diagnostic challenges in polycystic ovary...
TRANSCRIPT
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The Phenotypes in Polycystic Ovary Syndrome and overlap with Functional
Hypothalamic Amenorrhea Roger A. Lobo MD
Columbia University
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Objectives
• Phenotypes of PCOS allowable using Rotterdam
• Focus on ovulatory function and anovulation – what causes this in PCOS
• Functional Hypothalamic Amenorrhea (FHA) – overlap with PCOS
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Various phenotypes possible in the diagnosis of PCOS
“NIH” definition
Rotterdam (ESHRE/ASRM)
AEPCOS
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The so called “NIH” definition
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“Accepted” definition of PCOS – the Rotterdam consensus conference
European focus on ovarian morphology accepted
PCOS diagnosed by: 1) POLYCYSTIC OVARIES 2) MENSTRUAL IRREGULARITY 3) HYPERANDROGENISM Any 2 0f the 3 Human Reproduction 19:41, 2004 Fertil Steril 81:19-25,2004
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Androgen Excess Society guidelines: endorsing the
importance of androgen excess
Hyperandrogenism: hirsutism and/or hyperandrogenemia
Ovarian Dysfunction: oligo-anovulation and/or polycystic ovaries
Exclusion of other disorders Azziz R. Position Statement. J Clin Endocrinol Metab 91: 4237-45, 2006
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The non hyperandrogenic phenotype possible in Rotterdam
Polycystic Ovaries and Irregular Cycles – no obvious Hyperandrogenism
Sometimes called phenotype D
How often does it occur? – minority ( 16% in Dewailly study – JCEM 2006; 91:3922-27)
Do these women resemble classic PCOS at all?
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Early characterization of phenotype D
Dewailly D J Clin Endocrinol Metab 2006; 91: 3922-7
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Dewailly, D. et al. J Clin Endocrinol Metab 2006;91:3922-3927
Box-and-whisker plots showing the distribution of individual values for BMI (A), waist circumference (B), and SHBG (C) in controls and in patients with
phenotypes A-D
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Evolving Cardio-Metabolic risks with various phenotypes relating to PCOS
AndrogensNORMAL
NORMAL
ELEVATED
NORMAL
ELEVATED
ELEVATED
ELEVATED
Cycles NORMAL
NORMAL
NORMAL
IRREG (ANOV)
NORMAL (OVULAT)
IRREG (ANOV)
IRREG (ANOV)
Ovaries NORMAL
PAO/PCO
NORMAL
PAO/PCO
PAO/PCO
“NORMAL”
PAO/PCO
CV/Metab Risk NORMAL
NORMAL (+/-)
NORMAL - SMALL INCREASE
SMALL INCREASE
SOME INCREASE
INCREASE
INCREASE
IH OV-PCOS “NIH” Classic PCOS “PCOS” - D
Spectrum of risk modified by weight and familial/genetic profile
Jovanovic and Lobo, F&S 2009
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In the Rotterdam diagnosis, ovarian ultrasound is a key feature
Ultrasound criteria are not constant and have changed with time
There has also been an attempt to use AMH for the diagnosis
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Fulghesu, A.M. et al. Hum. Reprod. 2007 22:2501-2508; doi:10.1093/humrep/dem202
Example of median ovarian section with outlined ovarian and stroma areas A1 is the total area and A2 is the stroma area
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FNPO appears to be the most sensitive and specific ovarian Ultrasound marker
Christ JP. Fertil Steril 2014; 101: 280-287
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Comparisons of various ultrasound criteria for the diagnosis of PCOS in
“classic” patients – “NIH” criteria
These data (n=82 PCOS) suggested FNPO of 28 (85% sensitivity; 98% specificity)
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Can AMH or various ultrasound criteria be used in the various phenotypes?
Carmina and Lobo. Endocrine Practice 2016; 22: 287-93
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AMH and ultrasound in various Phenotypes
Carmina and Lobo. Endocrine Practice 2016; 22: 287-93
A/B
C
D
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AMH is only helpful in “classic” patients while FNPO is helpful in all phenotypes
Carmina and Lobo. Endocrine Practice 2016; 22: 287-93
ROC analyses
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What causes anovulation in PCOS? Candidates:
• Androgen
• Insulin resistance
• BMI – obesity/cytokines
• Inherent ovarian characteristics (morphology/AMH)
• Inherent dysfunction of hypothalamic pituitary axis (GnRH/LH/FSH) ??? No definitive data except suggestion by GWAS
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The effects of androgen on ovarian function in PCOS
• GnRH/LH effects
• Correlates of response to ovulation induction – could be at central or ovarian level
• Androgens may be a less potent negative influence on ovulatory function – eg. Ovulatory PCOS “C” (elevated androgens)
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Insulin resistance and ovulatory function
• Known relationship
• In PCOS, women with irregular cycles (phenotypes A, B, D) have IR
• Treatments which decrease IR (insulin sensitizers such as metformin) improve menstrual function
• Direct mechanism unclear – probably multiple – related to cytokines
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Influence of adipocytokines and IR with hyperinsulinemia affecting
ovarian function
ADIPOCYTOKINES IR
HYPERINSULINEMIA
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BMI/obesity on ovulatory function
• Related to IR
• Hypothalamic component – simple obesity (non PCOS)
• Adipocytokines
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Escobar-Morreale HF. Trends in Endocrinol Metab 2007; 18: 266-72
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Inherent ovarian characteristics affecting ovarian function in PCOS
• Elevated AMH levels – proxy for abnormal morphology and follicular counts (other issues – stromal androgen etc.)
• AMH – correlates of ovulatory function documented
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Relative importance of ovarian morphological characteristics/AMH
influencing menstrual/ovulatory function
• Important but not absolute
• Ovulatory PCOS – phenotype C with elevated AMH and follicle counts
• “PAO” or “PCO” in “normal” women in the general population
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Rank order of relative importance in determinng ovulatory function
(less to more)
• Ovarian morphology
• Androgens
• Insulin resistance and adipose mass (BMI)
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IR and menstrual function: chicken or egg?
• Menstrual irregularity “irreparably ?” tied to IR
• Does menstrual irregularity lead to IR; or does IR contribute to menstrual irregularity?
• The latter
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Influence of adipocytokines and IR with hyperinsulinemia affecting
ovarian function
ADIPOCYTOKINES IR
HYPERINSULINEMIA
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Multiple factors affecting CV/Metabolic/ Reproductive Health
CHEMERIN
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Acute increases in Leptin affecting ovulation and progesterone production
Not mediated by leptin receptors – poss via PGs, NO
IN VIVO
IN VITRO
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Positive effects of adiponectin on oocytes and embryo development
Decreased adiponectin in obesity; well documented in PCOS even after adjusting for BMI
Abnormal L/A ratios in Obesity and PCOS
Strong evidence that increasing adiponectin is beneficial for follicle growth and embryos (low adiponectin is detrimental) Richards JS Fertil Steril 2012; 98: 471-9
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Best correlates of fat content and IR seen with Chemerin and L/A ratio
Kort and Lobo. Gynecol Endocrinol 31: 152-5, 2015
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CHEMERIN correlates with FAT and HOMA-IR in PCOS
Kort and Lobo Gynecol Endocrinol 31: 152-5, 2015
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Chemerin induces follicular arrest in a rat model
Kim JY. Endocrinology 2013; 154: 2912-23
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Functional Hypothalamic Amenorrhea versus PCOS diagnosed by Rotterdam
• Lower LH, FSH, estrogen and amenorrhea in FHA compared to PCOS
• There is overlap in these diagnoses – some women with FHA have polycystic ovaries – what does this mean?
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Rotterdam Phenotype D versus FHA – if we accept Rotterdam, there should
be no confusion here
• Phenotype D – controversial because of no demonstable androgen excess (irregular menses and polycystic ovaries)
• Functional Hypothalamic Amenorrhea (FHA) – amenorrhea (mainly not merely irregular menses); low gonadotropins (LH, FSH); low estrogen status
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Hypothalamic Amenorrhea and PCOS
• PAO observed in women with FHA: androgenic responses to gonadotropins in some women with FHA Shoham Z, Fertil Steril 1992; 58: 37-45; Schachter M, Gynecol Endocrinol 1996; 10: 327-35; Wang JG, J Clin Endocrinol Metab 2008; 93: 1394-97
• With spontaneous “ recovery” of FHA, some women develop regular features of PCOS Wang and Lobo J Clin Endocrinol 2008; 93: 1394-97
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FHA/PCOM during COH: higher responses and increased androgen secretion
Wang and Lobo. J Clin Endocrinol Metab 2008;93:1394-7
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Long term follow up – with recovery, emergence of a PCOS picture in some
Wang and Lobo. J Clin Endocrinol Metab 2008; 93: 1394-7
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Retrospective assessment of women diagnosed with FHA: 41/122 with
evidence of “underlying” PCOS
Su and Warren. Fertil Steril 2009; 92:2106-9
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FHA in a French cohort – 38% were PCO-like
Robin G. JCEM 2012; 97: 4236-43
FHA FHA
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Androgen levels slightly elevated
FHA FHA
Robin G. JCEM 2012; 97: 4236-43
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Characteristically very low LH and FSH in FHA – whether PCOS like or not
FHA FHA
Robin G. JCEM 2012; 97: 4236-43
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A survey of 40 women with FHA to determine the possible co-existence of
PCOS
Carmina and Lobo, Am J Obstet Gynecol 2016; 214, 714 e 1-6
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Our approach was a little different – we assessed women with FHA with high AMH
13/40 (32.5%) had elevated AMH; these women had larger ovaries
Carmina and Lobo Am J Obstet Gynecol 2016; 214, 714 e 1-6
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The 13 women with elevated AMH had higher but non-statistically elevated androgens
4 women (10% of all) had increased ovarian volume and borderline elevated androgens
Carmina and Lobo Am J Obstet Gynecol 2016; 214, 714 e 1-6
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Of the women with FHA suspected of having co-existing PCOS, cycles were
regular prior to the development of FHA
Could these women have had undiagnosed PCOS - Phenotype C?
Is phenotype “C” a vulnerability state
for FHA?
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Possibilities for the FHA/PCOS overlap: the finding of PAO in FHA is common
• This could just be women with FHA, who happen to have polycystic ovaries (up to 20% of population)
• These are women with underlying PCOS – phenotype C (ovulatory phenotype) who develop FHA – and can revert
• Women with PCOS may be more susceptible to developing FHA?
• “Normal” women with asymptomatic polycystic ovaries are more susceptible to developing FHA?
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Conclusions • Rotterdam criteria (with various phenotypes) have been
adopted
• AMH is only helpful for the diagnosis in “classic” patients
• Follicle counts are the most diagnostic ultrasound criterion – and can diagnose a polycystic ovary in all phenotypes
• Anovulation in PCOS is principally explained by IR and adipocytokine secretion (enhanced by overweight status); less so by elevated androgens
• Some women with FHA may have a cryptic form of PCOS – the finding of overlap is common
• There could be some vulnerabilities in PCOS/PAO in developing FHA?
• Treatment should be directed at FHA and the women followed over time
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Escobar-Morreale HF. Trends in Endocrinol Metab 2007; 18: 266-72
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Conclusions on the effects of various factors on ovarian function in PCOS:
using Model of Phenotype D
• Less importance of androgens and BMI in “D”
• Irregularity is probably explained by IR (when BMI is increased) and ovarian morphological features
• Since AMH is lower than in classic phenotypes (A/B) and IR may not be as severe, the menstrual irregularity may not be chronic and may alternate with regular cycles (Panidis, 2015)