Association between hyperandrogenism and adverse pregnancy outcomes in patients with different polycystic ovary syndrome phenotypes undergoing in

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Association between hyperandrogenism and

adverse pregnancy outcomes in patients with

different polycystic ovary syndrome phenotypes

undergoing in vitro fertilization/intracytoplasmic

sperm injection: a systematic review and meta-analysis

Linna Ma, Yurong Cao, Yue Ma & Jun Zhai

To cite this article: Linna Ma, Yurong Cao, Yue Ma & Jun Zhai (2021): Association between hyperandrogenism and adverse pregnancy outcomes in patients with different polycystic ovary

syndrome phenotypes undergoing in vitro fertilization/intracytoplasmic sperm injection: a systematic

review and meta-analysis, Gynecological Endocrinology, DOI: 10.1080/09513590.2021.1897096

To link to this article: https://doi.org/10.1080/09513590.2021.1897096

View supplementary material Published online: 11 Mar 2021.

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ORIGINAL ARTICLE

Association between hyperandrogenism and adverse pregnancy outcomes in

patients with different polycystic ovary syndrome phenotypes undergoing in vitro fertilization/intracytoplasmic sperm injection: a systematic review and

meta-analysis

Linna Maa,b, Yurong Caoa,b, Yue Maa,band Jun Zhaia,b

a

Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China;bHenan Key Laboratory of

Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

ABSTRACT

Objective: To study the association between hyperandrogenism (HA) and adverse pregnancy outcomes

in patients with different polycystic ovary syndrome phenotypes undergoing in vitro fertilization (IVF)/

intracytoplasmic sperm injection (ICSI)

Methods: We reviewed all eligible articles published up to October 2020 after searching in PubMed,

Embase, Cochrane Library, Web of Science, Wanfang Data, and CNKI databases The primary outcomes

were the clinical pregnancy rate (CPR), miscarriage rate (MR), and live birth rate (LBR), whereas the

sec-ondary outcomes were the number of retrieved oocytes and endometrial thickness Risk ratios (RRs) or

mean differences with 95% confidence intervals (CIs) were calculated to estimate the HA impact on IVF/

ICSI outcomes in patients with polycystic ovary syndrome (PCOS) phenotypes

Results: Of the 789 trials identified, nine retrospective studies involving 3037 patients with PCOS were

included Compared to the PCOS group with normal androgen levels, the PCOS group with HA exhibited

increased MR (RR: 1.56, 95% CI: 1.13, 2.16); the CPR (RR: 0.88, 95% CI: 0.77, 1.01) and LBR (RR: 0.79, 95%

CI: 0.55, 1.11) were not significantly different between these groups Subgroup analysis revealed that the

CPR was lower in the polycystic ovarian (PCO)-morphologyþ HA þ oligo-anovulation (AO) group than in

the PCOþ AO group (RR: 0.81, 95% CI: 0.67, 0.99) Among Asians, the PCOS/HA group had increased MR

(RR: 1.56, 95% CI: 1.06, 2.31) and showed thinner endometrial thickness However, among Caucasians, no

differences were observed between the two groups

Conclusions: HA may have adverse effects on clinical pregnancy and miscarriage outcomes in different

PCOS phenotypes, particularly among Asians

ARTICLE HISTORY Received 12 November 2020 Revised 3 February 2021 Accepted 25 February 2021 Published online 11 March 2021

KEYWORDS Hyperandrogenism; in vitro fertilization/intracytoplasmic sperm injection; polycystic ovary syndrome; pregnancy outcome; meta-analysis

Introduction

Polycystic ovary syndrome (PCOS) is the most common

endo-crine and metabolic disorder among women PCOS is

character-ized by hyperandrogenism (HA), presence of polycystic ovaries,

and anovulation following the exclusion of other endocrine

causes such as hyperprolactinemia and nonclassical congenital

adrenal hyperplasia [1,2] The prevalence of PCOS in

reproduct-ive-age women ranges from 6 to 10% [3,4] As women with

PCOS are infertile, they often receive assisted reproductive

tech-nology (ART) fertility treatment [5] While the etiology of PCOS

remains largely unknown, PCOS likely represents a complex

multigenic disease under environmental influences [6] HA is

considered as a PCOS phenotype according to the diagnostic

cri-teria from the European Society of Human Reproduction and

Embryology/American Society for Reproductive Medicine

con-sensus meeting held in Rotterdam, the National Institutes of

Health criteria, and the Androgen Excess Society criteria The

prevalence of hyperandrogenemia is fairly high among patients

with PCOS, ranging from 70 to 78% [7]

There has been increasing controversy regarding the potential

adverse effects of HA on pregnancy outcomes after infertility

treatment [8,9] Whether antiandrogen pretreatment is beneficial

to PCOS patients with HA who have received ART treatment is currently unknown HA reportedly does not affect the pregnancy outcomes in women with PCOS andmore oocytes can be obtained from patients with HA during controlled ovarian stimulation, which is more conducive to the acquisition of high-quality embryos [8] Nevertheless, HA adversely affects the clin-ical pregnancy rate (CPR) during ART treatment [10]

This study aimed to study the association between HA and adverse pregnancy outcomes in patients with PCOSvia a system-atic review and meta-analysis to provide guidance for HA pre-treatment prior to in vitro fertilization (IVF) in patients with PCOS

Methods

Search strategy

Articles published from January 1950 until May 2020 were searched in PubMed, Embase, Cochrane Library, Web of Science, Wanfang Data, and CNKI databases to identify eligible studies from English- and Chinese-language journals Electronic database searches were supplemented with manual search and literature

CONTACT Jun Zhai bestzhai2005@163.com No.1, Jianshe East Road, Zhengzhou 450052, China

Supplemental data for this article can be accessed here

ß 2021 Informa UK Limited, trading as Taylor & Francis Group

Treatment protocol

2 ;

± (continued

Treatment protocol

review Our search strategy based on the following key terms and Medical Subject Headings was employed: ((hyperandrogen-ism or hyperandrogenic), (polycystic ovary syndrome, PCOS, or different polycystic ovary syndrome phenotypes), and (preg-nancy, infertility, IVF, assisted reproductive technology or ART)) In all searches, limitations were set for human character-istics and clinical trials

Inclusion and exclusion criteria

The following studies were included in the analysis: (1) observa-tional studies such as cohort, case–control, and cross-sectional studies; (2) studies investigating PCOS patients with or without

HA or those evaluating PCOS patients with different phenotypes, the diagnosis of which was in accordance with the 2003 Rotterdam criteria; and (3) studies that had CPR, miscarriage rate (MR), live birth rate (LBR), number of retrieved oocytes, and endometrial thickness as the primary or secondary out-comes However, the following studies were excluded: (1) repeated studies, studies with incomplete data, conference abstracts without detailed contents, and literature reviews; (2) studies with missing, inexact, or contradictory experimental results; (3) studies that did not specify the diagnostic criteria for PCOS; (4) studies that did not compare the pregnancy outcomes between the PCOS patients with and without HA or among patients with different PCOS phenotypes; and (5) studies that did not involve outcomes

Literature filtering, data extraction, and quality assessment

Two investigators filtered the articles, extracted the data, and independently conducted quality assessment Any disagreements were resolved through discussion or by a third investigator until

a consensus was reached Data, including general characteristics, type of studies, participants, factors, and outcomes, were extracted according to a predesigned table PCOS was diagnosed based on different classifications Cases of polycystic ovarian morphology (PCO) þ oligo-anovulation (AO) þ HA, PCOþ HA, and HA þ AO were included into the HA group, whereas those with PCOþ AO were included into the normal androgen level (NA) group The Newcastle–Ottawa Scale was used to assess study quality [11] Scores were reported as total values of 0 9

Statistical analysis

Meta-analysis was performed using Review Manager version 5.3 (Cochrane Collaboration, Copenhagen, Denmark) and Stata ver-sion 12.0 (StataCorp, College Station, TX, USA) Dichotomous variables were expressed as risk ratios (RRs) with 95% confidence intervals (95% CIs), whereas continuous variables were presented

as mean differences (MDs) with 95% CIs The enrolled articles were examined for heterogeneity using thev2

test and I2

Studies were considered heterogeneous whenp  1 and I2 50%; when

p > 1 and I2 < 50%, studies were regarded to show no hetero-geneity when no heterogeneity among various studies was detected, meta-analyses were performed using a fixed-effects model Otherwise, meta-analyses were conducted using a ran-dom-effects model, the source of heterogeneity was further ana-lyzed, and possible confounding factors were explored in subgroup analysis Differences with p < 05 were considered stat-istically significant Publication bias was assessed using Begg’s

Treatment protocol

and Egger’s tests, with values of p > 05 indicating no

publica-tion bias

Results

Literature search results

Overall, 789 articles were initially searched After reading their

titles and abstracts, 746 articles were removed Subsequently, 43

articles were further evaluated by full-text reading After

screen-ing, nine retrospective articles were ultimately included in the

meta-analysis [10,12–19] The screening flowchart and results are

presented inSupplemental Figure 1

Characteristics and quality assessment of the

included studies

Overall, the nine included articles were cohort studies involving

3037 patients; of these patients, 1719 and 1318 were assigned to

the HA gand NA group All studies reported the average age and

body mass index of patients, and only two studies did not

indi-cate the serum androgen levels [18,19] The age and BMI of all

patients were comparable The basic characteristics and quality

assessment of the included studies are shown in Table 1 and

Primary outcomes Clinical pregnancy rate

Eight articles involving a total of 2388 patients with PCOS (1348 and 1040 patients in the PCOS/HA and PCOS/NA groups, respectively) reported the CPR [10,12,13,15–19] Meta-analysis was conducted using a random-effects model because of the het-erogeneity among various studies (p ¼ 008, I2 ¼ 63%) The results indicated an insignificant difference in the CPR between the PCOS/HA and PCOS/NA groups (RR: 0.94, 95% CI: 0.77, 1.15) (Figure 1(A))

Miscarriage rate

Six articles involving a total of 995 patients with PCOS (557 and

438 patients in the PCOS/HA and PCOS/NA groups, respect-ively) evaluated the MR [10,12,13,15,17,18] Asno heterogeneity was observed (p ¼ 53, I2¼ 0.0%), a fixed-effects model was used for meta-analysis The results revealed a statistically significant difference in the MR between the PCOS/HA and PCOS/NA groups (RR: 1.56, 95% CI: 1.13, 2.16) (Figure 1(B))

Live birth rate

Four articles involving a total of 884 patients (534 and 350 patients in the PCOS/HA and PCOS/NA group, respectively) investigated the LBR [10,14,15,17] Meta-analysis was performed

Figure 1 Effect of hyperandrogenism on IVF/ICSI outcomes (A) clinical pregnancy rate, (B) miscarriage rate, and (C) live birth rate.

using a random-effects model due to the heterogeneity among

various studies (p ¼ 03, I2 ¼ 67%) The results failed to show a

significant difference between the PCOS/HA and PCOS/NA

groups (RR: 0.84, 95% CI: 0.69, 1.12) (Figure 1(C))

Secondary outcomes

Number of retrieved oocytes

Because of the different grouping methods that were used by the

included studies, continuous variables could not be pooled Two

articles involving a total of 1293 individuals (782 and 511

individuals in the HA and NA groups, respectively) compared the number of retrieved oocytes between the HA and NA groups [15,17] No significant difference in the number of retrieved oocytes was identified between the two groups (MD: 0.71, 95% CI:0.10, 1.53, I2 ¼ 14%) Furthermore, four studies included different phe-notypes, with the number of retrieved oocytes being comparable

Endometrial thickness

Two articles assessed endometrial thickness in the HA (782 patients) and NA groups (511 patients) on the day of human

Table 2 Meta-analysis of outcomes according to different phenotype, ethnicity.

Outcomes Factor Phenotype (n) vs Phenotype (n) No of studies

Risk ratio (95% CI) I 2 (%) Model used

(434)

PCO þ AO

AO þ HA

（197） PCO(189)þ AO

PCO þ HA

PCO þ AO þ HA

PCO þ AO þ HA

AO þ HA (159)

PCO þ HA (149)

Ethnicity Asians All

HA (323)

NA (678)

(489)

NA (182)

(1348)

NA (1040)

AO þ HA

（159） PCO(134)þ AO

PCO þ HA (167)

PCO þ AO (251)

PCO þ AO þ HA (295)

AO þ HA

PCO þ AO þ HA

AO þ HA

Ethnicity Asians All

HA

(234)

PCO þ AO (207)

AO þ HA (103)

PCO þ AO (32)

PCO þ HA (137)

PCO þ AO (207)

PCO þ AO þ HA (168)

AO þ HA (103)

PCO þ AO þ HA (234)

PCO þ HA

AO þ HA

Ethnicity Asians All

HA

(534)

NA

Note The results formatted in bold in the table are statistically significant.

chorionic gonadotropin (hCG) administration or embryo transfer

(ET) [15,17] The meta-analysis indicated that the endometrium

was thinner in the HA group in the HA group than the in NA

group, with the difference being statistically significant (MD:

0.37, 95% CI: 0.57, 0.17, I2 ¼ 0%) (Supplemental Figure 3,

Sensitivity analysis

Sensitivity analysis was conducted to identify the heterogeneity

source After removing the included studies one by one, we

found that the Man W study had a considerable influence on the

heterogeneity of results (Supplemental Figure 4) After ruling out

the study, the results revealed that the CPR did not differ

between the two groups (RR: 0.88, 95% CI: 0.77, 1.01)

Subgroup analysis

Subgroup analysis according to different PCOS phenotypes and

ethnicity was performed The subgroup analysis results are

pre-sented in Table 2 The CPR was lower in the PCOþ AO þ HA

than in the PCOþ AO group (RR: 0.81, 95% CI: 0.67, 0.99);

nevertheless, no difference in other phenotypes was observed

Concerning miscarriage, the results failed to show any difference

in the MR between the subgroups Furthermore, there was no

difference in the LBR between the subgroups Regarding to

eth-nicity, among Asians, the PCOS/HA group had an increased MR

(RR: 1.56, 95% CI: 1.06, 2.31); additionally, the CPR (RR: 0.86,

95% CI: 0.73, 1.00) and LBR (RR: 0.83, 95% CI: 0.69, 1.00) were

decreased, albeit without statistically significant difference

However, no difference was observed among Caucasians

Publication bias

Begg’s and Egger’s tests were used to assess publication bias

MR, and LBR The results indicated that there was no

publica-tion bias

Discussion

This is the first meta-analysis that evaluated the HA effects of on

the outcomes of IVF/intracytoplasmic sperm injection (ICSI) in

patients with different PCOS phenotypes Nine articles were

included in this t study In this meta-analysis, MR was

signifi-cantly different between the PCOS/HA and PCOS/NA groups

Nonetheless, the results of subgroup analysis indicated no

differ-ence in the MR among the phenotypes We speculate that these

results may be attributable to the small sample size While we

did not conclude that there were significant differences in the

CPR and LBR between the PCOS/HA and PCOS/NA groups,

our subgroup analysis revealed that the CPR decreased in the

PCOþ HA þ AO group, compared to that in the PCO þ AO

group (RR: 0.81, 95% CI: 0.67, 0.99) When other phenotypes

were compared, no difference in the CPR was identified We

analyzed the included studies from the literature and observed

that patients with PCOþ HA þ AO had higher serum androgen

levels than those with other phenotypes Yilmaz et al reported

that compared to patients with other subtypes, those with

PCOþ HA þ AO exhibited the highest incidence of metabolic

syndrome [20] Different PCOS phenotypes do not represent the

same metabolic disorder Batcheller et al observed that the CPR

was significantly lower in the PCOS/HA group than in the PCOS/NA group (39.5 vs 69.6%; odds ratio: 0.306, 95% CI: 0.12, 0.85, p ¼ 034) [21] The subgroup meta-analysis revealed that PCOS/HA had a negative effect on IVF/ICSI outcomes among Asians; however, no effect was detected among Caucasians The ethnicity impact on pregnancy outcomes remains unknown A possible reason is that the effects of ethnicity on endometrial thickness and endometrial receptivity in patients with PCOS vary across different races

We performed a meta-analysis of endometrial thickness and showed that among Chinese individuals, the endometrium was thinner in the HA group than in the NA group on the day of hCG administration or ET Nevertheless, the number of retrieved oocytes did not differ among phenotypes HA above a certain level may reduce the clinical pregnancy outcomes of IVF/ICSI A possible mechanism by which HA influences the pregnancy out-comes of IVF/ICSI is its effects on endometrial receptivity and embryo implantation PCOS is reportedly an independent factor for recurrent pregnancy loss [22,23] Androgen levels are higher

in women who had experienced recurrent miscarriages than in normal fertile controls The prevalence of hyperandrogenemia in recurrent miscarriages was approximately 11% [24] HA may have adverse effects on the endometrium Palomba et al revealed that Testosterone reportedly is a novel negative regulator of endometrial HOXA10 expression and also impairs the LIF-STAT3 pathway, and reduces the uterineavb3 integrin and gly-codelin levels, which may contribute to poor endometrial func-tion[25] HA affects the utilization of glucose by endometrial stromal cells, which is necessary for endometrial decidualization and embryo implantation [26] Subendometrial and endometrial blood flow (vascularization index) is considerably impaired in PCOS/HA women, compared to that in PCOS/NA patients (3.17

vs 1.59% and 1.11 vs 0.57%, respectively) [27] High androgen levels may have a negative impact on oocyte competence Hyperandrogenism may cause abnormal gene expression, which are essential for ovarian growth and cumulus expansion, such as IGF2R, TXNIP and HAS2 [28] Additionally, HA may have adverse effects on maternal and neonatal health Patients with PCOS, particularly the HAþ AO þ PCO phenotype, have a higher risk of developing gestational diabetes mellitus, preg-nancy-induced hypertension, and premature delivery than the control group, leading to a lower LBR [29] Hyperandrogenism may contribute to the increased risk of obstetric and neonatal complications [30]

This study had some limitations First, a limited number of cohort studies were included Additionally, the grouping meth-ods of articles included in this meta-analysis were not identical Randomized controlled trials are required to determine whether PCOS patients with HA would benefit more from HA pretreat-ment prior to IVF or ICSI

Conclusion

This meta-analysis analyzed the influence of hyperandrogenemia

on the pregnancy outcomes of IVF/ICSI in patients with PCOS Our results indicated that hyperandrogenemia might increase the

MR in the PCOS/HA group Hyperandrogenemia had significant adverse effects on IVF/ICSI outcomes among Asians

Ethical approval

This article did not contain any studies with human participants performed by any of the authors

Author contributions

Linna Ma was responsible for the writing of the paper, Wenrong

Dai and Yunrong Cao were responsible for the collection of

materials They all undertook the screening and sorting of data,

Professor Zhai Jun gave guidance and modification of the article

Disclosure statement

No potential conflict of interest was reported by the author(s)

Funding

This research was financially supported by the National Natural

Science Foundation of China [82071649]

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