¹Dr. Kulvinder Kaur Centre For Human Reproduction, India

²Ex-Rotunda-A Centre for Human Reproduction, India

³Consultant Neurologist, Swami Satyanand Hospital, India

*Corresponding author: Dr. Kulvinder Kochar Kaur, MD, Scientific Director, Dr. Kulvinder Kaur Centre for Human Reproduction 721, GTB. Nagar, Jalandhar-144001, Punjab, India, Tel: 91-181-9501358180, 91-181-4613422, Fax: 91-181-4613422, ORCID: 0000-0003-1473-3419; Email: [email protected]

Received Date: October 17, 2022

Published Date: November 03, 2022

Citation: Kaur KK, et al. (2022). Optimizing Fertility in Paediatric Disorders that Possess the Potential of Reducing Fertility and Maximization of Avoidance of Development of Male Infertility in Long Term: A Systematic Review. Mathews J Gynecol Obstet. 6(2):21.

Copyrights: Kaur KK, et al. © (2022). 

ABSTRACT

Worldwide male factor Infertility contributes to 20-70% of couples attempting to conceive. Some male Pediatric generational disorders inclusive of Cryptorchidism, hypospadias, testicular besides other acquired cancers of childhood, infections, torsions, Spina Bifida along with Pediatric varicocoele have correlated with future infertility. Early timely fertility preservation, in particular in those waiting for chemotherapy or in cases of genetic disorders like Klinefelters syndrome(KS), Congenital Adrenal Hyperplasia need to be taken into account robustly in patients anticipated to generate testicular depletion. Despite no clarification regarding ideal timing in view of absence of long term prospective studies, early diagnosis as well as targeting treatment might cause maximization of fertility potential in adult hood. Here we conducted a systematic review utilizing search engine PubMed, Google Scholar; Web of Science; Embase; Cochrane review library utilizing the MeSH terms like Cryptorchidism; hypospadias, testicular cancers; torsion; other cancers of childhood; infections; Spina Bifida; paediatric varicocoele; Klinefelters syndrome (KS); Congenital Adrenal Hyperplasia from 1980’s till date in 2022. We found a total of 300 articles out of which we selected 97 articles for this review. No meta-analysis was done. Thus here we summarize how these disorders need to be tackled for optimizing long-term fertility potential.

Keywords: Male factor Infertility, Pediatric cancers, Fertility preservation Cryptorchidism, Klinefelters syndrome

INTRODUCTION

Infertility might take place in 15% of the couples trying to conceive with male factor Infertility contribution escalating regarded as a global problem. In the United States (US) men alone aid in 20-30% of Infertility couples being implicated in about 50% of cases. Whereas, in the remaining world 2.5-12% of men carry a label of Infertility which is responsible for 20-30% of Infertility in couples with maximum rates in Africa, and Europe [1]. In fact, male factor Infertility has been attributed to be the commonest etiological factor regarding those attending assisted reproductive technology (ART) clinics in Australia, and the United Kingdom [2]. ART as Intrauterine insemination (IUI), in-vitro fertilization (IVF) as well as Intracytoplasmic sperm injection (ICSI) has aided numerous couples in attaining pregnancy in men with male factor Infertility. However, these approaches cause important financial taxation for couples in particular in the US where there is no provision of insurance regarding fertility expenses coverage [3]. Despite no existing factors that can be delineated in maximum men with a presentation of reduction of sperm generation. A subset of them might possess a disorder that might be recognizable in the childhood perse which required treatment or certain modifications which might impact future fertility. Recognition besides timely initiation of therapy for these childhood disorders might influence fertility with a probability of reduction of infertility prevalence.

Despite numerous congenital abnormalities being implicated along with acquired diseases of childhood believed to be responsible for male Infertility, the acquisition of insight regarding the probability of impact of these situations poses restrictions secondary to postponed diagnosis. treatment besides reproductive age.

It is without any argument that any disorder impacting testicular function or resulting in testicular depletion at the time of childhood would impact fertility. Testicular impairment at the time of fetal generation might associate infertility with usual generational along with acquired situations, like testicular maldescent, torsion, cancer, besides hypospadias that is projected in the testicular dysgenesis syndrome posit [4]. Testicular impairment or depletion might be acquired from other cancers as well as their treatment, infections along with formation of a varicocoele. Spina bifida is a frequent kind of congenital spinal impairment, which further might impact fertility besides sexual functions in patients afflicted with this. Additionally, numerous boys are born with genetic conditions that are associated with syndromes that can be recognized. Earlier we have already focused on rare conditions of idiopathic Hypogonadotropic Hypogonadism like Kallmann syndrome (KS), along with other rare syndromes inclusive of kisspeptin deficiency correlated KS, paediatric varicocoele, how to tackle fertility issues in paediatric cancer survival [5-13]. Thus we reviewed the different paediatric conditions that In later life might aid in the generation of male infertility besides early diagnosis along with treatment for avoidance of male infertility later.

METHODS

Here we conducted a systematic review utilizing search engine PubMed, Google Scholar; Web of Science; Embase; Cochrane review library utilizing the MeSH terms like Cryptorchidism; hypospadias, Testicular cancers; torsion; other cancers of childhood; infections; Spina Bifida; paediatric varicocoele; Klinefelters syndrome (KS); Congenital Adrenal Hyperplasia from 1980’s till date in 2022.

RESULTS

We found a total of 300 articles out of which we selected 100 articles for this review. No meta-analysis was done.

Cryptorchidism

Cryptorchidism alias undescended testis (UDT) represents the absence of testis descending into the scrotum which is the commonest abnormality of the male sexual generation. It is common knowledge regarding the association of UDT with testicular torsion, cancer, as well as inguinal hernia, besides impacting fertility as well [14]. Cryptorchidism is inclusive of a broad type of manifestations that might possess variable influences on testicular generation along with function. Boys that are afflicted might have unilateral or bilateral UDT, with existence of testis that might be variable based on the path of the normal generational descent varying from intra-abdominal to just in area above the scrotum [15]. Cryptorchidism (aliasUDT), might be congenital, ascending/acquired, or retractile based on testicular localization at birth. While ascending cryptorchidism is when an earlier intrascrotal testis assumes an extra scrotal location mostly at the time of linear growth. Lastly, a retractile testis is intrascrotal, however, moves with ease out from the scrotum in view of intense cremasteric reflex. It needs to be taken into account regarding with gentle manual pressure easy manipulation of the testis into scrotum is feasible [16]. Despite, congenital UDT might descend towards the appropriate scrotal location by 6 mth with a gestation age that is appropriate, no clarification exists regarding the natural history of acquired UDT [17]. In view of the heterogeneity of this disease, acquisition of insight regarding the proper epidemiology, and influence on testicular function, besides the ideal time of repair as orchidopexy has continued to be ill-understood. At present both the American as well as European Society of Urology Associations advocate repair at the age of around 18 months since reduction of germ cells is seen with malpositioning of testis for longer duration [15, 17,18].

The diagnosis of cryptorchidism is a clinical one with estimation of true prevalence being tough in view of the subjective nature of examination. A recent systematic review determined UDT to be existent in 1-4% of full term along with 45% of premature newborn boys [19]. Unilateral UDT contributes to 60-70% of nonsyndromic cryptorchidism of which 70% take place on right side [20]. A familial association is present in 4.3% of half-brothers,7.5% of full brothers along with16.7% of monozygotic twins dizygotic as well as 26.7% of monozygotic twins [21]. Apart from hereditary factors, perinatal milieu exposure might escalate the risk of cryptorchidism. Maternal factors like alcohol intake, smoking besides continued analgesic utilization have demonstrated escalated cryptorchidism incidence while occupation, weight, along with estrogen exposure have not shown any such relation [22]. Despite, hereditary along with maternal risk factors identification full insight regarding normal descent in addition to abnormal descent continues to elude us.

Testicular descent is a complicated event where testicular hormone signaling probably has a critical part. Briefly around 12 weeks gestation age (GA), the mullerian ducts along with mesonephros get disrupted while the testis growth starts along with swelling of the gubernaculums. The swelling of the gubernaculum is a significant process that is persistent till week 14-20, resulting in broadening of the inguinal canal, generation of the cremasteric muscle’s along with migration of processes vaginalis [23]. At this time peak amounts of follicle-stimulating hormone (FSH). Luteinizing hormone (LH) testosterone (T) along with insulin like peptide 3(INSL3) besides its receptor (RXFP2) are seen, addition to in non-human animal model have illustrated a direct influence of testicular hormones on gubernaculum generation [24, 25] (see Figure 1 & 2). Although such models show a correlation amongst INSL3/ RXFP2 mutations along with cryptorchidism there is inconsistency regarding penetrance in human studies [26]. Subsequent to this the testes travels via the inguinal canal, at weeks 20-28 along with caudal motion of testis into the scrotum persists till birth [23]. The part of testicular hormones pointed to that testicular function along with generation might be dysfunctional in cryptorchidism prior to only. Besides not due to extrascrotal location at birth.

Figure 1. Courtesy [24] The path of testicular descent and classification of testicular position according to the John Radcliffe Hospital Cryptorchidism Study.

Figure 2. Courtesy [24] Minipuberty of infancy. Schematic presentation of the changes in reproductive hormone levels during the first year of life in healthy boys. The peak hormone levels are observed between 1-3 months of age. LH and testosterone levels decrease by 6 months of age, but FSH and inhibin B levels remain elevated longer. AMH levels increase from birth to 3 months of age, then slightly decrease but remain higher than in adults until puberty. Penile length and testicular volume increase and testicular descent continue during minipuberty.

With the scrotal location of testis provision of ideal temperature regarding spermatogenesis to take place; nevertheless, the influence of extrascrotal milieu regarding the generating prepubertal testis is not clarified. It can be corroborated that type A dark spermatogonia generate immediately subsequent to birth at 3-6 moths. A state of ‘’minipuberty‘’ surge of Gonadotropins, T, Inhibin B, AMH at this time are comparable to histological studies illustrating reduction in gonocytes amounts (alias the male germ cells, along with escalated amounts of spermatogonia [27]. This event might be ameliorated regarding cryptorchid testes since numerous studies have illustrated the existence of reduction of germ cells/seminiferous tubules cross section ratio (G/T) on biopsying cryptorchid testes contrasted to control samples [28-30]. Reduction in G/T has been observed to be associated with reduction in Inhibin B along with enhanced FSH, whose utilization is commonly done regarding anticipation of fertility potential [28-30]. Furthermore, Huff et al. [31], illustrated reduction of G/T in the opposite testis of unilateral cryptorchidism that pointed to an escalated surrounding temperature might not give reasoning completely regarding the reduction of germ cells or that signaling from the cryptorchid testes possesses harmful actions on the opposite testis [31]. Zhao et al. [32], in 2021 revealed that subsequent to conducting ambulatory orchidopexy, in a 8 years retrospective study of 4972 cases, this correctly timed repair rate escalated from 25.7%to37%(P<0.001) along with the proportion of patients, undergoing surgery prior to the age of 1 year enhanced statistically significant rates from 3.5to8.6%(P<0.001). The percentage of correctly timed repair in patients with ambulatory medical paraphernalia availability was significantly greater contrasted to patients without ambulatory medical paraphernalia (15.6 vs 58.2% P<0.001). Significant alterations in the surgical rates prior to 1yr were further seen among the 2 groups (2.4% vs 14.8% P<0.001) [32]. Utilization of G/T for testicular size at the time of orchidopexy has been done in prospective studies in the form of anticipation of further fertility. Reduction in G/T is existent in 25% of cryptorchid boys, with greater rates of reduced ratios for the ones with postponement of repair following 1-3 years [28-31]. The actions of postponed repair were akin for testicular growth in case unilateral cryptorchid infants were randomized for repair at 9 months vs 3 years. In the group with early surgical management the testicular growth was sustained whereas not in postponed group [33]. To our misfortune, no clarity exists regarding the association of surrogate markers with future sperm generation/paternity rates.

Utilization of paternity besides ART rates has been carried out in Retrospective studies in cryptorchid boys for fertility assessment. Paternity rates were determined at 50-65% for bilateral along with 81-90% for unilateral cryptorchidism [34]. Significant reduction of paternity was existent in bilateral UDT, while that of unilateral UDT was akin to controls [35]. In a large population dependent cohort study from Western Australia, Schneuer et al. [14], documented on paternity rates in these boys. The paternity rates for the full cohort was 31.2% along with earlier cryptorchid men just 26.9% with lesser paternity for bilateral contrasted to unilateral UDT.1% reduction in paternity with each 6 months age escalation along with twice the chances for need for ART utilization contrasted to non-influenced boys, with a reduction to1.3 times in case orchidopexy had been done prior to age 18mths.On contrasting semen evaluation(SE) in the couple’s infertility clinic amongst men with a history of UDT along with, without bilateral UDT was correlated with lesser testicular volumes besides just 12% of men possessed the chances for normal sperm amounts (≥15million/ml). Finally, azoospermia was estimated in 28% along with 40% men with unilateral along with bilateral UDT respectively [36].

Cryptorchidism represents a heterogenous disease that might result in inimical actions on male reproduction. Despite, the ideal time of orchidopexy has not been worked out. A robust proof regarding early repair is of benefit for maximization of fertility probability. Although the histological outcomes of early infancy reveal reduction of germ cells amounts by the age of 3-6 months, clinical results pointed to an advantageous fertility probability once the orchidopexy has been conducted by 18 months of age. For reduction of the gap along with achieving even greater fertility maximization certain investigators are attempting use of LHRH for reverting the germ cells reduction besides decline in amounts of type a spermatogonia. Despite occasional patients with bilateral UDT got success in this study greater intense trials are warranted for assessment, of effectiveness along with safety of gonadotropins delivery to children [37].

Hypospadias

Hypospadias is further correlated with future fertility, represents a frequent penile generational conditions. Where opening of the urethra is proximal contrast to normal glandular localization on the ventral side of the penis [14]. This meatal localization might vary from the distal towards the coronal to the proximal part of perineum. With further upstream localizations that pointed to greater complicated disease needing complex repair. Based on the robustness of Hypospadias it might further be correlated with a ventral bending, scrotum that is bifid or penoscrotal translocation. Despite, the existence of a functional erectile tissue, sexual impairment might be existent with greater frequency in disease which is proximal even though repair for correction attempted [38]. Hypospadias generation might take place in view of underlying testicular impairment in utero which might reason out the association amongst Hypospadias along with infertility.

Hypospadias takes place in 0.3-0.8% of live births with an escalating trend might be present [39]. Clarification regarding the underlying genetic factors are not there. However, the population cohort studies illustrated a robust hereditary recurrence risks amongst identical twins along with first, second besides third degree relatives irrespective of maternal or paternal hereditary. Additionally, despite, certain syndromic correlation with hypospadias, it commonly is a lone occurrence in >90% of patients [40].

The Embryological formation of hypospadias is ill-understood. There is partial dependence of generation of male external genitalia on dihydrotestosterone (DHT) that gets catalyzed via 5α reductase (5AR) from T [41]. Upto7 weeks there is existence of common external genitalia that is made up of a genital tubercle along with uro genital membrane that in males are the future glans along with urethra respectively [42]. Based on the impact of the sex-determining area of the Y chromosomes. Leydig cell differentiation, as well as generation of T get initiated in 9-10 week. Subsequently DHT results in growth of prostate in addition to elongation of the genital tubercle besides phallus [43]. Once there is elongation of the genital tubercle for the generation of the pedunculous urethra along with glans, canalization of the urethral plate takes place from the proximal urethra towards the distal urethra, with fusion of urethral folds, finishing the formation of the penile urethra. Whereas, hypospadias is thought to be secondary to halt of this event. The glandular urethra generates at this time by invagination from the genital tubercle shifting proximally, hence a purely proximal urethra does not exist as per Embryology [42]. Reduction in androgens might possess variable actions on the formation of male external genitalia. In case of genetic males possessing 5AR deficiency. Hence no generation of DHT, generate female external genitalia, while rats in utero exposed to 5 AR hampering agents has resulted in the generation of hypospadias [43]. This might point to the requirement of comparatively little quantities of DHT for the masculinization of indifferent genitalia, however, greater quantities are needed regarding normal penile generation. Multiple other genes are responsible for hypospadias generation whose invention was initially made via variable syndromes. noticeably the WT1-correlated syndromes. Since hypospadias is generally observed in. WAGR (Wilms tumor–aniridia-genitourinary aberrations. mental retardation), Denys–Drash along with Fraser’s syndromes.

Population dependent studies have illustrated that a 13-21% decrease in the chances of acquisition of fatherhood. With greater robust hypospadias was correlated with reducing paternity rates [14,44]. Cryptorchidism, exists in up till 18% of patients might further complicate these observations as once the diagnosis of male infertility is apparently correlated with greater proximal hypospadias, however on elimination of cryptorchid men from evaluation, no significance was associated with this action [45]. Akin to that men with hypospadias along with associated simultaneously existent genital aberrations or greater proximal hypospadias possessed greater incidence of subfertility contrasted to isolated hypospadias. Intriguingly all hypospadias inclusive of isolated hypospadias possessed greater average quantities of FSH, LH along with lesser T that pointed to a subtle testicular impairment irrespective of semen results [46]. Furthermore, reduction in paternity rates might be reasoned by sexual impairment which might present in adults despite childhood repair. Generally, men documented sustenance of erectile function. Sexual desire along with sensation, however, might have dyspareunia secondary to the left curvature/ejaculatory impairment [36,47]. Dyspareunia might present in 8.5% of patients, while uptill34% might reveal an ejaculation or minimum spraying ejaculate [36]. Trying assessment of a hypospadias patient presenting with infertility, besides assessing the associated congenital genital abnormalities, semen, along with hormones is needed. Obtaining exhaustive sexual history that target any type of sexual impairment that might get corrected is significant. Furthermore, the group of Nordenvall et al. [47], for the first time described the association of neurodevelopmental disorders with hypospadias which has been corroborated by Jin et al. [ 48].

Testicular Cancer

Reviewed in detail by us in references [11,13].

Torsion in Paediatric Patients

Testicular torsion presents in the form of an emergency Urologic situation that takes place in around 5 in 100,000 men with variation from ages of 1 to 25 year/s [49]. Maximum of these Paediatric events occur in perinatal or pubertal time duration which along with a RAF1gene mutation might escalate the chances of neonatal torsion situation [50]. The mode of damage in torsion is the ischemia occurring following solitary testis torsion which might result in depletion of function in case there is absence of recapitulation of blood flow at the time of the insult [51]. Classification of torsion in the form of i) intravaginal (alias rotation of the spermatic cord within the tunica vaginalis) [52]. ii) Testicular torsion that gets diagnosed at the perinatal time duration are extravaginal, which even following surgical treatment, results in depletion of tissue viability [53]. Clarification regarding the risk of infertility subsequent to intravaginal testicular torsion with repair is non-existent.

Posit regarding the pathophysiology of escalating infertility rates are inclusive of reperfusion damage by Reactive oxygen species (ROS) subsequent to an ischemic process as well as alloimmunization [54]. Numerous assessment attempts have been made for deriving information regarding the potential association amongst testicular torsion as well as the infertility status. Puri et al. [55], along with Arap et al. [56], observed no correlation via case series evaluation. Puri et al. [55], investigated patients at the time of prepubertal time duration (n=18] along with Arap et al. [56], observed no variation of hormone quantities as well as SA in the ones with history of testicular torsion. In agreement with these observations, Gielchinsky et al. [57], found no variation in pregnancy rates amongst patients with history of torsion along with general population [57]. No statistically significant, variation was noticed regarding paternity rates by Makela et al. [58], for the patients who had orchidopexy vs torsion repair contrasted to control population [58]. Conversely, Identification of significant alterations in SA of 67 patients with prior history of torsion was made by Thomas et al. [59], with conclusions of reduction in fertility potential [59]. On extension of their study they saw escalation of infertility status as well as reduction in pregnancy rates amongst a subgroup of these patients studied [59]. Woodruff et al. [60], presented an Intriguing Paediatric patient with history of following solitary testis who experienced a continued testicular torsion process. On counselling the patients family regarding the risk of infertility inspite surgical therapy, patient finally went via cryopreservation as well as orchidopexy [60]. Despite maximum studies pointed that there is no apparent correlation amongst testicular torsion as well as reduction in fertility potential. Lack of consensus makes it essential to get further insight so that appropriate counselling of the patients is done at the time of diagnosis.

Varicocoele in Paediatric Patients

The Prevalence of Varicocoele in Paediatric Patients varies from 4.1-35.1% [61]. The Identification of average age of manifestation has been 15.2±3.6 years [62]. Clarification regarding the influence of Varicocoele on reduction of fertility is not present since maximum men with Varicocoele are fertile, the mechanistic explanation regarding the pathogenesis are inclusive of Oxidative stress (OS), bad tissue reperfusion, stress of temperature as well as hormone aberrations [63]. The common reasons regarding, surgical treatment despite dependent on the subjective assessment of the treating Physician are i) disparity amongst the testicular sizes ii) pain in testicular area. iii) Abnormal SA parameters [64]. The intervention regarding treatment might implicate Varicocoelectomy or embolization, with multiple studies illustrated recovery if attempted for the reasons cited above Madhusudanan et al. [65], recently illustrated an enhancement in responses of over a year subsequent to Varicocoelectomy that further corroborated that repair in boys besides adolescents rather than postponement till reproductive age reached [65]. Basically, it is a grey area warranting future assessment for acquisition of greater insight regarding actual actions on future fertility [66]. Adequate counselling by the Urologist is required for patients as well as their families on long term potential that is male reproductive health results related.

Urogenital Infections in Paediatric Patients

Acute epididymites/epididymoorchitis (E/EO) along with chronic orchitis are the commonest genitourinary infections in Paediatric patients which might influence the probability of fertility. Regarding the Paediatric Patient population, sexually tra nsmitted like Neisseria gonorrheae as well as Chlamydia trichomatis need to be taken into account besides the enteric pathogens. Weidner et al. [67], demonstrated that maximum patients presenting with E/EO just temporary dysfunction in semen parameters was observed. Subsequent to successful treatment evaluation on follow up revealed enhancement back towards baseline in the span of subsequent 6mths with minimum number of patients had continuation of the aberrant parameters [67]. Conversely etiology of chronic mumps orchitis is generally secondary to viral infections like mumps [68]. This diagnosis is feasible only by the utilization of a testicular biopsy. The histological observation s was inclusive of seminiferous tubules injury besides peritubal lymphocytes infiltration. It was posited that this T cell modulated responses in selected Acute E/EO as well as chronic orchitis is what results in the future male infertility. Long term influence of testicular infections might lead to obstructive azoospermia which needs microsurgical re-construction or the vasa or testicular sperm extraction along with hence in vitro fertilization (IVF) [69]. Chronic mumps orchitis generally needs IVF in view of rete testes obstruction due to ischaemia. Finally, it is of considerable importance to diagnose these patients at correct time of infection for preservation of fertility probability.

Spina Bifida

Prevalence of Spina Bifida represents a congenital disease event where the fetal Spinal cord generation does not occur appropriately in utero. In US its Prevalence is around 25000 patients amongst the age of 0 along with 19 years [70]. The commonest presentation encountered by the Urologist is the neurogenic bladder, however Sexual impairment along with infertility have acquired a greater Prevalence, secondary to escalation of life expectancy of these patients [71]. Over 85% of these patients is in their thirties [72]. Large scale population studies for the Identification of the Prevalence of infertility have not been conducted in these patients. However, collected smaller observation studies have documented lesser paternity rates. Both Spina Bifida along with Spinal cord injured men possessed the capacity of becoming a father in particular since the of generation of ART methodologies [73].

Mechanistically the etiology regarding infertility in case of Spina Bifida patients are secondary to spermatogenic abnormalities along with ejaculatory impairments [74], 4/9 men possessed no sperms in their ejaculate as per Hultling et al. [75], besides having aberrant semen parameters. Different studies regarding Spinal cord injured men illustrated that Spina Bifida patients possessed greater inimical Semen quality contrasted to those of injured men that posited that there was existence of probability of significance of early neurological gonadal intervention [76]. The presentation of ejaculatory impairments is in general is as an ejaculation, with the requirement of penile vibratory stimulation/electro ejaculation [77]. Future studies are warranted in the population for getting more insight, regarding the risk for infertility, aiding the treating doctors to tackle these issues in a more advantageous manner for long term therapy.

Assessment of sexual impairment has been studied more exhaustively in these patients. The Prevalence of erectile impairment has been documented in 12-79%. Contradictory results have been revealed with Diamond et al. [78] observing erectile function in 70% of patients. However, Schurtlef et al. [79], documented, it in just 4% [78,79]. A questionnaire was prepared by Hirayama et al. [80] that illustrated reduction in satisfaction along with rigidity despite giving history of positive erections [80]. This might account for greater understanding regarding this patient population where erectile impairment is in general not fully taken into account that results in insufficient transportation of sperm for pregnancy. In these types of patients enough therapy with 5omg sildenafil has been illustrated to relieve symptoms by 96% [81]. With proven effectiveness of correct treatment it becomes significant to highlight the Sexual dysfunction in this patient population.

A significant issue for maximization of these patient’s long-term fertility results is in the hands of transfer, of these patients from the paediatric towards adult urology handling. Maximum physicians do not even detail regarding fertility besides problems besides treatment strategies as corroborated by a questionnaire in Netherlands illustrating just 12% fertility consultation at the time of their visits [78]. Just similar to the patients who were survivors of oncologic treatment it is of equivalent significance along with following Guidelines laid down regarding early counselling [82]. Despite, numerous publications regarding highlighting this issue transitional urology remains a significant topic for early education of these Physicians [83]. With the escalated generation in this field it would have major impact on ensuring ideal long-term fertility results in Spina Bifida patients [84].

Male Infertility correlated with Genetic factors

Male infertility implicates an occurrence with numerous factors, based on crosstalk amongst, genetics, epigenetics factors, post-transcriptional controllers, along with the microenvironment. Changes in the Molecular pathways or inadequate expression of relevant factors possess the capacity of resulting in male infertility. Clinical presentations of the unregulated alterations are inclusive of aberrations in the formation of internal along with external genitalia. Germ cell generation, hormonal homeostasis, spermatogenesis, and sperm quality [85]. As per certain authors, genetic factors are implicated in 15030% of male infertility [86].

Correlation of azoospermia with greater amounts of genetic differences contrasted to the ones with enhancement of sperm generation [87]. Additional observations were karyotypic aberrations were present in around 0.6% of population in general along with 2-14% of patients with male infertility [88]. Although our anticipation is of finding innovative genomic variants with future work regarding the etiologies of idiopathic male infertility patients. Generally, the genetic syndrome with diagnosis in childhood that is correlated with reduced fertility is inclusive of Klinefelters syndrome (KS along with) congenital adrenal hyperplasia (CAH), which are detailed here, although there are certain disorders with rare prevalence [5-7,10,89-91,95].

Klinefelters syndrome (KS)

Klinefelters syndrome (KS) represents a group of symptoms secondary to the presence of an excess of X chromosomes in male subjects. The commonest karyotype is 47XXY, which occurs in 80-90%of KS patients. Furthermore, mosaicism might be existent, besides correlated with a milder phenotype, while other genotypes possessing an excess of X chromosome (like 48 XXYY, 48 XXXY,49 XXXXY,49 XXXYY) possess a correlation with greater robust phenotypes [92]. KS further is the commonest syndromic etiology of non-obstructive azoospermia. that is in general associated with Hypogonadotropic Hypogonadism (HH). Classically KS patients are tall statured that possess eunuchoid body stature along with gynaecomastia. Other Clinical characteristics are inclusive of motor, language generational postponement, learning problems, reduction in T amounts, broadened hips, small testicles with hyalinization, fibrosis of the seminiferous tubules, leydig cell hyperplasia besides metabolic impairment. whose presentation might take place at the time of adolescence. In view of subtle or subclinical manifestation, in some cases, its diagnosis might get delayed, despite the existence of symptoms in childhood along with adolescence. The diagnosis of these patients are in general postponed till adulthood or at the time of infertility assessment.

For maximization of fertility potential, in KS needs initiation early at the time of adolescence since germ cells depletion is impacted at the time of puberty initiation that continues all through life. Thus assessment of fertility needs to be initiated at adolescence. Figure 3 depicts the treatment pattern. Irrespective of age in case sperms are existent in the ejaculate, families need to take into account cryopreservation with robustness. Those whose presentation is with low T, serum FSH, LH need to be determined along with rectified by use of aromatase inhibitors, clomiphene, or HCG, if feasible prior to any testicular biopsy or sperm extraction. Gonadotropins-directed T treatment can enhance the opportunity of probability of successful sperms getting retrieved, with utilization of post therapy T amounts as anticipator for success (77% for ≥250ng/dl vs 55% for <250 ng/dl; p=0.05) [93]. KS patients might possess some bit of spermatogenic failure, with occasional spermatozoa in the ejaculate in young adults varying from 4.3-8.4% along with in adolescents from 0-5%. Additionally, it has been pointed that successful TESA sperms getting retrieved, reduce with age from 81% at 25-29 years to 22% at 40-44 years emphasizing the significance of early diagnosis along with management [94,95] (Figure 3).

Figure 3. Courtesy ref no-95-Recommended evaluation and treatment algorithm for adolescent males with Klinefelters syndrome. AI = aromatase inhibitor; E = estrogen; SA = semen analysis; SERM = selective estrogen receptor modulator; TESE = testicular sperm extraction; TRT = testosterone replacement therapy.

Congenital Adrenal Hyperplasia (CAH)

Congenital Adrenal Hyperplasia (CAH) represents a group of autosomal recessive conditions that might takes place secondary to deficiencies of certain enzymes, implicated in adrenal steroid bio-generation pathways which resulted in the impairment of cortisol bio generation. Different clinical presentations of CAH might be existent inclusive of classical along with non-classical presentations; i) 21 hydroxylase deficiency constitutes the commonest abnormality [96]. It has been pointed that greater adrenal androgens amounts in implicated males can cause HH. Both gonadal impairments along with precocious puberty have been documented in CAH patients, with >40% presenting with oligospermia/azoospermia [97]. Of the major factor implicated in fertility in men with CAH is benign testicular adrenal rest tumors (TARTs), that exist in 27-47% patients. TARTs take place secondary to ectopic adrenal cells whose descent accompanies that of testes at the time of fetal life along with their growth occurring with the stimulation of ACTH along with Angiotensin II. In general TARTs are bilateral, with localization at the hilum of the testes, which possess the capacity of injuring the normal testicular tissue besides the probability of resulting in obstructive pathology. In view of this at the time of childhood, frequent monitoring with the utilization of ultrasound has to be initiated [95,98]. Steroid replacement therapy can enhance long term fertility potential in CAH patients that can result in reduction of ACTH along with Angiotensin II, thus prevention of TART growth. With adequate therapy, surgical treatment with testicular sperm extraction (TESA) is rarely required; nevertheless, cryopreservation still is to be offered in view of the risk of TARTs propagation [100].

CONCLUSIONS

Acquisition of insight regarding the correct influence on childhood generational, acquired along with genetic situations, along with the right time besides kind of treatment will persist as hurdles. Whereas prospective studies are required for illustrating the right time by which the boys achieve the maximum fertility potential at the time of adulthood, although this might not be possible taking into account the long-term follow-up which might be needed. Realization of the possible influence on fertility potential along with the Sexual function of a broad category of Paediatric disorders promotes early diagnosis besides treatment fashioned those aids in enhancement of pregnancy results. A high suspicion index has to be borne in mind of Physician regarding which might alter the potential for any fertility along with referral to the appropriate reproductive endocrinology specialist/urologist if needed besides counselling for fertility preservation with patients/parents/guardians as per their availability or level of understanding. Prepubertal testicular tissue cryopreservation besides Gonadotropins modulation at the time of childhood is future investigational areas. Recently Deigoulfe et al. [100], summarized the indications where Testicular tissue Banking is required for fertility preservation in young boys & where not needed. Thus in summary there are numerous paediatric disorders that if not received correct attention can become the reason for future need for ART.

REFERENCES

1. Agarwal A, MulgundA, HamadaA, Reene Chyatte M. (2015). A unique view on male Infertility around the globe. Reprod Biol Endocrinol. 13:37.
2. Human Fertilization and Embryology Authority. Fertilization treatment 2014-2016-trends and figures. Available at: http://www.hfea.gov.uk/media/2563/hfea-fertility-trends-and-figures-2017-v2pdf. Accessed December 15.2019.
3. Connolly MP, Hoorens S, Chambers GM. (2010). The costs and consequences of assisted reproductive technology: an economic perspective. Hum Reprod Update. 16(6): 603-613.
4. Skakkebaek NE, Rajper de Meyts E, Main KM. (2001). Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod. 16(5): 972-978.
5. Kochar Kaur K, Allahbadia GN, Singh M. (2016). Idiopathic hypogonadotropic hypogonadism- an update on the aetiopathogenesis, management of IHH in both males and females-an exhaustive review. Advances in Sexual Medicine. 6(4): 50-78.
6. Kochar Kaur K, Allahbadia GN, Singh M. (2018). An Update on Genetics of Disorders of Sexual Development Along with Signal Transduction Pathways-Clinical Implications: A Review. Int J Genet Sci. 4(2): 1-12.
7. Kochar Kaur K, Allahbadia GN, Singh M. (2018). Importance of Varicocele Treatment for Male Infertility in the Days of Assisted Reproductive Technology. Surg Med Open Acc J. 2(2): SMOAJ.000531.2018.
8. Kochar Kaur K, Allahbadia GN, Singh M. (2019). An Update on Aetiopathology, Various Genetic Causes and Management of Delayed Puberty-A Minireview. J Pediatr Neonatal Biol. 4(1): 1-8.
9. Kulvinder KK, Gautam A, Mandeep Singh. (2019). Treatment of Adolescent and Pediatric Varicocele-Continues to be A Dilemma-A Mini Review. Arch Reprod Med Sex Health. 2(I1): 1-11.
10. Kulvinder KK. (2020). Editorial-Prevention of Male Infertility by Early Detection of Congenital Hypogonadotropic Hypogonadism (CHH) Along with Sertoli Cell Dysfunction in Prepubertal and Transition Phase Starting from Neonatal Phase to Transition Phase–Time has Come. Acta Scientific Paediatrics. 3(3): 01-02.
11. Kochar Kaur K, Allahbadia GN, Singh M. (2020). How Far Have We Reached with Regards to Our Endeavours in Testicular Tissue Transplantation Along with in Vitro Spermatogenesis After Success in Animals-A Systematic Review. Archives of Urology. 3(2): 1-15.
12. Kochar Kaur K, Allahbadia GN, Singh M. (2021). An update on the Advances in the management of Congenital hypogonadotrophic hypogonadism-A Minireview. J Pediatrics and Child Health. 2(1).
13. Kochar Kaur K, Allahbadia GN, Singh M. (2021). Significance of Fertility Preservation in Patients Undergoing Cancer Chemotherapy Specifically in Adolescents/Young Adults Requiring Alkylating Agent-A Short Communication. Acta Scientific Cancer Biology. 5(10): 1-4.
14. Schneuer FJ, Milne E, Jamieson SE, et al. (2018). Association between male genital anomalies and adult male reproductive disorders: a population-based data linkage study spanning more than 40 years. Lancet Child Adolesc Health. 2(10): 736-743.
15. Kolon TF, Herndon CD, Baker LA, et al. (2014). American Urology Association Evaluation and treatment of Cryptorchidism: AUA Guidelines. J Urol. 192: 337-345.
16. LaScala GC, Ein SH. (2004). Retractile testes: an outcome analysis on 150 patients. J Peds Surg. 39(7): 1014-1017.
17. Berkowitz GS, Lapinski RH, Dolgin SE, etal. (1993). Prevalence and natural history of Cryptorchidism. Paediatrics. 92(1): 44-49.
18. Radmayr C, Dogan HS, Hoebeke P, etal. (2016). Corrigendum to Management of undescended testes. European Society of Urology / European Society of Paediatrics Urology Guidelines. J Paediatr Urol. 12: 335-343.
19. Sljtermans K, Hack WW, Meijer RW, et al. (2008). The frequency of undescended testes from birth to adulthood: A review. Int J Androl. 31(1): 1-11.
20. Cendron M, Keating Ma, Huff DS, et al. (1993). Anatomical, morphological and volumetric analysis: A review of 759 cases of testicular maldescent. J Urol. 149(3): 570-573.
21. Jensen MS, Toft G, Thulstrup AM, et al. (2010). Cryptorchidism concordance in monozygotic and dizygotic twin brothers, full brothers and half brothers. Fertil Steril. 93(1): 124-129.
22. Hackshaw A, Rodeck C, Boniface S. (2011). Maternal smoking in pregnancy and birth defects: a systematic review based on 173687 malformed cases and 11.7 million controls. Hum Reprod Update. 17(5): 589-604.
23. BarteckoKJ, JacobMI. (2000). The testicular descentin human. Origin, development an fate of gubernaculum hunteri, processus vaginalisperitonei and gonadal ligaments. Adv Anat Embryol Cell Biol. 156: 1-98.
24. Kuiri-Hainninen T, Koskenniemi J, Dunkel L, Toppari J, Sankilampi U. (2019). Post natal testicular activity in healthy boys and boys with Cryptorchidism. Front Endocrinol (Lausanne). 10: 489.
25. Kaftanoskaya EM, Huang Z, Barbara AM, et al. (2012). Cryptorchidism in mice with an androgen receptor ablation in gubernaculums testis. Mol Cell Endocrinol. 26(4): 598-607.
26. Forresta C, Zucarello D, Garolla A, et al. (2008). Role of hormones, genes and environment in human cryptorchidism. Endocr Rev. 29(5): 560-580.
27. Loebenstein M, Throup J, Cortes D, et al. ( 2020). Cryptorchidism. gonocyte development, and the risk of germ cells malignancy and infertility :a systematic review. J Paeds Surg. 55(7): 1201-1210.
28. Hadziselimovic F, Hertzog B. (1984). The value of testicular biopsy in Cryptorchidism. Urol Res. 12(3): 171-174.
29. Hildorf S, Classen Linde E, Cortes D, Thorup J. (2020). Fertility potential is compromised in about20%-25% of non syndromic cryptorchid boys despite orchidopexy with in the first year of life. J Urol. 203(4): 832-840.
30. Hildorf S, Classen Linde E, Cortes D, Thorup J. (2021). Fertility potential is impaired in boys with bilateral ascending testes. J Urol. 205(2): 586-594.
31. Zhao T, Deng F, Jia W, Gao X, Li Z, Tang X, et al. (2021). Ambulatory orchidopexy is a potential solution to improve the timely repair of cryptorchid boys: An 8 years retrospective study of 4972 cases. Front Paediatr. 9: 671578.
32. Huff DS, Fenig DM, Canning DA, Carr MG, Zderic SA, Synder IIIHM. (2001). Abnormal germ cells development in cryptorchidism. Horm Res. 55(1): 11-17.
33. Kollin C, Karpe B, Hesser U, Granholm T, Ritzen EM. (2007). Surgical treatment of unilaterally undescended testes: testicular growth after randomization to orchidopexy at age 0 months or 3 years. J Urol. 178(4S): 1589-1593.
34. Lee PA. (2005). Fertility after cryptorchidism: Epidemiology and other outcome studies. Urology. 66(2): 427-431.
35. Rohayem J, Luberto A, Nieschlag E, Zitzmann M, Kliesch S. (2017). Delayed treatment of undescended testes may promote hypogonadism and infertility. Endocrine. 55(3): 914-924.
36. Thorup J, Classen Linde E, Dong L, et al. (2018). Selecting infants with cryptorchidism and high risk infertility for optimal adjuvant hormonetherapy and cryopreservation of germ cells: experience from a pilot study. Front Endocrinol. 9: 299.
37. Bubanj TB, Perovic SV, Milicevic RM, Jovcic SB, Marjanovic ZO, Djordjevic MM. (2004). Sexual behavior and sexual function of adults after hypospadias surgery: a comparative study. J Urol. 171(5): 1876-1879.
38. Nordenvall AS, Frisen L, Nodenstom A, Lichtenstein P, Nordenskjold A. (2014). Population based nationwide study of hypospadias in Sweden 1973-2009: incidence and risk factors. J Urol. 191(3): 783-789.
39.  Schnack TH, Zdrakovic S, Myrup C, et al. (2008). Familial aggregation of hypospadias: a cohort study. Am J Epidemiol. 167(3): 251-256.
40. Auchus RJ. (2004). The backdoor pathway to dihydrotestosterone. Trends Endocrinol Metab. 15(9): 432-438.
41. Baskin l. (2000). Hypospadias and urethral development. J Urol. 163(3): 95-96.
42. Ray RA, Grinspon RP. (2011). Normal male sexual differentiation and etiology of disorders of sexual development. Best Pract Res Clin Obstet Gynaecol. 25(2): 221-238.
43. Clark RL, Anderson CA, Grossmann SJ, et al. (1990). External genitalia abnormalities in male rats exposed in utero to finasteride, a 5 alpha-reductase inhibitor. Teratology. 42(1): 91-100.
44. Nordenvall AS, Chen Q, Norrby C, et al. (2020). Fertility in adult men born with hypospadias:a nationwide register- based cohort study on birth rates use of assisted reproductive technology and infertility. Andrology. 8(2): 372-380.
45. Kumar S, Tomar V, Yadav SS, et al. (2016). Fertility potential in adult hypospadias. J Clin Diagn Res. 10(8): PC01- PC05.
46. OortqvistL, Fossum M, Andersson M, et al. (2017). Sexuality and fertility in men with hypospadias: improved outcomes. Andrology. 5(2): 86-93.
47. Butwicka A, Lichtenstein M, Landen M, Nordenvall AS, Nodenstom A, et al. (2015). Hypospadias and risk for neurodevelopmental disorders.J Child Psychol Psychiatr. 56(2): 155-161.
48. Jin T, Wu W, Shen M, Feng H, Wang Y, Liu S, et al. (2022). Hypospadias and increased risk of psychiatric symptoms in both childhood and adolescence: a literature review. Front Psychiatr. 13: 799335.
49. Marsbach JM, Forbes P, Peters C. (2005). Testicular torsion and risk factors for orchiectomy. Arch Paediatr Adolesc Med. 159(12): 1167-1171.
50. Kohn TP, Lopategui DM, Arora H, Griswold AJ, Ramasamy R. (2019). Whole–exome sequencing, Identifies novel RAF1 heterogenous mutation in families with neonatal testicular torsion. Urology. 129: 60-67.
51. Feher AM, Bajory Z. (2016). A review of main controversial aspects of acute testicular torsion. J Acute Dis. 5(1): 1-8.
52. Sharp VI, Kieran K, Arien AM. (2013). Testicular torsion, diagnosis, evaluation and management. Am Farm Physician. 88(12): 835-840.
53. Monga M, Hellstrom WJG. (1997). The effects of testicular torsion on fertility. In: Hellstrom WJG (ed.). Male sexual dysfunction. NewYork, Springer. p. 323-324.
54. Kylat R. (2017). Neonatal testicular torsion: is it time for consensus? J Clin Neonatol. 6(2): 53-56.
55. Puri P, Barton D, O’Donnel B, et al. (1985). Prepubertal testicular torsion: subsequent fertility. J Paediatr Surg. 20(6): 598-601.
56. Arap MA, Vicentin FC, Cocuzza M. (2007). Late hormone levels, semen parameters and presence of anti-sperm antibodies in patients treated for testicular torsion. J Androl. 28(4): 528-532.
57. Gielchinsky I, Suraqui E, Hidas G, et al. (2016). Pregnancy rates after testicular torsion. J Urol. 196(3): 852-855.
58. Makela EP, Roine RP, Taskinen S. (2020). Paternity,erectile function and healthrelated quality of life in patients operated for Paediatric testicular torsion. J Paediatr Urol. 16(1): 44e1-44.e4
59. Thomas WE, Cooper MJ, Crane GA, Lee G, Williamson RC. (1984). Testicular exocrine malfunction after torsion. Lancet. 2(8416): 1357-1360.
60. Woodruff DY, Horwitz G, Weigel J, Nangia AK. (2010). Fertility preservation following torsion and severe ischemic injury of a solitary testis. Fertil Steril. 94(1): 352e4-352e5.
61. Zamperi N, Cervellione RM. (2008). Varicocele in [6] adolescents: a 6 year longitudinal and follow up-observational study. J Urol. 180(4 Suppl): 1653-1656.
62. Kurtz MP, Zurakowski D, Rosoklija J, Bauer SB, Borer JG, Johnson KL, et al. (2015). Semen parameters in adolescents with varicocele association with testis volume differential and total testicular volume. J Urol. 193(5 Suppl): 1843-1847.
63. Sheehan MM, Ramasamy R, Lamb DJ. (2014). Molecular mechanism involved in varicocele associated infertility. J Assist Reprod Genet. 31(5): 521-526.
64. Pastuszak AW, Kumar V, Shah A, et al. (2014). Diagnostic and management approaches to pediatric and adolescent varicocele. Urology. 84(2): 450-455.
65. Madhusudanan V, Patel P, Blatchman-Braun R, Ramasamy R. (2019). Semen parameter improvements after microsurgical subinguinal varicocele repair are more durable for more than 12 months. Can Urol Assocn J. 14(3): E80-E83.
66. Jacobson DL, Johnson EK. (2017). Varicocele in the Paediatric and adolescent population: threat for future fertility. Fertil Steril. 108(3): 370-377.
67. Weidner W, Garbe C, Weissbach L, et al. (1990). Initial therapy of acute epididymites using ofloxacin.II Andrological findings. Urologe A. 29(5): 277-280.
68. Rusz A, Pilatz A, Wagenlehner F, et al. (2012). Influence of urogenital infections and inflammation on Semen quality and male fertility. World J Urol. 30(1): 23-30.
69.  Schuppe HC, Meinhardt A. (2005). Immune privilege and inflammation of the testis. Chem Immunol Allergy. 88: 1-14.
70. Shin M, Beser LM, Siffel C, et al. (2010). Prevalence of Spina Bifida amongst children and adolescents in 10 regions of United States. Paediatrics. 126(2): 274-279.
71. Althouse R, Wald N. (1980). Survival and handicap of infants with Spina Bifida. Arch Dis Child. 55(11): 8435-8450.
72. Berry JG, Bloom S, Foley S, Palfrey JS. (2010). Health inequity in children and youth with chronic health conditions. Paediatrics. 126(Suppl3): S111-S119.
73. Brackett NL, Lynne CM, Ibrahim E, Ohl DA, Sonksen J. (2010). Treatment of infertility in men with Spinal cord injury. Kurtz Nat Rev Urol. 7(3): 162-172.
74. Deng N, Thirumavalavan N, Beilan JA, et al. Sexual dysfunction and infertility in the male Spina Bifida patient. Trans Androl Urol. 7(6): 941-949.
75. Hultling C, Levi R, Amark SP, Sjoblom P, etal. (2000). Semen retrieval and analysis of men with myelomeningocoele. Dev Med Child Neurol. 42(10): 681-684.
76. Brackett NL, Lynne CM, Weizman MS, Bloch WE, Abae A. (1994). Endocrine profiles and Semen quality of Spinal cord injuryed men. J Urol. 151(1): 114-119.
77. Korse NS, Nicolai V, Both S, Vleggeert Langamp CLA, Elsevier HW. (2016). Discussing reproductivehealth in Spinal care, part II: female issues. Eur Spine J. 25(9): 2945-2951.
78. Diamond DA, Rickwood AM, Thomas DG. (1986). Penile erections in myelomeningocoele patients. BrJ Urol. 58(4): 434-435.
79.  Schurtlef DB, Hayden PW, Chapman WH, Broy AB, Hill ML. (1975). Myelomeningocoele problem of long term social function. West J Med. 122(3): 199-205.
80. Hirayama A, Yamada K, Tanaka Y, et al. (1995). Evaluation of Sexual function in adults with myelomeningocoele. Hinyokika Kiyo. 41(12): 985-989.
81. Palmer JS, Kaplan WE, Firlit CF. (2000). Erectile dysfunction in patients with Spina Bifida is a treatable condition. J Urol. 164(3 Pt2): 958-961.
82. Halpern JA, Hill R. Braanigan RE. (2020). Guidelines based approach to male fertility preservation. Urol Oncol. 38(1): 31-35.
83. Choi EK, Ji Y, Han SW. (2017). Sexual function and quality of life in young men with Spina Bifida: could it beneglected aspects in Clinical practice? Urology. 108: 225-232.
84. Kovell RC, Skokan AJ, Weiss DA. (2018). Translational Urology care for patients with Spina Bifida. Curr Paediatr Rep. 6: 229-236.
85. Skakebaek NE, Rajpert–deMeyls E, Buck Luis GM, et al. (2016). Male reproductivedisorders and fertility trends: influence of environment and genetic susceptibility. Physiol Rev. 96(1): 55-97.
86. Flannigan R, Schlegel PN. (2017). Genetic diagnosis of male infertility in Clinical practice. Best Pract Res Clin Obstet Gynaecol. 44: 26-37.
87. Krausz C, Riera Escarnilla A. (2018). Genetics of male fertility. Nat Rev Urol. 15(6): 369-384.
88. Harton GL, Tempest HG. (2012). Chromosomal disorders and male fertility. Asian J Androl. 14(1): 32-39.
89. Weidler EM, Pearson M, van Leeuwen K, Garvey E. (2019). Clinical management in mixed gonadal dysgenesis with chromosomal mosaicism in newborns and adolescents. Semin Paediatr Surg. 28(5): 150841.
90. Ferlin A, Dkipresa D, Delbarba A, et al. (2019). Contemporary Genetics based diagnostics of male infertility. Expert Rev Mol Diagn. 19(7): 623-633.
91. Lanciotti L, Cofini M, Leonardi A, Bertozzi M, Penta L, Esposito S. (2019). Different Clinical presentation and management of complete androgens insensitivity syndrome (CAIS). Int J Environ Res Public Health. 16(7): 1268.
92. Song SH, Chiba K, Ramasamy R, Lamb DJ. (2016). Recent advances in the Genetics of testicular failure. Asian J Androl. 18(3): 350-355.
93. Ramasamy R, Ricci JA, et al. (2009). Successful fertility treatment for Klinefelters syndrome. J Urol. 182(3): 1108-1113.
94. Rives N, Rives A, Ronandanino C, Castanet M, Cuny A, Silbert L. (2018). Fertility preservation in Klinefelters syndrome patients during the transition period. Endocr Dev. 33: 149-157.
95. Nassau DE, Chu KY, Blatchman-Braun R, Castellan M, Ramasamy R. (2020). The Paediatric patient and future fertility: optimizing long term male reproductive health outcomes. Fertil Steril. 113(3): 489-499.
96. El Maouche D, Arlt W, Merke DP. (2017). Congenital Adrenal Hyperplasia. Lancet. 390(10108): 2194-2210.
97. Lekarev O, Lin Su K, Vogiatzi MG. (2015). Infertility and reproductive function in patients with Congenital Adrenal Hyperplasia: pathophysiology, advances in management and recent outcomes. Endocrinol Metab Clin North Am. 44(4): 705-722.
98. Chaudhary M, Johnson EK, Dajusta D, Nahala L. (2018). Testicular adrenal rest tumors screening and fertility counselling among male with Congenital Adrenal Hyperplasia. J Paediatr Urol. 14(2): 155.e1-155.e6.
99. King TF, Lee MC, Williamson EE, Conway GS. (2016). Experience in optimizing fertility outcomes In menwith Congenital Adrenal Hyperplasia due to 21 hydroxylase deficiency. Clin Endocrinol (Oxf). 84(6): 830-836.
100. Deigoulfe E, Bray A, Goosens E. (2022). Testicular tissueBanking for fertility preservation in young boys: which patients should be included. Front Endocrinol (Lausanne). 13: 854186.