Interpretation:
There are strong scientific evidences in the literature suggesting there
may be a relationship between the uterine cavity abnormalities and PCOS
disease which comprised with abnormal sex steroid and AMH levels in
utero and adult life. It has been known that correct patterning and
differentiation of the Müllerian Duct is dependent on a complex network
of Hox and Wnt genes.5-14 And these
genes are regulated mainly AMH and sex steroids which both of them are
main topics of PCOS under discussion. It has been shown that the
patients with HOXA10 mutations had uterine defects ranging from
septate uterus to a didelphys uterus indicative of MD fusion
defects.15,16 In a review, it was clearly shown that
intrauterine hyper-exposure to testosterone influences the expressing
genes.17 There may be other mechanisms be responsible
for increased intrauterine hyper androgens linked with intrauterine AMH
function. During normal pregnancy, the fetus is protected from maternal
androgens by placental aromatase. It is possible, however, that
placental dysfunction may expose the fetus to higher concentrations of
androgens, although it has yet to be proven empirically but shown that
Anti-müllerian hormone was able to reduce placental aromatase
activity.18,19 Also, recent evidence has shown that
GnRH-positive neurons express AMH receptors and that exogenous AMH
potently increases GnRH neuron firing and GnRH release in murine living
tissue explants.20 Prenatal AMH treatment triggers the
neuroendocrine disturbances of PCOS in the offspring via GnRH neuronal
activation.21
Also, the high levels of maternal serum AMH levels during pregnancy in
PCOS patients may be a cause of formation of PCOS in female fetus in
utero. Since AMH is secreted from granulosa cells in females, AMH
secretion is not expected until the granulosa cells activated. Previous
studies reported that the expression of AMH in the ovary is switched on
soon after birth and concluded that there is no detectable ovarian
production during normal fetal.22-24 Although this,
many authors reported that the expression patterns of AMH within human
fetal ovarian specimens, in the end of gestation at 36 weeks in
granulosa cells of preantral follicles.25-27 The
different structure and physiology of granulosa cells in PCOS patients
may also be in the intrauterine period and cord blood AMH levels may be
higher in the in female fetuses, whom will later develop PCOS. Tata B
et. all reported that AMH levels is higher in pregnant PCOS subjects
than in pregnant control women and suggested that elevated prenatal
anti-mullerian hormone reprograms the fetus and induces polycystic
ovary.21 However, umbilical cord blood AMH and sex
steroid levels of later developing PCOS patients in intrauterine period
is not known.
The estimated prevalence of müllerian abnormalities is approximately 5
%, from mild to severe, in the general population and increase up to 13
% in women with infertility.27 We were not able to
find an article published among the frequency of uterine abnormalities
in PCOS patients in the literature. Our research is the first research
seeking up the relationship between the shape of uterine cavity and
PCOS.
In our study, the frequency of the abnormal uterine cavity was
statistically significantly higher in PCOS group than controls when
evaluated in both classifications. According to the both
classifications, The frequency of U1a, U2a, U2b (ESHRE-ESGE) and Va,
Vb,VII (ASRM) was found statistically significantly higher in PCOS group
than controls as subgroup analysis.
The frequency of type VI cavity (arcuate) considered as an abnormality
to ASRM but as a variation of normal to ESHRE-ESGE was not different in
PCOS and control patients which support the assertion of ESHRE-ESGE.
The hypothesis and mechanisms reported in the literature to explain the
possible relationship between uterine abnormalities and PCOS were shown
in Figure-3. In sight of these hypothesis, it would be expected to find
the serum AMH levels much higher in the patients who had uterine
abnormality but we could not find any differences and correlation
between the levels of AMH and uterine abnormality. We think that this
may be related not to maternal AMH levels but related to umbilical cord
AMH levels. The only study in the literature focusing thoroughly this
topic by Hart R et all., maternal blood samples were collected at 18 and
34 weeks and umbilical cord blood was collected at 870 singleton
deliveries. The cohort included 1800 adolescents aged 16 to 18 years.
Cord blood of adolescent girl was available for 77 of the 244 girls
consented to research. No statistically significant associations between
maternal and cord androgens and AMH in adolescents were
found.28
Positive correlation was found between the frequency of uterine cavity
abnormality and maternal serum free testosterone levels according to
ESHRE-ESGE classification. The explanation of lack of correlation when
ASRM classification was taken into consideration is that the arcuate
uterine cavity is accepted as normal in ESHRE-ESGE classification.
Positive correlation between serum free testosterone levels and the
presence of intrauterine cavity abnormalities can be explained that the
resorption process may not be completed intrauterine period and may be
under process during adulthood.
PCOS is associated with a variety of complications in pregnancy,
including risk of miscarriage and preterm birth.2-4The pathophysiological mechanisms behind the increased risk of adverse
pregnancy outcomes among women with polycystic ovary syndrome are not
fully known. This association may be explained with the presence of
uterine abnormalities. The question looking forward to be answered is
the relationship between increased pregnancy complications and uterine
cavity abnormalities.