The Phenotypes in Polycystic Ovary Syndrome and overlap with Functional

Hypothalamic Amenorrhea Roger A. Lobo MD

Columbia University

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

Various phenotypes possible in the diagnosis of PCOS

“NIH” definition

Rotterdam (ESHRE/ASRM)

AEPCOS

The so called “NIH” definition

“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

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

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?

Early characterization of phenotype D

Dewailly D J Clin Endocrinol Metab 2006; 91: 3922-7

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

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

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

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

FNPO appears to be the most sensitive and specific ovarian Ultrasound marker

Christ JP. Fertil Steril 2014; 101: 280-287

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)

Can AMH or various ultrasound criteria be used in the various phenotypes?

Carmina and Lobo. Endocrine Practice 2016; 22: 287-93

AMH and ultrasound in various Phenotypes

Carmina and Lobo. Endocrine Practice 2016; 22: 287-93

A/B

C

D

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

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

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)

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

Influence of adipocytokines and IR with hyperinsulinemia affecting

ovarian function

ADIPOCYTOKINES IR

HYPERINSULINEMIA

BMI/obesity on ovulatory function

• Related to IR

• Hypothalamic component – simple obesity (non PCOS)

• Adipocytokines

Escobar-Morreale HF. Trends in Endocrinol Metab 2007; 18: 266-72

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

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

Rank order of relative importance in determinng ovulatory function

(less to more)

• Ovarian morphology

• Androgens

• Insulin resistance and adipose mass (BMI)

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

Influence of adipocytokines and IR with hyperinsulinemia affecting

ovarian function

ADIPOCYTOKINES IR

HYPERINSULINEMIA

Multiple factors affecting CV/Metabolic/ Reproductive Health

CHEMERIN

Acute increases in Leptin affecting ovulation and progesterone production

Not mediated by leptin receptors – poss via PGs, NO

IN VIVO

IN VITRO

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

Best correlates of fat content and IR seen with Chemerin and L/A ratio

Kort and Lobo. Gynecol Endocrinol 31: 152-5, 2015

CHEMERIN correlates with FAT and HOMA-IR in PCOS

Kort and Lobo Gynecol Endocrinol 31: 152-5, 2015

Chemerin induces follicular arrest in a rat model

Kim JY. Endocrinology 2013; 154: 2912-23

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?

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

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

FHA/PCOM during COH: higher responses and increased androgen secretion

Wang and Lobo. J Clin Endocrinol Metab 2008;93:1394-7

Long term follow up – with recovery, emergence of a PCOS picture in some

Wang and Lobo. J Clin Endocrinol Metab 2008; 93: 1394-7

Retrospective assessment of women diagnosed with FHA: 41/122 with

evidence of “underlying” PCOS

Su and Warren. Fertil Steril 2009; 92:2106-9

FHA in a French cohort – 38% were PCO-like

Robin G. JCEM 2012; 97: 4236-43

FHA FHA

Androgen levels slightly elevated

FHA FHA

Robin G. JCEM 2012; 97: 4236-43

Characteristically very low LH and FSH in FHA – whether PCOS like or not

FHA FHA

Robin G. JCEM 2012; 97: 4236-43

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

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

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

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?

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?

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

Escobar-Morreale HF. Trends in Endocrinol Metab 2007; 18: 266-72

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)