Gonadotropin receptor

polymorphisms (FSHR N680S and

LHCGR N312S) are not predictive of
clinical outcome and live birth in
assisted reproductive technology
Paul Pirtea, MD,a,b Dominique de Ziegler, MD,a Diego Marin, PhD,b,c Li Sun, PhD,d Xin Tao, PhD,d
Jean Marc Ayoubi, MD,a Jason Franasiak, MD,b,c and Richard T. Scott Jr., MDb,c
a
^ pital FOCH, Suresnes, France; b Instituto Valenciano de Infertilidad Reproductive Medicine Associates, Basking Ridge,
Ho
New Jersey; c Thomas Jefferson University, Philadelphia, Pennsylvania; and d Foundation for Embryonic Competence,
Basking Ridge, New Jersey

Objective: To study the consequences of specific genotype profiles of follicle-stimulating hormone receptor (FSHR) and luteinizing
hormone choriogonadotropin receptor (LHCGR) on assisted reproductive technology outcomes when preimplantation genetic testing
for aneuploidy is used for controlling the embryo ploidy status. The most common reported single-nucleotide polymorphisms in the
amino acid position for the FSHR (N680S; N: asparagine, S: serine; [rs6166]) and the LHCGR (N312S variant; N: asparagine,
S: serine [rs2293275]) were chosen for this study.
Design: Retrospective cohort study.
Setting: Private Fertility Clinic.
Patient(s): All women aged 18–40 years undergoing their first assisted reproductive technology cycle with aneuploidy screening be-
tween 2006 and 2017 with body mass index of >18 and <40 kg/m2 were included.
Intervention(s): All patients received both recombinant follicle-stimulating hormone and human menopausal gonadotropin or low
dose human chorionic gonadotropin. Genomic DNA was isolated from patients’ blood. Genotyping of the FSHR and LHCGR
polymorphisms was performed using TaqMan genotyping assays. Associations between both receptor genotypes and clinical
outcomes were assessed using generalized regression and ANOVA.
Main Outcomes Measure(s): Live birth rate was the primary outcome. Secondary outcomes included oocyte yield, mature oocytes,
blastulation rate, usable blastocyst rate, and implantation rate.
Result(s): A total of 1,183 patients met the inclusion criteria and generated reliable genotype results. The overall genotype frequencies
in the study population for the FSHR gene were as follows: 21.7% homozygous for S in codon 680, 29.2% homozygous for N680, and
48.1% heterozygous (N680S). As for the LHCGR, 15.6% were homozygous for N312, 38.5% homozygous for S312 and 45.9% hetero-
zygous (N312S). Our study population consisted of 53.8% non-Hispanic white; 6.1% Hispanic white; 4.1% Afro-American; 15.4%
Asian; and 20.6% other or unknown. No significant association was found with any of the studied variables (oocyte yield, usable
blastocyst rate, implantation rate, live birth) when genotypes were analyzed per receptor or in combination with one another. There
was a statistically significant but clinically irrelevant difference in the rate of mature oocytes across different variant combinations.
Conclusion(s): Our findings suggest that the presence of gonadotropin receptor polymorphisms in both FSHR N680S and LHCGR
N312S are not associated with assisted reproductive technology outcomes; therefore, these variants should not be considered reproduc-
tive predictors. (Fertil SterilÒ 2022;118:494-503. Ó2022 by American Society for Reproductive Medicine.)
El resumen está disponible en Español al final del artículo.
Key Words: Gonadotropin receptor polymorphisms, FSHR N680S, LHCGR N312S, PGT-A, ART

DIALOG: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/34976

Received March 21, 2022; revised and accepted June 13, 2022; published online July 13, 2022.
P.P. has nothing to disclose. D.d.Z has nothing to disclose. D.M. has nothing to disclose. L.S. has nothing to disclose. X.T. has nothing to disclose. J.M.A. has
nothing to disclose. J.F. has nothing to disclose. R.T.S. has nothing to disclose
Reprint requests: Paul Pirtea, MD, Ho ^ pital FOCH, 40 rue Worth, Suresnes 92150, France (E-mail: paulpirtea@gmail.com).

Fertility and Sterility® Vol. 118, No. 3, September 2022 0015-0282/$36.00

Copyright ©2022 American Society for Reproductive Medicine, Published by Elsevier Inc.
https://doi.org/10.1016/j.fertnstert.2022.06.011

494 VOL. 118 NO. 3 / SEPTEMBER 2022


A
ssisted reproductive technology (ART) treatments rely
on ovarian stimulation (OS), in which the use of
exogenous gonadotropins remains essential. Despite
years of experience, choosing the optimal gonadotropin
dose varies widely depending on the physicians’ experience
and policies established in various clinics. Moreover, there
is a general quest for choosing OS protocols that prioritize
the quality rather than the quantity of the oocytes retrieved.
In the natural cycle, the development of the ovulating oocyte
is controlled by both follicle-stimulating hormone (FSH) and
luteinizing hormone (LH). In ART, OS regimens using human
menopausal gonadotropin containing low dose human chori-
onic gonadotropin (hCG) for exerting LH effects are used in
some, but not all protocols.
Nowadays, pharmacogenetics has gained attention by
evaluating how genes influence individual responses to med-
ications. Increasing evidence indicates that specific genetic
characteristics of gonadotropin receptors could influence
the ovarian response to exogenous gonadotropins. Specif-
ically, a frequent single-nucleotide polymorphism (SNP) of
the FSH receptor (FSHR) (rs6166) has been associated with
the use of high doses of FSH during OS (1). This polymorphism
is found in the Caucasian populations; approximately 20%
are homozygous for S, whereas 30% are homozygous for N
and 50% are heterozygous (N680S) (2, 3). Increased basal
levels of FSH in its carriers have been associated with the
SNP of the FSHR, which suggests intrinsically different re-
sponses to both endogenous and exogenous gonadotropins
by the carriers of polymorphism (4–7). Yao et al. (1)
reported a meta-analysis in which data from 1,421 cases
were collected from 8 studies. Among these cases, a signifi-
cantly lower basal FSH level was observed in patients
harboring the NN genotype than in those carrying the SS ge-
notype both in Asian (weighted mean difference [WMD],

2.57 mIU/mL; 95% CI:
2.96 to
2.19; P< .0001) and
Caucasian (WMD,
1.86 mIU/mL; 95% CI:
2.07 to
1.66;
P< .0001) retrospective groups, with no heterogeneity. More-
over, carriers of the SS genotype required higher FSH doses
than carriers of the NN genotype (WMD,
268.82 IU; 95%
CI,
561.28 to 23.63; P¼ .07). Similarly, a suboptimal
response to in vitro fertilization (IVF) was observed in the
SNP carriers of the gene encoding the LH b subunit (8, 9).
Recently, LH receptor SNPs (LHCGR, rs2293275) found in
the Caucasian populations, approximately 18% homozygous
for N312, 49% heterozygous (N312S), and 33% homozygous
for S312 (10), were reported to affect OS and ART outcomes
(11–13). These findings prompted the hypothesis that a
lower response to gonadotropin therapy could be related to
specific genotype characteristics (7, 13).
Gonadotropins exert their actions through the FSHR ex-
pressed in the granulosa cells and LH choriogonadotropin re-
ceptor (LHCGR) expressed by the theca and granulosa cells.
Both receptors belong to the G protein–coupled receptor fam-
ily. They mainly act through the classical Gas/30 ,50 -cyclic
adenosine monophosphate (cAMP)/ protein kinase A pathway
(14). The FSHR and LHCGR genes are both closely located on
chromosome 2.
The FSHR gene may contain several SNPs; however, so
far, only FSHR (rs6166; amino acid position 680; N680S,
VOL. 118 NO. 3 / SEPTEMBER 2022
Fertility and Sterility®
N: asparagine, S: serine) seems to play a prominent role in
response to the OS. Biological analyses revealed that the
FSHR p.N680S N variant has a faster intracellular cAMP pro-
duction in vitro in response to stimulation than the S variant
(15). However, despite these differences in the early
response, both FSHR variants ultimately resulted in similar
final cAMP levels. Despite the linkage disequilibrium be-
tween FSHR (rs6165) and FSHR (rs6166), we decided to
report the second polymorphism for 2 reasons. First, the
linkage disequilibrium between them is not universal (6).
Second, only FSHR (rs6166) seems to be associated with
different OS outcomes.
Gene polymorphism of LHCGR, on the other hand, is
more frequent, for example, in polycystic ovary syndrome.
In the Sardinian population, it has been reported that hetero-
zygous women for N312S (N: asparagine, S: serine;
rs2293275) had a 2-fold increased incidence of polycystic
ovary syndrome. Furthermore, those homozygous for N
had a 3-fold increased incidence in the same population
(16). In addition, a few cohort studies have proposed that
the N variant may render the LHCGR more sensitive to
gonadotropins (17, 18), and other studies (12, 19) have
reported that good quality embryos after OS are produced
by women homozygous for S in the LHCGR N312S
position. Only 1 study (12) reported ongoing pregnancy
rates in relation to LHCGR (rs2293275). Differences in
terms of ongoing pregnancy rates were observed among
other variations, with high prevalence in SS carriers.
A large cohort trial recently looked at the combined
gonadotropin receptor variants and reported that women
homozygous for S in both FSHR N680S and LHCGR N312S
had almost double the chance of having a livebirth after
ART compared with women homozygous for N at these
loci (19). These investigators suggested that the gonado-
tropin receptor polymorphisms could serve as a biomarker
of ART outcome, facilitating the design of more effective
treatment strategies and predicting live birth rates. The latter
indeed appeared 40% higher in women homozygous for S in
both FSHR (rs 6166) and LHCGR (rs 2293275). Other investi-
gators (20) have reported evidence, in a large cohort study,
suggesting that FSHR (rs6166) and LHCGR (rs2293275) allele
S carriers had a 4-fold increased chance of pregnancy vs. N
carriers of both polymorphisms. Moreover, they also re-
ported that the number of mature oocytes was significantly
higher in subjects with FSHR (rs1394205) SS plus FSHR
(rs6166) NN genotypes than in other genotype combinations
of these polymorphisms (20).
Given the important implications of these findings and
their possible impact on clinical practice, we conducted a
retrospective analysis on combinations of the most
commonly identified, during screening for mutations, SNP
of FSHR N680S (rs6166) and LHCGR N312S (rs2293275)
(4), and studied their effects on ART outcome. In addition,
compared with previous reports, the present study was con-
ducted exclusively in women undergoing ART with preim-
plantation genetic testing for aneuploidy (PGT-A) with
euploid embryo transfers to improve the clinical meaning-
fulness of the results and decrease the risk of population
biases.
495
ORIGINAL ARTICLE: ASSISTED REPRODUCTION
MATERIALS AND METHODS
Study Population
We conducted a retrospective study on all female patients un-
dergoing their first IVF cycle with aneuploidy screening be-
tween January 2006 and April 2017 at a private center and
whose DNA sample was available at the time of our investiga-
tion. The included patients were aged 18–40 years and had a
body mass index (BMI) of >18 and <40 kg/m2. We excluded
patients undergoing egg donation, gestational carriers, hav-
ing severe male factors with surgically retrieved sperm, and
undergoing preimplantation genetic testing for monogenic
diseases. Moreover, we only included women who were per-
forming their first IVF cycle in the clinic and whose uteri
were morphologically normal uteri on saline sonography
and/or hysteroscopy. For this study, we included only 1
oocyte retrieval. For those who performed several cycles, we
retained only the first one. Finally, 1,183 transvaginal oocyte
retrieval (TVOR) cycles from 1,183 patients were included, of
which 1,142 had usable blastocysts. At each transfer, euploid
embryo(s) with the best morphology, determined according to
the Gardner’s scale, were transferred first (21). All embryos
underwent PGT-A at the blastocyst stage using quantitative
real-time polymerase chain reaction (22) or next-generation
sequencing-based platforms (23). Endometrial preparation
for frozen embryo transfers (FET) of blastocysts was achieved
using standard regimens of oral estradiol and intramuscular
progesterone supplementation. The FET of euploid blasto-
cyst(s) was performed on the sixth day of progesterone
administration after verifying that the endometrial thickness
exceeded 7 mm.
No embryos were biopsied specifically for the purpose of
this study. Access and processing of patient DNA samples for
polymorphism genotyping was approved by the institutional
review board (420090165).
Patient Treatment
Ovarian stimulation. The ART treatment followed our prac-
tice routine. Highly purified urinary gonadotropins, recombi-
nant FSH (follitropin a-Gonal-F; Merck-Serono, KGaA,
Darmstadt, Germany and follitropin b -Follistim; Organon),
menotropins (Menopur; Ferring Pharmaceuticals, Parsip-
pany, NJ), or low dose hCG in a ration as per clinic routine
protocol, were used to achieve OS (24). For OS, individually
set doses of hormones were used, ranging from 150–450 IU
of FSH per day, individually adjusted, based on age and
ovarian reserve markers (antral follicular count, antim€
uller-
ian hormone) in an antagonist gonadotropin-releasing hor-
mone (GnRH) protocol. Medical care providers were not
aware of the polymorphism genotyping results before OS.
The development of ovarian follicles was monitored by trans-
vaginal ultrasound (TVUS) beginning on the sixth day of OS.
If required, hormonal doses were adjusted to generate an
optimal response. As soon as 1 follicle reached 14 mm in
diameter, the GnRH antagonist was introduced. Final oocyte
maturation was typically induced with 5,000–10,000 IU of
hCG either alone or combined with the GnRH agonist 2-mg
Lupron (AbbVie Pharmaceuticals Inc., North Chicago, IL),
496
according to physicians’ preference, when R3 mature folli-
cles of R18 mm were confirmed by TVUS. Transvaginal
oocyte retrieval was performed 36 hours after hCG and or
GnRH agonist administration. When the GnRH agonist was
used alone, a second dose of 2-mg Lupron was administered
12 hours after the first trigger.
Insemination was accomplished via intracytoplasmic
sperm injection given the intent to perform PGT-A. Normally
fertilized zygotes were cultured in cleavage medium in a
low-oxygen 5% tension environment. On day 3 of embryo
development, all cleaved embryos underwent laser-assisted
hatching of the zona pellucida. All embryos were then placed
in extended culture regardless of the size or quality of the
cohort. Blastocysts were considered usable if suitable for bi-
opsy and vitrification for future use. All usable expanded
blastocysts with inner cell mass and trophectoderm grade C
or better underwent PGT-A (25).
Embryo genetic testing. Embryo chromosome analysis was
accomplished using quantitative real-time polymerase chain
reaction (22, 26–28) or next-generation sequencing-based
platforms (23, 29) at the Foundation for Embryonic Compe-
tence, New Jersey. The PGT-A was performed on approxi-
mately 5–10 trophectoderm cells (25).
Endometrial preparation for embryo transfer. In a subse-
quent cycle, patients were administered hormones for endo-
metrial preparation before embryo transfer. Patients began
oral estrogen (Estrace; Accerus Pharmaceuticals, CA), 2 mg
twice a day for the first 4–6 days and 3 times a day thereafter,
to induce endometrial proliferation while suppressing follic-
ular development.
Endometrial thickness was monitored on TVUS, whereas
serum estradiol and progesterone levels were checked to rule
out premature ovulation before the initiation of progesterone
supplementation. Progesterone was administered by intra-
muscular injections of 50 mg once daily starting 5 days before
FET. On the sixth day of progesterone administration, a
warmed euploid blastocyst was transferred. When >1 euploid
embryo was available, the choice was made based on morpho-
logical grading following the modified Gardner scale. The FET
was performed under transabdominal ultrasound guidance
using a soft catheter.
Daily estrogen and progesterone administration were
continued until the pregnancy test. If pregnancy was
achieved, hormone administration was continued until the
expected luteoplacental shift, at approximately 8–9 weeks
of gestation.
Polymorphism genotyping. Genomic DNA (gDNA) was ex-
tracted and purified from 1,183 patients from either the blood
or follicular fluid samples using the QIAmp DNA Blood Maxi
Kit (Qiagen, Germany) and following the manufacturer’s in-
structions. Isolated gDNA was stored at
80  C before further
processing. For the genotyping of the aforementioned vari-
ants, allelic discrimination for the FSHR and LHCGR receptor
polymorphisms were performed using TaqMan genotyping
assays. or each SNP (FSHR N680S and LHCGR N312S) a pre-
designed TaqMan SNP genotyping assay was used to deter-
mine which alleles were present in each patient, as
described elsewhere (30). The assays IDs were
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 Fertility and Sterility®

C_2676874_10 and C____460917_1_(Thermofisher Scienti-
fic) for FSHR N680S (SNP ID rs6166) and LHCGR N312S
(SNP ID 2293275), respectively. Polymerase chain reaction
amplification was performed in a 384 well plate, and the final
reaction was set in quadruplicate 5 mL reactions with 2 mL of
the gDNA (5 ng/mL), 0.25 mL of each TaqMan genotyping
assay (20X), and 2.5 mL of TaqMan genotyping Master Mix.
A ViiA 7 real-time PCR system was use for the detection of
probes, and allelic discrimination plots were generated.
Hardy-Weinberg equilibrium was tested for the 2 SNPs. On
the basis of the genotype of FSHR N680S and LHCGR
N312S, there were 9 different combination groups
(Supplemental Table 1, available online).
Data analysis
Data query. All patients having their first IVF cycle between
January 2006 and April 2017 and meeting the inclusion and
exclusion criteria were included.
Statistical analysis. For the demographic characteristics of
patients, descriptive statistics and P values of testing null hy-
pothesis of no difference in the ART outcome among all geno-
type groups were calculated. For age at retrieval, BMI nearest
to retrieval, and maximum day 3 FSH level, the means and
standard deviations were calculated as descriptive statistics,
and ANOVA with chi-square tests were used to test differ-
ences among groups. For the proportion of patients who
ever smoked, means and 95% binomial confidence intervals
and chi-square test of independence were used.
For clinical outcomes of patients, descriptive statistics
and results of hypothesis testing were provided. The primary
outcome was the live birth rate. The secondary outcomes
include oocyte yield, mature oocyte (MII) rate, usable blastu-
lation rate, and implantation rate. The oocyte yield was the
number of oocytes retrieved. The means and standard devia-
tions for each genotype group were provided. Association
with genotypes was assessed using quasi-Poisson regression,
adjusted for age at retrieval, trigger type, and BMI. For MII
rates (number of MII oocytes/number of retrieved oocytes),
usable blastocyst rates (number of usable blastocysts divided
by number of fertilized oocytes), and euploid rates (number of
euploids divided by number of biopsied embryos), the means
and 95% binomial confidence intervals were provided. Asso-
ciations with genotypes were assessed using b regression. The
response (y) was transformed using formula <E>
ðy
0:5Þ  0:8 þ 0:5 <e> to avoid 0s and 1s. The square
root of oocyte yield, fertilized oocytes, and biopsied embryos
were used to predict dispersion parameters for MII, usable
blastocyst, and euploid rates, respectively. For the MII rate,
cycles with <5 retrieved oocytes were removed from the
model to reduce variance (1,095 cycles left). Oocyte age, num-
ber of oocytes retrieved, and trigger type were controlled for
adjusted P value. For the usable blastocyst rate, cycles with
<4 fertilized oocytes were removed (1,084 cycles left). Age,
number of oocytes retrieved, and trigger type are controlled
for adjusted P values. For euploidy rate, cycles with <3 bio-
psied embryos were removed (904 cycles left). Oocyte age
was controlled for adjusted P value. For implantation rate
(number of positive fetal heart activity divided by number
of transferred embryos), the means and 95% binomial confi-
dence intervals were provided. For live birth rate (number of
live births divided by number of transferred embryos), the
means and 95% binomial confidence intervals were provided.
Associations with genotypes were assessed using logistic
regression adjusted for age at retrieval, number of usable
blastocysts, and BMI. For live birth rate (probability of having
any live birth), the means and 95% binomial confidence inter-
vals were provided. Associations with genotypes were as-
sessed using logistic regression adjusted for age at retrieval,
number of usable blastocysts, and number of embryo(s)
transferred.
All analyses were conducted in R 3.5.0, with packages
‘‘lmtest’’ (0.9–36), betareg (3.1–1), and ‘‘boot’’ (1.3–20).
RESULTS
Patients’ Characteristics
In total, 1,183 patients met the inclusion criteria, and both
polymorphisms were successfully genotyped for each patient.
The average patient age in the study cohort was 34.32  3.49

TABLE 1

Baseline characteristics of the 9 different possible combined gonadotropin receptors variants of FSH N680S and LH N312S.
Age (y) Basal serum
Group n (%) (mean ± SD) BMI (mean ± SD) FSH (mean ± SD) Smoker (%)a SET (%)a
NN:NN 44 (3.7) 34.93  3.22 26.13  5.04 7.19  2.63 11.4 (3.8–24.6) 68.2 (52.4–81.4)
NN:NS 169 (14.3) 34.36  3.7 24.83  4.66 7.51  2.24 16.6 (11.3–23) 67.9 (60.2–74.9)
NN:SS 132 (11.2) 34.01  3.32 24.35  3.97 7.88  2.97 16.7(10.7–24.1) 64.8 (55.9–73.1)
NS:NN 93 (7.9) 34.27  3.3 25.58  5.04 8.21  2.72 9.8 (4.6–17.8) 70.3 (59.8–79.5)
NS:NS 258 (21.8) 34.39  3.51 25.41  4.83 8.04  3.64 15.9 (11.7–20.9) 63.3 (57–69.3)
NS:SS 230 (19.4) 34.17  3.46 24.85  4.48 8.13  2.83 15.2 (10.8–20.5) 64 (57.3–70.3)
SS:NN 47 (4.0) 33.99  3.94 25.75  4.27 9.25  4.44 19.1 (9.1–33.3) 60 (44.3–74.3)
SS:NS 116 (9.8) 34.55  3.32 25.71  4.86 8.26  2.8 13.8 (8.1–21.4) 65.8 (56.2–74.5)
SS:SS 94 (7.9) 34.56  3.67 24.3  4.12 8.85  3.01 13.8 (7.6–22.5) 64.8 (53.9–74.7)
P value .822 .06 .003 .852 .943
Test ANOVA, chi-square test ANOVA, chi-square test ANOVA, chi-square test chi-square test chi-square test
a
The numbers in parenthesis indicate 95% confidence intervals for the percentages listed.
Note: BMI ¼ body mass index; FSH ¼ follicle-stimulating hormone; LH ¼ luteinizing hormone; SET ¼ single embryo transfer.
Pirtea. Gonadotropin receptor polymorphisms in ART. Fertil Steril 2022.

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ORIGINAL ARTICLE: ASSISTED REPRODUCTION

TABLE 2

Assisted reproductive technology outcomes after controlled ovarian stimulation when considering the FSHR N680S and LHCGR N312S genotype groups.
No. of oocytes
Polymorphism Genotype retrieveda (mean ± SD) Mature oocyte rateb Usable blastocyst ratec Euploid rated Implantation ratee Live birth ratef
FSHR N680S NN 17.44  10.1 77.8 (76.7–78.9) 44.5 (43.1–46) 72.3 (70.3–74.3) 68.8 (63.6–73.8) 60.6 (55.9–65.1)
NS 16.86  10.72 74.9 (74–75.8) 43.4 (42.3–44.6) 74.1 (72.5–75.6) 65.4 (61.3–69.4) 60.6 (57–64.1)
SS 17.29  11.51 74.7 (73.4–76) 42.6 (40.9–44.3) 73.3 (70.8–75.7) 63.5 (57.1–69.6) 59.5 (54–64.8)
P P .7 .075 .226 .085 .373 .939
P adjusted P adjusted .785 .066 .23 .066 .358 .908
LHCGR N312S NN 17.12  10.66 73.9 (72.3–75.4) 41.6 (39.6–43.6) 74.1 (71.2–76.9) 62.8 (55.3–69.9) 58.6 (52–64.9)
NS 17.22  10.51 75.1 (74.2–76) 44.3 (43.2–45.5) 73.6 (72–75.2) 67.2 (63–71.2) 61.3 (57.6–64.9)
SS 17  11 77.2 (76.3–78.2) 43.5 (42.3–44.8) 72.8 (71–74.5) 66 (61.3–70.4) 59.9 (55.9–63.9)
P P .95 .072 .616 .497 .564 .726
P adjusted P adjusted .88 .065 .647 .372 .599 .705
Model Model Quasi-Poisson regression b regression b regression b regression Logistic regression Logistic regression
Note: CI ¼ confidence interval; ET ¼ embryo transfer; TVOR ¼ transvaginal oocyte retrieval.
a
Number of oocytes retrieved from 1,183 TVOR cycles. The means and standard deviations are reported. Oocyte age, trigger type, and body mass index are controlled for adjusted P value.
b
Number of mature oocytes retrieved from 1,095 TVOR cycles after excluding TVOR cycles that retrieved <5 oocytes. The means and 95% binomial CIs are reported. Oocyte age, number of oocytes retrieved, and trigger type are controlled for adjusted P value.
c
Number of usable blastocysts/number of fertilized oocytes from 1,084 TVOR cycles after excluding TVOR cycles that fertilized <4 oocytes. The means and 95% binomial CIs are reported. Oocyte age, number of oocytes retrieved, and trigger type are controlled for
adjusted P value.
d
Number of euploids/number of biopsied embryos from 904 TVOR cycles after excluding TVOR cycles with <3 embryos were biopsied. The means and 95% binomial CIs are reported. Oocyte age is controlled for adjusted P value.
e
Number of implanted embryos/number of transferred embryos from 1,142 TVOR cycles with ET cycles. The means and 95% binomial CIs are reported. Oocyte age, BMI, and number of usable blastocysts are controlled for adjusted P value.
f
Any live birth from the 1,142 TVOR cycles with ET cycles. The means and 95% binomial CIs are reported. Single embryo transfer/double embryo transfer, oocyte age, and number of usable blastocysts are controlled for adjusted P value.
Pirtea. Gonadotropin receptor polymorphisms in ART. Fertil Steril 2022.
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TABLE 3

Assisted reproductive technology outcomes of the 9 different possible combined gonadotropin receptors variants of FSH N680S and LH N312S
analyzed.
No. of oocytes Mature oocyte Usable blastocyst
Group retrieveda rateb ratec Euploid rated Implantation ratee Live birth ratef
n 1,183 1,095 1,084 904 1,142 1,142
All 17.12  10.72 75.7 (75.1–76.3) 43.6 (42.8–44.4) 73.4 (72.3–74.4) 66 (63.2–68.8) 60.4 (57.9–62.8)
NN:NN 17.36  10.03 76.3 (73.2–79.3) 40.2 (36.2–44.3) 70.7 (64.4–76.5) 56.8 (41–71.7) 53.4 (39.9–66.7)
NN:NS 17.33  9.79 77.3 (75.7–78.8) 44.3 (42.2–46.3) 73.1 (70.2–75.9) 69.7 (62.1–76.6) 60.1 (53.3–66.6)
NN:SS 17.61  10.57 79 (77.2–80.6) 46.2 (44–48.6) 71.9 (68.6–74.9) 71.9 (63.2–79.5) 63.6 (55.9–70.8)
NS:NN 16.97  10.96 73 (70.7–75.2) 42.3 (39.5–45.2) 75.7 (71.6–79.6) 61.5 (50.8–71.6) 57.6 (48.2–66.7)
NS:NS 17.1  10.75 74.5 (73.1–75.7) 44.7 (43–46.4) 73 (70.6–75.3) 65.3 (59–71.2) 60.8 (55.3–66)
NS:SS 16.54  10.63 76.2 (74.8–77.6) 42.5 (40.7–44.3) 74.6 (72.1–77.1) 67.1 (60.5–73.3) 61.6 (55.8–67.1)
SS:NN 17.21  10.84 73.3 (70.1–76.3) 41.5 (37.5–45.6) 74.2 (68.1–79.6) 71.1 (55.7–83.6) 65.1 (52–76.7)
SS:NS 17.33  11.06 73.3 (71.3–75.2) 43.6 (41–46.2) 75.9 (72.2–79.2) 67.6 (58–76.1) 64.4 (56.2–72.1)
SS:SS 17.29  12.47 77.1 (75–79.2) 41.9 (39.2–44.7) 69.8 (65.6–73.8) 54.5 (43.6–65.2) 50.4 (41.1–59.7)
P .997 .207 .576 .275 .19 .348
P adjusted .985 .191 .552 .191 .247 .353
Model Quasi-Poisson regression Beta regression Beta regression Beta regression Logistic regression Logistic regression
Note: CI ¼ confidence interval; ET ¼ embryo transfer; FSH ¼ follicle-stimulating hormone; LH ¼ luteinizing hormone; TVOR ¼ transvaginal oocyte retrieval.
a
Number of oocytes retrieved from 1,183 TVOR cycles. The means and standard deviations are reported. Oocyte age, trigger type, and body mass index are controlled for adjusted P value.
b
Number of mature oocytes retrieved from 1,095 TVOR cycles after excluding TVOR cycles that retrieved <5 oocytes. The means and 95% binomial CIs are reported. Oocyte age, number of oocytes
retrieved, and trigger type are controlled for adjusted P value.
c
Number of usable blastocysts/number of fertilized oocytes from 1,084 TVOR cycles after excluding TVOR cycles that fertilized <4 oocytes. The means and 95% binomial CIs are reported. Oocyte
age, number of oocytes retrieved, and trigger type are controlled for adjusted P value.
d
Number of euploids/number of biopsied embryos from 904 TVOR cycles after excluding TVOR cycles with <3 embryos were biopsied. The means and 95% binomial CIs are reported. Oocyte age is
controlled for adjusted P value.
e
Number of implanted embryos/number of transferred embryos from 1,142 TVOR cycles with ET cycles. The means and 95% binomial CIs are reported. Oocyte age, BMI, and number of usable
blastocysts are controlled for adjusted P value.
f
Any live birth from the 1,142 TVOR cycles with ET cycles. The means and 95% binomial CIs are reported. Single embryo transfer/double embryo transfer, oocyte age, and number of usable blas-
tocysts are controlled for adjusted P value.
Pirtea. Gonadotropin receptor polymorphisms in ART. Fertil Steril 2022.

years (mean  SD), average BMI was 25.09  4.62 kg/m2
(mean  SD), and mean basal endogen serum FSH level was
8.08  3.06 mIU/mL (mean  SD). With respect to ethnicity,
53.8% of the study population was non-Hispanic white,
15.4% Asian, 6.1% Hispanic white, 4.1% Afro-American,
and 20.6% other or unknown. The participants were mostly
never smokers (84.9%), and 65.2% patients had single euploid
embryo transfer (Table 1 and Supplemental Table 2). Patients
with homozygous S in FSHR N680S showed significantly
higher levels of basal endogenous serum FSH than patients
with homozygous N or heterozygous N and S in FSHR
N680S (Supplemental Table 2). The SS variants registered a
basal serum FSH level of 8.65  3.24 (mean  SD), compared
with 8.1  3.19 (mean  SD) for the NS variant and 7.61 
2.51 (mean  SD) for the NN variant. For the 9 combined ge-
notype group, the basal endogen serum FSH level was signif-
icantly different across the groups (P¼ .003) (Table 1). There
were no other differences in the baseline characteristics
observed among the groups (Table 1 and Supplemental
Table 2).
Genotyping
For the FSHR N680S polymorphism, the genotype frequencies
in our population were as follows: 21.7% homozygous for S,
29.2% homozygous for N, and 48.1% heterozygous. For the
LHCGR N312S polymorphism, the frequencies were 15.6%
homozygous for N, 38.5% homozygous for S, and 45.9% het-
erozygous. Allele frequencies and genotype distributions
were of balanced proportions, similar to previously reported
study populations. The allele frequencies of both
polymorphisms were in Hardy-Weinberg equilibrium (c ¼
0.7, P>.05 for FSHR N680S and c ¼ 0.31, P>.05 for LHCGR
N312S) (Supplemental Table 3).
ART Outcomes
No significant association was found with any of the studied
variables (oocyte yield, rate of MIIs, usable blastocyst rate,
implantation rate, live birth) among individual FSHR N680S
and LHCGR N312S genotype groups and the 9 combined ge-
notype groups (Tables 2 and 3).
For the FSHR N680S and LHCGR N312S variants, no sig-
nificant difference was noted when comparing the total
gonadotropin dose used in controlled ovarian stimulation in
each different genotype group (Table 4).
When analyzing the number of oocytes retrieved, MII,
and usable blastulation rates of all 9 genotypes combined,
no association was found with the genotype variant. In the
present study, the number of oocytes retrieved was 17.44 
10.1 (mean  SD), (Padj¼ .985), MII rate was 75.7%
(75.1%–76.3%, Padj¼ .191), and usable blastulation rate
was 43.6% (42.8%–44.4%, Padj¼ .552).
The euploidy rate across all 9 genotypes combined was
73.4% (72.3%–74.4%, Padj¼ .191) from 904 TVOR cycles af-
ter excluding TVOR cycles with less than 3 embryos were bio-
psied, and no association was found with the genotype
variant.
When analyzing implantation and live birth rates of all 9
genotypes combined, no association was found with the ge-
notype variant. In the present study 66% (63.2%–-68.8%,

VOL. 118 NO. 3 / SEPTEMBER 2022 499

ORIGINAL ARTICLE: ASSISTED REPRODUCTION

Padj¼ .247) of patients obtained a pregnancy and 60.4%

(factor[LH_
(nums) (genotype) genotype) genotype]) genotype) genotype])
(57.9%–62.8%, Padj¼ .353) delivered.

.07477
.2231

.8455
DISCUSSION

.7294
(LH_

.566

.229
The main findings of this study were that regardless of the 9
possible combined gonadotropin receptors variants—FSH and
(FSH_ (factor[FSH_
Total gonadotropin dose used for controlled ovarian stimulation in the 9 different possible combined gonadotropin receptors variants of FSH N680S and LH N312S analyzed.

.07517 LH—there were no differences in the ART outcome. These re-

.3119

.7078
P value

sults are therefore at odds with the previously formulated hy-

pothesis that gonadotropin receptor variants predict the ART
outcome (19). In particular, our findings failed to validate the
.05871
.3898

.5106

report that gonadotropin receptor polymorphism type—FSHR

(rs6166) genotype distribution—affects the number of oocytes
retrieved in a Cochrane meta-analysis by Alviggi et al. (13).
.3444

.1364

.8431

Several gonadotropin receptors’ variations and combinations

exist in different proportions, depending on populations,
1455.1  769 1392.6  646.7 1267.7  634.8 1337.3  646.7 1462.7  687.8 1440.8  772 1231.1  750.5 1489.9  740.8 1411  648.9 .2971

92.8  64.3 .4714

801.2  348.4 679.6  277.9 .596

which might be responsible for certain particularities as those

reported previously, such as high levels of basal endogenous
FSH or different ovarian response to OS, but they do not
SS:SS

75

appear to imbalance ART outcomes.

Our results show that patients with homozygous S in
FSHR N680S have significantly higher levels of basal endog-
enous FSH than patients with homozygous N or heterozygous
97  64
SS:NS

N and S in FSHR N680. For the 9 combined genotype variant

92

group, the endogenous basal FSH levels were significantly

different across the groups. However, the baseline characteris-
tics did not differ among the groups. Some degree of resistance
709.1  320.4 765.2  351.9 738.2  375.7 715  284.6

92  76.2
SS:NN

to FSH response for the p.N680S S allele was reported in a pre-

37

vious clinical trial (31), which was believed to reflect the differ-
ences in ovarian response to OS. FSHR (rs6166) also affects the
endogenous levels of FSH as shown by the finding of higher
89.9  55.4
NS:SS

baseline serum FSH levels in SS carriers than in NN carriers.

178

Moreover, the FSHR (rs6166) genotype did not significantly

affect the number of oocytes retrieved (32). Lindgren et al.
(12) claimed that the different responses expressed by the
Note: FSH ¼ follicle-stimulating hormone; hCG ¼ human chorionic gonadotropin; LH ¼ luteinizing hormone.
89.3  59.4
NS:NS

FSHR variants should be considered when selecting OS proto-

196

cols. In our opinion, differences in the baseline FSH levels

might suggest that a slightly larger amount of exogenous
FSH is required to attain the normal ovarian response from
85.4  45.9

the cohort of follicles on day 3. Although this has traditionally

NS:NN

69

been described as resistance to hormone effect, such a termi-

nology implies an adverse impact. In our study, we found no
such adverse impact and we believe that although slightly
649.3  304

87.3  62.1

Pirtea. Gonadotropin receptor polymorphisms in ART. Fertil Steril 2022.

more exogenous FSH may be required to attain early follicular

NN:SS

108

dynamics, there is no reason to believe that those subtle

changes in balances in any way inhibit the maximum or
optimal follicular development once pharmacologic levels of
697.8  225.5 735.9  461.6

81.8  39.3

exogenous FSH are provided.

NN:NS

129

In our study, no significant association was found with

any of the outcome variables (oocyte yield, rate of MIIs, us-
able blastocyst rate, implantation rate, live birth) among in-
Low dose hCG 111.8  79.9

dividual FSHR N680S and LHCGR N312S genotype groups

NN:NN

or the combined genotype group. Therefore, our results do

31

not support the conclusion of one of the latest systematic re-

views (13), which indicated that gonadotropin receptor var-
TABLE 4

iants affect ART outcome.

N ¼ 915

N ¼ 626
Frequency

Our data suffer from the limits of the retrospective na-

Menopur
FSH rec

ture. Gonadotropin doses administered to patients could be

adjusted by physicians on the basis of patients’ anticipated

500 VOL. 118 NO. 3 / SEPTEMBER 2022


responses, which could have mitigated response variables.
Another limitation of our study is represented by the exclu-
sion of patients with <4 fertilized oocytes, but this was per-
formed with the goal to identify gonadotropin variants
predictive value in those with euploid embryos. Our study
cannot exclude the predictive value of these gonadotropin re-
ceptor variants for the ART outcomes in patients with poor
prognosis because of our study design. Overall, the euploidy
rate in our study is high at 73.4% but is as expected, given
that the mean age of patients was 34 years. The large size
of the cohort studied—over 10 years—partially compensates
for the weakness of the design. An important strength of
our study is that systematic PGT-A allowed to only study
the outcome of euploid embryo transfers.
In summary, apart from the significant differences in
basal endogenous FSH levels between the different gonado-
tropin variants, there are no other differences in the quantita-
tive parameters of follicular stimulation or the qualitative
indices of oocyte quality, including implantation rates.
CONCLUSION
Across the genotype distribution of gonadotropin receptor
variants, homozygous for S in both FSHR N680S showed
significantly higher levels of basal FSH than homozygous
for N or heterozygous N and S in FSHR N680S. Conversely,
the differences in LH receptor genotypes had no significant
consequences. The subtle changes in FSH responsiveness,
although reported, do not appear to impact the follicular
response and quality of the oocytes produced. Despite the dif-
ferences in baseline FSH levels, there was no difference in
quantitative or qualitative differences in responses to OS
and notably, no differences in ART outcome.
As the presence of gonadotropin receptor polymorphisms
is not associated with ART outcome, these variants should, at
least for the time being, not be considered reproductive
predictors.
DIALOG: You can discuss this article with its authors and
other readers at https://www.fertstertdialog.com/posts/
34976
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Los polimorfismos en el receptor de gonadotropina (FSHR N680S y LHCGR N312S) no predicen resultado clínico y nacido vivo en
tecnología de reproduccion asistida.
Objetivo: Estudiar las consecuencias de los perfiles genotípicos específicos del receptor de la hormona estimulante del folículo (FSHR) y
el receptor de la coriogonadotropina de la hormona luteinizante (LHCGR) en los resultados de la tecnología de reproducci on asistida
cuando se utilizan pruebas geneticas previas a la implantaci
on para detectar aneuploidía para controlar el estado de ploidía del embri
on.
Los polimorfismos de un s olo nucleotido informados con mayor frecuencia en la posici on de aminoacido para el FSHR (N680S; N: as-
paragina, S: serina; [rs6166]) y el LHCGR (variante N312S; N: asparagina, S: serina [rs2293275]) fueron elegidos para este estudio.
~o: Estudio de cohorte retrospectivo.
Disen
Lugar: Clínica Privada de Fertilidad.
Paciente(s): Se incluyeron todas las mujeres de 18 a 40 a~
nos que se sometieron a su primer ciclo de tecnología de reproducci
on asistida
con tamizaje de aneuploidías entre 2006 y 2017 con índice de masa corporal >18 y <40 kg/m2.
Intervencion(es): Todos los pacientes recibieron hormona estimulante del folículo recombinante y gonadotropina menopausica hu-
mana o gonadotropina cori onica humana en dosis bajas. El ADN gen omico se aisl
o de la sangre de los pacientes. El genotipado de
los polimorfismos de FSHR y LHCGR se realiz o mediante ensayos de genotipado TaqMan. Las asociaciones entre ambos genotipos
de receptores y los resultados clínicos se evaluaron mediante regresi
on generalizada y ANOVA.
Medida(s) de resultados principal(es): La tasa de nacidos vivos fue el resultado primario. Los resultados secundarios incluyeron el
rendimiento de ovocitos, los ovocitos maduros, la tasa de blastulaci
on, la tasa de blastocistos utilizables y la tasa de implantaci
on.
Resultado(s): Un total de 1183 pacientes cumplieron los criterios de inclusi
on y generaron resultados genotípicos confiables. Las fre-
cuencias genotípicas generales en la poblacion de estudio para el gen FSHR fueron las siguientes: 21,7 % homocigotos para S en el
codon 680, 29,2 % homocigotos para N680 y 48,1 % heterocigotos (N680S). En cuanto al LHCGR, el 15,6% eran homocigotos para
N312, el 38,5% homocigotos para S312 y el 45,9% heterocigotos (N312S). Nuestra poblaci on de estudio consisti
o en 53.8% de blancos
no hispanos; 6,1% blancos hispanos; 4,1% afroamericano; 15,4% asiatico; y 20,6% otros o desconocidos. No se encontr o asociaci
on
significativa con ninguna de las variables estudiadas (rendimiento de ovocitos, tasa de blastocistos utilizables, tasa de implantaci
on,
nacidos vivos) cuando se analizaron los genotipos por receptor o en combinaci on entre sí. Hubo una diferencia estadísticamente sig-
nificativa, pero clínicamente irrelevante en la tasa de ovocitos maduros entre diferentes combinaciones de variantes.
Conclusion(es): Nuestros hallazgos sugieren que la presencia de polimorfismos del receptor de gonadotropina tanto en FSHR N680S
como en LHCGR N312S no estan asociados con los resultados de la tecnología de reproducci
on asistida; por lo tanto, estas variantes no
deben considerarse predictores reproductivos.

VOL. 118 NO. 3 / SEPTEMBER 2022 503