tumours, Cushing’s syndrome) The concensus of National Institute of Health (1990):The concensus of National Institute of Health (1990):
  9. 9. Current option in pharmacology Apart from oligo-ovulation and hyperandrogenism, other common findings in women with PCOS include obesity, hyperlipidemia, descreased SHBG, infertility and insulin resistance. Of all these sequelae, insulin resistance is potentially the most dangerous. ( Wei and Pritts : Therapy for PCOS, current option in Pharmacology, 2003)
  10. 10. PCOS is a hormonal imbalance linked to the way the body processes insulin after it has been produced by the pancreas to regulate blood sugar (glucose) Insulin resistance. The underlying cause of PCOS, insulin resistance, has many factors that contribute to its presence in the body. Polycystic ovarium syndrome : from the ovary to the pacreas
  11. 11. 4. F cells  Pancreatic polypeptide 1. α cells ( 20%)  Glucagon 2. β cells ( 75%)  Insulin and Amylin 3. D cells  Somatostatin Islets ofIslets of LangerhansLangerhans PANCREASPANCREAS
  12. 12. Insulin receptors & Insulin action Fat (adipose), liver, and muscle cells, the three major tissues specialized for energy storage Many cells of the body appear to have specific cell surface insulin receptors. These receptors bind insulin rapidly, with high specificity and affinity to bind picomolar amounts.
  13. 13. In the absence of insuline,In the absence of insuline, glucose cannot enter the cell.glucose cannot enter the cell.
  14. 14. promoter Coding reg transcription mRNA Modified from Howard L. Foyt et al. Synthesis GLUT 4 translocation PPARγ PPRE Insulin receptor Insulin RXR Glucose Asman Manaf, Sub Bagian Metabolik Endokrinologi, Bagian I. Penyakit Dalam FK UNAND/RSUP Dr M Jamil Padang ECF =Extra cellular fluidECF =Extra cellular fluid ADIPOCYTESADIPOCYTES (FAT CELLS)(FAT CELLS)
  15. 15. PPARγ promoter Coding reg +RXR Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed. PPRE receptor Insulin Insulin resistance Glucose mRNA Synthesis GLUT 4 X X transcription ECF =Extra cellular fluidECF =Extra cellular fluid Asman Manaf, Sub Bagian Metabolik Endokrinologi, Bagian I. Penyakit Dalam FK UNAND/RSUP Dr M Jamil Padang ADIPOCYTESADIPOCYTES (FAT CELLS)(FAT CELLS)
  16. 16. Insulin resistance  PCOS Insulin resistance vastly reduces the number of insulin receptor sites or doorways on the walls of cells. 20.00020.000 5.0005.000 HealthyHealthy personperson HyperglHyperglyycaemiacaemia LiverLiverFatFat Blood streamBlood stream throughtoutthroughtout the bodythe body Central obesityCentral obesity PCOSPCOS InsulinInsulin resistanceresistance 11 Insulin resistance  PCOS Insulin resistance vastly reduces the number of insulin receptor sites or doorways on the walls of cells. Insulin resistance  PCOS Insulin resistance vastly reduces the number of insulin receptor sites or doorways on the walls of cells. Insulin resistance  PCOS 20.00020.000 HealthyHealthy personperson
  17. 17. Insulin resistance  PCOS GeneticGenetic predispositionpredisposition Stress andStress and UnhealthyUnhealthy livelive stylestyle Overproduction ofOverproduction of insulin by pancreasinsulin by pancreas The cells will protect itself byThe cells will protect itself by reducing the number of itsreducing the number of its receptor sitesreceptor sites Unbalance hormoneUnbalance hormone levels in PCOSlevels in PCOS Ovaries produceOvaries produce large amounts oflarge amounts of testosteronetestosterone InfertilityInfertility AndrogensAndrogens EstrogensEstrogens Weight gainWeight gain Formation ofFormation of cysticcystic folliclesfollicles 22 Atresia of granulosa cellsAtresia of granulosa cells Atresia and prematurity ofAtresia and prematurity of developing folliclesdeveloping follicles
  18. 18. INSULIN RESISTANCE ….a ratio of less than 4.5 of fasting glucose to insulin levels correlates significantly with insulin resistance and has been studied for use as a screening test in obese patients in PCOS. ( Richardson: Current Perspective in PCOS,Am Fam Phys, 68(4): 687- 704, 2003 )
  19. 19. (This slide is addopted from Muharam presentation, PIT Batam)(This slide is addopted from Muharam presentation, PIT Batam)
  20. 20. Worsening glucose intolerance PCOS with insulin intolerance Beta cells dysfunction Impaired glucose tolerance Beta cells exhaution Frank diabetes. (Roy Homburg)(Roy Homburg)
  21. 21. Main disturbances in PCOS Insulin resistance 80% of80% of obeseobese PCOSPCOS 30%-40%30%-40% of leanof lean PCOSPCOS Genetic post-receptor defect unique to PCOSGenetic post-receptor defect unique to PCOS Exaggerated by obesityExaggerated by obesity
  22. 22. Metabolic syndrome (Any 3 out of 5 ) • Abdominal obesity (waist > 88 cm) • Triglycerides (> 150 mg/dl). • HDL cholesterol (< 50 mg/dl). • Blood pressure (>130 / > 85 mmHg). • Glucose (fasting >110  2 hrs >140 mg/dl) Risk factor for developing Type-2Risk factor for developing Type-2 Diabetes and Cardiovascular disease.Diabetes and Cardiovascular disease.
  23. 23. GLUCOSE TRANSPORTGLUCOSE TRANSPORT INTO LIVERINTO LIVER Glucose transport into lever cells (hepatocytes) is not directly insulin-dependent but will be influenced by the presence or absence of insulin.
  24. 24. In fed state, liver cell takes upIn fed state, liver cell takes up glucoseglucose
  25. 25. In fasted state, liver cell makes glucoseIn fasted state, liver cell makes glucose and transports it out into the blood toand transports it out into the blood to help maintain glucose homeostasishelp maintain glucose homeostasis HepatocyteHepatocyte
  26. 26. Glucose transport in skeletal muscle 1.1. Exercising skeletal muscle is not dependentExercising skeletal muscle is not dependent on insulin activity for its glucose uptake.on insulin activity for its glucose uptake. 2.2. When muscle contract GLUT-4 transportersWhen muscle contract GLUT-4 transporters are inserted into the mebrane and glucoseare inserted into the mebrane and glucose uptake increases.uptake increases. 3.3. The intracellular signal for this is unclear, butThe intracellular signal for this is unclear, but appears to involve Caappears to involve Ca2+2+ and decreased ofand decreased of inorganic phosphatase (Pi).inorganic phosphatase (Pi).
  27. 27. ββ cells ofcells of PancreasPancreas InsulinInsulin LiverLiver GlucolysisGlucolysis GlycogenesisGlycogenesis LipogenesisLipogenesis Protein synthesisProtein synthesis Muscle andMuscle and AdiposeAdipose Glucose transportGlucose transport Plasma glucosePlasma glucose Plasma glucosePlasma glucose αα CCells ofells of PancreasPancreas 1.1. Increases glucose transportIncreases glucose transport into insuline sensitive cell.into insuline sensitive cell. 2.2. Enhances cellular utilizationEnhances cellular utilization and storage of glucose.and storage of glucose. 3.3. Enhances utilization ofEnhances utilization of amino acid (proteinamino acid (protein synthesis)synthesis) 4.4. Promote fat synthesis.Promote fat synthesis. Fed-stateFed-state metabolismmetabolism NegativeNegative feedbackfeedback Insulin is anInsulin is an anabolic hormonanabolic hormon
  28. 28. αα CCells ofells of PancreasPancreas GlucagonGlucagon LiverLiver MuscleMuscle andand adiposeadipose tissuetissue Plasma glucosePlasma glucose Plasma glucosePlasma glucose ββ CCells ofells of PancreasPancreas NegativeNegative feedbackfeedback InsulinInsulin GlucogenolysisGlucogenolysis GluconeogenesisGluconeogenesis LactaseLactase PyruvatePyruvate Amino acidAmino acid ProlongedProlonged hypoglycaemiahypoglycaemia KetonesKetones For use by brain andFor use by brain and peripheral tissuesperipheral tissues Faty acidFaty acid
  29. 29. Insulin disorder Central obesity Infertility Menstrual disturbances Hersutism Endocrine Manifestation Long term squelae Insulin ↑ Hepar Ovarium Kel. adrenal SHBG ↓ Aktivitas androgen ↑ ? Glucose intolerance Hypertension Dyslipidemia Vascular disease Clinical manifestation Metabolic manifestation
  30. 30. (This slide is addopted from Muharam presentation, PIT Batam)(This slide is addopted from Muharam presentation, PIT Batam)
  31. 31. The choice of treatment of PCOS depends on the patient’s age and the presence of infertility factors and must be individualized under two main categories: (Saleh and Halil, 2004) • obese or non-obese PCOS • with or without insulin resistance
  32. 32. Obese PCOS women Ideally , for obese PCOS women, a combination of dietary restriction and exercise remains the best form of treatment. Weight loss of more than 5% of pretreatment weight • Reducing LH 45% decreased. • Fasting insulin 40% decreased •Testosterone 35% decreased • Progression of type 2 DM 58% • Restored menstrual function regularity in 89% 30% achieved spontaneous pregnancy
  33. 33. INSULIN RESISTANCEINSULIN RESISTANCE
  34. 34. Metformin and homocysteine • Homocysteine levels higher in PCOS, associated with insulin resistance. • Increased risk of CVD – damages arterial endothelium, accelerates thrombosis and artheroseclerosis. • Metformin may increase homocystein levels in PCOS • Give folic acid + Vitamin B Complex with metformin. (Legro 2001, Boushey, 1995, Vibrikova 2002, and Killedag, 2005).
  35. 35. Metformin • Metformin improves insulin resistance and associated dyslipidemia which may result in a decrease in cardiovascular risk • Long term use of insulin sensitizing agents for avoidance of metabolic complications of PCOS cannot as yet be recommended. (RCOG Guidance no.33, May 2003)
  36. 36. Lifestyle intervention “Significantly more effective than metformin in reducing the incidence of diabetes.” Diabetes Prevention Research Group (Knowler et.al, 2002, NEJM)
  37. 37. Conclusions • While the basic dysfunction of PCOS seems to lie within the ovary, the clinical expression and severity of the symptoms dependent on extra- ovarian factors • PCOS is a hormonal imbalance linked to the way the body processes insulin after it has been produced by the pancreas to regulate blood sugar (glucose). • PCOS has systemic sequelae that can contribute to long-term morbidity; of all these sequelae, insulin resistance is potentially the most dangerous. • The traditional target for therapie in PCOS is altering steroid hormone, while the new target is treating insulin resistance
  38. 38. PCOS and Hyperinsulinemia PCOS +PCOS + HyperinsulinemiaHyperinsulinemia PCOS + Non-PCOS + Non- HyperinsulinemiaHyperinsulinemia Higher in testosteron levelsHigher in testosteron levels Lower SHBGLower SHBG Higher inermenstrual intervalHigher inermenstrual interval ><><
  39. 39. LH ↑ FSH ↓ Androst ↑ Estrone ↑ SHBG ↓ Free Estradiol ↑ Testost ↑ Endometrial cancer Pilosebaceous unit Atresia Granulosa cells Weight ↑ Insulin receptor disorders Insulin ↑ IGFBP-1 ↓ Theca (IGF-1) Free testosterone ↑ +
  40. 40. promoter Coding reg transcription mRNA Modified from Howard L. Foyt et al. Synthesis GLUT 4 translocation PPARγ PPRE Muscle contraction RXR Glucose Asman Manaf, Sub Bagian Metabolik Endokrinologi, Bagian I. Penyakit Dalam FK UNAND/RSUP Dr M Jamil Padang ECF =Extra cellular fluidECF =Extra cellular fluid MUSCLEMUSCLE CELLCELL CaCa 2+2+ and decreasedand decreased Inorganic phosphataseInorganic phosphatase
  41. 41. Fed stateFed state Insulin dominatesInsulin dominates
  42. 42. Screening for insulin resistance in PCOS • Insulin resistance is not a diagnostic • Does not influence treatment. • Clinical response to insulin lowering treatments not related to magnitude of insulin resistance • Very difficult to quantity. Should we make a formal assessment of insulin resistance in all women with PCOS ? No
  43. 43. 1. High of ovulation and pregnancy rate 2. May decrease abortion rate 3. More cost-effective than gonadotropin therapy 4. Prolonged therapeutic effect 5. Shorten time to pregnancy Advantages of Laparoscopic Ovarian Drilling (LOD): 
  44. 44. SUGGESTED STEPWISE TREATMENT SCHEME FOR INFERTILITY ASSOCIATEDSUGGESTED STEPWISE TREATMENT SCHEME FOR INFERTILITY ASSOCIATED WITH PCOSWITH PCOS Oligo/anovulasi with PCOS Weight loss + metformin Pregnancy Clomiphene citrate Pregnancy Add metformin No response Ovulatory cycles x 6 Pregnancy Low dose FSH Pregnancy Ovulatory cycles x 6 IVF/ET LOD PregnancyPregnancy Roy Homburg, Best Practice & Research Clin Obstet Gynecol. 18(5):773-88,2004)
  45. 45. Metabolism is controlledMetabolism is controlled by insulin and glucagonby insulin and glucagon
  46. 46. Glucose transport in fat cells

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