Kinetics of the testicular steroidogenic response to stimulation with placental gonadotropin in the prepuberal boy

The kinetics of the plasma level responses of steroid hormones to a single injection of human chorionic gonadotrophin (hCG) (100 Ul/kg) was studied for one week in 7 prepubertal boys. Plasma testosterone levels progressively increased up to 8.22 +/- 1.33 nmol/l, usually at the 100th hour. The kinetics of dihydrotestosterone was quite similar. On the other and, progesterone, 17 alpha-hydroxyprogesterone and delta 4-androstenedione did not change significantly; 17 beta-estradiol slightly increased 5 to 7 days later. This profile of response is deeply different from those observed in adults, in whom are observed an early response (24 hrs) of 17 alpha-hydroxyprogesterone and estradiol and a two-phase response of testosterone. These results show that the hCG-induced steroidogenic desensitization is present only in patients previously exposed to a certain level of gonadotrophic stimulation (endogenous or exogenous).     

Evaluation of testicular function following long-term treatment for acute lymphoblastic leukemia

A study of reproductive function was carried out in 31 patients following long-term treatment of acute lymphoblastic leukemia (mean: 4 1/12 years); 17 prepubertal; nine pubertal, and five adults. Spontaneous clinical pubertal development was observed in 4 of 17 prepubertal patients. Serum testosterone response to hCG was normal or increased in the nine prepubertal patients studied. Intratesticular testosterone concentration was normal in 11 out of 12 patients. Only two of 14 prepubertal patients had a reduced number of germ cells. Normal progress of spermatogenesis was seen in six out of seven pubertal patients and only moderate hypospermatogenesis with focal hyalinosis was found in the five adults. Two of them had normal sperm count and one fathered two children. In six out of 14 prepubertal patients unexpected early signs of pubertal stimulation were found. Serum gonadotrophins response to LH-RH was normal in most patients. Testicular infiltration of blastic cells was found in four of 26 biopsies, but only one of 23 patients was without clinical signs of testicular relapse. Computerized axial tomography was normal in 10 out of 13 patients. Bone age was significantly below chronological age in four out of 15 patients. This study suggests that the gonad is moderately injured by long-term antileukemic therapy. In addition, microscopic testicular infiltration is not frequent in subjects without testicular enlargement.     

Hypothalamo-hypophyseal-testicular function in prepubertal boys with acute lymphoblastic leukemia following chemotherapy and testicular radiotherapy

Hypothalamo-hypophyseal-testicular function was studied in twenty-eight prepubertal boys with ALL in clinical and haematological remission. Eighteen were treated with combined systemic chemotherapy (24-36 months) and the other ten, who had testicular leukemic infiltrates, received chemotherapy (38-60 months) and testicular radiotherapy (2 000 rad). Plasma levels of LH and FSH were measured before and after stimulation with LHRH (100 micrograms i.v.) and plasma levels of testosterone before and after stimulation with hCG (1 500 IU/48 h/7 doses). In patients treated with chemotherapy alone, mean basal LH and FSH, mean responses to LHRH stimulation and mean testosterone levels after stimulation with hCG did not significantly differ from those of the controls. Five of these patients who had normal testosterone values after three doses of hCG had testosterone values below the normal range after seven doses. In patients treated with chemotherapy and testicular radiotherapy, mean basal FSH and mean responses to LHRH stimulation were significantly higher than those of the controls. Testosterone values after stimulation with hCG were low in three and very low in the other seven. In both groups of patients data from testicular biopsies were consistent with functional results. We conclude that chemotherapy causes slight testicular damage, but chemotherapy and testicular radiotherapy produce severe testicular damage in patients with testicular leukemic infiltrates.     

Prepubertal testicular teratomas.

Testicular teratomas in prepubertal children are distinct from adult testicular teratomas as well as from teratomas located elsewhere in the body, both with respect to their pathologic features and biologic behavior. Over a period of 12 years, testicular teratomas comprised 25% (5 of 20) of all testicular tumors in prepubertal children, treated at our institution. Their clinical presentation and pathologic profile was analysed. Their mean age at presentation was 6.7 m (range 1 m to 18 m) with the mass having been noted at birth in 3 infants. The right testis was involved in all except one patient. Serum AFP was elevated preoperatively in only one case with an immature (grade II) teratoma containing fetal liver tissue. Immunohistochemical staining for AFP and alfa-1-antitrypsin were positive in these fetal liver cells. Serum AFP levels returned to normal after orchiectomy in this patient. While a high inguinal orchiectomy was the standard operative procedure, testicular-sparing surgery was planned in the last two patients. However the tumor had replaced the entire testis in one of these patients, while in the other, the mass was homogeneous, with no visible cystic areas or dermal elements on cut section. Hence both of these patients also underwent orchiectomy. Histologic examination and immunohistochemical staining for AFP were performed on the specimen. Peri-tumor testicular parenchyma was found to be unremarkable and did not stain for placental alkaline phosphatase, a marker for carcinoma in situ. All these children are doing well with no evidence of residual or recurrent disease at a mean follow-up of 4.7 years (range 4 m to 11 yrs).     

Pseudo-precocious puberty caused by bilateral idiopathic testicular hyperplasia

A boy aged two years presenting with advanced development of the genitalia, but with prepubertal testes, and accelerated growth is described. Investigation indicated pseudo-precocious puberty, due to idiopathic interstitial cell hyperplasia. Difficulties in interpretation of the hormonal studies were encountered due to an aberrant left testicular vein. This rare condition which has been called Testotoxicosis is probably due to an inborn error of metabolism not yet identified.     

Kinetics of the steroidogenic response to single versus repeated doses of human chorionic gonadotropin in boys in prepuberty and early puberty

There is accumulating evidence that in adult men excessive amounts of gonadotropins induce testicular desensitization to further gonadotropin stimulus. We evaluated the effects of endogenous gonadotropins and of repeated doses of exogenous human chorionic gonadotropin (hCG) on steroidogenesis by studying prepubertal and pubertal boys. The boys received either two intramuscular injections of hCG 4 days apart (protocol I) or four injections at 3- to 4-day-intervals (protocol II). In protocol I, serum testosterone, 17 alpha-hydroxyprogesterone, and estradiol were measured basally and for 6 days after the second injection, and in protocol II, before each injection and 4 days after the last injection. In the prepubertal-boys, serum testosterone increased from very low basal levels to 10.3 (protocol I) and 8.3 nmol/liter (protocol II). In protocol I the increase after the first injection was 64-fold and in protocol II there was an increase after each injection to a final level 144-fold of the basal. No significant changes were seen in the estradiol levels. In the pubertal boys at genital stage G2, the serum testosterone levels increased after the first two injections, but at genital stage G3, the levels increased only after the first injection. Maximal testosterone increases were 27- and 8-fold, respectively. In pubertal boys estradiol levels increased progressively throughout the stimulation. The major testosterone response ws seen after the first dose of hCG and repeated doses, at least in the pubertal boys, increased estradiol but not testosterone levels, thus causing an estrogen-mediated 17,20-lyase block. We therefore suggest that a single-dose hCG test deserves further evaluation for diagnostic use.     

How to evaluate gonadal function in the cryptorchid boy. Lessons from new testicular markers

In normal clinical practice, testicular evaluation in boys has relied on palpation and testosterone determination after hCG stimulation, which reflects the activity of interstitial Leydig cells. However, the most active compartment of the testis before puberty is the seminiferous tubule compartment, in which Sertoli cells proliferate and secrete anti-Müllerian hormone (AMH) and inhibin B. The recent development of commercially available assays for these two peptides has provided the pediatrician with excellent tools to assess the existence of functional testicular tissue in boys with no need for hCG stimulation. Serum AMH determination is also useful to assess testicular tissue mass and function in patients with intersex disorders. The determination of testosterone, its precursors and dihydrotestosterone, after hCG stimulation, should be reserved for situations in which Leydig cell function needs to be specifically assessed.     

Evaluation of human chorionic gonadotropin stimulation tests in prepubertal and early pubertal boys

We evaluated the diagnostic significance of single versus repeated human chorionic gonadotropin (hCG) stimulation of testicular steroidogenesis in 25 boys (10 prepubertal group A; 15 early pubertal, group B) with suspected hypogonadism. All subjects received a single injection of hCG (5000 U/1.7 m²) and 1 month later, three repeated injections of 1500 U, one each on alternate days. In 19 out of the 25 boys, testosterone increased normally in both tests: from 20±6 to 156±82 ng/dl and from 107±105 to 615±293 ng/dl, following a single hCG injection, and from 30±19 to 439±298 ng/dl and from 94±55 to 826±272 ng/dl, following repeated injections in groups A and B, respectively. The difference between the tests was significant (P<0.01).Conclusion Single hCG injection used as a screening test in the evaluation of hypogonadism is conclusive when positive. Only when the initial test is negative may a repeated test help establish the diagnosis.     

Hypothalamo-Hypophyseal-Testicular Function in Prepubertal Boys with Acute Lymphoblastic Leukemia following Chemotherapy and Testicular Radiotherapy

ABSTRACT. Hypothalamo-hypophyseal-testicular function was studied in twenty-eight prepubertal boys with ALL in clinical and haematological remission. Eighteen were treated with combined systemic chemotherapy (24–36 months) and the other ten, who had testicular leukemic infiltrates, received chemotherapy (38–60 months) and testicular radiotherapy (2000 rad). Plasma levels of LH and FSH were measured before and after stimulation with LHRH (100 μg i.v.) and plasma levels of testosterone before and after stimulation with hCG (1500 IU/48 h/7 doses). In patients treated with chemotherapy alone, mean basal LH and FSH, mean responses to LHRH stimulation and mean testosterone levels after stimulation with hCG did not significantly differ from those of the controls. Five of these patients who had normal testosterone values after three doses of hCG had testosterone values below the normal range after seven doses. In patients treated with chemotherapy and testicular radiotherapy, mean basal FSH and mean responses to LHRH stimulation were significantly higher than those of the controls. Testosterone values after stimulation with hCG were low in three and very low in the other seven. In both groups of patients data from testicular biopsies were consistent with functional results. We conclude that chemotherapy causes slight testicular damage, but chemotherapy and testicular radiotherapy produce severe testicular damage in patients with testicular leukemic infiltrates.     

激素辅助治疗对隐睾儿童睾丸生精功能影响的系统评价和Meta分析

目的 评价激素辅助治疗对于隐睾儿童睾丸生精功能的影响。 方法 计算机检索PubMed、EMBASE、The Cochrane Library、中国生物医学文献数据库、中国知网、万方数据库和维普数据库,获得激素对隐睾儿童睾丸生精功能影响的干预性研究,检索时限均从建库至2015年9月30日。由2名研究者独立行文献筛选、资料提取,并评价纳入研究的偏倚风险。以睾丸固定术中睾丸活检每曲细精管横断面精原细胞数（S/T）为近期指标,以均数差(MD)及其95%CI作为效应指标;以成年后患者精子密度正常比例为远期指标,以相对危险度（RR）及其95%CI作为效应指标。采用RevMan 5.3软件行Meta分析,根据异质性检验结果选择相应的效应模型合并效应量。 结果 8篇文献进入Meta分析,4篇为RCT,4篇为NRCT。8篇文献的偏倚风险均较大。3篇文献报道了绒毛膜促性腺激素（hCG）+手术和单纯手术睾丸活检S/T水平,文献间具同质性,Meta分析结果显示,hCG+手术S/T水平显著低于单纯手术, MD=-0.08,95%CI：-0.13~-0.03, P=0.002。4篇文献汇总的随机效应模型Meta分析结果显示,促黄体生成素释放激素（LHRH）+手术S/T显著高于单纯手术,差异有统计学意义,MD=0.34,95%CI：0.04~0.64, P=0.03;按部位行亚组分析显示,单侧或双侧隐睾LHRH+手术均较单纯手术S/T显著增加。2篇文献汇总的随机效应模型Meta分析结果显示, hCG+LHRH+手术与单纯手术比较,成年后精子密度正常比例差异无统计学意义,RR=1.46,95%CI：0.24~9.06, P=0.68。 结论 hCG辅助治疗对短期睾丸生精功能有损伤;LHRH辅助治疗可改善短期睾丸生精功能;而hCG+LHRH对于远期生精功能无显著影响。考虑纳入文献数量较少且偏倚风险高,仍有待更多的研究。     

Intermittent testicular torsion

Testicular torsion is the most common cause of acute scrotal pain in prepubertal and adolescent boys and should be foremost in the minds of primary care physicians evaluating these children. Intermittent testicular torsion is a separate entity that should be considered in all young males with a history of scrotal pain and swelling. Acute and intermittent sharp testicular pain and scrotal swelling, interspersed with long intervals without symptoms, are characteristic. Physical findings may include horizontal or very mobile testes, an anteriorly located epididymis, or bulkiness of the spermatic cord from partial twisting. Awareness of this entity and early elective orchiopexy will improve testicular salvage in patients with intermittent testicular torsion.     

Normal testicular volume in school children

A cross sectional study was conducted on 1000 school children between the ages of 8–16 years, to find out the normal testicular volume. At 8 years the testicular volume averaged 1.4 ml. This increased at the rate of 0.5 ml per year, till it reached 2.9 ml at the age of 11 years. A spurt in testicular growth (increment of 1.6 ml) was recorded between 11 and 12 years. This accelerated growth continued at a rate of about 2.5 ml to 4.0 ml/year, so as to attain a mean testicular volume of 15.6 ml by 16 years of age. It is suggested that a testicular size upto 2.0 ml may be considered infantile as this size correlated with prepubertal stages G1 and PH1 and an increase in the size beyond this may be regarded as the earliest evidence of puberty.     

Gonadal development and function after immature testicular tissue banking as part of high-risk gonadotoxic treatment

Background

Experimental fertility preservation programs have been started to safeguard the future fertility of prepubertal and pubertal males requiring high-risk gonadotoxic treatment protocols. However, long-term follow-up studies evaluating the effects on their gonadal development and function related to the testicular biopsy procedure are rather limited.

Design

This two-center follow-up study (between 2002 and 2020) evaluated the gonadal development and function of a cohort of 59 prepubertal and pubertal males who have been offered immature testicular tissue banking (TTB) prior to conventional high-risk chemo- and/or radiotherapy (HR-C/R) or conditioning therapy before hematopoietic stem cell transplantation (CT-HSCT). The aim is to investigate the long-term impact of the testicular biopsy procedure and the high-risk gonadotoxic treatment. Testicular growth and the reproductive hormones luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), and inhibin B (INHB) were analyzed after treatment completion, and compared between males accepting TTB and those refusing TTB (control) as well as between HR-C/R and CT-HSCT treatment protocols.

Results

Of the 59 prepubertal and pubertal males included, 25 were treated by HR-C/R and 34 required CT-HSCT. TTB was accepted for 39 males and refused for 20 males. Most patients were prepubertal at diagnosis (85%), at TTB (79%), and at treatment completion (76%), and pubertal or postpubertal at their last follow-up visit (66%). After 5.0 (1.0–13.0) years post treatment, most patients show normal testicular volumes (83%) and normal LH (89%), FSH (87%), T (87%), and INHB (79%) serum levels. The testicular biopsy procedure did not have an effect on testicular growth, LH, FSH, T, and INHB. Significantly more small postpubertal testicular volumes (p = .0278) and low INHB serum levels (p = .0130) were recorded after CT-HSCT, especially after myeloablative conditioning.

Conclusion

The clinical follow-up data demonstrate no effect related to the biopsy procedure, but a substantial risk for impaired gonadal development after high-risk gonadotoxic treatment, in particular myeloablative CT-HSCT. Longer follow-up studies with a larger study population are needed to confirm these preliminary findings.     

Both gonadotropin and testosterone fail to reverse estrogen-induced cryptorchidism in fetal mice: further evidence for nonandrogenic control of testicular descent in the fetus

Estradiol benzoate (E₂B) causes cryptorchidism in fetal mice, with suppression of androgen secretion. Simultaneous gonadotropin (hCG) injection was reported to restore Leydig cell function and testosterone mediates testicular descent. To investigate whether hCG or testosterone fully reverses the cryptorchidism as well as testosterone secretion, fetal mice were exposed to E₂B with or without hCG/testosterone. Normal transabdominal testicular descent was significantly inhibited by E₂B or diethylstilbestrol injection on day 14 of gestation (n = 41; P < 0.005). Both hCG 50–100 IU (n = 59) and testosterone 5 mg (n = 45) given simultaneously with E₂B failed to restore normal testicular descent (P < 0.005), with the testicular position the same as after E₂B treatment alone. Mean testicular testosterone content at birth after E₂B administration was 66±55 pg/testis (n = 15), while following E₂B plus hCG it was 115±58 pg/testis (n = 10). Normal control mice had a testicular testosterone content of 882±422 pg/testis (n = 12). These results make the view that hCG or testosterone can reverse estrogen-induced cryptorchidism in the fetus questionable. It is proposed that estrogen not only suppresses the hypothalamic-pituitary axis and androgen secretion, but also has a direct inhibitory effect on testicular descent unrelated to androgen action. The action of müllerian inhibiting substance is known to be inhibited by estrogen during müllerian duct regression, and this may be the mechanism by which estrogen inhibits testicular descent.This work was supported by grants from the National Health and Medical Research Council (Australia) and the Research Foundations of the Royal Children's Hospital and the Royal Australasian College of Surgeons. Offprint requests to: J. M. Hutson     

Gonadal function after testicular radiation for acute lymphoblastic leukaemia.

Pubertal maturation, growth, and gonadal function were assessed in 13 boys with acute lymphoblastic leukaemia who had received direct testicular irradiation three to nine years earlier as treatment for testicular relapse or prophylaxis against this complication. Six boys had reached Tanner stage III-V puberty, five of whom had normal growth velocities and bone ages equivalent to chronological age. One boy exhibited maturational arrest on entering stage IV. The remaining seven children (54%) showed evidence of complete pubertal delay or arrested development in stage II, with absence of the pubertal growth spurt and often with delayed bone age. Basal gonadotrophins were abnormally high in all 13 boys, and those with delayed puberty had prepubertal concentrations of testosterone. Testicular irradiation given before puberty causes permanent Leydig cell damage in a high proportion of subjects, necessitating testosterone supplementation. The extent of damage may be related to the age at which radiation is delivered.     

Plasma testosterone response at 1st and 4th day after short- and long-term hCG stimulation test

Human chorionic gonadotropin (hCG) stimulation test is a reliable dynamic test for the evaluation of testicular function during childhood. Several protocols have been recommended but their reliability is controversial. In order to decide the best timing to measure stimulated testosterone levels in short- and long-term hCG protocols, we evaluated 83 prepubertal patients in two group. In group A, 34 patients with isolated micropenis and in group B, 49 inguinal cryptorchidic patients were enrolled. In group A short-term hCG protocol (3000 IU/m2/im/3 days) and in group B long-term hCG protocol (1500 IU/m2/im; thrice a week for 3 weeks) was administered. Blood samples were drawn at the initiation of the test and then at the 1st and 4th days after the last hCG injection. Each case's peak stimulated testosterone (Tmax) and the incremenet in plasma testosterone (deltaT) were calculated and compared with the 1st and 4th day responses within the group. In the short-term protocol the 4th day responses were higher than the 1st day responses (p<0.01). Interestingly, while four patients had insufficient responses at the 1st day, three had sufficient Leydig cell response at the 4th day. In the long-term protocol group, in contrast to the short-term group, the 1st day responses were higher than the 4th day (p<0.01). According to our results, while performing hCG test in a patient, if a short-term protocol is planned, it is more convenient to check the 4th day testosterone response. On the other hand, in a long-term protocol it is best to check the 1st day response. We suggest that even if a patient's 1st day response is inadequate, the 4th day response should be checked in order to avoid misdiagnosis.     

Optimizing potential for fertility: fertility considerations for the pediatrician

Whether for the prepubertal or pubertal child, the goal of fertility preservation is to obtain cells or tissues to be used to produce future children. For the prepubertal child, preservation efforts involve germ cells, earlier forms of sperm, and immature follicles, rather than mature spermatozoa or follicles. Options for prepubertal children include for boys freezing testicular tissue and extracting testicular sperm or for girls obtaining ovarian cortical or follicular tissue for storage. These procedures involve extraction and storage of immature gametes for subsequent in vitro maturation, although attempts for sperm currently involve only animal studies. For adolescent subjects who have sufficient gonadal development and reserve, sperm, oocytes, and ovarian cortex can be retrieved as among adults.     

Primary testicular tumors in childhood. Observations in 21 cases and a discussion of the necessity of metastasis prevention]

A retrospective analysis of 21 primary testicular tumors in childhood is presented. Histologic review revealed 4 differentiated teratomas, 14 yolk sac tumors, 1 rhabdomyosarcoma of testicular envelopes and 1 paratesticular sarcoma. One tumor could not be classified. Two patients with yolk sac tumor and the patient with the paratesticular sarcoma died. In 4 of the 14 patients with yolk sac tumor iliac and/or paraaortic lymphnodes were removed 8-15 days after hemicastration but no tumor cells were found. Of 3 children with yolk sac tumor who developed metastases, one had had prophylactic resection and another one prophylactic irradiation of the draining lymphnodes. 8 patients with yolk sac tumor received prophylactic chemotherapy, and none developed metastases. For patients with yolk sac tumor prophylactic chemotherapy is indicated, particularly if more than 2 months have elapsed between the first detection of a testicular mass and operation. In prepubertal boys with testicular teratoma no prophylactic therapy to prevent dissemination is necessary. Patients with yolk sac tumor have an age distribution comparable to that of patients with an embryonal tumor.     

Prognosis of hormonal treatment of undescended testis related to testicular position at birth

The effect of treatment of 73 boys (mean age 7 years) with undescended testes with human chorionic gonadotropin (hCG) was related to the testicular status at birth as recorded in their birth charts. In 24 boys with diagnosed congenital cryptorchidism, hCG treatment was unsuccessful in 19 cases and operation was performed. In the remaining 5 boys hCG treatment alone was sufficient. Forty-nine boys had normal scrotal testes at birth and hCG therapy was successful in 38, while the remaining 11 required surgical correction. It is concluded that knowledge of the testicular status at birth is of value in clinical practice to evaluate the prognosis of treatment with hCG.