Plasma homocysteine, fasting insulin, and

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Plasma homocysteine, fasting insulin, and serum
androgens as a function of sonographic ovarian
features
E.Scott Sills, M.D. Georgia Reproductive
Specialists Atlanta, Georgia 30342 USA
?
IVF.com
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Polycystic ovary syndrome (PCOS) has
been associated with poor oocyte quality in in
vitro fertilization
? oocyte yield at retrieval ? overall
fertilization rate
Could impaired follicular vascularity contribute
to this problem?
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Why is PCOS relevant to current clinical practice?
Most common endocrine dysfxn among women age 14-45
Hull Gynecol Endocrinol 19871235-45
May occur in up to 7 of reproductive age women
Nestler Fertil Steril 199870811-2
Dx associated w/ abnl GTT, ? risk for type-2 DM
and HTN
Fibrinolytic and lipid derangements are observed
in PCOS
Lobo Carmina Ann Intern Med 2000132989-93
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Follicular oxygenation defects and suboptimal
oocyte competence

• Oxygen tension critical to oocyte health
• Persistent oxygen starvation impairs oocyte
  metabolism
• Oocytes retrieved from PCOS pts. are poorly
  oxygenated
• Hypoxia gtgt Cytoplasmic/chromosomal disorders

Van Blerkom J Assist Reprod Genet
199815226-234 Chui et al Hum Reprod
199712191-196 Gosden Byatt-Smith Hum
Reprod 1986165-68
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What is polycystic ovary syndrome?
There is uncertainty about the constellation of
symptoms that appear in this disorder.
Hacihanefioglu Fertil Steril
2000731261-1262
PCOS vs. polycystic-appearing ovaries
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What is polycystic ovary syndrome?

• 1990 NIH/NICHD Conference on PCOS
• No single PCOS criterion was endorsed as
• definite or probable by gt64 of expert
  respondents
• Insulin resistance, ?LHFSH ratio, and polycystic
  ovaries
• were regarded as possible criteria
• Mitwally
  Casper Middle East Fertil Soc J 200052-12

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The presence of polycystic ovaries and/or PCOS
cannot be elicited by a cursory evaluation alone
No Yes
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Cincinnati PCOS criteria
total sample ? 1 pregnancy
(n149) (n41) oligomenorrhea 100
100 hirsutism 98
98 BMI gt27 88
88 polycystic-appearing ovaries 79
90 androstenedione gt250ng/dl 29
24 acanthosis nigricans 20
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Glueck et al Metabolism 1999481589-1595
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PCOS Consistent definition or description is
needed
A chronic multisystem endocrine disorder
characterized by irregular menses, hirsutism,
obesity, hyperlipidemia, androgenization,
insulin resistance, subfertility, and enlarged
polycystic ovaries Sills et al
Eur J Obstet Gynecol Reprod Biol 200091148-153
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PCOS vs. polycystic-appearing ovaries

• Chronic anovulation (? PCOS) has been associated
• w/ ? risk for vascular disease
• Solomon et al Am Heart Assoc 1999 Ann
  Meeting
• Polycystic ovary phenotype is not mandatory to dx
  PCOS
• Absence of polycystic ovaries cannot r/o PCOS
• Does a vascular marker exist to identify these
• women at high risk for poor reproductive
  outcome?

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PCOS vs. polycystic-appearing ovaries

• Some women with laboratory findings consistent w/
• PCOS do not manifest any important alteration
• in ovarian morphology
• Polson et al Lancet 19881(8590)870-872
  
• Clayton et al Clin Endocrinol (Oxf)
  199237127-134

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Which marker and in what population?
NH3
S-CH2-CH2-HC
COO-
Healthy women with polycystic-appearing
ovaries referred for infertility evaluation
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Entry and exclusion criteria for study

• Well-nourished nonsmoking women on regular diet,
• not yet taking prenatal vitamins/folate
• Pregnancy, lactation, coagulopathy, renal dz.,
• alcoholism/substance abuse, digestive
  disorder,
• diabetes mellitus.
• IRB approval secured informed consent obtained

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Measured parameters

• TV-sonographic ovarian appearance (1polycystic
  0nl)

• Age, BMI, menstrual cycle day, infertility
  duration,
• BUN/Cr, plasma homocysteine, fasting insulin
  glucose,
• androstenedione, total testosterone, DHEAS
• MTHFR (C ?T 677) gene polymorphism status

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methionine adenosyltransferase
NH3
adenosine
NH3
-
CH2-S-CH2-CH2-HC
CH2-S-CH2-CH2-HC
COO-
COO-
methionine
S-adenosylmethionine
CH3 (to acceptor)
N,N-dimethylglycine
adenosine
NH3
-
H4-folate
S-CH2-CH2-HC
betaine-homocysteine S-methyltransferase
COO-
S-adenosylhomocysteine
cystathionine
CH3-(B12)
glycine betaine
cystathionine ß-synthase
5-methyl H4-folate
B6
serine
homocysteine S-methyltransferase
NH3
adenosine
S-CH2-CH2-HC
COO-
homocysteine
Homocysteine and polycystic ovaries
E.S.Sills et al
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Homocysteine and polycystic ovaries E.S.Sills et
al
Results
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Homocysteine (mmol / ml)
8
6
4
2
0
Figure 1. Distribution of plasma homocysteine
values as measured by fluorescence polarization
immunoassay method in 54 women with polycystic
( ) and non-cystic ( ) ovaries. Median
plasma levels were identical in both groups
(7mmol/ml).
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Table 1. Characteristics of 54 study patients
referred for infertilty evaluation as a function
of general sonographic ovarian appearance.
ovarian morphology
non-cystic polycystic (n18)
(n36) age (yr)1 32.0
28.034.8 29.6 26.033.0 BMI
27.5 22.333.6 33.5
25.537.5 infertility duration (mo.)
30.0 12.048.0 25.2 024.0 BUN
(mg/dl) 11.8 10.014.8 12.3
10.013.3 Cr (mg/dl) 0.83
0.730.90 0.85 0.800.30 MTHFR
C677T gene status2 aa (homozygous) 1 2
Aa (heterozygous) 9 9 AA (no
mutation) 8 25 Notes BMIbody mass index
(kg/m2) MTHFRmethyltetrahydrofolate reductase
1Summary data reported as mean (IQR2575).
There were no significant differences in the two
groups (pgt0.05, by Students t-test with unequal
variances). 2Presented as number of patients.
Polymorphism status was independent of genotype
for all subsets (morphology vs. aa/Aa/AA,
p0.18 morphology vs. any mutation, p0.08), by
Chi-square test.
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Conclusions and directions for future studies

• Median plasma homocysteine was identical in both
  study
• populations

• When standard sonographic criteria are used to
  define
• PCOS, concomitant plasma homocysteine
  derangements
• are unlikely

• Role of homocysteine in reproductive health among
  older
• women with polycystic ovaries and/or PCOS ?

• How does homocysteine change with aging in this
  group?

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Plasma homocysteine / IVF.com collaborative study
group
E.Scott Sills, M.D. Mark Perloe, M.D. Georgia
Reproductive Specialists (Atlanta)
Marc G. Genton, Ph.D. Massachusetts Institute of
Technology (Cambridge)
Alexander Bralley, Ph.D. R.M.David Ph.D
Metametrix Clinical Laboratory (Atlanta)
D.P.Levy, M.D. Service de Gynécologie,
Hotel Dieu (Paris)