Pcos medan

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



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





20.00020.000Healthy Healthy personperson


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


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



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

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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



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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Pcos medan