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Study Question: Does standardised treatments used in children and adolescents with haematologic malignancies, including acute lymphoblastic (ALL) or myeloid leukaemia (AML) and non-Hodgkin lymphoma (NHL), affect endocrine function of the developing testes?, Summary Answer: Therapy of haematologic malignancies do not provoke an overt damage of Sertoli and Leydig cell populations, as revealed by normal levels of anti-Müllerian hormone (AMH) and testosterone, but a mild primary testicular dysfunction may be observed, compensated by moderate gonadotropin elevation, during pubertal development., What Is Known Already: Evidence exists on the deleterious effect that chemotherapy and radiotherapy have on germ cells, and some attention has been given to the effects on Leydig and Sertoli cells of the adult gonads, but information is virtually non-existent on the effects of oncologic treatment on testicular somatic cell components during childhood and adolescence., Study Design, Size, Duration: A retrospective, analytical, observational study included 97 boys with haematological malignancies followed at two tertiary paediatric public hospitals in Buenos Aires, Argentina, between 2002 and 2015., Participants/materials, Setting, Methods: Clinical records of males aged 1-18 years, referred with the diagnoses of ALL, AML or NHL for the assessment of gonadal function, were eligible. We assessed serum levels of AMH and FSH as biomarkers of Sertoli cell endocrine function and testosterone and LH as biomarkers of Leydig cell function., Main Results and the Role of Chance: All hormone levels were normal in the large majority of patients until early pubertal development. From Tanner stage G3 onwards, while serum AMH and testosterone kept within the normal ranges, gonadotropins reached mildly to moderately elevated values in up to 35.9% of the cases, indicating a compensated Sertoli and/or Leydig cell dysfunction, which generally did not require hormone replacement therapy., Limitations, Reasons for Caution: Serum inhibin B determination and semen analysis were not available for most patients; therefore, we could not conclude on potential fertility impairment or identify whether primary Sertoli cell dysfunction resulted in secondary depleted spermatogenesis or whether primary germ cell damage impacted Sertoli cell function., Wider Implications of the Findings: The regimens used in the treatment of boys and adolescents with ALL, AML or NHL in the past two decades seem relatively safe for endocrine testicular function; nonetheless, a mild primary testicular endocrine dysfunction may be observed, usually compensated by slightly elevated gonadotropin secretion by the pituitary in adolescents, and not requiring hormone replacement therapy. No clinically relevant risk factor, such as severity of the disease or treatment protocol, could be identified in association with the compensated endocrine dysfunction., Study Funding/competing Interest(s): This work was partially funded by grants PIP 11220130100687 of Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) and PICT 2016-0993 of Fondo para la Investigación Científica y Tecnológica (FONCYT), Argentina. R.A.R., R.P.G. and P.B. have received honoraria from CONICET (Argentina) for technology services using the AMH ELISA. L.A.A. is part-time employee of CSL Behring Argentina. The other authors have no conflicts of interest to disclose., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Introduction: Originally limited to the assessment of disorders of sex development, anti-Müllerian hormone (AMH) measurement has more recently been extended to several conditions affecting the reproductive axis in males and females. Follicle-stimulating hormone (FSH) regulation of gonadal function has been extensively studied, but its role on AMH production has been explored only recently., Areas Covered: We addressed the relationship between FSH action on the gonads and the usefulness of AMH as a marker in conditions affecting the reproductive axis., Expert Opinion: Sertoli cells are the most active cell population in the prepubertal testis. Serum AMH is an excellent marker of FSH action on Sertoli cell proliferation and function in patients with hypogonadotropic hypogonadism. Low serum AMH is expected to predict low sperm production and prompts initial FSH treatment followed by human chorionic gonadotropin (hCG) or luteinizing hormone (LH) addition. Gonadotropin treatment may be more effective if installed to mimic the postnatal activation stage of the hypothalamic-pituitary-testicular axis. In females, AMH secretion by small antral follicles is stimulated by FSH. Elevated AMH indicates increased follicle numbers and should be considered as a potential contraindication of gonadotropin treatment in infertile patients due to an increased risk of developing ovarian hyperstimulation syndrome.

Objective: Compensatory hypertrophy has been classically described in patients with monorchidism. However, it remains unclear whether there is a functional compensatory activity of the different cell populations. Our aim was to assess the functional capacity of the solitary testis in monorchid males from infancy through puberty in order to determine whether the remaining gonad is capable of compensating the functional activity of Sertoli and Leydig cells of the absent gonad., Design: In a retrospective, cross-sectional, analytical study performed at a tertiary paediatric public hospital, we included 89 boys with monorchidism and 358 healthy controls, aged 6 months-18 years. Testicular volume and circulating levels of reproductive hormones were compared between patients with monorchidism and normal boys. Serum anti-Müllerian hormone (AMH) and FSH were used as biomarkers of the functional mass of prepubertal Sertoli cells, whereas serum testosterone and LH were used as biomarkers of Leydig cells., Results: In the vast majority of the cases, the testicular volume of monorchid boys was smaller than the sum of the volume of both testes of healthy controls. Serum AMH was lower and FSH was higher in patients with monorchidism than in controls aged <3 and >13 years. Serum testosterone and LH did not differ significantly between patients and controls., Conclusion: In boys and adolescents with monorchidism, there is a dissociated capacity of the remaining testis to compensate for the absence of the other gonad: while Leydig cell function is largely compensated, Sertoli cell proliferation and function was lower than in controls., (© 2016 European Society of Endocrinology.)

During childhood, the pituitary-testicular axis is partially dormant: testosterone secretion decreases following a drop in luteinising hormone levels; follicle-stimulating hormone (FSH) levels also go down. Conversely, Sertoli cells are most active, as revealed by the circulating levels of anti-Müllerian hormone (AMH) and inhibin B. Therefore, hypogonadism can best be evidenced, without stimulation tests, if Sertoli cell function is assessed. Serum AMH is high from fetal life until mid-puberty. Testicular AMH production increases in response to FSH and is potently inhibited by androgens. Inhibin B is high in the first years of life, then decreases partially while remaining clearly higher than in females, and increases again at puberty. Serum AMH and inhibin B are undetectable in anorchid patients. In primary or central hypogonadism affecting the whole gonad established in fetal life or childhood, all testicular markers are low. Conversely, when hypogonadism only affects Leydig cells, serum AMH and inhibin B are normal. In males of pubertal age with central hypogonadism, AMH and inhibin B are low. Treatment with FSH provokes an increase in serum levels of both Sertoli cell markers, whereas human chorionic gonadotrophin (hCG) administration increases testosterone levels. In conclusion, measurement of serum AMH and inhibin B is helpful in assessing testicular function, without need for stimulation tests, and orientates the aetiological diagnosis of paediatric male hypogonadism.

Sertoli cells are the most active cell population in the testis during infancy and childhood. In these periods of life, hypogonadism can only be evidenced without stimulation tests, if Sertoli cell function is assessed. AMH is a useful marker of prepubertal Sertoli cell activity and number. Serum AMH is high from fetal life until mid-puberty. Testicular AMH production increases in response to FSH and is potently inhibited by androgens. Serum AMH is undetectable in anorchidic patients. In primary or central hypogonadism affecting the whole gonad and established in fetal life or childhood, serum AMH is low. Conversely, when hypogonadism affects only Leydig cells (e.g. LHβ mutations, LH/CG receptor or steroidogenic enzyme defects), serum AMH is normal or high. In pubertal males with central hypogonadism, AMH is low for Tanner stage (reflecting lack of FSH stimulus), but high for the age (indicating lack of testosterone inhibitory effect). Treatment with FSH provokes an increase in serum AMH, whereas hCG administration increases testosterone levels, which downregulate AMH. In conclusion, assessment of serum AMH is helpful to evaluate gonadal function, without the need for stimulation tests, and guides etiological diagnosis of pediatric male hypogonadism. Furthermore, serum AMH is an excellent marker of FSH and androgen action on the testis.

In Sertoli cells, anti-Müllerian hormone (AMH) expression is upregulated by FSH via cyclic AMP (cAMP), although no classical cAMP response elements exist in the AMH promoter. The response to cAMP involves NF-κB and AP2; however, targeted mutagenesis of their binding sites in the AMH promoter do not completely abolish the response. In this work we assessed whether SOX9, SF1, GATA4, and AP1 might represent alternative pathways involved in cAMP-mediated AMH upregulation, using real-time RT-PCR (qPCR), targeted mutagenesis, luciferase assays, and immunocytochemistry in the Sertoli cell line SMAT1. We also explored the signaling cascades potentially involved. In qPCR experiments, Amh, Sox9, Sf1, and Gata4 mRNA levels increased after SMAT1 cells were incubated with cAMP. Blocking PKA abolished the effect of cAMP on Sox9, Sf1, and Gata4 expression, inhibiting PI3K/PKB impaired the effect on Sf1 and Gata4, and reducing MEK1/2 and p38 MAPK activities curtailed Gata4 increase. SOX9 and SF1 translocated to the nucleus after incubation with cAMP. Mutations of the SOX9 or SF1 sites, but not of GAT4 or AP1 sites, precluded the response of a 3,063-bp AMH promoter to cAMP. In conclusion, in the Sertoli cell line SMAT1 cAMP upregulates SOX9, SF1, and GATA4 expression and induces SOX9 and SF1 nuclear translocation mainly through PKA, although other kinases may also participate. SOX9 and SF1 binding to the AMH promoter is essential to increase the activity of the AMH promoter in response to cAMP.

In the prepubertal male, Sertoli cells are the most active testicular cell population. Without stimulation tests, prepubertal hypogonadism can only be evidenced if Sertoli cell function is assessed. Anti-müllerian hormone (AMH) is a distinctive marker of the prepubertal Sertoli cell. Serum AMH is high from fetal life until puberty. In postnatal life, AMH testicular production is stimulated by FSH and potently inhibited by androgens. In anorchid patients, AMH is undetectable. In prepubertal males with fetal- or childhood-onset primary or central hypogonadism affecting the whole gonad, serum AMH is low. Conversely, when hypogonadism only affects Leydig cells (i.e., LH/human chorionic gonadotrophin receptor or steroidogenic enzyme defects), serum AMH is normal/high. AMH is also normal/high in patients with androgen insensitivity. In patients of pubertal age with central hypogonadism, AMH is low for Tanner stage - reflecting lack of FSH stimulus, - but high for age - reflecting lack of testosterone inhibitory effect. FSH treatment results in serum AMH rise, whereas human chorionic gonadotrophin treatment increases testosterone levels which inhibit AMH production. In conclusion, AMH determination is helpful in assessing gonadal function, without need for stimulation tests, and orientates the aetiological diagnosis of paediatric male hypogonadism. Furthermore, serum AMH is an excellent marker of FSH and androgen action in the testis., (Copyright 2010 S. Karger AG, Basel.)

Anti-Müllerian hormone (AMH) is a Sertoli cell-secreted glycoprotein involved in male fetal sex differentiation: it provokes the regression of Müllerian ducts, which otherwise give rise to the Fallopian tubes, the uterus and the upper part of the vagina. In the first trimester of fetal life, AMH is expressed independently of gonadotropins, whereas from the second trimester onwards AMH testicular production is stimulated by FSH and oestrogens; at puberty, AMH expression is inhibited by androgens. AMH has also been suggested to participate in testicular descent during fetal life, but its role remains unclear. Serum AMH is a wellrecognized biomarker of testicular function from birth to the first stages of puberty. Especially in boys with nonpalpable gonads, serum AMH is the most useful marker of the existence of testicular tissue. In boys with cryptorchidism, serum AMH levels reflect the mass of functional Sertoli cells: they are lower in patients with bilateral than in those with unilateral cryptorchidism. Interestingly, serum AMH increases after testis relocation to the scrotum, suggesting that the ectopic position result in testicular dysfunction, which may be at least partially reversible. In boys with cryptorchidism associated with micropenis, low AMH and FSH are indicative of central hypogonadism, and serum AMH is a good marker of effective FSH treatment. In patients with cryptorchidism in the context of disorders of sex development, low serum AMH is suggestive of gonadal dysgenesis, whereas normal or high AMH is found in patients with isolated androgen synthesis defects or with androgen insensitivity. In syndromic disorders, assessment of serum AMH has shown that Sertoli cell function is preserved in boys with Klinefelter syndrome until mid-puberty, while it is affected in patients with Noonan, Prader-Willi or Down syndromes. [ABSTRACT FROM AUTHOR]

Background: The suspicion of a disorder of sex development (DSD) often arises at birth, when the newborn presents with ambiguous genitalia, or even during prenatal ultrasound assessments. Less frequently, the aspect of the external genitalia is typically female or male, and the diagnosis of DSD may be delayed until a karyotype is performed for another health issue, or until pubertal age when a girl presents with absence of thelarche and/or menarche or a boy consults for gynaecomastia and/or small testes. Summary: In this review, we provide a practical, updated approach to clinical and hormonal laboratory workup of the newborn, the child, and the adolescent with a suspected DSD. We focus on how to specifically address the diagnostic approach according to the age and presentation. Key Message: We particularly highlight the importance of a detailed anatomic description of the external and internal genitalia, adequate imaging studies or surgical exploration, the assessment of reproductive hormone levels – especially testosterone, anti-Müllerian hormone, 17-hydroxyprogesterone, and gonadotropins – and karyotyping. [ABSTRACT FROM AUTHOR]

The diagnosis of male central (or hypogonadotropic) hypogonadism, typically based on low luteinizing hormone (LH) and testosterone levels, is challenging during childhood since both hormones are physiologically low from the sixth month until the onset of puberty. Conversely, follicle-stimulating hormone (FSH) and anti-Müllerian hormone (AMH), which show higher circulating levels during infancy and childhood, are not used as biomarkers for the condition. We report the case of a 7-year-old boy with a history of bilateral cryptorchidism who showed repeatedly low FSH and AMH serum levels during prepuberty. Unfortunately, the diagnosis could not be ascertained until he presented with delayed puberty at the age of 14 years. A gonadotropin-releasing hormone (GnRH) test showed impaired LH and FSH response. By then, his growth and bone mineralization were partially impaired. Gene panel sequencing identified a variant in exon 15 of FGFR1 , affecting the tyrosine kinase domain of the receptor, involved in GnRH neuron migration and olfactory bulb morphogenesis. Testosterone replacement was started, which resulted in the development of secondary sexual characteristics and partial improvement of bone mineral density. This case illustrates the difficulty in making the diagnosis of central hypogonadism in boys during childhood based on classical criteria, and how serum FSH and AMH assessment may be helpful if it is suspected before the age of puberty, and confirm it using next-generation sequencing. The possibility of making an early diagnosis of central hypogonadism may be useful for a timely start of hormone replacement therapy, and to avoid delays that could affect growth and bone health as well as psychosocial adjustment. [ABSTRACT FROM AUTHOR]

Disorders of Sex Development (DSD) are congenital anomalies in which there is a discordance between chromosomal, genetic, gonadal, and/or internal/external genital sex. In XY individuals, the process of fetal sex differentiation can be disrupted at the stage of gonadal differentiation, resulting in gonadal dysgenesis, a form of early fetal-onset primary hypogonadism characterized by insufficient androgen and anti-Müllerian hormone (AMH) production, which leads to the development of ambiguous or female genitalia. The process of sex differentiation can also be disrupted at the stage of genital differentiation, due to isolated defects in androgen or AMH secretion, but not both. These are forms of fetal-onset hypogonadism with dissociated gonadal dysfunction. In this review, we present a perspective on impaired testicular endocrine function, i.e., fetal-onset male hypogonadism, resulting in incomplete virilization at birth. [ABSTRACT FROM AUTHOR]

The classical definition of hypogonadism, used in adult medicine, as gonadal failure resulting in deficient steroid and gamete production, and its classification into hypergonadotropic and hypogonadotropic refer to primary gonadal and hypothalamic–pituitary disorders respectively and may lead to under- or misdiagnosis in pediatrics. Indeed, in children with primary gonadal failure, gonadotropin levels may be within the reference range for age. Conversely, since gonadotropins and steroids are normally low during childhood, it may prove impossible to show the existence of a hypogonadotropic state before pubertal age. Anti-Müllerian hormone (AMH) and inhibin B arise as more adequate biomarkers to assess gonadal function and increase the possibility of making an earlier diagnosis of hypogonadism in children, which may positively impact on timely management. Like many other definitions of clinical conditions, that of hypogonadism has been coined for adults. The disregard of a broader definition applicable to all developmental stages may result in underdiagnosis, especially in pediatric patients. Fetal hypogonadism in males results in ambiguous or female genitalia if established in the first trimester, and in small male genitalia and cryptorchidism if established in the second or third trimester, whereas in females it is clinically unremarkable. While gonadotropins and sex steroids are informative for the diagnosis of hypogonadism in infancy, pubertal age, and adulthood, Sertoli and granulosa cell biomarkers – AMH and inhibin B – are the only useful biomarkers during childhood. In childhood, primary hypogonadism is not always hypergonadotropic and the diagnosis can be missed in up to ∼70% of the cases if based on serum gonadotropin measurement. With the currently available clinical and biochemical assessments, the diagnosis of central (hypogonadotropic) hypogonadism is virtually impossible to prove during childhood. Chronic hormone replacement of hypogonadism is usually not necessary during childhood, but could prove beneficial during infancy. [ABSTRACT FROM AUTHOR]

Introduction: The functional capacity of the testes in prepubertal boys with cryptorchidism before treatment has received very little attention. The assessment of testicular function at diagnosis could be helpful in the understanding of the pathophysiology of cryptorchidism and in the evaluation of the effect of treatment. Anti-Müllerian hormone is a well-accepted Sertoli cell biomarker to evaluate testicular function during childhood without the need for stimulation tests. Objective: The aim of the study was to assess testicular function in prepubertal children with cryptorchidism before orchiopexy, by determining serum anti-Müllerian hormone (AMH). We also evaluated serum gonadotropins and testosterone and looked for associations between testicular function and the clinical characteristics of cryptorchidism. Materials and methods: We performed a retrospective, cross-sectional, analytical study at a tertiary pediatric public hospital. All clinical charts of patients admitted at the outpatient clinic, and recorded in our database with the diagnosis of cryptorchidism, were eligible. The main outcome measure of the study was the serum concentration of AMH. Secondary outcome measures were serum LH, FSH, and testosterone. For comparison, serum hormone levels from a normal population of 179 apparently normal prepubertal boys were used. Results: Out of 1,557 patients eligible in our database, 186 with bilateral and 124 with unilateral cryptorchidism were selected using a randomization software. Median AMH standard deviation score was below 0 in both the bilaterally and the unilaterally cryptorchid groups, indicating that testicular function was overall decreased in patients with cryptorchidism. Serum AMH was significantly lower in boys with bilateral cryptorchidism as compared with controls and unilaterally cryptorchid patients between 6 months and 1.9 years and between 2 and 8.9 years of age. Serum AMH below the normal range reflected testicular dysfunction in 9.5-36.5% of patients according to the age group in bilaterally cryptorchid boys and 6.3-16.7% in unilaterally cryptorchid boys. FSH was elevated in 8.1% and LH in 9.1% of boys with bilateral cryptorchidism, most of whom were anorchid. In patients with present testes, gonadotropins were only mildly elevated in less than 5% of the cases. Basal testosterone was mildly decreased in patients younger than 6 months old, and uninformative during childhood. Conclusion: Prepubertal boys with cryptorchidism, especially those with bilaterally undescended gonads, have decreased AMH production. Although serum AMH may fall within the normal range, there is a considerable prevalence of testicular dysfunction during childhood in this frequent condition. [ABSTRACT FROM AUTHOR]

Commonly known for testosterone secretion, the testes also produce the protein hormones anti-müllerian hormone (AMH), inhibin B, and insulin-like factor 3 (INSL3). AMH and inhibin B are secreted by Sertoli cells, whereas INSL3 is a Leydig cell product. AMH is involved in fetal sex differentiation and induces the regression of the anlagen of the uterus and fallopian tubes. INSL3 participates in fetal testicular descent. Serum testicular protein hormone assessment can be very useful and complementary to testosterone measurements in patients with DSD. AMH and inhibin B determination is extremely helpful during childhood, when basal testosterone is normally low. Serum AMH and inhibin B above the female range are indicative of the presence of testicular tissue, and their circulating levels reflect the amount of functional Sertoli cells. In DSD patients with normal male levels of AMH and inhibin B, the diagnosis of gonadal dysgenesis can be ruled out, and isolated androgen secretion deficiency or androgen insensitivity should be suspected. In externally virilized XY patients with persistent müllerian ducts, serum AMH levels determine the diagnosis to AMH deficiency or resistance. At pubertal age, inhibin B levels serve to predict spermatogenic development. [ABSTRACT FROM AUTHOR]

We aimed to describe the functional changes of Sertoli cells, based on the measurement of serum anti-Müllerian hormone (AMH) and inhibin B during treatment with GnRHa and after its withdrawal in boys with central precocious puberty. Six boys aged 0.8 to 5.5 yr were included. AMH was low at diagnosis in patients >1 yr but within the normal range in younger patients. AMH increased to normal prepubertal levels during treatment. After GnRHa withdrawal, AMH declined concomitantly with the rise in serum testosterone. At diagnosis, inhibin B was elevated and decreased throughout therapy, remaining in the upper normal prepubertal range. In patients with testicular volume above 4mL AMH remained higher in spite of suppressed FSH. After treatment withdrawal, inhibin B rose towards normal pubertal levels. In conclusion, AMH did not decrease in patients <1 yr reflecting the lack of androgen receptor expression in Sertoli cells in early infancy. Serum inhibin B might result from the contribution of two sources: the mass of Sertoli cells and the stimulation exerted by FSH. Sertoli cell markers might provide additional tools for the diagnosis and treatment followup of boys with central precocious puberty. [ABSTRACT FROM AUTHOR]

Male hypogonadism implies decreased function of one or more testicular cell population, i.e. germ, Leydig and/or Sertoli cells. In the normal prepubertal boy, Sertoli cells are very active, as indicated by high anti-Müllerian hormone (AMH) and inhibin B secretion, whereas the functional activity of Leydig cells is minimal, as evidenced by low testosterone production, and germ cells do not undergo the full spermatogenic process. Klinefelter syndrome is the most frequent cause of hypogonadism in the adult male. In this review, we discuss whether the gonadal failure is already established during infancy and childhood. In Klinefelter syndrome, there is increased germ cells degeneration from mid-foetal life - resulting in a decreased number at birth - which persists during infancy and childhood and becomes dramatic during puberty. Controversial results exist in the literature regarding Leydig cell function in Klinefelter boys: while some authors have found normal to low testosterone levels in infancy and childhood, others have reported normal to high values. Sertoli cell products AMH and inhibin B are normal in prepubertal boys and only decline during mid- to late puberty. Klinefelter syndrome is a primary hypogonadism affecting all testicular cell populations. Germ cells are affected from foetal life, and a severe depletion occurs at puberty. Leydig cell function may be normal or mildly affected in foetal and early postnatal life. Sertoli cell function is not impaired until mid- to late puberty, as reflected by normal AMH and inhibin B in Klinefelter boys. [ABSTRACT FROM AUTHOR]

Fetal sex development consists of three sequential stages: a) the undifferentiated stage, when identical primitive structures develop in the XY and XX embryos, b) gonadal differentiation into testes or ovaries, and c) the differentiation of internal and external genitalia, which depends on the action of testicular hormones. Disorders of sex development (DSD) may result from defects in any of these stages. Abnormal formation of the anlagen of internal and/or external genitalia in early embryonic development results in Malformative DSD. In patients with a Y chromosome, defects in testis differentiation drive to early-onset fetal hypogonadism affecting whole testicular function, a condition named Dysgenetic DSD. In Non-dysgenetic DSD, the underlying pathogenesis may involve early-onset fetal hypogonadism affecting specifically either Leydig or Sertoli cell function, or male hormone end-organ defects in patients devoid of fetal hypogonadism. Understanding the pathogenesis is useful for an efficient early diagnosis approach, which is necessary for adequate decision making in the management of DSD. [ABSTRACT FROM AUTHOR]

Androgens and anti-Müllerian hormone (AMH), secreted by the foetal testis, are responsible for the development of male reproductive organs and the regression of female anlagen. Virilization of the reproductive tract in association with the absence of Müllerian derivatives in the XX foetus implies the existence of testicular tissue, which can occur in the presence or absence of SRY. Recent advancement in the knowledge of the opposing gene cascades driving to the differentiation of the gonadal ridge into testes or ovaries during early foetal development has provided insight into the molecular explanation of XX maleness. [ABSTRACT FROM AUTHOR]