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POLYCYSTIC OVARY SYNDROME (PCOS) :
From the Ovary to the Pancreas
Division of Reproductive Endocrinology and FertilityDepartment of Obstetrics and Gynecology
Faculty of Medicine, Gadjah Mada University Yogyakarta
Mochamad Anwar
POLYCYSTIC OVARIESAbnormal 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)
PATHOPHYSIOLOGYWhile 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 in Single defect in action and secretion action and secretion
of insulineof insuline
Primary Primary neuroendocrine neuroendocrine
defectdefect
Defect of Defect of androgen androgen sysynnthesisthesis
Alteration in Alteration in cortisol cortisol
metabolismmetabolism
Hyperinsulinemia Hyperinsulinemia and insulin and insulin resistanceresistance
Increased pulse Increased pulse frequency and frequency and
amplitudo of LH amplitudo of LH
increased increased production of production of
ovarian androgenovarian androgen
Increased Increased production of production of
adrenal androgenadrenal androgen
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)
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
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)
(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.
The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group
1. Chronic anovulation2. 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 anovulation2. Clinical and/or biochemiocal signs of hyperandrogenism3. Polycystic ovariesAnd 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):
Current option in pharmacologyApart 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)
PCOS is a hormonal imbalance l inked 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
4. F cells Pancreatic polypeptide
1. α cells ( 20%) Glucagon
2. β cells ( 75%) Insulin and Amylin3. D cells Somatostatin
Islets of Islets of LangerhansLangerhans
PANCREASPANCREAS
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.
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
Insulinreceptor
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)
PPARγ
promoter Coding reg
+RXR
Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.
PPRE
receptor
InsulinInsulin
resistanceGlucose
mRNASynthesis 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)
Insulin resistance PCOS
Insulin resistance vastly reduces the number of insulin receptor sites or doorways on the walls of cells.
20.00020.000 5.0005.000Healthy Healthy personperson
HyperglHyperglyycaemiacaemia
LiverLiverFatFatBlood stream Blood stream throughtout throughtout
the bodythe body
Central obesity Central obesity PCOSPCOS
Insulin Insulin 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
20.00020.000Healthy Healthy personperson
Insulin resistance PCOS
GeneticGenetic predispositionpredisposition
Stress and Stress and Unhealthy Unhealthy live live
stylestyle
Overproduction of Overproduction of insulin by pancreasinsulin by pancreas
The cells will protect itself by The cells will protect itself by reducing the number of its reducing the number of its
receptor sites receptor sites
Unbalance hormone Unbalance hormone levels in PCOSlevels in PCOS
Ovaries produce Ovaries produce large amounts of large amounts of
testosteronetestosterone
InfertilityInfertility
Androgens Androgens
EstrogensEstrogens
Weight gainWeight gain
Formation of Formation of cystic cystic
folliclesfollicles
22
Atresia of granulosa cellsAtresia of granulosa cells
Atresia and prematurity of Atresia and prematurity of developing folliclesdeveloping follicles
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 )
(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 exhaution
Frank diabetes.
(Roy Homburg)(Roy Homburg)
Main disturbances in PCOS
Insulin resistance
80% of 80% of obese obese PCOSPCOS
30%-40% 30%-40% of lean of lean PCOSPCOS
Genetic post-receptor defect unique to PCOSGenetic post-receptor defect unique to PCOS
Exaggerated by obesityExaggerated by obesity
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-2 Risk factor for developing Type-2 Diabetes and Cardiovascular disease.Diabetes and Cardiovascular disease.
GLUCOSE TRANSPORT GLUCOSE 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.
In fed state, liver cell takes up In fed state, liver cell takes up glucoseglucose
In fasted state, liver cell makes glucose In fasted state, liver cell makes glucose and transports it out into the blood to and transports it out into the blood to help maintain glucose homeostasishelp maintain glucose homeostasis
HepatocyteHepatocyte
Glucose transport in skeletal muscle
1.1. Exercising skeletal muscle is not dependent Exercising 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 transporters When muscle contract GLUT-4 transporters are inserted into the mebrane and glucose are inserted into the mebrane and glucose uptake increases.uptake increases.
3.3. The intracellular signal for this is unclear, but The intracellular signal for this is unclear, but appears to involve Caappears to involve Ca2+2+ and decreased of and decreased of inorganic phosphatase (Pi).inorganic phosphatase (Pi).
ββ cells of cells of PancreasPancreas
InsulinInsulin
LiverLiver
GlucolysisGlucolysis GlycogenesisGlycogenesis LipogenesisLipogenesis Protein synthesisProtein synthesis
Muscle and Muscle and AdiposeAdipose
Glucose transportGlucose transport
Plasma glucosePlasma glucose
Plasma glucosePlasma glucose
αα CCells of ells of PancreasPancreas
1.1. Increases glucose transport Increases glucose transport into insuline sensitive cell.into insuline sensitive cell.
2.2. Enhances cellular utilization Enhances cellular utilization and storage of glucose.and storage of glucose.
3.3. Enhances utilization of Enhances utilization of amino acid (protein amino acid (protein synthesis)synthesis)
4.4. Promote fat synthesis.Promote fat synthesis.
Fed-state Fed-state metabolismmetabolism NegativeNegative
feedbackfeedback
Insulin is an Insulin is an anabolic hormonanabolic hormon
αα C Cells of ells of PancreasPancreas
GlucagonGlucagon
LiverLiver MuscleMuscle and and adiposeadipose tissue tissue
Plasma glucosePlasma glucose
Plasma glucosePlasma glucose
ββ CCells of ells of PancreasPancreas
NegativeNegative
feedbackfeedback
InsulinInsulin
GlucogenolysisGlucogenolysis GluconeogenesisGluconeogenesis
Lactase Lactase Pyruvate Pyruvate
Amino acid Amino acid
Prolonged Prolonged hypoglycaemiahypoglycaemia
KetonesKetones
For use by brain and For use by brain and peripheral tissuesperipheral tissues
Faty acidFaty acid
Insulin disorder Central obesity
InfertilityMenstrual disturbances
Hersutism
EndocrineManifestation
Long term squelae
Insulin ↑
Hepar
Ovarium
Kel. adrenal
SHBG ↓
Aktivitas androgen ↑
?
Glucose intolerance
HypertensionDyslipidemia
Vascular disease
Clinical manifestation
Metabolic manifestation
(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 individualized under two main categories:
(Saleh and Halil, 2004)
• obese or non-obese PCOS • with or without insulin resistance
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
INSULIN RESISTANCEINSULIN RESISTANCE
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).
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)
Lifestyle intervention
“Significantly more effective than metformin in reducing the incidence of diabetes.”
Diabetes Prevention Research Group(Knowler et.al, 2002, NEJM)
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
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
><><
LH ↑FSH ↓
Androst ↑
Estrone ↑
SHBG ↓
Free Estradiol ↑
Testost ↑
Endometrial cancer
Pilosebaceous unit
AtresiaGranulosa
cells
Weight ↑
Insulin receptor
disorders
Insulin ↑ IGFBP-1 ↓
Theca (IGF-1) Free testosterone ↑
+
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
MUSCLE MUSCLE CELLCELL
Ca Ca 2+2+ and decreased and decreased Inorganic phosphatase Inorganic phosphatase
Fed state Fed state Insulin dominatesInsulin dominates
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
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 Dri l l ing (LOD):
SUGGESTED STEPWISE TREATMENT SCHEME FOR INFERTILITY ASSOCIATED SUGGESTED 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)
Metabolism is controlled Metabolism is controlled by insulin and glucagonby insulin and glucagon
Glucose transport in
fat cells
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