Silvia Gottlieb

Establishment of testicular endocrine function impairment during childhood and puberty in boys with Klinefelter syndrome.

Objective  To precisely characterize the chronology of testicular endocrine function impairment during childhood and adolescence in patients with Klinefelter syndrome.

Male hypogonadism: an extended classification based on a developmental, endocrine physiology‐based approach

Normal testicular physiology results from the integrated function of the tubular and interstitial compartments. Serum markers of interstitial tissue function are testosterone and insulin‐like factor 3 (INSL3), whereas tubular function can be assessed by sperm count, morphology and motility, and serum anti‐Müllerian hormone (AMH) and inhibin B. The classical definition of male hypogonadism refers to testicular failure associated with androgen deficiency, without considering potential deficiencies in germ and Sertoli cells. Furthermore, the classical definition does not consider the fact that low basal serum testosterone cannot be equated to hypogonadism in childhood, because Leydig cells are normally quiescent. A broader clinical definition of hypogonadism that could be applied to male patients in different periods of life requires a comprehensive consideration of the physiology of the hypothalamic‐pituitary‐testicular axis and its disturbances along development. Here we propose an extended classification of male hypogonadism based on the pathophysiology of the hypothalamic‐pituitary‐testicular axis in different periods of life. The clinical and biochemical features of male hypogonadism vary according to the following: (i) the level of the hypothalamic‐pituitary‐testicular axis primarily affected: central, primary or combined; (ii) the testicular cell population initially impaired: whole testis dysfunction or dissociated testicular dysfunction, and: (iii) the period of life when the gonadal function begins to fail: foetal‐onset or postnatal‐onset. The evaluation of basal testicular function in infancy and childhood relies mainly on the assessment of Sertoli cell markers (AMH and inhibin B). Hypergonadotropism should not be considered a sine qua non condition for the diagnosis of primary hypogonadism in childhood. Finally, the lack of elevation of gonadotropins in adolescents or adults with primary gonadal failure is indicative of a combined hypogonadism involving the gonads and the hypothalamic‐pituitary axis.

Hormonal Parameters and Testicular Volume in Children and Adolescents with Unilateral Varicocele: Preoperative and Postoperative Findings

Preoperative and postoperative testicular volume, serum testosterone, follicle-stimulating hormone and luteinizing hormone were determined in 25 patients 8 to 19 years old (mean age 13.2 +/- 1.63) with grades 2 and 3 unilateral varicocele. Testicular growth arrest was considered significant when volume loss was greater than 2 ml. in the ipsilateral testis compared to the contralateral side. Baseline serum testosterone, follicle-stimulating hormone and luteinizing hormone as well as post-gonadotropin releasing hormone stimulation were determined preoperatively and at 4 to 6 months postoperatively. Data are presented as mean plus or minus standard deviation. Results showed an increase in serum testosterone in Tanners stages 1 (p < 0.028) and 2 to 3 (p < 0.008). No differences were recorded in basal luteinizing hormone and follicle-stimulating hormone, as well as maximal follicle-stimulating hormone levels before and after surgery. A decrease of maximal luteinizing hormone response to gonadotropin releasing hormone test was noted postoperatively in pubertal stages 4 to 5, when compared to preoperative values. Postoperative ipsilateral testicular volume increased in all Tanner stages (p < 0.045, p < 0.008 and p < 0.012, respectively). Our observations suggest that varicocele may be initially responsible for interstitial dysfunction with preservation of germinal function and unilateral testicular growth arrest, however reversible, after pubertal surgical correction. This study supports previous reports suggesting that varicocelectomy in children who show anatomic and functional changes is advisable.

Clinical Presentation of Klinefelter's Syndrome: Differences According to Age.

The aim of the study was to establish the characteristics of presentation of 94 patients with Kinelfelters syndrome (KS) referred to the endocrinologist at different ages. The diagnosis of KS was more frequent in the age group between 11 and 20 years (46.8%). Most of the patients (83.7%) showed the classic 47,XXY karyotype and 7.1% showed a 47,XXY/46,XY mosaicism. Half of the patients younger than 18 years presented mild neurodevelopmental disorders. The most frequent clinical findings were cryptorchidism in prepubertal patients, and small testes, cryptorchidism, and gynecomastia in pubertal patients. FSH, LH, AMH, and inhibin B levels were normal in prepubertal patients and became abnormal from midpuberty. Most adults were referred for small testes, infertility, and gynecomastia; 43.6% had sexual dysfunction. Testosterone levels were low in 45%. Mean stature was above the 50th percentile, and 62.5% had BMI ≥25.0 kg/m2. In conclusion, the diagnosis of Klinefelter syndrome seems to be made earlier nowadays probably because pediatricians are more aware that boys and adolescents with neuro-developmental disorders and cryptorchidism are at increased risk. The increasing use of prenatal diagnosis has also decreased the mean age at diagnosis and allowed to get insight into the evolution of previously undiagnosed cases, which probably represent the mildest forms. In adults average height and weight are slightly higher than those in the normal population. Bone mineral density is mildly affected, more at the spine than at the femoral neck level, in less than half of cases.

Altered serum profile of inhibin B, Pro‐αC and anti‐Müllerian hormone in prepubertal and pubertal boys with varicocele

objective  Anti‐Müllerian hormone (AMH) and inhibin B are reliable markers of Sertoli cell function. The aim of the present study was to assess the functional state of Sertoli cells in order to detect early changes in the testicular function of prepubertal and pubertal patients with untreated grade II or III varicocele.

Gonadotrophin secretion pattern in anorchid boys from birth to pubertal age: pathophysiological aspects and diagnostic usefulness.

Context  The biphasic ontogeny of serum gonadotrophins observed in normal children also exists in girls with gonadal dysgenesis, although with higher levels. However, limited data exist in prepubertal boys with anorchia.

Sertoli cell markers in the diagnosis of paediatric male hypogonadism

Abstract 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.

Spreading the Clinical Window for Diagnosing Fetal-Onset Hypogonadism in Boys

In early fetal development, the testis secretes – independent of pituitary gonadotropins – androgens and anti-Müllerian hormone (AMH) that are essential for male sex differentiation. In the second half of fetal life, the hypothalamic–pituitary axis gains control of testicular hormone secretion. Follicle-stimulating hormone (FSH) controls Sertoli cell proliferation, responsible for testis volume increase and AMH and inhibin B secretion, whereas luteinizing hormone (LH) regulates Leydig cell androgen and INSL3 secretion, involved in the growth and trophism of male external genitalia and in testis descent. This differential regulation of testicular function between early and late fetal periods underlies the distinct clinical presentations of fetal-onset hypogonadism in the newborn male: primary hypogonadism results in ambiguous or female genitalia when early fetal-onset, whereas it becomes clinically undistinguishable from central hypogonadism when established later in fetal life. The assessment of the hypothalamic–pituitary–gonadal axis in male has classically relied on the measurement of gonadotropin and testosterone levels in serum. These hormone levels normally decline 3–6 months after birth, thus constraining the clinical evaluation window for diagnosing male hypogonadism. The advent of new markers of gonadal function has spread this clinical window beyond the first 6 months of life. In this review, we discuss the advantages and limitations of old and new markers used for the functional assessment of the hypothalamic–pituitary–testicular axis in boys suspected of fetal-onset hypogonadism.

Basal Follicle-Stimulating Hormone and Peak Gonadotropin Levels after Gonadotropin-Releasing Hormone Infusion Show High Diagnostic Accuracy in Boys with Suspicion of Hypogonadotropic Hypogonadism

CONTEXT Differential diagnosis between hypogonadotropic hypogonadism (HH) and constitutional delay of puberty in boys is challenging. Most tests use an acute GnRH stimulus, allowing only the release of previously synthesized gonadotropins. A constant GnRH infusion, inducing de novo gonadotropin synthesis, may allow a better discrimination. OBJECTIVE We evaluated the diagnostic accuracy of basal and peak gonadotropins after GnRH infusion, measured by ultrasensitive assays, to confirm the diagnosis in boys with suspected HH. DESIGN AND SETTING We conducted a validation study following Standards for Reporting of Diagnostic Accuracy criteria at a tertiary public hospital. PATIENTS AND METHODS A GnRH i.v. infusion test was performed in 32 boys. LH and FSH were determined by immunofluorometric assay at 0-120 min. DIAGNOSIS ASCERTAINMENT: The following diagnoses were ascertained: complete HH (n = 19; testes < 4 ml at 18 yr), partial HH (n = 6; testes enlargement remained arrested for > or = 1 yr or did not reach 15 ml), and constitutional delay of puberty (n = 7; testes > or = 15 ml at 18 yr). MAIN OUTCOME MEASURES Sensitivity, specificity, positive and negative predictive values, and diagnostic efficiency were assessed. RESULTS Basal FSH less than 1.2 IU/liter confirmed HH with specificity of 1.00 (95% confidence interval = 0.59-1.00), rendering GnRH infusion unnecessary. In patients with basal FSH of at least 1.2 IU/liter, the coexistence of peak FSH less than 4.6 IU/liter and peak LH less than 5.8 IU/liter after GnRH infusion had high specificity (1.00; 95% confidence interval = 0.59-1.00) and diagnostic efficiency (76.9%) for HH. CONCLUSIONS Basal FSH less than 1.2 IU/liter confirms HH, which precludes from further testing, reducing patient discomfort and healthcare system costs. In patients with basal FSH of at least 1.2 IU/liter, a GnRH infusion test has a high diagnostic efficiency.

Predictive Value of Anatomical Findings and Karyotype Analysis in the Diagnosis of Patients with Disorders of Sexual Development

We assessed the predictive value of anatomical findings and karyotype for establishing a diagnostic orientation in patients with disorders of sex development (DSD). We performed a retrospective chart analysis of 228 patients, grouped into 4 categories: 46,XX DSD, non-dysgenetic testicular DSD, dysgenetic testicular DSD and ovotesticular DSD. Degree of virilisation, presence of vagina, presence of palpable gonads, size of gonads and a plain karyotype was available for all cases. 46,XX DSD due to congenital adrenal hyperplasia counted for 59.2% of the cases, non-dysgenetic testicular DSD for 13.6%, dysgenetic testicular DSD for 21.5% and ovotesticular DSD for 5.7%. Excluding congenital adrenal hyperplasia (CAH), a karyotype with at least one 46,XX cell line had a high diagnostic efficiency for ovotesticular DSD. In these patients, anatomical findings were not as useful to predict the gonadal phenotype. The existence of a 45,X cell line predicted with very high efficiency dysgenetic testicular DSD. Genital palpation was only partially helpful to predict the existence of testicular tissue. Non-dysgenetic testicular DSD could be ruled out with high efficiency in patients with an abnormal karyotype. Anatomical findings were helpful in 46,XY patients: palpated masses predicted non-dysgenetic testes with high accuracy. In all cases assessment of gonadal volume was less useful.