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Infertility and PCOSInfertility and PCOS
Erinn Myers, M4 Erinn Myers, M4
Department of Obstetrics and GynecologyDepartment of Obstetrics and GynecologyUniversity of Tennessee Health Science CenterUniversity of Tennessee Health Science Center
January 28, 2007January 28, 2007
Learning ObjectivesLearning Objectives
Following the presentation Following the presentation “Infertility and PCOS“Infertility and PCOS” ” participants should be able to:participants should be able to:
– Diagnose PCOS.Diagnose PCOS.– Understand the differences between PCO, Understand the differences between PCO,
PCOS and PCOM.PCOS and PCOM.– Decide on possible treatment.Decide on possible treatment.– Exclude other problems.Exclude other problems.
DEFINITION
Inability to conceive after a year of exposure to conception.– Six months > 35 years old.– A disability and a disease…
NOT an elective condition.– Great societal and demographic impact
FactorsFactors
MaleMale
OvarianOvarian
CervicalCervical
Peritoneal Peritoneal
TubalTubal
UterineUterine
UnexplainedUnexplained
OvulationOvulation
An LH (luteinizing hormone) surge An LH (luteinizing hormone) surge occurs 24 to 36 hours prior to ovulation occurs 24 to 36 hours prior to ovulation (Follicular rupture = It is the ovary’s job (Follicular rupture = It is the ovary’s job to make a cyst and rupture it.) to make a cyst and rupture it.)
Progesterone is increasingly produced Progesterone is increasingly produced after the LH surgeafter the LH surge
Secretory changes occur in the Secretory changes occur in the endometrium due to progesterone.endometrium due to progesterone.
OvulationOvulation
Pregnancy is absolute proof of ovulation.Pregnancy is absolute proof of ovulation.
Serum progesterones are 99%+ proof of Serum progesterones are 99%+ proof of ovulation. These are done:ovulation. These are done:– 8 days after a positive ovulation test8 days after a positive ovulation test– 7 days after ovulation on a monitor7 days after ovulation on a monitor– Day 21 and 24 if ovulation day is uncertain.Day 21 and 24 if ovulation day is uncertain.
Ovulation DisordersOvulation Disorders
PCOSPCOS
HypothyroidismHypothyroidism
HyperprolactinemiaHyperprolactinemia
Weight Loss / Weight GainWeight Loss / Weight Gain
PCOSPCOS
DiagnosisDiagnosis– Somatic HyperandrogenismSomatic Hyperandrogenism– Lab HyperandrogenismLab Hyperandrogenism– Oligo-anovulationOligo-anovulation– PCOM (polycystic ovarian morphology)PCOM (polycystic ovarian morphology)
1990 NIH/NICHD1990 NIH/NICHD
PCOS diagnosisPCOS diagnosis– Ovulatory dysfunctionOvulatory dysfunction– Clinical hyperandrogenism and/or Clinical hyperandrogenism and/or
hyperandrogenemiahyperandrogenemia– Exclusion of other disorders such asExclusion of other disorders such as
Non-classical adrenal hyperplasiaNon-classical adrenal hyperplasia
Androgen secreting tumorAndrogen secreting tumor
HyperprolactinemiaHyperprolactinemia
ThyroidThyroid
2003 ESHRE/ASRM2003 ESHRE/ASRM
PCOS diagnosisPCOS diagnosis– At least 2 of the following featuresAt least 2 of the following features
Oligoovulation or anovulationOligoovulation or anovulation
Clinical and/or biochemical signs of Clinical and/or biochemical signs of hyperandrogenismhyperandrogenism
Polycystic ovarian morphology (sonography)Polycystic ovarian morphology (sonography)
– Exclusion of other disordersExclusion of other disorders
– 2003 Rotterdam ESHRE/ASRM Consensus. Fertil Steril 81:19, 20042003 Rotterdam ESHRE/ASRM Consensus. Fertil Steril 81:19, 2004
PCOSPCOS
Diagnosis is more clinical than lab.Diagnosis is more clinical than lab.– Androgenism (hirsute, acne, central obesity)Androgenism (hirsute, acne, central obesity)– Oligo-anovulatoryOligo-anovulatory– PCOM (polycystic ovarian morphology)PCOM (polycystic ovarian morphology)– Elevated androgensElevated androgens
Androgens decrease with ageAndrogens decrease with age
– Decreased HDL and SHBGDecreased HDL and SHBG
PCOMPCOM
PCOM (polycystic ovarian morphology)PCOM (polycystic ovarian morphology)– > > 12 follicles at 2 - 9 mm in at least 1 ovary12 follicles at 2 - 9 mm in at least 1 ovary– Volume > 10ccVolume > 10cc– Does not apply if on BCPsDoes not apply if on BCPs– If a follicle is >10mm, repeat scan next cycle.If a follicle is >10mm, repeat scan next cycle.
2003 Rotterdam ESHRE/ASRM Consensus. Fertil Steril 81:19, 20042003 Rotterdam ESHRE/ASRM Consensus. Fertil Steril 81:19, 2004
PCOMPCOM
PCOM (polycystic ovarian morphology)PCOM (polycystic ovarian morphology)
PCOMPCOM
PCOM (polycystic ovarian morphology)PCOM (polycystic ovarian morphology)
PCOM vs. FolliclesPCOM vs. Follicles
PCOM (polycystic ovarian morphology) PCOM (polycystic ovarian morphology) vs. Pre- ovulatory Folliclesvs. Pre- ovulatory Follicles
Screening TestsScreening Tests
FSH and E2FSH and E2
ProlactinProlactin
TSHTSH
17-OHP17-OHP
Lipids / HDL decreasedLipids / HDL decreased
SBHG decreasedSBHG decreased
2 hour glucose to screen for diabetes 2 hour glucose to screen for diabetes
ExcludeExcludeNon-classical 17-hydroxylase deficiency Non-classical 17-hydroxylase deficiency can look like PCOScan look like PCOSHAIRAN - hyperandrogenic insulin HAIRAN - hyperandrogenic insulin resistance and acanthosis nigricansresistance and acanthosis nigricansAdrenal tumorAdrenal tumorCushing’sCushing’sProlactinProlactinThyroidThyroidPituitary insufficiencyPituitary insufficiencyHypothalamic amenorrheaHypothalamic amenorrhea
Stop UsingStop Using
““Inappropriate LH" as a diagnosisInappropriate LH" as a diagnosis
LH / FSH ratio as it is not sufficiently LH / FSH ratio as it is not sufficiently predictivepredictive
Fasting insulin as it is not sensitiveFasting insulin as it is not sensitive
Dexamethasone therapy can induce insulin Dexamethasone therapy can induce insulin resistance resistance
Utility of LH/FSH RatioUtility of LH/FSH Ratio
Study designed to understand the biological Study designed to understand the biological variability of the LH/FSH ratio in women with variability of the LH/FSH ratio in women with PCOS vs. women with normal menstruation over PCOS vs. women with normal menstruation over one full cycleone full cycleWill assess the diagnostic utility of the LH/FAH Will assess the diagnostic utility of the LH/FAH ratioratio10 consecutive blood samples were taken at 4 10 consecutive blood samples were taken at 4 day intervals in 12 PCOS patients and 11 age day intervals in 12 PCOS patients and 11 age and weight matched controls and weight matched controls – Cho, LW, et. al. Bio variation of the LH/FSH ratio in normal women and
those with PCOS. Endocrine Abstracts (2005) 9 p80
Utility of LH/FSH RatioUtility of LH/FSH Ratio
7.6% of PCOS and 15.6% of controls had 7.6% of PCOS and 15.6% of controls had LH/FSH ratio above 3LH/FSH ratio above 3Sensitivity 7.6%Sensitivity 7.6%Specificity 33.7%Specificity 33.7%Therefore, the biological variation of the Therefore, the biological variation of the LG/FSH ratio is at least as wide in the LG/FSH ratio is at least as wide in the control group as in the PCOS groupcontrol group as in the PCOS group– Cho, LW, et. al. Bio variation of the LH/FSH ratio in normal women and
those with PCOS. Endocrine Abstracts (2005) 9 p80
LH/FSH RatioLH/FSH Ratio
Study to determine the incidence of abnormal Study to determine the incidence of abnormal LH/FSH ratio in women with PCOS with LH/FSH ratio in women with PCOS with normoinsulinemia and hyperinsulinemianormoinsulinemia and hyperinsulinemia
Access the influence of elevated LH/FSH ratio on Access the influence of elevated LH/FSH ratio on selected endocrine and biochemical parametersselected endocrine and biochemical parameters
LH/FSH ratio119 patients with PCOS was calculated LH/FSH ratio119 patients with PCOS was calculated and underwent hormonal and metabolic analysisand underwent hormonal and metabolic analysis
– Banaszewska B, et. al., Incidence of elevated LH/FSH ration in PCOS women
with normo- and hyperinsulinemia. Pocz Acad Med Bialymst. 2003;48:131-4
LH/FSH RatioLH/FSH Ratio
45.4% had an LH/FSH >2, Normal45.4% had an LH/FSH >2, Normal
55% had normal gonadotropin ratio55% had normal gonadotropin ratio
Statistically significant differences between Statistically significant differences between groups with normal and elevated LH/FSHgroups with normal and elevated LH/FSH– BMI, serum insulin, LH levelsBMI, serum insulin, LH levels
Majority of women with elevated insulin Majority of women with elevated insulin had a normal LH/FSH ratiohad a normal LH/FSH ratio– Banaszewska B, et. al., Incidence of elevated LH/FSH ration in PCOS women
with normo- and hyperinsulinemia. Pocz Acad Med Bialymst. 2003;48:131-4
LH/FSH RatioLH/FSH Ratio
LH/FSH ratio is not a characteristic attribute of LH/FSH ratio is not a characteristic attribute of ALL PCOS womenALL PCOS women– This study found ratio to be elevated <50%This study found ratio to be elevated <50%
Most of PCOS patients with normal Most of PCOS patients with normal gonadotropin levels also had hyperinsulinemia gonadotropin levels also had hyperinsulinemia and obseityand obseity
Patients with hyperinsulinemia and elevated LH Patients with hyperinsulinemia and elevated LH had increased adrenal androgenic activityhad increased adrenal androgenic activity– Banaszewska B, et. al., Incidence of elevated LH/FSH ration in PCOS women with normo-
and hyperinsulinemia. Pocz Acad Med Bialymst. 2003;48:131-4
PCOSPCOS
TreatmentTreatment– Weight loss and exerciseWeight loss and exercise– Clomid (clomiphene citrate) (3 months)Clomid (clomiphene citrate) (3 months)– Letrozole (FemaraLetrozole (Femara®®) (aromatase inhibitor) (3 ) (aromatase inhibitor) (3
months)months)– Metformin (6 months)Metformin (6 months)
Note that the combination of metformin and Note that the combination of metformin and clomiphene are more productive at months 4-6 clomiphene are more productive at months 4-6 compared with months 1-3 .compared with months 1-3 .
– GonadotropinsGonadotropins
PCOSPCOS
Weight lossWeight loss– Poor results if BMI > 50Poor results if BMI > 50– Requires a dedicated program of diet and Requires a dedicated program of diet and
exerciseexercise– Use dieticians who work with diabeticsUse dieticians who work with diabetics– Liposuction of cutaneous fat is not the same Liposuction of cutaneous fat is not the same
as loss of visceral weightas loss of visceral weightRichard S. Legro, MD, Penn State College of Medicine, Hershey Richard S. Legro, MD, Penn State College of Medicine, Hershey PCOS PG Course, ASRM, New Orleans, October 2006PCOS PG Course, ASRM, New Orleans, October 2006
PCOSPCOS
MedicationsMedications– BCPs may be better with thin patients that have BCPs may be better with thin patients that have
normal HDL and SHBGnormal HDL and SHBG– Metformin causes more nausea and weight loss Metformin causes more nausea and weight loss
than metformin-XL than metformin-XL – Sibutrimine (Meridia ®) – for weight lossSibutrimine (Meridia ®) – for weight loss– Androgen receptor antagonists for hirsutismAndrogen receptor antagonists for hirsutism
Spironolactone (Aldactone®) and Flutemide Spironolactone (Aldactone®) and Flutemide (Propecia®)(Propecia®)
– Ketaconazole (Nizoral®)Ketaconazole (Nizoral®)– Florinithine (Vaniqa®) creamFlorinithine (Vaniqa®) cream
Letrozole and ClomipheneLetrozole and ClomipheneBirth DefectsBirth Defects
There is no increase in birth defects for There is no increase in birth defects for letrozole or clomiphene if used when not letrozole or clomiphene if used when not pregnant.pregnant.
Letrozole associated with fewer birth Letrozole associated with fewer birth defects than clomiphene but this is not defects than clomiphene but this is not statistically significant.statistically significant.
Tulandi T. Fertil Steril 85:1761, 2006Tulandi T. Fertil Steril 85:1761, 2006
PCOSPCOS
Metformin Therapy – Long TermMetformin Therapy – Long Term– WeightWeight– HyperandrogenismHyperandrogenism– Increases FertilityIncreases Fertility– Decreases Cardiac DiseaseDecreases Cardiac Disease– Decreases DiabetesDecreases Diabetes
MonitorMonitor– SHBG (decreased with PCO)SHBG (decreased with PCO)– HDL (decreased with PCO)HDL (decreased with PCO)– 2 Hour Glucose2 Hour Glucose
Long Term ManagementLong Term Management
BCPs may be better with a thin patient and BCPs may be better with a thin patient and normal HDL and SHBGnormal HDL and SHBG
ConclusionsConclusionsPCOS DiagnosisPCOS Diagnosis– Somatic or Lab HyperandrogenismSomatic or Lab Hyperandrogenism– Oligo-anovulationOligo-anovulation– Polycystic Ovarian MorphologyPolycystic Ovarian Morphology
ExcludeExclude– Non-classical 17-hydroxylase deficiency, HAIRAN, adrenal Non-classical 17-hydroxylase deficiency, HAIRAN, adrenal
tumor, Cushing’s, prolactinemia, thyroid disorders, tumor, Cushing’s, prolactinemia, thyroid disorders, hypothalamic amenorrheahypothalamic amenorrhea
PCOS ConceptsPCOS Concepts– Decreased HDL and SHBG Decreased HDL and SHBG – LH/FSH ratio is not useful.LH/FSH ratio is not useful.
TreatmentTreatment– Weight loss, exercise, clomiphene, aromatase inhibitors, Weight loss, exercise, clomiphene, aromatase inhibitors,
metformin, gonadotropinsmetformin, gonadotropins
AcknowledgementAcknowledgement
Dan C. Martin, MD, UTHSC, MemphisDan C. Martin, MD, UTHSC, Memphis
ASRM PCOS Course, New Orleans, 2006ASRM PCOS Course, New Orleans, 2006
