Discussion:
This study has started with this hypothesis that ”the incidence of
uterine abnormalities, mainly Y shaped uterine cavity, in PCOS patients
is higher than normo-ovulatory patients and this can be related to
maternal serum AMH levels” and ended with 2 scientifically interpretable
results.
1.The rate of abnormalities in the uterine cavity was found to be higher
in patients who underwent ART in PCOS patients than the patients who
underwent ART because of male factor.
2. Maternal serum AMH levels do not correlate with the presence of
uterine abnormalities.”
Our study was based on the observation that intrauterine cavity is
different than the normal structure when evaluating the cavity on HSG
evaluation in PCOS patients. And the presence of scientific evidences in
the literature indicating that in pregnant diagnosed with PCOS had a
higher preterm delivery rate, especially those whom had higher AMH
levels, emboldened us to plan this research.(8–10)
When PCOS patients are evaluated within themselves, the most frequently
detected abnormality was Figure II which is classified as class VI in
ASRM classification and is accepted as a variance of normal, not
abnormality, in ESGE - ESHRE classification, named as arcuate. When the
arcuate cavity is considered normal as in the ESGE - ESHRE
classification, in terms of uterine cavity abnormalities, the
statistically significant difference disappears between PCOS and control
patients. (11.86 % versus 20.16 %)
PCOS is associated with a variety of complications in pregnancy,
including risk of miscarriage and preterm birth.5-7The 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 estimated prevalence of mullerian abnormalities is approximately 5
%, from mild to severe, in the general population and increase up to 13
% in women with infertility.1 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 the relationship between the shape of uterine cavity and PCOS.
We found that the uterine cavity abnormalities in PCOS patients is 54.1
%, 31.7 %, 10.7 % including groups (II + III + IV+ V+ VI), (III + IV + V+ VI),
(III + IV), respectively.
The common feature of the figures II, III, IV and VI which are
statistically higher in PCOS group than controls is presence of
indentation of the fundal area indicating the resorption defect during
the development of mullerian system.
It has been known that correct patterning and differentiation of the
Mullerian Duct is dependent on a complex network of Hox andWnt genes.(11–20) And these genes mainly regulate AMH and sex
steroids both of which are main topics of PCOS under discussion. It has
been shown that patients with HOXA10 mutations had uterine
defects ranging from septate uterus to a didelphys uterus indicative of
MD fusion defects.(21–23) In a review, it was clearly shown that
intrauterine hyper exposure to testosterone influences the expressing
genes.(23) There may be other mechanisms that are 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 and it was shown
that Anti-mullerian hormone was able to reduce placental aromatase
activity.(24,25) 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.(26) Prenatal AMH treatment triggers the neuroendocrine
disturbances of PCOS in the offspring via GnRH neuronal activation.(10)
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 are 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.(27–30) In spite of this, many
authors reported the expression patterns of AMH with in human fetal
ovarian specimens, in the end of the gestation, in the granulosa cells
of preantral follicles.(31–33) 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 female fetuses,
who will later develop PCOS. Tata B et al. reported that AMH levels are
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.(33) However, umbilical cord blood
AMH and sex steroid levels of later developing PCOS patients in
intrauterine period is not known.
The only study in the literature thoroughly researching this topic is by
Hart R et al., in which 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.
The 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.(34)
In the literature, there is no study investigating the relationship
between maternal AMH levels and the frequency of uterine abnormality. In
our study, no difference was found between maternal serum AMH levels and
the presence of uterine abnormalities in all study groups and PCOS
subgroup analysis. We can comment that maternal serum AMH levels do not
have any effect on the presence of uterine abnormalities.”
In our study, the rate of T shaped uterine abnormality which is fıgured
as V was not found to be statistically different in PCOS group than in
controls. However, the rates of figures II, III, and IV were much higher
in PCOS than in controls. T shape uterus is not a resorption abnormality
and the first T shaped uterus case was reported after DES exposure. In
the presence of the T shape uterus, the fundus of the uterine cavity is
completely normal. The T shaped uterus is different from the other
anomalies by the mechanism of formation. Mechanism of formation of T
shaped is related to the hyperplasia of the mesenchymal tissue connected
to WNT genes driving by DES and other factors.(35) In our study, the
high frequency of T-shaped uterine cavity and no differences between
PCOS and control group can be explained by the fact that the diagnostic
criteria of the T-shaped uterus is not fully defined. We report and
suggest that the T shape cavity abnormality is not related to PCOS
disease.
There is no place of Y shaped cavity in the classifications in both
classifications.(2) However, besides the defined cavity abnormalities in
the classifications, there is a common observation by the REI
specialists & REI Surgeons who are focused on this topic, called Y and
I shaped cavities which is under discussion and accepted as normal
today. The most important study in this topic is Y shaped uterus defined
and emphasized on clinical importance reported by Di Spiezio Sardo
A.(36) In this study, although the Y shape is not classified as an
abnormality other than the T shape, in the annotated figure of the
surgical technique, it is clearly understood that the cases are Y shaped
and surgical treatment is performed with this principle. And in this
study, it is reported a net increase of uterine volume was found, as
measured by hysteroscopy and three-dimensional transvaginal ultrasound,
uterine morphology improved in all patients, clinical pregnancy rate was
57% and term delivery rate 65%.
In a review published by Alonso L., it was stated that the morphologic
conditions like T, Y and I shaped uterine abnormalities must be
investigated as a structural and functional disorder.(37)
Y shaped cavity which was figured as 6 in our study, although not
defined as an abnormality in the classifications, exists and was higher
in the PCOS patients as 7.4% than in controls. Its clinical
significance is not fully known. It needs further research.