unsuccessful infertility treatment N Ghasemi Abortion Research Center Reproductive S ciences Institute Yazd Shahid sadoughi Medical Sciences University Infertility is a significant global health problem and socioeconomic burden affecting 15 of childbearingage individuals w ID: 931451
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Slide1
The effect of genetic variation in unsuccessfulinfertility treatment
N
Ghasemi
Abortion Research Center
Reproductive
S
ciences Institute
Yazd
Shahid
sadoughi
Medical Sciences University
Slide2Infertility is a significant global health problem and socioeconomic burden, affecting 15% of childbearing-age individuals worldwide and with an increasing prevalence over the last two
decades.
Assisted reproduction technology (ART) has provided a critical tool for addressing reproductive challenges in men and women.
Introduction
Slide3ART
remains an area with unmet clinical needs
. According to the International Committee for Monitoring Assisted Reproductive Technology (ICMART), the global in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) combined delivery rates per fresh aspiration and frozen embryo transfer cycles in 2013 were 24.2% and 22.8%, respectively, with a cumulative delivery rate per aspiration of 30.4%.
Introduction
Slide4Introduction
A critical step of ART is ovarian stimulation using gonadotropins
The aim of which is to obtain an optimum number of mature oocytes without the risk of ovarian hyperstimulation
syndrome (OHSS
).
Responses to gonadotropin stimulation are highly variable and dependent on individual factors
.
The prediction of ovarian response is critical to enable optimal and individualized management of ovarian stimulation.
Slide5Current ovarian stimulation protocols use several parameters to predict ovarian response and optimize the dose of gonadotropins accordingly, including age, body mass index, ovarian reserve tests such as anti-Müllerian hormone (AMH), antral follicular count (AFC), endocrine status and baseline serum follicle stimulating hormone (FSH
).
The mechanisms underlying this unexpected ovarian resistance to ovarian stimulation are not fully understood, but it is believed that an individual’s genetics play a significant role.
Introduction
Slide6Effect of Genetic Variants of Gonadotropins and
their
receptors on Ovarian Stimulation Outcomes has been surveyed by Longobardi et al. (2022). Delphi consensus was conducted to evaluate the influence of single nucleotide polymorphisms (SNPs) in genes encoding gonadotropin and gonadotropin receptors on clinical ovarian stimulation outcomes following assisted reproductive technology (ART) treatment
.
This Delphi consensus provides clinical perspectives from a diverse international group of experts
.
Slide7Overview of the Delphi consensus process and outcomes
Slide8Slide9Slide10Slide111.
SNP in the follicle stimulating hormone receptor (FSHR), rs6166 (c.2039A>G, p.Asn680Ser) : Ser/Ser carriers have higher basal FSH levels than Asn/
Asn
carriers
.
Ser
/
Ser
carriers require higher amounts of gonadotropin during ovarian stimulation than
Asn
/
Asn
carriers.
Ser
/
Ser
carriers produce fewer oocytes during ovarian stimulation than Asn/Asn or Asn/Ser carriers. There is mixed evidence supporting an association between this variant and ovarian hyperstimulation syndrome.
Summary of the consensus reached statements
Slide12Summary of the consensus reached statements
SNP
of FSHR, rs6165 (c.919G>A, p.Thr307Ala): Few studies suggest
Thr
/
Thr
carriers require a shorter duration of gonadotropin stimulation than
Thr
/Ala or Ala/Ala carriers
.
SNP
of FSHR, rs1394205 (−29G>A)
:
Limited
data in specific ethnic groups suggest that A/A allele carriers may require higher amounts of gonadotropin during ovarian stimulation and produce fewer oocytes than G/G
carriers.
Slide13SNP of FSH β-chain (FSHB), rs10835638 (−211G>T
) :
There is contradictory evidence supporting an association between this variant and basal FSH levels or oocyte number.SNPs
of luteinizing hormone β-chain (LHB) and LH/
choriogonadotropin
receptor (LHCGR)
genes:
T
hese
may influence ovarian stimulation outcomes and could represent potential future targets for
pharmacogenomic
research in ART, although data are still very
limited
Summary of the consensus reached statements
Slide14The inconsistency between some
studies,
is likely due to differences in inclusion criteria between studies: The use of different gonadotropin products and
doses
A
llowance
for dose adjustments during
treatment
All of them highlight
the need for new prospective studies in this field.
Slide15PCOS
Polycystic ovary syndrome (PCOS) is a common endocrine disorder in females, especially in women of reproductive age.
The worldwide prevalence of PCOS is estimated to be 5–10%.PCOS could be diagnosed by infertility, acne, amenorrhea or oligomenorrhea, hirsutism, insulin resistance, obesity,
hyperandrogenism
, and polycystic ovaries by ultrasonography.
Association of PCOS with infertility is well studied and is thought to be responsible for 40% of female infertility.
Slide16The level of gonadotrophin-releasing hormone, follicular stimulating hormone(FSH
), luteinizing-hormone (LH) and prolactin is also disturbed incase of PCOS.
Apart from the environmental factors, there are genetic factors that are responsible for the etiology of PCOS. Its cause involves candidate genes, SNP’s. According to databases (PCOSKB) PCOS etiology involves 241 gene variations.
Slide17Polymorphism or any nucleotide change cause a defect in the transcriptional activity of a gene that leads to PCOS .
Mostly genes that encode for the androgen receptor, Luteinizing Hormone receptors, Follicular Stimulating Hormone receptors, Leptin receptors are responsible.
Gene defect perturbs the biochemical pathway and leads to dysfunction of an ovary. Polymorphism such as
StAR
(steroidogenic acute regulatory) polymorphism
, FSHR polymorphism, FTO
(fat mass and obesity associated) polymorphism
,
VDR (vitamin D receptor)
polymorphism, IR
(insulin receptor) and
IRS polymorphism,
GnRHR
polymorphism are found to be involved in PCOS cause.
Slide18Although IVF-ET artificially offers supports such as selecting high-quality embryos the implantation rate of patients with PCOS remains low which urges deeper investigation on that therapy
With the development of DNA technology and boosting of genomic knowledge, genetic factors involving in failed implantation can also be explored, particularly some single nucleotide polymorphisms (SNPs).
Slide192 SNPs rs13429458 and rs12478601 located in it were identified to be associated with PCOS.
It
has been reported that rs2479106 in DENND1A, rs13405728 in LHCGR and rs13429458 in THADA all showed strong relation with PCOSAs a previous genome-wide association study demonstrated, the SNP variants rs12478601 and rs13405728 in the THADA, DENND1A as well as LHCGR genes were found to be in dependently correlated with PCOS.
Slide20LHCGR rs13405728, THADA rs12478601, and DENND1A rs2479106 were related to the efficacy of IVF-ET in treating PCOS.
T
he rate of abortion of patients with the THADA rs13405728 TT genotype increased and the rate of high quality embryo and the rate of clinical gestation significantly decreased.
through analysis of several SNPs this study proved that PCOS patients with the LHCGR rs13405728 TT genotype, THADA rs12478601 CC genotype and DENND1A rs2479106 AG +GG genotype had worse IVF-ET efficacy.
PCOS patients with the CC genotype had increased serum LDL level even after adjusting difference in age and BMI, and high LDL level as a significant component of metabolic syndrome as well as a risk factor of cardio-vascular disease would also result in
hyperlipemia
and other severe co
mplication
Slide21The
results may set a theoretical base for patients undergoing IVF-ET to select a more suitable treatment according to their specific genotypes and thus have better
therapeutic outcomes.
Slide22The
expression of
GnRH and its receptor has been clearly observed in numerous extrapituitary tissues such as cancer cell lines, ovary, placenta, breastThe PCOS group had a higher progesterone level in the serum before HCG injection, more retrieved oocytes and embryos, higher occurrence rates of OHSS and transplantation cancellation, as well as a downregulated fertilization rate compared with the control group.
CC+CT
genotypes of the rs12644822C>T, rs3756159C>T and rs13138607C>T in the
GnRHR
gene increase the risk of PCOS, and that these three positions are all risk factors that affect the outcome of PCOS patients undergoing IVF-ET.
Slide23Recent Genome wide association studies (GWAS) have identified several genetic variants being genome wide significantly associated with PCOS. Amongst those are variants in or near the
LH
and FSH receptor genes as well as a variant in the FSH-β gene.Some polymorphisms might affect some clinical features of PCOS as well as treatment outcome.
Women having the
Ser
/
Ser
variant needed more exogenous FSH during their ovarian stimulation phase during IVF treatment cycles
This
suggest that this FSHR variant is less sensitive to FSH.
The
Ala307Thr SNP was more frequently associated with a higher ovarian responsiveness to exogenous FSH.
Slide24Of the
polymorphisms studied,
only three SNPs (in the genes coding for FSHR, ESR2 and p53) and one SNP combination (FSHR Asn680Ser/AMH Ile49Ser) appeared to be significantly associated with the number of mature oocytes retrieved after COH.The women who were homozygous for the FSHR Ser680 variant were less likely to have been low responders and more likely to have been high responders.
FSHR Asn680Ser is associated with a low E2 level during ovarian stimulation. To achieve similar
oestradiol
peak levels, homozygous FSHR Ser680 women were found to need more exogenous FSH than women with FSHR Asn680 and tended to need more stimulation days.
Slide25Women
who were homozygous for the FSHR Ser680 polymorphism were more at risk of a high response and iatrogenic OHSS after similar ovarian stimulation.
Women who were homozygous for both the FSHR Ser680 and the AMH Ser49 alleles had a significantly greater mean number of mature oocyte numbers than women who were homozygous for FSHR Asn680 and/or homozygous for AMH Ile49.An increased likelihood of a high response was observed for women who were homozygous for both the FSHR Ser680 and the AMH Ser49 alleles, when compared with women who were homozygous for FSHR Asn680 and/or homozygous for AMH Ile49
Slide26They investigated the association between single nucleotide polymorphisms (SNPs) in the fat mass and obesity associated (FTO) gene (rs9926289 A/G, rs79206939 A/G, rs9930506 A/G, rs8050136 A/C, and rs1588413 C/T) and polycystic ovary syndrome (PCOS), as well as outcomes of in vitro fertilization (IVF).
These findings suggest that rs8050136 and rs1588413 are associated with PCOS susceptibility, and that women with risk alleles have less ovulation numbers but higher implantation rates than those with other genotypes.
Slide27There
are a significant association of the VEGF 405 polymorphism (rs2010963) and the VEGFR1-519 polymorphism (rs111458691) with the occurrence of OHSS.
These findings also open the possibility of a correlation between other fertility-related pathologies (e.g., PCOS, endometriosis) with this SNP that require IVF therapy.
Slide28Thrombophilia is not a risk factor for infertility; however several studies
have shown an association between inherited thrombophilia
and repeated IVF failuresFVL mutation is the most common thrombophilia
Slide29Thrombophilia and failure of assisted reproduction
Thrombophilia leads to an increased risk of microthrombosis at the implantation site, impairing initial invasion of maternal vessels by the syncytiotrophoblast
T
hrombosis
of maternal vessels, which might reduce the perfusion of the
intervillous
space leading to placentation failure
Thrombosis in the placental vessels leads to
hypoperfusion
of the
intervillous
space and may cause placental dysfunction.
Pooled data from 8 case-control studies showed a 3-fold increased risk of assisted reproduction failure in patients with the factor V Leiden
mutation
None of the other inherited
thrombophilic
abnormalities (prothrombin gene mutation,
antithrombin
deficiency, protein C deficiency, or protein S deficiency) were associated with an increased risk of failure
Slide30The MTHFR enzyme plays an essential role in folate metabolism, and it is essential for cell division, embryo development, and early pregnancy.
The two most common polymorphisms of the MTHFR gene are MTHFR A1298C (rs1801131) and MTHFR C677T (rs1801133)
The 1298AA/677CC haplotype can increase the risk of embryo aneuploidy and result in a high risk of miscarriage
and low implantation failure
According to the gene-gene combination analysis, the MTHFR 677/MTHFR 1298 (TT/AA) and MTHFR 677/TS 1494 (TT/6bp6bp) genetic combinations were associated with relatively higher risks
in
RIF patients compared to the CC/AA (MTHFR 677/MTHFR 1298) and TT/6bp6bp (MTHFR 677/TS 1494) combinations, respectively.
Slide31MTHFR 677TT genotype is associated with decreased number of transferable embryos, decreased number of good-quality embryos, and decreased cumulative live birth rate in the first complete cycle in patients undergoing
GnRHa
short protocolmaternal variant in MTHFR C677T polymorphism is associated with poorer quality of oocytes and lower viability of embryos. Paternal MTHFR C677T mutation is reported to be associated with the production of
aneuploid
embryos
MTHFR
C677T mutation is very likely to impact the IVF/ICSI-ET outcomes
Slide32MTHFR 677TT homozygous mutation is associated with a significantly lower number of oocytes than was expected based on the AMH concentrations
M
aternal variant in MTHFR C677T polymorphism is associated with poorer quality of oocytes and lower viability of embryosPaternal
MTHFR 677TT homozygous mutation is significantly associated with male
infertility and the
production of
aneuploid
embryos
Slide33S
upplementation
of folic acid for 3 months could improve sperm DNA fragmentation index in patients with MTHFR 677TT genotype as well as tend to increase the live birth rate
MTHFR 677TT genotype affects the ovarian response during ovarian stimulation and quality of gametes/embryos
T allele of the C677T MTHFR polymorphism is associated with
hyperhomocysteinemia
, vitamin D concentrations and natural killer cell cytotoxicity, all of these factors could affect reproductive outcomes
T
esting
of MTHFR could be of great clinical value, identifying patients at high risk of implantation failure and revealing the most viable embryos during in vitro
fertilisation
(IVF) cycles
.