PCOSTreatment Guidelines

& Review of

Newer Medical Treatment in Infertility

Dr. Sharda JainDr. Jyoti Agarwal Dr. Jyoti Bhaskar

ESHRE/ ASRM sponsored PCOS Consensus Workshop

• 1st workshop (2004) on Diagnosis• 2nd workshop (2008) on Infertility• 3rd workshop (2011) Women’s Health

Aspects of PCOS

Must Reading for all of you

PCOS Phenotypes as per Rotterdam criteria

PCOS Phenotype Oligo – or an ovulation

Biochemical hyperandrogenemia or clinical

manifestation of hyperandrogene

mia

Polycystic ovaries in transvaginal

ultrasound

1- Severe PCOS + + +

2- Oligo – or anovulation and hyperandrogene

mia

+ + -

3- ovulatory PCOS - + +

4- MILD pcos + - +

MENSTRUAL DISORDERS: PCOS mostly produces oligomenorrhea  or amenorrhea.

INCREASED LH/FSH RATIO - Prevents follicular maturation resulting in anovulation

HIGH LEVELS OF ANDROGEN HORMONE: The most common signs are acne, acanthosis nigricans, androgenic alopecia & hirsutism.

METABOLIC SYNDROME: This appears as a tendency towards  central obesity and other symptoms associated with  insulin resistance.

Common Symptoms of PCOSOther than INFERTILITY

Serum insulin, insulin resistance and homocysteine levels are higher in women with PCO.

Look for C0- morbidities in PCOS coming for infertility Treatment

•HERSUITISM & ACNE

•CENTRAL OBESITY

•TYPE-2 DIABETES

•HIGH BLOOD PRESSURE

•CHOLESTEROL ABNORMALITIES

•HYPOTHYROIDISM

•HYPERPROLACTINEMIA

Management of Infertility in PCOS

WHO Group – II Ovulation Disorder

Classic PCOS

Anovulatory

PCOSOvulatory

PCOS

NICE/ ASRM Guidelines

Women with WHO group II anovulatory infertility with PCOS who have a BMI of 30 or over must lose weight. Inform them that this alone may restore ovulation, improve their response to ovulation induction agents, and have a positive impact on pregnancy outcomes

Life style managementof Weight Reduction

(NICE 2013)

Life style managementof Weight Reduction

• 50% treatment of PCOS is simply – weight control. • Even if one loses 5-10 kg - the effect is tremendous .

Experience

One of the following treatments taking into account potential adverse effects, ease and mode of use, the women’s BMI

• Clomifene Citrate or• Metformin or• A combination of the above

ESRE / ASRM consensus workshop on PCOS Anovulatory Infertility

Cycle clinical follicle monitoring needed: (NICE 2013)

Clomifene Citrate

• For women who are taking clomifene citrate, do not continue treatment for longer than 6 months

•Women prescribed metformin should be informed of the side effects associated with its use (such as nausea, vomiting and other gastrointestinal disturbances)

(NICE 2004)

(NICE 2013)

Experience of Infertility Experts onRole of Metformin in PCOS

• CC compared with metformin aloneresults in higher ovulation , conception, pregnancy & live birth rate

• CC + Metformin results in no substantial benefits except, patients with BMI >35 or abnormal GTT

Fertile sterile 2008,89;505

PCOS Patients with Anovulation & Ovulation disorder

RESISTANT TO CLOMIFENE CITRATE: For women with PCOS who are known to be resistant to clomifene citrate, consider one of the following SECOND – LINE TREATMENT, depending on clinical circumstances and the women’s preference• Laparoscopic Ovarian drilling or

• Combined treatment with clomifene citrate and metformin if not already offered as fist – line treatment or

• Gonadotrophines(NICE 2013)

CLOMIFENE CITRATE + Metformin

However, Recent Study showed CC+ metformin combination therapy results in hyper rates of LIVE BIRTHS compared with other treatments.

Jungheim et. all fertil steril 2010;94:2659

Caution Women with PCOD who are being treated with gonadotrophins should not be offered treatment with gonadotrophin – releasing hormone agonist concomitantly because it does not improve pregnancy rates and it is associated with an increase risk of ovarian hyperstimulation

(NICE 2004)

The use of Adjuvant Growth Hormone treatment with gonadotrophins – releasing hormone agonist and / or human menopausal gonadotrophin during ovulation induction in women with PCOS who do not respond to clomifene citrate is not recommended because it does not improve pregancy rates

Caution

(NICE 2004)

INTRODUCING Concepts & Rationale

ofA NEW LINE OF TREATMENT

↓Still not approved by NICE GUIDELINES

& ASRM

PATHOGENESIS of PCOS

INSULIN RESISTANCE

HYPERINSULINEMIA

THECA CELL

PROLIFERATION

HYPERANDROGENISM

PCOS

Infact, No Body Knows exact Cause !!

Oxidative Stress & Infertility

Basis of Newer Drugs use

Summary of Review of literature shows

MELATONIN

•Recent entry

•Melatonin is also known as N-acetyl-5 methoxytryptamine

•An hormone secreted during the dark hours by pineal gland.

•Regulates a variety of important central and peripheral

•actions related to circadian rhythms and reproduction.

However, the discovery of melatonin as adirect free radical scavenger has greatly

broadened the understanding of melatonin’s mechanisms

which benefit reproductive physiology.

MELATONIN

•It has been discovered that melatonin is a powerfulfree radical scavenger and a broad-spectrum antioxidant.

Because of its small size and highly lipophilic & hydrophilic properties, melatonin crosses all cell membranes & easily reaches subcellular compartments,including mitochondria and nuclei, where it seems to accumulate in high concentrations.

•Melatonin prevents lipid peroxidation, protein, andDNA damage.

MELATONIN

Melatonin, secreted by pineal gland, is taken up into the follicular fluid from the blood.

ROS produced within the follicles, especially during the ovulation process, were scavenged by melatonin, and reduced oxidative stress involved in oocyte maturation and embryo development

Melatonin increases intra-follicular melatonin concentrations, reduces intra-follicular oxidative damage

Elevates fertilization and pregnancy rates.

MELATONIN

Comes from the amino acid l-cysteine. Amino acids are the building blocks of protein

Improves insulin sensitivity & decreases androgen level

Prevents follicular cohort atresia

Improves quality of cervical mucus

N-ACETYLCYSTEINE

•Decreases circulating insulin & serum total testosterone

•Reduces acne & weight

•Reduces hirsutism and hyperandrogenism and ameliorates the abnormal metabolic profile of women with hirsutism

After 3 months of inositol administration, free testosterone, insulin and HOMA index resulted in significantly reduced. Both hirsutism and acne decreased after 6 months of therapy.

MYO-INOSITOL

 

Is an analogue of vitamin D used for supplementation in humans .

More useful form of vitamin D supplementation, mostly due to much longer half-life and lower kidney load

Improves insulin secretion.

ALFACALCIDOL

Chromium polynicotinate consists of pure niacin-bound chromium

Chromium polynicotinateis more effective than other types of chromium, because it binds to niacin also know as vitamin b-3.

This provides a biologically active form of chromium, and makes it easier for the body to absorb

CHROMIUM POLYNICOTINATE

•Active component of glucose tolerance factor which is responsible for binding insulin to cell membrane receptor sites

•Improves insulin sensitivity

•Stimulates the metabolism of sugar, fat & cholesterol

CHROMIUM POLYNICOTINATE:

Is the natural, active form of folic acid used at the cellular level for DNA reproduction and the regulation of homocysteine among other functions.

Reduces homocysteine levels and prevent cardiovascular risk factors associated with PCOS.

The un-methylated form, folic acid (vitamin B9), is a synthetic form of folate found in nutritional supplements.

L-METHYLFOLATE

Recap

• 50% treatment of PCOS is simply – weight control. • Even if one loses 5-10 kg - the effect is tremendous .

Experience

Please RemembersThere is NO approval of these drugs in NICE &

ASRM Guidelines& Drugs controlled of India for Ovulation Induction

Few Drug House have stared marketing NAC & combination of

NAC with these drugs to be given with CC

Please Note

Summary Infertility in PCOS

• Exclude other diseases & other fertility disorders in the couple.

• Life style modification particularly weight loss increase exercise, smoking cessation & decrease alcohol consumption is highly recommended.

• The Pharmacological treatment approved by NICE/ ASRM is CC or CC+ metformin.

•Second line treatment i.e. gonadotrophines or laparoscopic ovarian drill if medical treatment fails.

•NICE & ASRM do not endorse use of newer drugs (2013)

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