Table of Contents  
Year : 2022  |  Volume : 24  |  Issue : 1  |  Page : 78-84

Surgical management and molecular diagnosis of persistent Müllerian duct syndrome in Chinese patients

1 Department of Urology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China Department of Genetics and Metabolism, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China Department of Endocrinology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China

Date of Submission31-May-2021
Date of Acceptance26-Aug-2021
Date of Web Publication19-Nov-2021

Correspondence Address:
Da-Xing Tang
Department of Urology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aja202175

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Persistent Müllerian duct syndrome (PMDS) is a rare clinically and genetically overlapping disorder caused by mutations in the anti-Müllerian hormone (AMH) gene or the anti-Müllerian hormone receptor type 2 (AMHR2) gene. Affected individuals present uterus and tubes in normally virilized males and are discovered unexpectedly during other surgeries. Since it is rare and complex, a definitive clinical diagnosis can be missed, and there are no guidelines regarding how to deal with the uterus. In the present study, exome sequencing and Sanger verification were performed for causal variants in 12 PMDS patients. Preoperative diagnoses were made by positive exome sequencing in 8 patients. Of them, 7 patients evoked on the basis of ultrasound indicating bilateral testes on the same side of the body. Twelve different AMH variants (2 frameshift/nonsense, 1 deletion, 8 missense, and 1 in-frame) in 9 patients and 6 different AMHR2 variants (5 missense and 1 splicing) in 3 patients were identified. Seven variants were classified as “pathogenic” or “likely pathogenic”, and 4 of them were novel. All but two patients with AMH defects showed low serum AMH concentrations, but all patients with AMHR2 defects showed elevated AMH levels. During surgery, an abnormal vas deferens was observed in half of the patients. Eight patients underwent orchidopexy with uterine preservation. Of them, 2 patients presented complications including irreducible cryptorchidism, and 3 patients developed Müllerian remnant cysts. Three patients underwent subtotal hysterectomy. Of them, one patient had complication of injury to the vas deferens, and one had hemorrhage after operation. This is the first report of PMDS involving a large Chinese population. The present study not only expands the variation spectrum but also provides clinical experience about the management of the uterus.

Keywords: AMH; AMHR2; disorders of sex development; persistent Müllerian duct syndrome

How to cite this article:
Tian HJ, Wu DH, Ru W, Wu DW, Tao C, Chen GJ, Yuan JN, Fu JF, Tang DX. Surgical management and molecular diagnosis of persistent Müllerian duct syndrome in Chinese patients. Asian J Androl 2022;24:78-84

How to cite this URL:
Tian HJ, Wu DH, Ru W, Wu DW, Tao C, Chen GJ, Yuan JN, Fu JF, Tang DX. Surgical management and molecular diagnosis of persistent Müllerian duct syndrome in Chinese patients. Asian J Androl [serial online] 2022 [cited 2022 May 19];24:78-84. Available from:

  Introduction Top

Persistent Müllerian duct syndrome (PMDS; OMIM# 261550) is a rare recessive disorder characterized by the persistence of Müllerian remnants (MRs), uterus, and tubes, in normally virilized males.[1] The karyotype of individuals with PMDS is 46,XY, the urethra opens normally at the glans, and both gonads are testes. PMDS has three main clinical presentations: bilateral cryptorchidism, unilateral cryptorchidism with inguinal hernia, and transverse testicular ectopia (TTE).[2] During the corrective surgery for cryptorchidism and inguinal hernia, the presence of MRs is usually an unexpected discovery.[2] The accurate diagnosis can be missed during the initial surgery, leading to reoperations. The uterus is usually an obstacle to testicular descent and at risk of malignant degeneration.[2],[3],[4],[5] However, removing the uterus almost unavoidably damages the vas deferens or the deferential artery.[2] Nowadays, it is difficult to identify PMDS preoperatively and the debate continues about how to deal with the uterus.

Biallelic loss-of-function variants in the anti-Müllerian hormone (AMH) gene and the anti-Müllerian hormone receptor type 2 (AMHR2) gene have been identified in patients with PMDS. The AMH gene is a 2.8-kb-long gene containing five exons located on chromosome 19p13.3, and its protein product is a glycoprotein dimer belonging to the transforming growth factor-beta (TGF-β) family that acts via its specific receptor (AMHR2). The AMHR2 gene contains 11 exons located on 12q13 and encodes a serine/threonine kinase belonging to the TGF-β-related protein family. To date, 85 different variants in AMH and 84 variants in AMHR2 have been identified according to the Human Gene Mutation Database (HGMD). However, few variants have been reported in Chinese individuals with PMDS.[6]

In this report, we studied the management experiences and genetic findings of 12 patients with PMDS in China. After a review of the literature, we presented procedures for the diagnosis and treatment of PMDS.

  Patients and Methods Top

The study included all patients with PMDS admitted to the Department of Urology at Children's Hospital, Zhejiang University School of Medicine (Hangzhou, China), from January 2012 to December 2020. The inclusion criteria were (1) normal male external genitalia; (2) a 46,XY karyotype; and (3) the presence of MRs ascertained by surgical exploration. The exclusion criteria included (1) a lack of molecular diagnosis, or (2) an absence of treatment or follow-up. Data on demographics, clinical presentations, molecular findings, AMH levels, surgical findings, and outcomes were retrospectively reviewed. This study was approved by the Ethical Committee of Children's Hospital, Zhejiang University School of Medicine (Approval No. 2018-IRB-076). Written informed consent was also obtained.

AMH levels were determined via the Immunotech AMH/Müllerian inhibiting substance (MIS) enzyme immunoassay (UniCel DXI800; Beckman Coulter, Fullerton, CA, USA). G-banding karyotyping was carried out using peripheral lymphocytes.

Targeted next-generation sequencing was performed. Genomic DNA was extracted from peripheral blood samples of patients using a QIAamp DNA Blood Mini Kit (Qiagen GmbH, Hilden, Germany). Paired-end libraries were generated with the Agilent Sure Select Target Enrichment System and an XT Inherited Disease Panel containing 2742 genes (Agilent Technologies Inc., Santa Clara, CA, USA) according to the manufacturer's instructions. Sequencing was performed on an Illumina HiSeq 2500 System (Illumina Inc., San Diego, CA, US). The analysis was carried out using an in-house pipeline adapted from BWA, GATK and SAMtools 1.8. Sanger sequencing was used to confirm the identified variants in the patients and their parents. When a confirmed origin of the observed variants was lacking in the patients, their parents also underwent exome sequencing. AMH/AMHR2 copy numbers were determined through CapCNV analysis followed by the CNVkit protocol (

To predict the possible impact of identified variants, multiple prediction tools such as ClinPred and REVEL were implemented. According to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) 2015 guidelines, the pathogenicity of the variants was classified as five levels: pathogenic, likely pathogenic, variants of uncertain significance (VUS), likely benign, and benign.[7]

All analyses were carried out using the SPSS software, version 20 (SPSS, Chicago, IL, USA).

  Results Top

Clinical findings

There were 12 patients with a median age of 10 (range: 2–49) months included during the study period [Table 1]. All the parents of the patients were unrelated. Among the patients, 6 patients presented with unilateral cryptorchidism (50.0%; [Figure 1]), 3 patients with bilateral cryptorchidism (25.0%), and 3 patients with TTE (25.0%). The preoperative diagnosis of PMDS was evoked by ultrasound in 7 patients and another one patient presenting with bilateral unpalpable cryptorchidism was diagnosed preoperatively by exome sequencing. The preoperative diagnosis rate of PMDS was 66.7%, as shown in [Figure 2]. Notably, patient 1 and 2 are brothers. Patient 1 was diagnosed as PMDS during surgery for henia. Later, his elder brother,patient 2, was confirmed to had PMDS postoperatively by exome sequencing.
Figure 1: Normally virilized external genitalia and unexpected Müllerian remnants in the pelvic cavity. (a) The length and size of the penis are normal-for-age and its urethra opens at the glans. The scrotum is empty. (b) There is a uterus between two intra-abdominal testes.

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Figure 2: Timing of PMDS diagnosis and detection methods. A preoperative diagnosis was made in 66.7% (8/12) of cases, including 7 cases evoked by ultrasonography and confirmed by exome sequencing, and 1 case diagnosed by exome sequencing. The postoperative diagnosis obtained by exome sequencing was unilateral testis because of his PMDS brother. The last three cases were identified due to the presence of the uterus during corrective surgery for hernia or cryptorchidism. PMDS: persistent Müllerian duct syndrome.

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Table 1: Clinical and genetic findings of patients with PMDS

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Molecular findings and AMH levels

We identified 12 different AMH variants (2 frameshift/nonsense, 1 deletion, 8 missense, and 1 in-frame) in 9 patients and 6 different AMHR2 variants (5 missense and 1 splicing) in 3 patients [Figure 3] and [Supplementary Table 1 [Additional file 1]]. The variants in AMH and AMHR2 occurred in the compound heterozygous form in all patients except for patient 7, who harbored a homozygous variant in AMH. The same nonsense variant (p.E389X) in AMH occurred in patient 5 and patient 7, while the same missense variant (p.G101R) occurred in patient 3, 6, and 8. The numbers of detected and independent variants in the N-terminal region of AMH were 8 and 5, respectively, while those in the TGF-beta-like domain were both 3. Three missense variants occurred in the activin type I and II receptor domain of AMHR2, and two occurred in the protein kinases catalytic domain. Of the 12 identified variants in AMH, 8 variants are novel, and 4 missense variants have been reported previously. According to the ACMG 2015 criteria, 7 variants were classified as pathogenic, or likely pathogenic, which were c.301G>A, c.1165G>T, c.707G> A, c.992C>T, c.1447T>C, and c.102dupC in AMH, and c.160C>T in AMHR2. Of them, 4 variants were novel: c.707G> A, c.992C>T, c.1447T>C and c.102dupC in AMH. Three detected variants occurred in activin types I and II receptor domain of AMHR2, and two variants occurred in protein kinase catalytic domain. Five of the 6 identified variants in AMHR2 were novel and VUS, and the other missense variant was classified as likely pathogenic.
Figure 3: Summary of reported variants and novel variants in the (a) AMH gene and (b) AMHR2 gene. Green dots represent variants found in the present study; yellow dots represent variants previously reported in the literature. Each point represents one affected family. The number in the circle represents the times of reports. Novel variants are indicated in red. Missense variants are indicated on the top, and others are indicated on the bottom. *Intron variants are indicated. Variants in each domain cluster together. PMDS: persistent Müllerian duct syndrome; AMH: anti-Müllerian hormone; AMHR2: anti-Müllerian hormone receptor type 2; TGF-β: transforming growth factor-beta.

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All but two patients with AMH gene defects showed low or undetectable serum AMH concentrations. Patient 3 with 80.88 ng ml−1 AMH and patient 9 with more than 168.57 ng ml−1 AMH were the exceptions. All patients with AMHR2 gene defects presented elevated AMH levels.

Intervention and follow-up

All patients underwent laparoscopic exploration and bilateral orchidopexy. Eight patients preserved the uterus until now. Three patients underwent subtotal hysterectomy, which was accompanied by complications of injury to the vas deferens in one patient and hemorrhage in another patient. The uterus in the last patient could not be detected by laparoscopy or imaging. During surgery, the vas deferens was observed to be blind and dissociated from the testes in six patients (50.0%). For histopathology, testicular biopsies were performed in 6 patients, and the examination of sections confirmed testicular microlithiasis (TM) in 3 patients (25.0%), while the others presented normal infantile testes. Patient 7 underwent retrograde urethrography showing a long narrow prostatic utricle [Figure 4]a and [Figure 4]b
Figure 4: Images of Müllerian remnants. (a) Posterior urethral cystoscopy (patient 7). Cystoscopy demonstrated the verumontanum to be in a normal location with an edematous slit-like opening in its center (cursor). (b) Retrograde urethrography (patient 7). The 3F catheter was inserted into the opening, which was long and narrow in the oblique coronal plane in retrograde urethrography. The cursor points to the confluence of the vagina and urethra. (c) Pelvic MRI (patient 10). This T2 coronal view demonstrates that the Müllerian remnants (yellow arrow) extend from the scrotum. (d) Pelvic MRI (patient 10). This T2 coronal view demonstrates that the Müllerian remnants (yellow arrow) extend along the groin and extend within the pelvic cavity on the normal side. The area measured 6.2 cm × 1.6 cm. MRI: magnetic resonance imaging.

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All patients were followed up, and the median follow-up time was 31 (range: 7–95) months. We observed complications in six patients. One patient suffered bilateral hernia recurrence, which was repaired during reoperation. Five of eight patients whose uterus was retained presented complications of irreducible cryptorchidism (2/8) and MR cysts (3/8). One patient with irreducible cryptorchidism was followed up without further intervention; the other underwent two additional surgeries to repair the normal-side testis. MR cysts occurred in the scrotum, groin, or pelvis. The size of the cyst in patient 4 was small and stable (2.3 cm × 0.8 cm), and the size in patient 9 was enlarged at one time point (6.3 cm × 4.0 cm) but has now been reduced (1.5 cm × 1.1 cm). Patient 10 exhibited a progressively enlarged cyst (6.2 cm × 1.6 cm) for 25 months after the operation and continued to undergo follow-up without further intervention [Figure 4]c and [Figure 4]d.

Description of the variant spectrum of the literature

Based on a review of 157 cases in 2017,[8] nine published peer-reviewed articles were identified. Adding with our patients in China, there were 93 families with 78 different variants in AMH [Supplementary Table 2 [Additional file 2]] and 94 families with 80 different variants in AMHR2 have been reported [Supplementary Table 3 [Additional file 3]].[6],[8],[9],[10],[11],[12],[13],[14],[15],[16] The relationship between the phenotypes and genotype of all patients was analyzed statistically [Supplementary Figure 1 [Additional file 4]]. There was no significant difference in anatomy between patients with either AMH or AMHR2 variants. A total of 56.6% of the patients presented with bilateral cryptorchidism, 20.8% with unilateral cryptorchidism, and 22.5% with TTE. Variants in AMH and AMHR2 were detected in 87.9% of all cases. Meanwhile, all TTE with PMDS has possible causative variants.

Variants occur along the whole length of AMH and AMHR2 [Figure 3]. The large N-terminal fragment is hit 70 times. The TGF-β like domain in C-terminus is hit 26 times. The variant rate in the N-terminal region was nearly 2.5 times that of the TGF-β-like domain. The activin types I and II receptor domain in AMHR2 is an extracellular domain and is hit 8 times. The protein kinase catalytic domain in AMHR2 is located in the intracellular domain and is hit 37 times and 4 times more than the receptor domain.

  Discussion Top

PMDS is one of the rarest causes of disorders of sex development (DSD) with clinical and genetic heterogeneity and is characterized by the presence of a bicornuate uterus, fallopian tubes, and the upper third of the vagina in normally masculinized 46,XY subjects.[1] The incidence has not been accurately determined. Since its initial description, the details of more than 250 cases have been published, and variants in AMH and AMHR2 have been identified in these patients. Thus far, few studies from China have reported the variant spectrum and management experiences of PMDS patients. In the current study, we report the clinical experiences and genetic findings of 12 new patients from China.

In our literature review, 56.6% of the included patients presented with bilateral cryptorchidism, 20.8% with unilateral cryptorchidism, known as hernia uteri inguinalis, and 22.5% with TTE [Supplementary Figure 1]. The data were updated and included newly reported patients and our Chinese patients.[2] However, in the current study, unilateral cryptorchidism present in more than half of the patients was the most common phenotype. We also found that the position of the testis was flexible and was always reset during laparoscopic exploration, although it was preoperatively detected on the contralateral side of the body (mostly in the groin) by ultrasound [Table 1]. It is easy to confuse TTE with unilateral cryptorchidism, and it is possible that there is no need to distinguish them. Moreover, the high flexibility of the testes due to the abnormal mobility of the uterus facilitates their torsion and may lead to uni- or bilateral testicular degeneration.[17] The testis of patient 2 was ascertained to be atrophied.

In children, PMDS is usually diagnosed due to an accidental discovery of uterus during corrective surgery for inguinal hernia or cryptorchidism. Most surgeons may not see any patient with PMDS due to its low incidence. The clinical manifestations of PMDS are a common presentation compared with other cryptorchidism. Testicular histology is generally performed for diagnosis during the first surgery without therapeutic surgery, and the morphology is usually normal.[2] Therefore, preoperative diagnosis is critical and can help to avoid unnecessary testicular biopsy and reoperations. Unilateral or bilateral cryptorchidism is not particularly evocative, although unilateral cryptorchidism with contralateral hernia, particularly TTE, should evoke suspicion. In the present study, the rate of preoperative diagnosis was as high as 66.7%. Further assessment was carried out when suspicion of PMDS arose from ultrasound in 7 patients, which revealed that the testis crossed to the contralateral side of the body. The results of exome sequencing were positive in these 7 patients and one bilateral cryptorchidism, which enable us to make a preoperative diagnosis. Pelvic ultrasound is routinely used to describe the internal anatomy in these patients, but limited in the identification of MRs. The sensitivity and specificity of ultrasound in localizing MRs is 54% and 50%, respectively.[18] If physical examination and ultrasound show any sign of a testis crossing the body midline to the contralateral side, PMDS should be considered. Moreover, preoperative gene sequencing can contribute to an accurate diagnosis when a damaging variant of AMH or AMHR2 is detected.

In our literature review, variants of AMH and AMHR2 were reported in 87.9% of all patients and were approximately equally distributed among the genes coding AMH and its type II receptor, AMHR2.[6],[8],[9],[10],[11],[12],[13],[14],[15],[16] Statistics indicated that AMH presented 78 different variants in 93 families, and 80 different alleles of AMHR2 were discovered in 94 families. In our Chinese patients, mutational analyses revealed possible causative variants in all patients. AMH variants occurred more frequently than AMHR2 variants, consistent with a previous report.[2] Variants are known to occur along the entire length of AMH, although exons 3 and 4 are very rarely involved [Figure 3]. The short C-terminal fragment is a TGF-β-like domain with biological activity. The large N-terminal region is not thought to be essential for activity, but exerts the ability to stabilize the C-terminus,[19] and shows nearly 2.5 times the hit of the C-terminus [Figure 3]. In our study, twelve variants, including eight new variants, were identified in AMH. The c.301G>A (p.G101R) and c.1165G>T (p.E389X) were recurrent in three and two unrelated families, respectively. The variant c.301G>A (p.G101R) has been previously described in four families, while c.1165G>T (p.E389X) has been reported in two families. The variant c.1637C>A (p.A546E) was also previously detected in one family. AMHR2 encodes a membrane protein and has 11 exons, which are all affected by variants [Figure 3]. Only two hits were observed in the transmembrane domain. The protein kinase catalytic domain was more conserved and showed nearly 5 times more hits than the activin types I and II receptor domains. In our Chinese patients, six variants in the AMHR2 gene were found, including five new VUS. The variant c.160C>T (p.R54C) was previously described in one family.[20] Functional studies have not been reported, so further studies are needed to investigate the harmfulness of these variants.

Normally, AMH concentrations are maintained at high levels during childhood and decrease at puberty.[21] Patients with AMH gene defects show low AMH levels from birth, whereas patients with variants in AMHR2 show elevated AMH levels, indicating insensitivity of the target tissues.[22] In contrast, patients 3 and 9 with variants in AMH presented increased AMH levels, indicating that the interactions between variants p.(R451H) and p.(G101R) and between p.(S35Qfs*46) and p.(Y483H) might affect hormone bioactivity but not the hormone secretion rate.[23]

The genotypes of AMH and AMHR2 are not related to the observed phenotypes.[2],[24] The phenotype can differ within the same family and shows no relationship to the type of genetic defect involved. The anatomical abnormalities common to all patients with PMDS result from the failure of the gubernaculum to anchor the testes at the base of the scrotum. The abnormal mobility of the uterus with the testes facilitates their torsion and may lead to uni- or bilateral testicular degeneration.[17] In the current study, the left testis of patient 1 was located in the left groin, while the testis of his brother, patient 2, was atrophied on the left side. Furthermore, neither laparoscopy nor imaging was able to detect Müllerian derivatives in patient 2, even though he harbored the same variants as his brother (patient 1) with PMDS. This suggests highly variable penetrance of the abnormal alleles and/or the existence of other genetic or epigenetic modifiers of gene expression.

The management of PMDS consists of the correction of cryptorchidism to prevent testis degeneration and preserve fertility.[2],[25] Because of the high mobility of the uterus with the testes, bilateral orchidopexy is recommended, as we performed in the current study. The rate of testicular malignancy is up to 33.0% in PMDS patients older than 18 years, which is higher than the rate among general cryptorchidism cases. Close follow-up of the testes is necessary with age.[2]

There is no consensus regarding whether MRs should be excised in PMDS patients. Previous reports have advocated retaining MRs to prevent damage to the vas deferens, considering that MRs present no risk of malignancy.[26],[27] In the current study, MRs were preserved in eight patients, but complications occurred in five patients. To our knowledge, this is the first study to report the emergence of MR cysts after MR preservation. The cysts were thought to be hydrocolpos caused by the accumulation of fluid due to congenital vaginal obstruction. In our experience, such cysts may decrease in size and remain stable, but long-term outcomes still need to be followed up. Irreducible cryptorchidism occurred in two patients following MR preservation, which may have been due to the mobilization of MRs.

Since 2002, three PMDS patients have been reported to have developed malignancy of MRs originating from the mucosa.[3],[4],[5] The preferred surgical procedure is to split the uterus in the middle, destroy the mucosal lining, and leave an intact pedicle of the myometrium.[25],[28],[29] This not only releases the testes to the ideal position but also protects the integrity and vascularity of the vas deferens and reduces the chance of malignancy. In the current study, three patients underwent partial hysterectomy, but two of them experienced side effects. One presented the complication of hemorrhage, indicating that complete hemostasis should be noticed. The vas deferens is injured in TTE because it is enclosed in MRs, so surgeons need to improve their surgical techniques and perform dissection carefully. In addition to malignant degeneration, retained MRs are known to cause hematuria, recurrent urinary tract infection, stones, and voiding disturbances,[29],[30] but these conditions were not noticed in our series.

Infertility is another problem observed in PMDS patients. The possible causes include congenital malformations of excretory ducts, long-term cryptorchidism, and damage to the testicular blood supply or the vas deferens during hysterectomy. In the present study, the incidence of vas deferens malformation was high, occurring in half of the patients. We also noted a high incidence of TM (25.0%), which may contribute to another cause of infertility.[31]

Follow-up is extremely important for these patients, especially the monitoring of malignancies of the testes and uterus, with concern for their fertility. Close follow-up of all of our patients continues in our clinic.

  Conclusion Top

We report 12 new Chinese PMDS patients with 13 novel possible causative variants in the AMH and AMHR2 genes. Bilateral orchidopexy with destruction of the uterine mucosa may be the optimum surgical procedure for PMDS.

  Author Contributions Top

HJT and DXT conceived and designed this study. DXT and JFF supervised this study. HJT and DHW wrote the manuscript. HJT and CT extracted clinical data. DWW analyzed the genetic variants. WR and JNY performed statistical analysis of the results with assistance and/or inputs from other authors. CT and GJC provided necessary study supports. All authors read and approved the final manuscript.

  Competing Interests Top

All authors declare no competing interests.

  Acknowledgments Top

The authors thank Jian Wang (Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Hangzhou, China) for the consultation on molecular knowledge, Rui Xiao (Boisan Biotechnology Co., Ltd., Hangzhou, China) for the guidance on writing, and Shu-Jie Zhang (Maternal and Child Heath Hospital of Guangxi Zhuang Autonomous Region, Nanning, China) for the consultation on chart drawing. This study was supported by National Key R&D Program of China (grant No. 2018YFC1002702).

Supplementary Information is linked to the online version of the paper on the Asian Journal of Andrology website.

  References Top

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1]


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