Polycystic Ovarian

Syndrome

Corsi permanenti di Fisiopatologia della Riproduzione Umana e Tecnologie della Riproduzione Assistita

XLVIII CORSO

A. Nazzaro, A. Salerno• UO di Fisiopatologia della Riproduzione Umana AORN “G. Rummo”, Benevento• Futuraivf – Centro di Procreazione Medicalmente Assistita

INTRODUCTION

• Most common cause of infertility in women

• Classic syndrome originally described by Stein and Levanthal

• Hyperandrogenism• Menstrual irregularity• Polycystic ovaries• Central adiposity

• Syndrome, not a diseaseSyndrome, not a disease—multiple potential etiologies with variable clinical expression

History

Originally described by Stein and Leventhal in 1935, first known as the “Stein-Leventhal syndrome”7 women with amenorrhea, hirsutism, and obesity, found to have a polycystic appearance to their ovaries.

What is PCOS?

• Disorder characterized by 2 of the following:– Hyperandrogenism– Oligoovulation or chronic anovulation– Polycystic ovaries

In the absence of pituitary or adrenal disease

• It is a syndrome, ie., no single test can establish the diagnosis.

Diagnostic and Therapeutic criteria• NICHD (1990) Diagnostic Criteria for PCOS is:

Clinical Hyperandrogenism (Ferriman-Gallwey Score >8) or Biochemical Hyperandrogenism (Elevated Total/Free Testosterone)ANDOligomenorrhea (Less Than 6-9 Menses per Year) or Oligo-OvulationANDPolycystic Ovaries on Ultrasound (>= 12 Antral Follicles in One Ovary or Ovarian Volume >= 10 cm3)

• Rotterdam (2003) Diagnostic criteria for PCOS - two out of three of:

Clinical Hyperandrogenism (Ferriman-Gallwey Score >8) or Biochemical Hyperandrogenism (Elevated Total/Free Testosterone)OROligomenorrhea (Less Than 6-9 Menses per Year) or Oligo-OvulationORPolycystic Ovaries on Ultrasound (>= 12 Antral Follicles in One Ovary or Ovarian Volume >= 10 cm3)

• Consensus on infertility treatment related to polycystic ovary syndrome:

Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group (2008).

• The Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group (2012):

Consensus on women's health aspects of polycystic ovary syndrome (PCOS)

Why is PCOS important?

• Affects 4-12% of women of reproductive age

• Significant association between obesity, insulin resistance, and PCOS.

• Huge impact on the reproductive, metabolic, and cardiovascular health of affected women.

Pathogenesis

INTRAOVARIAN ANDROGEN EXCESS

Pathogenesis

1. Hyperandrogenism

2. Insulin resistance

Pathogenesis: Hyperandrogenism

• Symptoms of androgen excess

• Reduced sex-hormone-binding globulin (SHBG) more free testosterone

• Insulin insensitivity

• Lipid abnormalities

• Abdominal obesity

Pathogenesis: Insulin resistance

• Favors anovulation, androgen excess, reduced SHBG

• Metabolic syndrome

• Abdominal obesity

Insulin resistance in PCOS: it’s not just a theory• Insulin resistance in PCOS is independent of obesity

– Obese women with PCOS tend to be more insulin resistant than nml-wt counterparts.

– Obesity is an independent risk factor for glucose intolerance or DM in PCOS

• 3-fold increased incidence of metabolic syndrome in PCOS, vs general population, independent of obesity.

• Insulin resistance ≠ glucose intolerance– Many insulin resistant PCOS pts have normal glucose

tolerance– 30-40% prevalence of glucose intolerance in PCOS women– 7-10% prevalence of type 2 DM in PCOS women– Insulin resistance worsens over time– Increased risk for impaired glucose tolerance and type 2 DM

Abnormal steroidogenenesis

• Intraovarian androgen excess results in excessive growth of small ovarian follicles

• Follicular maturation is inhibited

• Excess androgen causes thecal and stromal hyperplasia

DIAGNOSTIC CRITERIA

AND

CLINICAL MANIFESTATIONS

• NIH Criteria **– Menstrual irregularity due to anovulation or

oligo-ovulation– Evidence of clinical or biochemical

hyperandrogenism• Hirsutism, acne, male pattern baldness• High serum androgen levels

– Exclusion of other causes (CAH, tumors, hyperprolactinemia)

DIAGNOSTIC CRITERIA

DIAGNOSTIC CRITERIA

• Rotterdam Criteria (2 out of 3)– Menstrual irregularity due to anovulation

oligo-ovulation– Evidence of clinical or biochemical

hyperandrogenism– Polycystic ovaries by US

• presence of 12 or more follicles in each ovary measuring 2 to 9 mm in diameter and/or increased ovarian volume

MENSTRUAL DYSFUNCTION

• Oligo or amenorrhea– Menstrual irregularity typically begins in the

peripubertal period– Delayed menarche

• Reduction in ovulatory events leads to deficient progesterone secretion

• Chronic estrogen stimulation of the endometrium with no progesterone for differentiation—intermittent breakthrough bleeding or dysfunctional uterine bleeding

• Increased risk for endometrial hyperplasia and/or endometrial CA

CLINICAL MANIFESTATIONS

HYPERANDROGENISM

• Hirsutism, acne, male pattern balding, alopecia

• 50-90% patients have elevated serum androgen levels

• Free testosterone levels most sensitive

• Rare: increased muscle mass, deepening voice, clitormegaly (should prompt search for underlying neoplasm)

Diagnosis

1. Hyperandrogenism (cont’d) Laboratory features

Elevated total testosterone Most values in PCOS <150 ng/dl (if >200 ng/dl, consider ovarian or

adrenal tumor) Free testosterone assays not reliable yet

DHEA-S Most normal or slightly high in PCOS If >800 mcg/dl, consider adrenal tumor

LH/FSH ratio Levels vary over menstrual cycle, released in pulsatile fashion,

affected by OCPs LH/FSH ratio >2 has little diagnostic sensitivity and need not be

documented

Diagnosis

2. Oligoovulation or anovulation Oligomenorrhea or amenorrhea Dysfunctional uterine bleeding Infertility

30-50% 1st trimester miscarriage rate

3-fold increased risk endometrial carcinoma

Diagnosis

3. Polycystic Ovaries Criteria by ultrasound

Increased ovarian area (>5.5 cm2) or volume (>11 ml) w/ presence of >12 follicles measuring 2-9 mm in diameter

Polycystic ovaries not specific for PCOS > 20% normal women have incidental

polycystic ovaries

OVARIAN ABNORMALITIES

• Thickened sclerotic cortex

• Multiple follicles in peripheral location

• 80% of women with PCOS have classic cysts

INFERTILITY

• Intermittent ovulation or anovulation

• Inherent ovarian disorder—studies show reduced rated of conception despite therapy with clomid

DIFFERENTIAL DIAGNOSIS

1. Hyperprolactinemia– Prominent menstrual dysfunction– Little hyperandrogenism

2. Congenital Adrenal Hyperplasia– morning serum 17-hydroxyprogesterone

concentration greater than 200 ng/dL in the early follicular phase strongly suggests the diagnosis

– confirmed by a high dose (250 mcg) ACTH stimulation test: post-ACTH serum 17-hydroxyprogesterone value less than 1000 ng/dL

DIFFERENTIAL DIAGNOSIS

3. Ovarian and adrenal tumors– serum testosterone concentrations are

always higher than 150 ng/dL– adrenal tumors: serum DHEA-S

concentrations higher than 800 mcg/dL– LOW serum LH concentrations

4. Cushing’s syndrome

5. Drugs: danazol; OCPs with high androgenicity

TREATMENT

WEIGHT LOSS

• Weight loss

• Weight loss

• Weight loss

Management:Immediate/Acute Issues• Regulation of menses

• Oral contraceptives

• Periodic progesterone withdrawal– Medroxyprogesterone 10 mg/day x 7-10 days,

every 3 months (approx 4 menses annually)

• Lifestyle modification/weight loss• Metformin- ie., hitting the “root cause”

– 500-1000 mg bid, 6 month trial reasonable for improvement of menses

Oligomenorrhea

• Combination estrogen-progestin pill first line when fertility is not desired– Decrease in LH secretion and decrease in

androgen production– Increase in hepatic production of sex-

hormone binding globulin– Decreased bioavailablity of testosterone– Decreased adrenal androgen secretion– Regular withdrawal bleeds– Prevention of endometrial hyperplasia

Management:

Immediate/Acute Issues

• Fertility issues– Lifestyle modification/weight loss

• Loss of >5% body wt, calorie-restricted diet, and exercise associated with improvement in spontaneous pregnancy rates (7.5-15% improvement)

– Clomiphene citrate– Most women with PCOS do not respond to normal dose—

20% ovulation rate!

Management:Immediate/Acute Issues• Fertility issues (cont’d)

– Metformin– OR 3.88 in achieving fertility (compared to

placebo), 4.4 (for metformin+clomiphene compared to clomiphene alone)

– Improved outcomes with in vitro fertilization (reduced risk of ovarian hyperstimulation when treated with FSH)

– Reduction in 1st trimester spontaneous abortions

– Thiazolidinediones• Early studies w/ rosiglitazone prior to

conception 30% improvement in fertility rates.

TREATMENT—no fertility desired

• Monophasic antiandrogenic OCP

TREATMENT— fertility desired

• Weight loss—reduction in serum testosterone concentration and resumption of ovulation

• Clomid: 80% will ovulate, 50% will conceive

• Metformin: when added to clomid, improves ovulatory rates

• FSH injections• Laparoscopic surgery: wedge resections,

laparoscopic ovarian laser electrocautery• IVF

Terapia farmacologia dell’ovaio policistico

Agente farmacologicoPrincipio attivo Meccanismo di azione

Estroprogestinico combinato Etinilestradiolo + drospirenone* “ + desogestrel “ + norgestimate

> SHBG; soppressione diFSH e LH; *antiandrogeno

Antiandrogeno Ciproterone acetato; spironolattone Inibizione competitiva con i recettori perifericiPer gli androgeni

GnRHa Triptorelina i.m., s.c.; LeuprolideNafarelin

Down regulation della secrezione di GnRH

GnRh ant Ganirelix, Cetrolerix Down regulation della secrezione di GnRH

Glucocorticoidi Prednisone; Desametazone Soppressione della produzione di ACTH e dellaproduzione surrenalica di androgeni

Inibitori della 5- reduttasi Finasteride Inibizione della 5- redattasi

Inibitori della ornitin-decarbossilasi Eflornithina Inibizione della ornitin-decarbossilasi

Clomifene citrato Clomifene citrato Antiestrogeno; > FSH ed LH

Induttori dell’ovulazione rFSH; HMG (+ HCG) Reclutamento follicolare; (maturazione)

Biguanidi Metformina < produzione di glucosio epatico? effetto diretto sulla steroidogenesi ovarica

Inositolo Myo-inositolo, D-Chiroinositolo 2° messaggero intracellulare dell’insulina

Thiazolidinedioni Troglitazone; Pioglitazone; Rosiglitazone >utilizzo periferico dell’insulinaEffetti diretti sulla steroidogenesi ovarica

TREATMENT— fertility desired

• Metformin– will restore ovulation and menses in > 50%

of patients– Treat with cyclic progestin to reduce

endometrial hyperplasia if regular menses not attained

• 10 mg for 7 to 10 days every two to four months

INFERTILITY TREATMENT

• Metformin– 500 mg daily

– Increase by 500 mg each week until:• Normal menses• Reached max dose• Side-effects

• Clomid– 50 mg days 3-7 for 3 months– 100 mg days 3-7 for 3 months

METFORMIN

• Decreases hepatic glucose production

• Reduces need for insulin secretion

• Improves insulin sensitivity (increases peripheral glucose uptake and utilization)

• Antilipolytic effect—reduces fatty acid concentrations and reduces gluconeogenesis

Metformin and Anovulation

• Evidence suggests that metformin frequently—but not universally—improves ovulation rates in women with PCOS.a

• In addition, pretreatment with metformin has been shown to enhance the efficacy of clomiphene for inducing ovulation.b

• Whether short-course metformin pretreatment (less than 4 weeks) is as effective as conventional long-course metformin remains uncertain.c

• N-acetylcysteine may also enhance the effect of clomiphene.d

SIDE EFFECTS

• Diarrhea, nausea, vomiting, flatulence, indigestion, abdominal discomfort– Caused by lactic acid in the bowel wall

– Minimized by slow increase in dosage

• Lactic acidosis—rare– Avoid in CHF, renal insufficiency, sepsis– Discontinue for procedures using contrast

(withhold X 48 hours)– Temporarily suspend for all surgical procedures

that involve fluid restriction

– Cimetidine causes increased metformin levels

METFORMIN DOSING

• Target—1500-2550 mg per day

• Clinically significant responses not regularly observed at doses less than 1000 mg per day

• Extended release formulations—fewer side-effects. Entire dose should be given with dinner

PCOS and IVF

performance ovulatoria

Weight loss Clomifene Citrate

Gonadotropine/LODMetformina

IVF and PCOS

• rFSH low dose step up

50/75 UI/die + 37,5/50 UI/die

GnRha

Metformina

Drilling ovarico perlaparoscopicoVEGF ?

Ovarian angiogenesis and PCOSOvarian angiogenesis and PCOS

VEGF

Metformin and IVF

Metformin treatment before and during IVF or ICSI in women with Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome (Review) polycystic ovary syndrome (Review)

Tso LO, Costello MF, Andriolo RB, Freitas V Tso LO, Costello MF, Andriolo RB, Freitas V The Cochrane Library, Issue 11, 2010. The Cochrane Library, Issue 11, 2010.

MetforminMetformin

Metformina e PMAMetformin reduces risk of ovarian hyperstimulation syndrome in patients with Metformin reduces risk of ovarian hyperstimulation syndrome in patients with polycystic ovary syndrome during gonadotropin-stimulated in vitro fertilization polycystic ovary syndrome during gonadotropin-stimulated in vitro fertilization cycles: a randomized, controlled trial.cycles: a randomized, controlled trial.

Stefano Palomba, Angela Falbo, Laura Carrillo, aria Teresa Villani, Francesco Orio, Tiziana Russo, Annalisa Di Cello, Fulvio Stefano Palomba, Angela Falbo, Laura Carrillo, aria Teresa Villani, Francesco Orio, Tiziana Russo, Annalisa Di Cello, Fulvio Cappiello, Sabina Capasso, Achille Tolino, Annamaria Colao, Pasquale Mastrantonio, Giovanni Battista La Sala, Fulvio Zullo, and Cappiello, Sabina Capasso, Achille Tolino, Annamaria Colao, Pasquale Mastrantonio, Giovanni Battista La Sala, Fulvio Zullo, and Ettore Cittadini.Ettore Cittadini.

Fertility and Sterility. Vol. 96, No. 6, December 2011Fertility and Sterility. Vol. 96, No. 6, December 2011

P. Platteau MD, MRCOGCentre for Reproductive Medicine

Brussels Free UniversityBelgium

P. Platteau MD, MRCOGCentre for Reproductive Medicine

Brussels Free UniversityBelgium

Antagonist study

A.Nazzaro, MDA.Salerno MSc, PhD

AORN “G. Rummo Italy

A.Nazzaro, MDA.Salerno MSc, PhD

AORN “G. Rummo Italy

Devroey et al., 2009

Ideal antagonist protocol

• Estroprogestin till Wednesday (last pill)• GnRh-antagonist started on Monday for 3 days• Blood test (E2 + P4 + LH)

• rFSH oh Thursday

• GnRh-antagonist added-back on the 6th day of COH• Blood test (E2 + P4 + LH) + US Tuesday and

Thursday• OPU between Monday and wednesday

if P4 >1 ng/ml one more antagonist ampule (rFSH started one day later)

Ideal antagonist protocol

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

rFSH (Tailored)

GnRh-ant

HCG OPU ET

GnRh-ant

Menses

EP

rLH

GnRH Antagonists vs. Agonists

Mioinositolo e PMA

Myo-inositol may improve oocyte quality in intracytoplasmic sperm injection Myo-inositol may improve oocyte quality in intracytoplasmic sperm injection cycles. A prospective, controlled, randomized trial.cycles. A prospective, controlled, randomized trial.

Enrico Papaleo, M.D.,Vittorio Unfer, M.D., Jean-Patrice Baillargeon, M.D.,Enrico Papaleo, M.D.,Vittorio Unfer, M.D., Jean-Patrice Baillargeon, M.D.,Francesco Fusi, M.D., Francesca Occhi, M.D.,and Lucia De Santis, B.Sc.Francesco Fusi, M.D., Francesca Occhi, M.D.,and Lucia De Santis, B.Sc.Fertility and Sterility Vol. 91, No. 5, May 2009Fertility and Sterility Vol. 91, No. 5, May 2009

MioinositoloMioinositolo

Mioinositolo e PMA

Myo-inositol may improve oocyte quality in intracytoplasmic sperm injection Myo-inositol may improve oocyte quality in intracytoplasmic sperm injection cycles. A prospective, controlled, randomized trial.cycles. A prospective, controlled, randomized trial.

Enrico Papaleo, M.D.,Vittorio Unfer, M.D., Jean-Patrice Baillargeon, M.D.,Enrico Papaleo, M.D.,Vittorio Unfer, M.D., Jean-Patrice Baillargeon, M.D.,Francesco Fusi, M.D., Francesca Occhi, M.D.,and Lucia De Santis, B.Sc.Francesco Fusi, M.D., Francesca Occhi, M.D.,and Lucia De Santis, B.Sc.Fertility and Sterility Vol. 91, No. 5, May 2009Fertility and Sterility Vol. 91, No. 5, May 2009

MioinositoloMioinositolo

Surgical Management• Aimed mainly at restoring ovulation.

• Ovarian wedge resection: This procedure has fallen out of favor because of postoperative adhesion formation and the introduction of ovulation-inducing medications.

• Laparoscopic surgery: Various laparoscopic methods, including electrocautery, laser drilling, and multiple biopsy, have been used with the goal of creating focal areas of damage in the ovarian cortex and stroma.

– Potential complications include formation of adhesions and ovarian atrophy.

– Multiple pregnancy rates are lower with ovarian drilling than with gonadotrophin treatment (1% versus 16%), but there are ongoing concerns about the long-term effects on ovarian function.28

In vitro maturation in subfertile women with polycysticIn vitro maturation in subfertile women with polycystic

ovarian syndrome undergoing assisted reproduction (Review)ovarian syndrome undergoing assisted reproduction (Review)

Siristatidis CS, Maheshwari A, Bhattacharya SSiristatidis CS, Maheshwari A, Bhattacharya SThe Cochrane Library, Issue 5, 2011.The Cochrane Library, Issue 5, 2011.

Reviewers' conclusionsData retrieved either from non-randomised comparisons of IVM and conventional ART and non-comparative case series, or from randomised trials comparing IVM protocols, show clearly that IVM is a feasible option for subfertile women with PCOS. Favorable maturation, fertilisation, pregnancy, and live birth rates as well as pregnancy complications, including congenital anomalies, with IVM that are similar to those of conventional IVF or ICSI have been reported. Unfortunately, and unexpectedly, thereare no data from randomised trials to support recommendations for clinical practice at present.

In vitro maturation (IVM)In vitro maturation (IVM)

Management

of

PCOS

Grades of Recommendations

• A- Requires at least one randomized controlled trial as part of a body of literature of overall good quality and consistency addressing the specific recommendation. (Evidence levels Ia, Ib)

• B- Requires the availability of well controlled clinical studies but no randomized clinical trials on the topic of recommendations (Evidence levels IIa, IIb, III)

• C- Requires evidence obtained from expert committee reports or opinions and/ or clinical experiences of respected authorities. Indicates an absence of directly applicable clinical studies of good quality. (Evidence level IV)

The following recommendations and conclusions are based on good and consistent scientific evidence (Level A):

• An increase in exercise combined with dietary change has consistently been shown to reduce diabetes risk comparable to or better than medication.

• Improving insulin sensitivity with insulin-sensitizing agents is associated with a decrease in circulating androgen levels, improved ovulation rate, and improved glucose tolerance.

• The recommended first-line treatment for ovulation induction remains the antiestrogen clomiphene citrate.

• The addition of eflornithine to laser treatment is superior in the treatment of hirsutism than laser alone.

The following recommendations and conclusions are based on limited and inconsistent scientific evidence (Level B):

• Women with a diagnosis of polycystic ovary syndrome (PCOS) should be screened for type 2 diabetes and impaired glucose tolerance with a fasting glucose level followed by a 2-hour glucose level after a 75-g glucose load.

• Women with PCOS should be screened for cardiovascular risk by determination of body mass index (BMI), fasting lipid and lipoprotein levels, and metabolic syndrome risk factors.

• Reduction in body weight has been associated with improved pregnancy rates and decreased hirsutism, as well as improvements in glucose tolerance and lipid levels.

• There may be an increase in pregnancy rates by adding clomiphene to metformin, particularly in obese women with PCOS.

• If clomiphene citrate use fails to result in pregnancy, the recommended second-line intervention is either exogenous gonadotropins or laparoscopic ovarian surgery.

The following recommendations and conclusions are based primarily on consensus and expert opinion (Level C):

• Combination low-dose hormonal contraceptives are most frequently used for long-term management and are recommended as the primary treatment of menstrual disorders.

• Women in groups at higher risk for nonclassical congenital adrenal hyperplasia and a suspected diagnosis of PCOS should be screened to assess the 17- hydroxyprogesterone value.

• A low-dose regimen is recommended when using gonadotropins in women with PCOS.

• There is no clear primary treatment for hirsutism in PCOS.

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