From biological marker to clinical application: the role of anti-Müllerian hormone for delayed puberty and idiopathic non-obstructive azoospermia in males

in Endocrine Connections
Authors:
Yuanyuan Zeng Human Sperm Bank, West China Second University Hospital of Sichuan University, Chengdu, Sichuan, China
Department of Andrology, West China Second University Hospital of Sichuan University, Chengdu, Sichuan, China
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, China

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Guicheng Zhao Human Sperm Bank, West China Second University Hospital of Sichuan University, Chengdu, Sichuan, China
Department of Andrology, West China Second University Hospital of Sichuan University, Chengdu, Sichuan, China
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, China

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Yi Zheng Human Sperm Bank, West China Second University Hospital of Sichuan University, Chengdu, Sichuan, China
Department of Andrology, West China Second University Hospital of Sichuan University, Chengdu, Sichuan, China
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, China

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Xiaohui Jiang Human Sperm Bank, West China Second University Hospital of Sichuan University, Chengdu, Sichuan, China
Department of Andrology, West China Second University Hospital of Sichuan University, Chengdu, Sichuan, China
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, China

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https://orcid.org/0009-0003-8532-2999

Correspondence should be addressed to X Jiang: xiaohuijiang@scu.edu.cn

This paper forms part of a themed collection on male reproductive health, investigating the causes of male infertility and identifying new therapeutic approaches. The collection editors were Channa Jayasena, Anu Sironen and Aldo E Calogero.

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Graphical abstract

Role of anti-Müllerian hormone (AMH) in male development and fertility prediction. (A) AMH levels in normal development, constitutional delay of growth and puberty (CDGP) and central hypogonadotropic hypogonadism (CHH) models. In normal males, AMH declines with puberty; in CDGP and CHH, AMH is normal or slightly elevated or abnormally low, indicating delayed or impaired pubertal progression. (B) AMH as a predictor of successful sperm retrieval (SSR) in idiopathic non-obstructive azoospermia. Lower AMH levels (<2.6 ng/mL) correlate with higher SSR in microdissection testicular sperm extraction.

Abstract

Anti-Müllerian hormone (AMH), a biomarker secreted by Sertoli cells in the testes, has emerged as a critical indicator of male reproductive function with significant clinical application potential. AMH reflects Sertoli cell activity and plays a pivotal role across different stages of male gonadal function. First, in prepubertal males, AMH levels are crucial for assessing testicular development and the progression of puberty, with delayed or insufficient AMH secretion often being associated with disorders such as delayed puberty. Second, in reproductive-age males, AMH serves as an important biomarker for evaluating spermatogenic capacity, particularly in cases of idiopathic non-obstructive azoospermia. In these patients, AMH levels can help predict the success of testicular sperm extraction, thereby influencing fertility treatment strategies. This review explores the physiological mechanisms of AMH and its diagnostic and prognostic significance in both delayed puberty and fertility disorders in reproductive-age males. While AMH shows great promise in the management of hypogonadism, further research is needed to validate its clinical utility and refine treatment protocols for optimizing patient outcomes.

Abstract

Graphical abstract

Role of anti-Müllerian hormone (AMH) in male development and fertility prediction. (A) AMH levels in normal development, constitutional delay of growth and puberty (CDGP) and central hypogonadotropic hypogonadism (CHH) models. In normal males, AMH declines with puberty; in CDGP and CHH, AMH is normal or slightly elevated or abnormally low, indicating delayed or impaired pubertal progression. (B) AMH as a predictor of successful sperm retrieval (SSR) in idiopathic non-obstructive azoospermia. Lower AMH levels (<2.6 ng/mL) correlate with higher SSR in microdissection testicular sperm extraction.

Abstract

Anti-Müllerian hormone (AMH), a biomarker secreted by Sertoli cells in the testes, has emerged as a critical indicator of male reproductive function with significant clinical application potential. AMH reflects Sertoli cell activity and plays a pivotal role across different stages of male gonadal function. First, in prepubertal males, AMH levels are crucial for assessing testicular development and the progression of puberty, with delayed or insufficient AMH secretion often being associated with disorders such as delayed puberty. Second, in reproductive-age males, AMH serves as an important biomarker for evaluating spermatogenic capacity, particularly in cases of idiopathic non-obstructive azoospermia. In these patients, AMH levels can help predict the success of testicular sperm extraction, thereby influencing fertility treatment strategies. This review explores the physiological mechanisms of AMH and its diagnostic and prognostic significance in both delayed puberty and fertility disorders in reproductive-age males. While AMH shows great promise in the management of hypogonadism, further research is needed to validate its clinical utility and refine treatment protocols for optimizing patient outcomes.

Introduction

Hypogonadism can lead to delayed puberty and idiopathic non-obstructive azoospermia (iNOA), conditions in which anti-Müllerian hormone (AMH) shows unique clinical potential for evaluation. AMH, secreted by Sertoli cells in the testes, is a critical biomarker for assessing Sertoli cell function and gonadal development, making it highly valuable in evaluating male reproductive health.

In cases of delayed puberty, constitutional delay of growth and puberty (CDGP) and central hypogonadotropic hypogonadism (CHH) have similar clinical manifestations, with CHH being associated with persistent Sertoli cell dysfunction. Traditional hormonal assessments, such as luteinizing hormone (LH), follicle stimulating hormone (FSH) and testosterone, reflect hypothalamic–pituitary–gonadal (HPG) axis activity, but they offer limited diagnostic value in differentiating CDGP from CHH (1, 2). In contrast, AMH directly reflects Sertoli cell activity, which may provide higher diagnostic specificity and can aid in guiding treatment decisions (3, 4). For reproductive-age patients with iNOA, AMH has emerged as an independent biomarker of Sertoli cell health and spermatogenic capacity by offering as a predictor of successful sperm retrieval (SSR) in microdissection testicular sperm extraction (micro-TESE) (5).

This review aims to provide a comprehensive overview of the physiological rhythms of AMH, the developmental characteristics of Sertoli cells, and the clinical applications of AMH, with a particular focus on its role in distinguishing CDGP from CHH and predicting micro-TESE outcomes in iNOA patients. By exploring the potential of AMH in these key clinical areas, this review intends to provide a theoretical foundation for personalized treatment strategies and promote more precise clinical decision-making.

Mechanisms of AMH secretion and its physiological variation across the male lifespan

The levels of AMH in males undergo dynamic changes throughout the male lifespan, reflecting the function of Sertoli cells and the development of the male reproductive system (Fig. 1A). From the embryonic period to old age, AMH is regulated by various mechanisms that correspond to different stages of development, maturation and senescence of the male reproductive system (6).

Figure 1
Figure 1

Regulation of AMH during male development. (A) Changes in serum levels of LH, FSH, T and AMH throughout life, highlighting peaks in fetal development, mini-puberty and puberty. (B) In early fetal development, AMH expression is primarily regulated by transcription factors such as SOX9, SF1 and GATA4, which promote AMH expression, while DAX1 acts as a repressor. (C) In later fetal stages and postnatally, AMH regulation shifts under the influence of FSH. FSH activates the cAMP-PKA pathway in Sertoli cells, enhancing the activity of transcription factors (e.g., SOX9, SF1 and NF-κB) and promoting Sertoli cell proliferation, which collectively increase AMH production.

Citation: Endocrine Connections 14, 3; 10.1530/EC-24-0630

In the early embryonic stage (before the 13th week), AMH expression is independent of FSH regulation (7, 8). In male embryos, the sex-determining region Y (SRY) gene initiates male sex differentiation by activating the transcription factor SOX9, a key regulator of AMH expression (9). SOX9 binds to specific DNA sequences on the AMH gene promoter, thereby initiating its transcription. In addition, transcription factors, such as SF1, GATA4 and WT1, work synergistically to enhance AMH expression, while DAX1 acts as a repressor by inhibiting the activity of SF1 and GATA4 (Fig. 1B) (10).

As fetal development progresses into the second and third trimesters, AMH expression becomes increasingly regulated by FSH. FSH interacts with its receptors to activate the cyclic AMP (cAMP) signaling pathway, leading to the activation of protein kinase A (PKA) (11). The activation of PKA promotes the nuclear translocation of key transcription factors, including SOX9 and SF1, enhancing their binding affinity to the AMH gene promoter and further promoting AMH transcription (8). In addition, the PKA pathway activates other transcription factors, such as NF-κB and AP2, which bind to specific sites on the AMH gene promoter, enhancing its transcriptional activity. Simultaneously, FSH stimulates the proliferation of Sertoli cells to increase the number of cells capable of producing AMH and consequently raising the overall level of AMH expression, which is crucial for the normal development of the gonads and the establishment of future reproductive function (Fig. 1C) (12).

After birth, AMH expression continues to be finely regulated. During the neonatal period, AMH levels remain high due to sustained proliferation of Sertoli cells and stimulation by FSH (13). In the first few months of life, male infants undergo a phase known as ‘mini-puberty’, during which the levels of gonadotropins, such as LH and FSH, temporarily increase to further enhance Sertoli cell activity and AMH secretion (14). AMH levels peak at approximately 1 year of age and subsequently remain at a relatively high level throughout childhood. This process helps to maintain the functional maturation of the gonads (15). During this stage, AMH expression reflects the baseline functional state of Sertoli cells and prepares the HPG for reactivation at puberty (16).

During puberty, with the reactivation of the HPG, intratesticular androgens rise to primarily stimulate Sertoli cells to promote spermatogenesis (17). At the same time, the increase in testosterone levels suppresses AMH expression, marking the transition of Sertoli cells from an immature state to a mature state, resulting in the decline of AMH levels (6). In early adulthood, AMH levels tend to stabilize, indicating the maturation and maintenance of Sertoli cell function (18). However, with aging, AMH levels gradually decrease, correlating with the decline in Sertoli cell function and overall reproductive capacity. In addition, alterations in gonadotropin regulation, lifestyle factors, environmental influences and health conditions (e.g., metabolic syndrome, diabetes and obesity) may further accelerate the decline in AMH levels and impact male reproductive health. This is accompanied by a significant reduction in testicular volume and function, with decreased or even halted spermatogenesis. Although AMH is no longer a primary marker of reproductive function at this stage, its marked reduction remains an important indicator of declining testicular function. Interestingly, AMHR2 has been detected in mature sperm cells, suggesting that AMH may also play a role in sperm motility, expanding its potential functions in male reproduction (19).

Sertoli cell function in prepubertal and pubertal stages

Prepubertal stage: Sertoli cell proliferation

Sertoli cells extend from the basal membrane of the seminiferous tubules in the testes, which extend toward the lumen of the tubules and envelop germ cells and spermatozoa at various stages of development to form an important structural scaffold for growth (20). Furthermore, the total length of the seminiferous tubules is directly determined by the number of Sertoli cells. Since each Sertoli cell can only support a limited number of germ cells, a greater number of Sertoli cells allow for longer seminiferous tubule growth (21) (Fig. 2). Their proliferation drives testicular development, and their final number directly influences the size of the testes and spermatogenic capacity in adulthood (22).

Figure 2
Figure 2

The role of Sertoli cells in prepubertal and pubertal stages. Prepubertally, Sertoli cells proliferate, expanding seminiferous tubules and secreting AMH to support testicular growth. As puberty begins, Sertoli cells mature, halt proliferation and form the BTB, which isolates and protects developing germ cells, facilitating the onset of spermatogenesis within a specialized microenvironment.

Citation: Endocrine Connections 14, 3; 10.1530/EC-24-0630

While traditional views often consider the prepubertal testes to be ‘quiescent’, with a volume of only 1–2 mL, Sertoli cells are the most abundant and metabolically active cell types in the prepubertal testes and play a critical role in their developmental process (23). Despite low levels of LH and FSH during prepuberty, FSH still promotes Sertoli cell proliferation and early function by binding to FSH receptors on these cells (24). This proliferative activity of Sertoli cells contributes to the expansion of seminiferous tubules and the increase in testicular volume. More precise assessments indicate that testicular volume increases from approximately 0.5 mL at birth to around 1 mL by the Tanner 1 stage. By the Tanner 5 stage, testicular volume reaches 15 mL, marking the clinical onset of puberty (25).

During the prepubertal phase, Sertoli cells remain functionally immature, with incomplete spermatogenic capacity and an underdeveloped blood–testis barrier (BTB). Despite this, these immature Sertoli cells secrete AMH. It is precisely due to their rapid proliferation at this stage that AMH levels peak at the highest point in life. Consequently, AMH can serve as a valuable biomarker in clinical testing, reflecting Sertoli cell activity and testicular development.

Late pubertal stage: maturation of Sertoli cells and the onset of spermatogenesis

Puberty represents a crucial period in male reproductive development, during which Sertoli cells undergo maturation and spermatogenesis begins. This stage is characterized by a shift in Sertoli cell activity from proliferation to a functional role that supports the development of germ cells – a process referred to as maturation (26). As this transition occurs, Sertoli cells cease to proliferate and take on critical functions such as providing structural support, regulating the seminiferous epithelium and supplying nutrients necessary for spermatogenesis (27). The maturation of Sertoli cells is signified by a gradual decline in AMH secretion, a hallmark of their functional transition. This decline in AMH not only reflects the progression of Sertoli cell maturation but also signals the readiness of these cells to support full-scale germ cell development. As Sertoli cells mature, germ cells proceed into advanced stages of development and enable the successful initiation of spermatogenesis (28). One of the central roles of Sertoli cells during this period is the formation and maintenance of the BTB, a key structural feature essential for the initiation and progression of spermatogenesis (29). The BTB is formed by gap junctions, ectoplasmic specializations, tight junctions and desmosomes between Sertoli cells, creating two distinct compartments within the seminiferous tubules: the basal and adluminal compartments (30). The basal compartment contains undifferentiated spermatogonia and early-stage germ cells, while the adluminal compartment houses meiotic and post-meiotic germ cells (31, 32). The BTB plays a crucial role in protecting developing germ cells from the body’s immune system and in maintaining the specialized microenvironment needed for spermatogenesis. The selective permeability of the BTB allows small molecules such as glucose, lactate and testosterone to pass through while restricting the entry of larger molecules and immune components. This selective barrier ensures the stability of the seminiferous tubule environment, which is vital for the development of post-meiotic germ cells that are particularly susceptible to immune attack (33). As puberty progresses, Sertoli cells not only sustain the structural integrity of the BTB but also dynamically regulate the BTB to allow the movement of germ cells from the basal compartment to the adluminal compartment, a process critical for spermatogenesis (34, 35). This dynamic regulation involves the temporary disassembly and reassembly of tight junctions, ensuring that the migration of spermatogonia and spermatocytes occurs without compromising the BTB’s protective function (36). Such regulation is essential for maintaining the delicate balance required for successful germ cell development.

AMH as a biomarker for the diagnosis of delayed puberty

Definition and clinical relevance of delayed puberty

Delayed puberty in males is commonly defined by the absence of testicular enlargement (testicular volume <4 mL) by the age of 14, signaling delayed sexual maturation (37, 38). CDGP is the most prevalent cause, accounting for 60–80% of cases, and is considered a benign developmental variation where spontaneous pubertal progression eventually occurs. In contrast, approximately 10% of cases are due to CHH, a condition characterized by insufficient hypothalamic or pituitary secretion of gonadotropins, leading to persistently low testosterone levels and impaired sexual development (39). Given the long-term reproductive implications of untreated CHH, early differentiation between CDGP and CHH is essential for appropriate management.

The primary diagnostic challenge in delayed puberty lies in distinguishing CDGP from CHH as the early clinical manifestations often overlap (3). Both CDGP and CHH patients may have delayed secondary sexual characteristics, including inadequate testicular enlargement, sparse body hair and lack of voice deepening – symptoms directly attributable to low testosterone levels (40). Although gonadotropin testing is typically employed in diagnostic workups, early hormone levels alone may be insufficient to definitively differentiate between these conditions due to their similar initial profiles. In addition, the chronic testosterone deficiency in CHH can delay epiphyseal closure, compromising skeletal development and potentially affecting adult height.

A critical developmental process affected by CHH is the proliferation of Sertoli cells during puberty. Puberty represents a key period of Sertoli cell expansion, which is essential for future spermatogenesis. Insufficient testosterone levels during this period can impair Sertoli cell proliferation and reduce the potential for spermatogenesis in adulthood. Thus, early diagnosis and intervention are vital to mitigate the physiological and psychological consequences of hypogonadotropic hypogonadism during adolescence, ensuring timely sexual maturation and safeguarding long-term reproductive health.

AMH as a diagnostic biomarker for delayed puberty

Recent studies have underscored the diagnostic value of AMH, a marker of Sertoli cell function, in evaluating delayed puberty. AMH levels offer critical insights into distinguishing constitutional delay of CDGP from CHH as these conditions have distinct pathophysiological profiles (Fig. 3).

Figure 3
Figure 3

The role of AMH in distinguishing causes of delayed puberty. (A) In normal development, FSH stimulates Sertoli cells to produce AMH, supporting puberty. (B) In CDGP, AMH levels are normal or slightly elevated due to intact Sertoli cell function despite delayed puberty. (C) In CHH, reduced FSH stimulation leads to significantly lower AMH, indicating impaired Sertoli cell activity and testicular development.

Citation: Endocrine Connections 14, 3; 10.1530/EC-24-0630

In CHH, impaired HPG axis function results in diminished or absent gonadotropin secretion, leading to compromised testicular function that particularly affects Sertoli cell activity. AMH secretion is significantly reduced in CHH due to the lack of adequate stimulation from FSH, which plays a crucial regulatory role in Sertoli cell function. Under normal physiological conditions, FSH stimulates Sertoli cells to thereby promote AMH production (41). However, in patients with CHH, insufficient FSH secretion results in reduced AMH levels, reflecting the deficient gonadotropic stimulation. Conversely, in patients with CDGP, Sertoli cell function typically remains intact despite the delay in pubertal onset. This preservation of Sertoli cell function implies that FSH activity is largely unaffected in CDGP. This enables CDGP patients to maintain normal or only slightly reduced AMH levels, which are significantly higher than those observed in CHH patients (42). For instance, in a study of prepubertal boys, CDGP patients demonstrated mean AMH levels of 44.9 ± 27.1 ng/mL, which were markedly higher than the 15.4 ± 8.3 ng/mL observed in CHH patients. Moreover, AMH levels above 20 ng/mL, combined with inhibin B levels exceeding 28.5 pg/mL, achieved a diagnostic specificity of 83% for distinguishing CDGP from CHH (43).

During the prepubertal stage, AMH testing is essential for differentiating between CDGP and CHH. Although these conditions share similar clinical manifestations, such as delayed pubertal development, their underlying pathophysiological mechanisms are distinct, making AMH a valuable diagnostic marker. In CHH patients, the deficiency of gonadotropins, particularly FSH, disrupts Sertoli cell function and downregulates AMH expression, which results in significantly lower AMH levels compared to CDGP patients. By contrast, CDGP patients exhibit relatively normal Sertoli cell function and their AMH levels typically remain within the normal range. Beyond distinguishing CDGP from CHH, AMH also holds potential for use in the individualized treatment of CHH. Monitoring changes in AMH levels, in conjunction with FSH levels, can provide valuable insights into Sertoli cell activity and the patient’s response to therapy as FSH plays a key role in regulating AMH expression, especially during the early stages of hormone replacement therapy. Preliminary data suggest that a significant decline in AMH levels following treatment initiation reflects effective activation of Sertoli cells, whereas persistently elevated levels may indicate a poor therapeutic response that necessitates adjustments to the treatment regimen (44, 45). This AMH-based individualized therapeutic approach has the potential to optimize treatment outcomes, improve fertility recovery rates and increase overall reproductive health. However, AMH alone is insufficient for a definitive diagnosis. A comprehensive evaluation of CHH should incorporate additional markers, including precise testicular volume assessment using ultrasonography, inhibin B levels, T/E2 ratio and detailed patient history. Genetic testing may be warranted to exclude underlying hereditary causes when clinically indicated. This integrative approach enhances diagnostic accuracy and aids in the differentiation between CDGP and CHH to reduce the risk of misdiagnosis.

Predictor of SSR in iNOA patients by AMH

The role of AMH in hypergonadotropic hypogonadism and iNOA

Hypogonadism can affect males across various age groups, ranging from delayed puberty to reproductive dysfunction in adulthood. In reproductive-aged males, iNOA is one of the most common manifestations of hypergonadotropic hypogonadism (46). iNOA patients are unable to naturally produce sperm due to intrinsic spermatogenic failure, making it a significant cause of male infertility. Histologically, the testes of iNOA patients typically exhibit widespread arrest in spermatocyte development or severely impaired spermatogenesis, which is closely tied to the underlying pathophysiology of hypogonadism (47).

In a mouse model, studies have demonstrated a close relationship between AMH expression in Sertoli cells and their maturation status. As shown in Fig. 4A, high AMH expression indicates immature Sertoli cells, while moderate AMH expression in Fig. 4B suggests a transitional phase toward maturation. Furthermore, it was observed that as Sertoli cells mature, AMH expression decreases, while the expression levels of key BTB proteins, such as Connexin 43 and Claudin 11, increase significantly. This finding indicates that Sertoli cell maturation is not only reflected by changes in AMH expression but also associated with enhanced BTB protein expression. These observations underscore the critical roles of AMH and BTB proteins in Sertoli cell maturation (48). The findings from this mouse model provide a valuable framework for investigating the underlying mechanisms of Sertoli cell dysfunction in iNOA patients. In preliminary findings from human samples, abnormally high AMH expression may be associated with structural abnormalities of the BTB and impaired Sertoli cell function. In iNOA patients, a substantial number of immature Sertoli cells are present, with compromised Sertoli cell function. Histologically, seminiferous tubules in iNOA patients with significantly elevated serum AMH exhibit abnormally high AMH expression, accompanied by marked thickening of the basement membrane (Fig. 4C). In this context, testicular endocrine function, including testosterone production and the activity of Sertoli cells, is often compromised (49). Dysfunction in these cells contributes to the impairment of spermatogenesis and sperm production. Clinically, SSR in iNOA patients, particularly via micro-TESE, shows considerable variability in success rates across individuals (Fig. 4D) (50, 51). Currently, micro-TESE is one of the most widely used therapeutic options for iNOA patients (52). However, predicting sperm retrieval success remains a significant challenge due to the limitations of traditional hormonal markers, such as FSH, LH and testosterone, in assessing testicular function and spermatogenic potential.

Figure 4
Figure 4

AMH as a predictor of sperm retrieval success in iNOA patients. AMH immunohistochemical staining in a mouse model shows high expression in immature Sertoli cells (A) and moderate expression in maturing Sertoli cells (B) (48). (C) AMH staining in an iNOA patient sample shows high expression and thickened basement membrane, indicating structural abnormalities and impaired Sertoli cell function. (D) Schematic of micro-TESE steps. Patients with lower AMH levels are more likely to have higher SSR. (E) Predictive model: AMH levels below 2.6 ng/mL correspond to an 85.42% sperm retrieval rate in iNOA, highlighting AMH’s value as a predictive biomarker.

Citation: Endocrine Connections 14, 3; 10.1530/EC-24-0630

In this regard, AMH has emerged as a promising biomarker. AMH not only reflects Sertoli cell quantity and functionality but also has the potential to serve as a valuable indicator of spermatogenic capacity in hypogonadal men. A previous study has established reference ranges for serum AMH and the AMH/tT ratio, further supporting its clinical utility (19). As a result, AMH is increasingly being recognized as a more reliable predictor of sperm retrieval outcomes in iNOA patients compared to traditional hormonal markers.

AMH as an independent predictor of sperm retrieval in iNOA patients

In iNOA patients, SSR remains a significant clinical challenge. Despite the use of various biomarkers to assess testicular sperm production capacity, identifying a reliable independent predictor continues to be critically important. In recent years, AMH has gained increasing attention as a promising biomarker for predicting SSR in iNOA patients. Research has demonstrated that AMH, as a reflection of Sertoli cell function, can effectively predict the success rate of micro-TESE. In a study of 261 iNOA patients, AMH levels above 2.60 ng/mL were significantly associated with increased risk of micro-TESE failure. Validation of the prediction model showed a high area under the receiver operating characteristic curve of 0.811, indicating strong predictive accuracy. In the validation cohort, the model accurately predicted outcomes in 85.42% of cases, confirming the utility of AMH as a robust independent predictor in preoperative evaluations for iNOA patients (Fig. 4E) (53). In addition, other studies support the independent predictive value of AMH. Multi-center research has established a significant positive correlation between lower AMH levels and higher SR success rates in iNOA patients. In a cohort of 117 iNOA patients, it was shown that those with AMH levels below 4 ng/mL had significantly higher SSR success rates. This finding was further validated through multivariable regression analyses adjusting for confounding factors. The threshold of AMH <4 ng/mL demonstrated high sensitivity and specificity, further solidifying AMH’s role as a predictive biomarker (54).

During reproductive age, the focus of AMH application shifts toward predicting sperm retrieval success in patients with iNOA. At this stage, fertility becomes the central concern, especially in iNOA patients where spermatogenesis is impaired. Sertoli cells play a critical role in maintaining the function of the BTB and creating an optimal environment for spermatogenesis. Impairment in BTB function can disrupt the spermatogenesis process and negatively affect sperm quality and fertility. Since AMH can indirectly reflect the functional status of the BTB, it serves as a marker for predicting sperm retrieval success in iNOA patients. By indicating the health of Sertoli cells, AMH also indirectly reflects BTB functionality, making it a valuable biomarker for assessing spermatogenic capacity. Studies have shown a significant correlation between higher AMH levels and increased success in sperm retrieval, which underscores its role as an independent predictor of spermatogenic potential in iNOA patients (Table 1). However, some studies have failed to establish a significant link between AMH levels and sperm retrieval success, likely due to differences in study design, sample size limitations and other confounding factors (55, 56).

Table 1

Predictive value of AMH for SSR in iNOA patients undergoing micro-TEST.

Study design Sample size (n) AMH threshold SSR Combined biomarkers Predictive accuracy Reference
Retrospective 261 2.60 ng/mL 85.42% N/A AUC = 0.81, sensitivity = 87.0%, specificity = 70.5% (53)
Prospective 48
Retrospective 47 4.62 ng/mL 49% AMH/total testosterone ratio <1.02 AUC = 0.95, sensitivity = 93.0%, specificity = 93.0% (57)
Retrospective 365 N/A 24.1% N/A AUC = 0.63 (58)
Prospective 117 4 ng/mL 48.7% N/A AUC = 0.70 (54)
Prospective 168 N/A 30.4% INHB/AMH ratio>3.19 AUC = 0.86, sensitivity = 86.3%, specificity = 53.8% (59)

Conclusion

AMH is a key biomarker of Sertoli cell function, playing a significant role in diagnosing male gonadal disorders, such as distinguishing between CDGP and CHH in the prepubertal phase and predicting sperm retrieval success in iNOA during reproductive years. However, the current body of research is limited by small sample sizes and a lack of multi-center validation, resulting in variability in findings. Future studies should focus on large-scale, multi-center trials and explore combining AMH with other biomarkers such as inhibin B and FSH to improve diagnostic accuracy. Standardizing AMH measurement methods across diverse populations is also crucial. Overall, while AMH shows great promise, further research is needed to refine its clinical utility in male reproductive health.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this work.

Funding

This work was supported by the Tianfu Jincheng Laboratory, City of Future Medicine (TFJC-2024-JB002).

References

  • 1

    Raivio T & Miettinen PJ . Constitutional delay of puberty versus congenital hypogonadotropic hypogonadism: genetics, management and updates. Best Pract Res Clin Endocrinol Metabol 2019 33 101316. (https://doi.org/10.1016/j.beem.2019.101316)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Pozo J & Argente J . Ascertainment and treatment of delayed puberty. Horm Res 2003 60 3548. (https://doi.org/10.1159/000074498)

  • 3

    Bollino A , Cangiano B , Goggi G , et al. Pubertal delay: the challenge of a timely differential diagnosis between congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty. Minerva Pediatr 2020 72 278287. (https://doi.org/10.23736/S0026-4946.20.05860-0)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Mosbah H , Bouvattier C , Maione L , et al. GnRH stimulation testing and serum inhibin B in males: insufficient specificity for discriminating between congenital hypogonadotropic hypogonadism from constitutional delay of growth and puberty. Hum Reprod 2020 35 23122322. (https://doi.org/10.1093/humrep/deaa185)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Tang D , Li K , He X , et al. Non-invasive molecular biomarkers for predicting outcomes of micro-TESE in patients with idiopathic non-obstructive azoospermia. Expert Rev Mol Med 2022 24 e22. (https://doi.org/10.1017/erm.2022.17)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Edelsztein NY , Valeri C , Lovaisa MM , et al. AMH regulation by steroids in the mammalian testis: underlying mechanisms and clinical implications. Front Endocrinol 2022 13 906381. (https://doi.org/10.3389/fendo.2022.906381)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Josso N , Lamarre I , Picard JY , et al. Anti-Müllerian hormone in early human development. Early Hum Dev 1993 33 9199. (https://doi.org/10.1016/0378-3782(93)90204-8)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Lasala C , Carré-Eusèbe D , Picard JY , et al. Subcellular and molecular mechanisms regulating anti-Müllerian hormone gene expression in mammalian and nonmammalian species. DNA Cell Biol 2004 23 572585. (https://doi.org/10.1089/dna.2004.23.572)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Arango NA , Lovell-Badge R & Behringer RR . Targeted mutagenesis of the endogenous mouse Mis gene promoter: in vivo definition of genetic pathways of vertebrate sexual development. Cell 1999 99 409419. (https://doi.org/10.1016/s0092-8674(00)81527-5)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Schteingart HF , Picard JY , Valeri C , et al. A mutation inactivating the distal SF1 binding site on the human anti-Müllerian hormone promoter causes persistent Müllerian duct syndrome. Hum Mol Genet 2019 28 32113218. (https://doi.org/10.1093/hmg/ddz147)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Lukas-Croisier C , Lasala C , Nicaud J , et al. Follicle-stimulating hormone increases testicular anti-Müllerian hormone (AMH) production through Sertoli cell proliferation and a nonclassical cyclic adenosine 5′-monophosphate-mediated activation of the AMH gene. Mol Endocrinol 2003 17 550561. (https://doi.org/10.1210/me.2002-0186)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Al-Attar L , Noël K , Dutertre M , et al. Hormonal and cellular regulation of Sertoli cell anti-Müllerian hormone production in the postnatal mouse. J Clin Invest 1997 100 13351343. (https://doi.org/10.1172/JCI119653)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Kuijper EAM , Ket JCF , Caanen MR , et al. Reproductive hormone concentrations in pregnancy and neonates: a systematic review. Reprod Biomed Online 2013 27 3363. (https://doi.org/10.1016/j.rbmo.2013.03.009)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Busch AS , Ljubicic ML , Upners EN , et al. Dynamic changes of reproductive hormones in male minipuberty: temporal dissociation of Leydig and Sertoli cell activity. J Clin Endocrinol Metab 2022 107 15601568. (https://doi.org/10.1210/clinem/dgac115)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Becker M & Hesse V . Minipuberty: why does it happen? Horm Res Paediatr 2020 93 7684. (https://doi.org/10.1159/000508329)

  • 16

    Bizzarri C & Cappa M . Ontogeny of hypothalamus-pituitary gonadal Axis and minipuberty: an ongoing debate? Front Endocrinol 2020 11 187. (https://doi.org/10.3389/fendo.2020.00187)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Rey RA . The role of androgen signaling in male sexual development at puberty. Endocrinology 2021 162 bqaa215. (https://doi.org/10.1210/endocr/bqaa215)

  • 18

    McLennan IS & Pankhurst MW . Anti-Müllerian hormone is a gonadal cytokine with two circulating forms and cryptic actions. J Endocrinol 2015 226 R45R57. (https://doi.org/10.1530/JOE-15-0206)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Benderradji H , Barbotin AL , Leroy-Billiard M , et al. Defining reference ranges for serum anti-Müllerian hormone on a large cohort of normozoospermic adult men highlights new potential physiological functions of AMH on FSH secretion and sperm motility. J Clin Endocrinol Metab 2022 107 18781887. (https://doi.org/10.1210/clinem/dgac218)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Iliadou PK , Tsametis C , Kaprara A , et al. The Sertoli cell: novel clinical potentiality. Hormones 2015 14 504514. (https://doi.org/10.14310/horm.2002.1648)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Meachem SJ , Mclachlan RI , de Kretser DM , et al. Neonatal exposure of rats to recombinant follicle stimulating hormone increases adult Sertoli and spermatogenic cell numbers. Biol Reprod 1996 54 3644. (https://doi.org/10.1095/biolreprod54.1.36)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    O’Donnell L , Smith LB & Rebourcet D . Sertoli cells as key drivers of testis function. Semin Cell Dev Biol 2022 121 29. (https://doi.org/10.1016/j.semcdb.2021.06.016)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Rey RA , Campo SM , Bedecarras P , et al. Is infancy a quiescent period of testicular development? Histological, morphometric, and functional study of the seminiferous tubules of the Cebus monkey from birth to the end of puberty. J Clin Endocrinol Metab 1993 76 13251331. (https://doi.org/10.1210/jcem.76.5.8496325)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Griswold MD . The central role of Sertoli cells in spermatogenesis. Semin Cell Dev Biol 1998 9 411416. (https://doi.org/10.1006/scdb.1998.0203)

  • 25

    Goede J , Hack WWM , Sijstermans K , et al. Normative values for testicular volume measured by ultrasonography in a normal population from infancy to adolescence. Horm Res Paediatr 2011 76 5664. (https://doi.org/10.1159/000326057)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Simorangkir DR , Ramaswamy S , Marshall GR , et al. Sertoli cell differentiation in rhesus monkey (Macaca mulatta) is an early event in puberty and precedes attainment of the adult complement of undifferentiated spermatogonia. Reproduction 2012 143 513522. (https://doi.org/10.1530/REP-11-0411)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Hai Y , Hou J , Liu Y , et al. The roles and regulation of Sertoli cells in fate determinations of spermatogonial stem cells and spermatogenesis. Semin Cell Dev Biol 2014 29 6675. (https://doi.org/10.1016/j.semcdb.2014.04.007)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Hero M , Tommiska J , Vaaralahti K , et al. Circulating anti-Müllerian hormone levels in boys decline during early puberty and correlate with inhibin B. Fertil Steril 2012 97 12421247. (https://doi.org/10.1016/j.fertnstert.2012.02.020)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Shi QH , Jiang XH , Bukhari I , et al. Blood-testis barrier and spermatogenesis: lessons from genetically-modified mice. Asian J Androl 2014 16 572580. (https://doi.org/10.4103/1008-682X.125401)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Mruk DD & Cheng CY . The mammalian blood-testis barrier: its biology and regulation. Endocr Rev 2015 36 564591. (https://doi.org/10.1210/er.2014-1101)

  • 31

    Cheng CY , Wong EW , Lie PP , et al. Regulation of blood-testis barrier dynamics by desmosome, gap junction, hemidesmosome and polarity proteins. Spermatogenesis 2011 1 105115. (https://doi.org/10.4161/spmg.1.2.15745)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Gao Y , Xiao X , yee LW , et al. Cell polarity proteins and spermatogenesis. Semin Cell Dev Biol 2016 59 6270. (https://doi.org/10.1016/j.semcdb.2016.06.008)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Kaur G , Thompson LA & Dufour JM . Sertoli cells - immunological sentinels of spermatogenesis. Semin Cell Dev Biol 2014 30 3644. (https://doi.org/10.1016/j.semcdb.2014.02.011)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Luaces JP , Toro-Urrego N , Otero-Losada M , et al. What do we know about blood-testis barrier? Current understanding of its structure and physiology. Front Cell Dev Biol 2023 11 1114769. (https://doi.org/10.3389/fcell.2023.1114769)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Siu MKY , Lee WM & Cheng CY . The interplay of collagen IV, tumor necrosis factor-α, gelatinase B (matrix metalloprotease-9), and tissue inhibitor of metalloproteases-1 in the basal lamina regulates Sertoli cell-tight junction dynamics in the rat testis. Endocrinology 2003 144 371387. (https://doi.org/10.1210/en.2002-220786)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Mruk DD & Cheng CY . Sertoli–Sertoli and Sertoli–germ cell interactions and their significance in germ cell movement in the seminiferous epithelium during spermatogenesis. Endocr Rev 2004 25 747806. (https://doi.org/10.1210/er.2003-0022)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Mohanraj S & Prasad HK . Delayed puberty. Indian J Pediatr 2023 90 590597. (https://doi.org/10.1007/s12098-023-04577-x)

  • 38

    Bozzola M , Bozzola E , Montalbano C , et al. Delayed puberty versus hypogonadism: a challenge for the pediatrician. Ann Pediatr Endocrinol Metab 2018 23 5761. (https://doi.org/10.6065/apem.2018.23.2.57)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Harrington J & Palmert MR . An approach to the patient with delayed puberty. J Clin Endocrinol Metab 2022 107 17391750. (https://doi.org/10.1210/clinem/dgac054)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40

    Bangalore Krishna K , Fuqua JS & Witchel SF . Hypogonadotropic hypogonadism. Endocrinol Metab Clin North Am 2024 53 279292. (https://doi.org/10.1016/j.ecl.2024.01.008)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    Young J , Chanson P , Salenave S , et al. Testicular anti-Müllerian hormone secretion is stimulated by recombinant human FSH in patients with congenital hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2005 90 724728. (https://doi.org/10.1210/jc.2004-0542)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Coutant R , Biette-Demeneix E , Bouvattier C , et al. Baseline inhibin B and anti-Mullerian hormone measurements for diagnosis of hypogonadotropic hypogonadism (HH) in boys with delayed puberty. J Clin Endocrinol Metab 2010 95 52255232. (https://doi.org/10.1210/jc.2010-1535)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Rohayem J , Nieschlag E , Kliesch S , et al. Inhibin B, AMH, but not INSL3, IGF1 or DHEAS support differentiation between constitutional delay of growth and puberty and hypogonadotropic hypogonadism. Andrology 2015 3 882887. (https://doi.org/10.1111/andr.12088)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    Sinisi AA , Esposito D , Maione L , et al. Seminal anti-Müllerian hormone level is a marker of spermatogenic response during long-term gonadotropin therapy in male hypogonadotropic hypogonadism. Hum Reprod 2008 23 10291034. (https://doi.org/10.1093/humrep/den046)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45

    Rohayem J , Hauffa BP , Zacharin M , et al. Testicular growth and spermatogenesis: new goals for pubertal hormone replacement in boys with hypogonadotropic hypogonadism? -a multicentre prospective study of hCG/rFSH treatment outcomes during adolescence. Clin Endocrinol 2017 86 7587. (https://doi.org/10.1111/cen.13164)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46

    Kumar R . Medical management of non-obstructive azoospermia. Clinics 2013 68 7579. (https://doi.org/10.6061/clinics/2013(Sup01)08)

  • 47

    Zhao L , Yao C , Xing X , et al. Single-cell analysis of developing and azoospermia human testicles reveals central role of Sertoli cells. Nat Commun 2020 11 5683. (https://doi.org/10.1038/s41467-020-19414-4)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48

    Michele FD , Poels J , Giudice MG , et al. In vitro formation of the blood-testis barrier during long-term organotypic culture of human prepubertal tissue: comparison with a large cohort of pre/peripubertal boys. Mol Hum Reprod 2018 24 271282. (https://doi.org/10.1093/molehr/gay012)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49

    Tao Y . Endocrine aberrations of human nonobstructive azoospermia. Asian J Androl 2022 24 274286. (https://doi.org/10.4103/aja202181)

  • 50

    Minhas S , Bettocchi C , Boeri L , et al. European association of urology guidelines on male sexual and reproductive health: 2021 update on male infertility. Eur Urol 2021 80 603620. (https://doi.org/10.1016/j.eururo.2021.08.014)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51

    Achermann APP & Esteves SC . Prevalence and clinical implications of biochemical hypogonadism in patients with nonobstructive azoospermia undergoing infertility evaluation. F S Rep 2024 5 1422. (https://doi.org/10.1016/j.xfre.2023.11.007)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52

    Achermann APP , Pereira TA & Esteves SC . Microdissection testicular sperm extraction (micro-TESE) in men with infertility due to nonobstructive azoospermia: summary of current literature. Int Urol Nephrol 2021 53 21932210. (https://doi.org/10.1007/s11255-021-02979-4)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53

    Zheng Y , Li DM , Jiang XH , et al. A prediction model of sperm retrieval in males with idiopathic non-obstructive azoospermia for microdissection testicular sperm extraction. Reprod Sci 2024 31 366374. (https://doi.org/10.1007/s43032-023-01362-1)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 54

    Pozzi E , Raffo M , Negri F , et al. Anti-Müllerian hormone predicts positive sperm retrieval in men with idiopathic non-obstructive azoospermia - findings from a multi-centric cross-sectional study. Hum Reprod 2023 38 14641472. (https://doi.org/10.1093/humrep/dead125)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 55

    Mostafa T , Amer MK , Abdel-Malak G , et al. Seminal plasma anti-Müllerian hormone level correlates with semen parameters but does not predict success of testicular sperm extraction (TESE). Asian J Androl 2007 9 265270. (https://doi.org/10.1111/j.1745-7262.2007.00252.xx)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 56

    Tsametis C , Mintziori G , Iliadou PK , et al. Dynamic endocrine test of inhibin B and anti-Müllerian hormone in men with non-obstructive azoospermia. Gynecol Endocrinol 2011 27 661665. (https://doi.org/10.3109/09513590.2010.521267)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 57

    Alfano M , Ventimiglia E , Locatelli I , et al. Anti-Mullerian hormone-to-testosterone ratio is predictive of positive sperm retrieval in men with idiopathic non-obstructive azoospermia. Sci Rep 2017 7 17638. (https://doi.org/10.1038/s41598-017-17420-z)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 58

    Zhang YX , Yao CC , Huang YH , et al. Efficacy of stepwise mini-incision microdissection testicular sperm extraction for nonobstructive azoospermia with varied etiologies. Asian J Androl 2023 25 621626. (https://doi.org/10.4103/aja2022125)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 59

    Deng C , Liu D , Zhao L , et al. Inhibin B-to-anti-Mullerian hormone ratio as noninvasive predictors of positive sperm retrieval in idiopathic non-obstructive azoospermia. J Clin Med 2023 12 500. (https://doi.org/10.3390/jcm12020500)

    • PubMed
    • Search Google Scholar
    • Export Citation

 

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  • Figure 1

    Regulation of AMH during male development. (A) Changes in serum levels of LH, FSH, T and AMH throughout life, highlighting peaks in fetal development, mini-puberty and puberty. (B) In early fetal development, AMH expression is primarily regulated by transcription factors such as SOX9, SF1 and GATA4, which promote AMH expression, while DAX1 acts as a repressor. (C) In later fetal stages and postnatally, AMH regulation shifts under the influence of FSH. FSH activates the cAMP-PKA pathway in Sertoli cells, enhancing the activity of transcription factors (e.g., SOX9, SF1 and NF-κB) and promoting Sertoli cell proliferation, which collectively increase AMH production.

  • Figure 2

    The role of Sertoli cells in prepubertal and pubertal stages. Prepubertally, Sertoli cells proliferate, expanding seminiferous tubules and secreting AMH to support testicular growth. As puberty begins, Sertoli cells mature, halt proliferation and form the BTB, which isolates and protects developing germ cells, facilitating the onset of spermatogenesis within a specialized microenvironment.

  • Figure 3

    The role of AMH in distinguishing causes of delayed puberty. (A) In normal development, FSH stimulates Sertoli cells to produce AMH, supporting puberty. (B) In CDGP, AMH levels are normal or slightly elevated due to intact Sertoli cell function despite delayed puberty. (C) In CHH, reduced FSH stimulation leads to significantly lower AMH, indicating impaired Sertoli cell activity and testicular development.

  • Figure 4

    AMH as a predictor of sperm retrieval success in iNOA patients. AMH immunohistochemical staining in a mouse model shows high expression in immature Sertoli cells (A) and moderate expression in maturing Sertoli cells (B) (48). (C) AMH staining in an iNOA patient sample shows high expression and thickened basement membrane, indicating structural abnormalities and impaired Sertoli cell function. (D) Schematic of micro-TESE steps. Patients with lower AMH levels are more likely to have higher SSR. (E) Predictive model: AMH levels below 2.6 ng/mL correspond to an 85.42% sperm retrieval rate in iNOA, highlighting AMH’s value as a predictive biomarker.

  • 1

    Raivio T & Miettinen PJ . Constitutional delay of puberty versus congenital hypogonadotropic hypogonadism: genetics, management and updates. Best Pract Res Clin Endocrinol Metabol 2019 33 101316. (https://doi.org/10.1016/j.beem.2019.101316)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Pozo J & Argente J . Ascertainment and treatment of delayed puberty. Horm Res 2003 60 3548. (https://doi.org/10.1159/000074498)

  • 3

    Bollino A , Cangiano B , Goggi G , et al. Pubertal delay: the challenge of a timely differential diagnosis between congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty. Minerva Pediatr 2020 72 278287. (https://doi.org/10.23736/S0026-4946.20.05860-0)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Mosbah H , Bouvattier C , Maione L , et al. GnRH stimulation testing and serum inhibin B in males: insufficient specificity for discriminating between congenital hypogonadotropic hypogonadism from constitutional delay of growth and puberty. Hum Reprod 2020 35 23122322. (https://doi.org/10.1093/humrep/deaa185)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Tang D , Li K , He X , et al. Non-invasive molecular biomarkers for predicting outcomes of micro-TESE in patients with idiopathic non-obstructive azoospermia. Expert Rev Mol Med 2022 24 e22. (https://doi.org/10.1017/erm.2022.17)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Edelsztein NY , Valeri C , Lovaisa MM , et al. AMH regulation by steroids in the mammalian testis: underlying mechanisms and clinical implications. Front Endocrinol 2022 13 906381. (https://doi.org/10.3389/fendo.2022.906381)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Josso N , Lamarre I , Picard JY , et al. Anti-Müllerian hormone in early human development. Early Hum Dev 1993 33 9199. (https://doi.org/10.1016/0378-3782(93)90204-8)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Lasala C , Carré-Eusèbe D , Picard JY , et al. Subcellular and molecular mechanisms regulating anti-Müllerian hormone gene expression in mammalian and nonmammalian species. DNA Cell Biol 2004 23 572585. (https://doi.org/10.1089/dna.2004.23.572)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Arango NA , Lovell-Badge R & Behringer RR . Targeted mutagenesis of the endogenous mouse Mis gene promoter: in vivo definition of genetic pathways of vertebrate sexual development. Cell 1999 99 409419. (https://doi.org/10.1016/s0092-8674(00)81527-5)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Schteingart HF , Picard JY , Valeri C , et al. A mutation inactivating the distal SF1 binding site on the human anti-Müllerian hormone promoter causes persistent Müllerian duct syndrome. Hum Mol Genet 2019 28 32113218. (https://doi.org/10.1093/hmg/ddz147)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Lukas-Croisier C , Lasala C , Nicaud J , et al. Follicle-stimulating hormone increases testicular anti-Müllerian hormone (AMH) production through Sertoli cell proliferation and a nonclassical cyclic adenosine 5′-monophosphate-mediated activation of the AMH gene. Mol Endocrinol 2003 17 550561. (https://doi.org/10.1210/me.2002-0186)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Al-Attar L , Noël K , Dutertre M , et al. Hormonal and cellular regulation of Sertoli cell anti-Müllerian hormone production in the postnatal mouse. J Clin Invest 1997 100 13351343. (https://doi.org/10.1172/JCI119653)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Kuijper EAM , Ket JCF , Caanen MR , et al. Reproductive hormone concentrations in pregnancy and neonates: a systematic review. Reprod Biomed Online 2013 27 3363. (https://doi.org/10.1016/j.rbmo.2013.03.009)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Busch AS , Ljubicic ML , Upners EN , et al. Dynamic changes of reproductive hormones in male minipuberty: temporal dissociation of Leydig and Sertoli cell activity. J Clin Endocrinol Metab 2022 107 15601568. (https://doi.org/10.1210/clinem/dgac115)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Becker M & Hesse V . Minipuberty: why does it happen? Horm Res Paediatr 2020 93 7684. (https://doi.org/10.1159/000508329)

  • 16

    Bizzarri C & Cappa M . Ontogeny of hypothalamus-pituitary gonadal Axis and minipuberty: an ongoing debate? Front Endocrinol 2020 11 187. (https://doi.org/10.3389/fendo.2020.00187)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Rey RA . The role of androgen signaling in male sexual development at puberty. Endocrinology 2021 162 bqaa215. (https://doi.org/10.1210/endocr/bqaa215)

  • 18

    McLennan IS & Pankhurst MW . Anti-Müllerian hormone is a gonadal cytokine with two circulating forms and cryptic actions. J Endocrinol 2015 226 R45R57. (https://doi.org/10.1530/JOE-15-0206)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Benderradji H , Barbotin AL , Leroy-Billiard M , et al. Defining reference ranges for serum anti-Müllerian hormone on a large cohort of normozoospermic adult men highlights new potential physiological functions of AMH on FSH secretion and sperm motility. J Clin Endocrinol Metab 2022 107 18781887. (https://doi.org/10.1210/clinem/dgac218)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Iliadou PK , Tsametis C , Kaprara A , et al. The Sertoli cell: novel clinical potentiality. Hormones 2015 14 504514. (https://doi.org/10.14310/horm.2002.1648)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Meachem SJ , Mclachlan RI , de Kretser DM , et al. Neonatal exposure of rats to recombinant follicle stimulating hormone increases adult Sertoli and spermatogenic cell numbers. Biol Reprod 1996 54 3644. (https://doi.org/10.1095/biolreprod54.1.36)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    O’Donnell L , Smith LB & Rebourcet D . Sertoli cells as key drivers of testis function. Semin Cell Dev Biol 2022 121 29. (https://doi.org/10.1016/j.semcdb.2021.06.016)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Rey RA , Campo SM , Bedecarras P , et al. Is infancy a quiescent period of testicular development? Histological, morphometric, and functional study of the seminiferous tubules of the Cebus monkey from birth to the end of puberty. J Clin Endocrinol Metab 1993 76 13251331. (https://doi.org/10.1210/jcem.76.5.8496325)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Griswold MD . The central role of Sertoli cells in spermatogenesis. Semin Cell Dev Biol 1998 9 411416. (https://doi.org/10.1006/scdb.1998.0203)

  • 25

    Goede J , Hack WWM , Sijstermans K , et al. Normative values for testicular volume measured by ultrasonography in a normal population from infancy to adolescence. Horm Res Paediatr 2011 76 5664. (https://doi.org/10.1159/000326057)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Simorangkir DR , Ramaswamy S , Marshall GR , et al. Sertoli cell differentiation in rhesus monkey (Macaca mulatta) is an early event in puberty and precedes attainment of the adult complement of undifferentiated spermatogonia. Reproduction 2012 143 513522. (https://doi.org/10.1530/REP-11-0411)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Hai Y , Hou J , Liu Y , et al. The roles and regulation of Sertoli cells in fate determinations of spermatogonial stem cells and spermatogenesis. Semin Cell Dev Biol 2014 29 6675. (https://doi.org/10.1016/j.semcdb.2014.04.007)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Hero M , Tommiska J , Vaaralahti K , et al. Circulating anti-Müllerian hormone levels in boys decline during early puberty and correlate with inhibin B. Fertil Steril 2012 97 12421247. (https://doi.org/10.1016/j.fertnstert.2012.02.020)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Shi QH , Jiang XH , Bukhari I , et al. Blood-testis barrier and spermatogenesis: lessons from genetically-modified mice. Asian J Androl 2014 16 572580. (https://doi.org/10.4103/1008-682X.125401)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Mruk DD & Cheng CY . The mammalian blood-testis barrier: its biology and regulation. Endocr Rev 2015 36 564591. (https://doi.org/10.1210/er.2014-1101)

  • 31

    Cheng CY , Wong EW , Lie PP , et al. Regulation of blood-testis barrier dynamics by desmosome, gap junction, hemidesmosome and polarity proteins. Spermatogenesis 2011 1 105115. (https://doi.org/10.4161/spmg.1.2.15745)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Gao Y , Xiao X , yee LW , et al. Cell polarity proteins and spermatogenesis. Semin Cell Dev Biol 2016 59 6270. (https://doi.org/10.1016/j.semcdb.2016.06.008)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Kaur G , Thompson LA & Dufour JM . Sertoli cells - immunological sentinels of spermatogenesis. Semin Cell Dev Biol 2014 30 3644. (https://doi.org/10.1016/j.semcdb.2014.02.011)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Luaces JP , Toro-Urrego N , Otero-Losada M , et al. What do we know about blood-testis barrier? Current understanding of its structure and physiology. Front Cell Dev Biol 2023 11 1114769. (https://doi.org/10.3389/fcell.2023.1114769)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Siu MKY , Lee WM & Cheng CY . The interplay of collagen IV, tumor necrosis factor-α, gelatinase B (matrix metalloprotease-9), and tissue inhibitor of metalloproteases-1 in the basal lamina regulates Sertoli cell-tight junction dynamics in the rat testis. Endocrinology 2003 144 371387. (https://doi.org/10.1210/en.2002-220786)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Mruk DD & Cheng CY . Sertoli–Sertoli and Sertoli–germ cell interactions and their significance in germ cell movement in the seminiferous epithelium during spermatogenesis. Endocr Rev 2004 25 747806. (https://doi.org/10.1210/er.2003-0022)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Mohanraj S & Prasad HK . Delayed puberty. Indian J Pediatr 2023 90 590597. (https://doi.org/10.1007/s12098-023-04577-x)

  • 38

    Bozzola M , Bozzola E , Montalbano C , et al. Delayed puberty versus hypogonadism: a challenge for the pediatrician. Ann Pediatr Endocrinol Metab 2018 23 5761. (https://doi.org/10.6065/apem.2018.23.2.57)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Harrington J & Palmert MR . An approach to the patient with delayed puberty. J Clin Endocrinol Metab 2022 107 17391750. (https://doi.org/10.1210/clinem/dgac054)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40

    Bangalore Krishna K , Fuqua JS & Witchel SF . Hypogonadotropic hypogonadism. Endocrinol Metab Clin North Am 2024 53 279292. (https://doi.org/10.1016/j.ecl.2024.01.008)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    Young J , Chanson P , Salenave S , et al. Testicular anti-Müllerian hormone secretion is stimulated by recombinant human FSH in patients with congenital hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2005 90 724728. (https://doi.org/10.1210/jc.2004-0542)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Coutant R , Biette-Demeneix E , Bouvattier C , et al. Baseline inhibin B and anti-Mullerian hormone measurements for diagnosis of hypogonadotropic hypogonadism (HH) in boys with delayed puberty. J Clin Endocrinol Metab 2010 95 52255232. (https://doi.org/10.1210/jc.2010-1535)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Rohayem J , Nieschlag E , Kliesch S , et al. Inhibin B, AMH, but not INSL3, IGF1 or DHEAS support differentiation between constitutional delay of growth and puberty and hypogonadotropic hypogonadism. Andrology 2015 3 882887. (https://doi.org/10.1111/andr.12088)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    Sinisi AA , Esposito D , Maione L , et al. Seminal anti-Müllerian hormone level is a marker of spermatogenic response during long-term gonadotropin therapy in male hypogonadotropic hypogonadism. Hum Reprod 2008 23 10291034. (https://doi.org/10.1093/humrep/den046)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45

    Rohayem J , Hauffa BP , Zacharin M , et al. Testicular growth and spermatogenesis: new goals for pubertal hormone replacement in boys with hypogonadotropic hypogonadism? -a multicentre prospective study of hCG/rFSH treatment outcomes during adolescence. Clin Endocrinol 2017 86 7587. (https://doi.org/10.1111/cen.13164)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46

    Kumar R . Medical management of non-obstructive azoospermia. Clinics 2013 68 7579. (https://doi.org/10.6061/clinics/2013(Sup01)08)

  • 47

    Zhao L , Yao C , Xing X , et al. Single-cell analysis of developing and azoospermia human testicles reveals central role of Sertoli cells. Nat Commun 2020 11 5683. (https://doi.org/10.1038/s41467-020-19414-4)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48

    Michele FD , Poels J , Giudice MG , et al. In vitro formation of the blood-testis barrier during long-term organotypic culture of human prepubertal tissue: comparison with a large cohort of pre/peripubertal boys. Mol Hum Reprod 2018 24 271282. (https://doi.org/10.1093/molehr/gay012)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49

    Tao Y . Endocrine aberrations of human nonobstructive azoospermia. Asian J Androl 2022 24 274286. (https://doi.org/10.4103/aja202181)

  • 50

    Minhas S , Bettocchi C , Boeri L , et al. European association of urology guidelines on male sexual and reproductive health: 2021 update on male infertility. Eur Urol 2021 80 603620. (https://doi.org/10.1016/j.eururo.2021.08.014)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51

    Achermann APP & Esteves SC . Prevalence and clinical implications of biochemical hypogonadism in patients with nonobstructive azoospermia undergoing infertility evaluation. F S Rep 2024 5 1422. (https://doi.org/10.1016/j.xfre.2023.11.007)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52

    Achermann APP , Pereira TA & Esteves SC . Microdissection testicular sperm extraction (micro-TESE) in men with infertility due to nonobstructive azoospermia: summary of current literature. Int Urol Nephrol 2021 53 21932210. (https://doi.org/10.1007/s11255-021-02979-4)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53

    Zheng Y , Li DM , Jiang XH , et al. A prediction model of sperm retrieval in males with idiopathic non-obstructive azoospermia for microdissection testicular sperm extraction. Reprod Sci 2024 31 366374. (https://doi.org/10.1007/s43032-023-01362-1)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 54

    Pozzi E , Raffo M , Negri F , et al. Anti-Müllerian hormone predicts positive sperm retrieval in men with idiopathic non-obstructive azoospermia - findings from a multi-centric cross-sectional study. Hum Reprod 2023 38 14641472. (https://doi.org/10.1093/humrep/dead125)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 55

    Mostafa T , Amer MK , Abdel-Malak G , et al. Seminal plasma anti-Müllerian hormone level correlates with semen parameters but does not predict success of testicular sperm extraction (TESE). Asian J Androl 2007 9 265270. (https://doi.org/10.1111/j.1745-7262.2007.00252.xx)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 56

    Tsametis C , Mintziori G , Iliadou PK , et al. Dynamic endocrine test of inhibin B and anti-Müllerian hormone in men with non-obstructive azoospermia. Gynecol Endocrinol 2011 27 661665. (https://doi.org/10.3109/09513590.2010.521267)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 57

    Alfano M , Ventimiglia E , Locatelli I , et al. Anti-Mullerian hormone-to-testosterone ratio is predictive of positive sperm retrieval in men with idiopathic non-obstructive azoospermia. Sci Rep 2017 7 17638. (https://doi.org/10.1038/s41598-017-17420-z)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 58

    Zhang YX , Yao CC , Huang YH , et al. Efficacy of stepwise mini-incision microdissection testicular sperm extraction for nonobstructive azoospermia with varied etiologies. Asian J Androl 2023 25 621626. (https://doi.org/10.4103/aja2022125)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 59

    Deng C , Liu D , Zhao L , et al. Inhibin B-to-anti-Mullerian hormone ratio as noninvasive predictors of positive sperm retrieval in idiopathic non-obstructive azoospermia. J Clin Med 2023 12 500. (https://doi.org/10.3390/jcm12020500)

    • PubMed
    • Search Google Scholar
    • Export Citation