1. Introduction

Earlier we have reviewed idiopathic hypogonadotropic hypogonadism ( IHH) in detail  and how congenital hypogonadotropic hypogonadism (CHH),represents a  rare problem that present secondary to  reduced synthesis,secretion ,or action of Gn RH ,continues to be a  difficult problem in paediatric endocrinology[1-7].Congenital hypogonadotrophic hypogonadism(CHH)is a rare genetic problem where reproductive disorder occurs secondary  to deficiency   in secretion or action of gonadotropin  releasing hormone(GnRH).Basically it has been thought to be a male predominant process with a male: female gender ratio3.6:1 for which cause remains unexplained(8).The main  clinical effect of CHH remain pubertal failure  as  well as  infertility .

Though thought to be a rare disorder ,proper finding out the prevalence of CHH is not possible due to literature being scarce.On the basis of a French study of potential military  service admission[9]  who attended medical examination ,as well as   more recently ,a retrospective study  where nationwide records  from Finland were collected [10], (both  of which had methodologically  underreporting), the prevalence  of male CHH of 1 in 4415 -15,000 is right now evaluated .

The genetic  deficiencies  responsible for CHH mainly fall in 2 main groups , i) those  leading to a neurodevelopment  disorder of GnRH neuron migration  usually  correlated  with non  reproductive defects ,mainly anosmia/hyposmia from olfactory axon routing abnormally (like Kallmann syndrome[KS] and ii) that ,which lead to purely neuroendocrine dysfunction of GnRH liberation or action (normosmic CHH). Underlying this simple looking disparity  lies the vast  differences of genetic mutations ,with >30 genetic loci  that have been thought to be involved  till now ,inspite of  practically half of the cases remaining unexplained.Further some genes were having implications both in  normosmic CHH  as  well as   Kallmann syndrome(KS) [11]. This complication is also seen in different ways of transmission feasible.like oligogenicity  along with Mendelian forms of classical Mendelian inheritance [11.12]. Moreover CHH   phenotypically remains heterogeneous.Other than different correlations with non  reproductive abnormalities ,like deafness ,synkinesis(or mirror movements),renal agenesis ,digital as  well as   dental abnormalities   as  well as   clefting , reproductive  sequences vary from absent puberty,pubertal arrest ,to even spontaneous  reversal of hypogonadism in small minority [13].Males of CHH usually come with cryptorchidism  as  well as   /or micropenis ,that are significant  property  of severe fetal infancy GnRH decrease (absent minipuberty)[6]. But patients experiences point that these early presentations  is rarely  recognized  leading to timely diagnosis as  well as  treatment getting started in early life.

Inspite of medical advances  in genetics ,diagnostics as  well as   therapy health results of CHH is disappointing, with a big chunk having the long term effects of suboptimal care[14].Here we try to review  the factors  leading to poor results  in  CHH, as  well as    the strategies  which can make the quality of life (QOL) as  well as  fertility potential, with special concentration   on utilizing the window of minipuberty  for early diagnosis  as  well as intervening.

2. Delay in Diagnosis as well as Therapy

Delayed puberty is the main method of presentation in CHH men. About 2/3^rd of CHH men-adolescents do not display any evidence of spontaneous puberty at >17yrs of life (testis volume <4ml), with the rest showing arrest of puberty [15].

It is unfortunate that biochemically CHH can’t be separated from constitutional delay in growth and puberty (CDGP) biochemically, with the latter representing 65% of Delayed puberty   in young teenage boys [16], but decreased markedly with advance in age at presentation. In both low sex steroids correlated with low or inappropriately normal follicle stimulating hormone (FSH) as  well as luteinizing hormone ( LH) amounts. As far as height is concerned ,the baseline height SD scores  as  well as   growth velocities  don’t seem to be significantly  variable  among  CDGP as  well as    CHH adolescents, varying from functional HH where   there are a chances of lower  height SD scores   as  well as    decreased  growth velocity (<3cm/yr [16]. But progressive decrease in height SDs has been seen in few CDGP boys  in the prepubertal years with final  height achieved  remaining short  of their genetic potential [17]. Conversely preservation of height relative to parental height in CHH has been pointed [18]. Thus proper history of  growth can add significant  information.

Despite different stimulation tests (like GnRH stimulation test as well as  HCG test) as well as  inhibin B(I_B) amounts (marker of sertoli cell function)have been posited, although still  no agreement on the ‘’gold standard’’ test to separate them reliably 19].Thus diagnosis of CHH continues to be a tough job,with clinicians usually move towards the expectant management, giving adolescents   adequate time  for the ones with  CDGP to go through spontaneous  pubertal initiation, to identify  those having CHH[20].In  big single centre retrospective series the combining of testicular volume  as well as   basal   I_B amount ,both can be got easily without utilization of complex dynamic test showed  aid in separating CDGP as  well as    CHH and hence  could be useful for broader use[reviewed in [2,3].

But constant misuse of “wait as well as  watch & reassure’’ guide (meant for subjects of undifferentiated pubertal delay) from those with red   flag markers of  CHH who need ,rather than get assumed  hypogonadal till proven otherwise and get sex hormone replacement from mean age of pubertal onset in that population i.e 12yrs in boys [13,21], while  therapy should not be unnecessarily held back  in those without  CHH features but have reached 14yrs age [22].

Hence the CHH diagnosis  as  well as   initiation  of clinically useful therapy gets unnecessarily delayed till late adolescence or early childhood .Inspite of various surveying methods  across various European countries ,data on the mean age  of CHH who have been Markedly consistent ,with Dwyer et al (web utilized, pan European; n=101) observed these to be 18±6 as  well as  19±5 yrs respectively [22],while Raivio et al (utilizing national Finnish cohort study)observing the median age  of initiating therapy  to be 18.3yr(range 11-34yrs)[23], as  well as   Quinton (case noted based survey ;n=200) observing it to be 18.9±9yrs [24].

A big mistake, commonly done was not laying significance to recognizing  cryptorchidsm,where about 2/3^rd had bilateral   undescended testis [15,25-27] .Conversely cryptorchidsm is rarely seen in CDGP.Just 2% of CDGP boys  had a   history of  cryptorchidsm as  compared to   36% in CHH,in a large series of boys  examined at a specialized  centre  referred from primary care for delayed puberty [27].A family   history of  cryptorchidsm, micropenis, Infertility  as well as  /or non reproductive presentations like anosmia, deafness ,synkinesis (or mirror movements), renal agenesis ,digital as  well as   dental abnormalities   as  well as   clefting could aid in valuables  signals if present concomitantly for early diagnosis of CHH, although this is missing in most of cases ,partially due to different  penetrance of disease   as well as  phenotypic expression ,along with oligogenic  inheritance  with unaffected parents [11,rev in 3,4].

Similarly the importance  of bilateral    undescended testis in neonates  as a probable pointer of CHH is classically not picked up.Persistence of  bilateral   cryptorchidsm is  observed in a quarter of  CHH infants  in contrast to <0.7% in a the general population .In a  big single centre retrospective series,only a third  of CHH males  with history of   bilateral     orchidopexy  in childhood were referred to paediatric endocrinology  for further examination ,with major of cases  again presenting later in life with absence of puberty  [25]. Present clinical guidelines  have mainly concentrated on trying to analyze for  congenital adrenal hyperplasia (CAH)  as well as   disorders of sexual development( DSD) and avoided giving enough attention ,essential for  the investigations essential  for cryptorchid boys  for trying to exclude CHH [28] causing a lost opportunity  to pick it up early.

Hence due to late diagnosis as well as   delay in therapy, the proper standard of care is not given  to patients with CHH,causing a significant  psychosocial   as well as   reproductive complications.

3.Health meets not met

3.1Psychological Health

Psychological morbidities  as well as  antidepressant  utilization are too much enhanced  among  men with CHH[23]An internation study with North as well as  South America ,European as well as   Australian participants ,practically 2/3^rd  were afflicted by depression, with most of them  showing moderate  to severe symptoms[30].A significant result  secondary   to chronic affective disorders  is poor compliance  to long term hormone replacement. What is worrying  is than >a third  of the survey reporters  documented   long gaps (>1yr) in therapy  that could  potentially exaggerate affective symptoms   in return as a vicious cycle .

The  Psychological effect of disease   is marked .An important  amount of patients  have anxiety as well as   low self esteem ,causing an inability  to develop  close relationships  as well as  social isolation .Thus in the above study  cohort[30],about 50% of the men were  not  in a stable relationship  during the survey , as well as   many never had a sexual partner.

What was positive though  is most of the men  evaluated had  got tertiary level education  as well as    had a gainful job  showing adequate socioeconomic  situation ,though this did not overcome the psychological effects   secondary to the disorder. Yet men having CHH that had adopted  or had biological children  had <chances of depressive   symptoms, pointing to the positive  influence of family companions , as well as  the vicious cycle broken.

The main reason that mental health  as well as    poor QOL is delay in diagnosing as well as  not delivering  age proper  secondary sex characteristics   in many of these   CHH men.Most   patients    start getting therapy  that is efficacious only in late adolescence (usually median age 18-19 yrs) classically following  a long  frustrating diagnostic journey (shared by females too though incidence lower).Thus they are at a risk of forming psychosocial  disorders correlated with pubertal delay , as well as   low self esteem ,social withdrawl,poor school performance  as well as   high risk  of substance abuse disorder [22,31,32]. Moreover ,improperly treated cryptorchidsm  as well as /or micropenis can cause long standing bad effect on their sexuality [23].

3.2Fertility Potential  Decreased

In case of young males having CHH, gonadotrophic therapy gets a markedly > positive influence  as compared to  testosterone(T) replacement on health –associated   QOL [33]. Although both treatments are efficacious  in getting the physical as well as  general  health  better ,those receiving  gonadotrophins  do better  in  psychosocial   domains  that are emotional  as well as  mental health ,especially  if sperms are isolated within the ejaculate .This strongly points  that   patients   psyche is markedly influenced  by their  anticipated  chances of getting   paternal hood.

In cases of   CHH patients infertility is secondary  to spermatogenic failure ,that can be potentially treated with either GnRH or  gonadotrophins therapy .Problem is  classic  spermatogenic  therapy –human chorionic  gonadotrophins  (HCG) monotherapy or  combined gonadotrophins therapy (HCG as well as FSH)is much <efficacious in men  with severe   CHH(testes<4ml) especially   those having  history of    bilateral  cryptorchidism, rather than in men having HH of postpubertal  origin like  due to acquired pituitary  disease[34].However in centres having experience in looking after  CHH patients,  till 3 quarters  can acquire   spermatogenesis   during hormonal   induction therapy [13,35], as well as  pregnancy   rates  can get be further escalated with artificial reproductive technology(ART) [13,36].

  Patients  presenting with rare medical problems ,by definition when a prevalence of <5 in 10,000 in the population ,usually  have it tough  due to no knowledge of the care givers[37,38].Need for specialized centers  having expertise in diagnosis  as well as  interdisciplinary therapy  of rare diseases  are  essential in  giving care to these    patients  [39]. On the same hand ,  patients   with CHH need to get tertiary level care for preventing   gaps in therapy , as well as  benefit  from latest advancements as well as   technologies  in the research field .Early diagnosis  would give the chance  for patients to get  proper as well as   consistent care as well as   support in specialized centers  without waste of time. Therapy can further be tailored  as per the  requirements  as well as   goals in various stages of life [13,40]. However in real  life  setup as per a survey ,it seems   that only few of   CHH men looking for fertility management   to attain the wanted results  on fertility-stimulating therapies[14]. It is not clear  how many of these men were treated at specialized centres ,having essential expertise ,but knowing that only half of the whole study cohort  are followed by  specialized centres, access to such places is going to be restricted.

3.4. Escalated risk of Low Bone Mineral Density

Chronic sex steroid deficiency   is a main  risk factor  for osteoporosis  as well as   fragility  fractures which involves both sexes. Since  CHH men have early onset of testosterone(T) deficiency ,a delay  as well as   /or absence of enough androgen replacement  would aid  in poor  bone mass  formation as well as    acceleration of bone loss [41].  Patients who get  T  at older age  seem to  acquire <bone mineral as compared to younger age ,that further corroborates  the significance  of timely therapy [42], Even for those who get diagnosed  as well as started on therapy  only later in life ,encouraging  BMD enhancement ,especially  at trabecular rich lumbar spine [43].

4.MiniPuberty –Key Time of genitalia Formation  and the Window of early Diagnosis

High  chance of cryptorchidsm   as well as    microphallus  is seen in CHH men due to absence of   MiniPuberty,that is a key  time in the ontogenesis  of the male repro tract when activation of the GnRH axis  in the early mths  postnatally .At this formation phase ,serum T, as well as    gonadotrophins amounts increase  rapidly  as well as   peak at the age  3,mths –markedly  correlating with adult male amounts –prior to mid childhood  quiescence  by about 6 mths of age [7,44,].

This marked hormonal action  is essential  for finishing the  total event  of inguino scrotal  testicular descent  as well as    anchoring  in the scrotum  as well as   penile growth ,that had started earlier  at the time of 3rd trimester .Particularly ,LH –stimulated liberation of T as well as  insulin like 3 peptide(INSL3)  peptide via leydig cells  are the crucial factors  involved in influencing these alterations [45].A concomitant escalation of  FSH stimulated I_B as well as    antimullerian hormone( AMH)  liberation ,pointing to active proliferation  of sertoli  as well as    germ cells as well as    seminiferous tubule development are crucial determinants  of future fertility  potential  and cause  90%of testicular volume  development  [46].Inspite of rapid   gonadotrophin action  as well as   T liberation  at this proliferative phase germ cells  maturation as well as    spermatogenesis  do not take place ,since androgen receptors  are not expressed  on Sertoli cells till 5 yrs of age[47].

After   MiniPuberty,the  Hypothalamo-Pituitary-Gonadal  (H-P-G) Axis  reverts back into silence  for the rest of childhood .Serum T,LH, as well as    FSH  amounts decrease to low levels till reactivation of gonadal axis  in early adolescence ,pointing to the initiation of puberty as well as    marked by testicular enlargement (≥4ml)followed as well as    by  penile  as well as   pubic hair growth.Here  sertoli cell maturation takes place,as seen by an escalation of   I_B amount  as well as    decrease in AMH amounts ,and spermatogenesis   gets attained  by the coordinated effects of FSH as well as   intertesticular  T[48] Hence pulsatile  GnRH liberation  in the neonatal period  seems to be of significant  for the formation  of male genitalia ,with a long reaching effect on male reproductive  phenotype  as well as    fertility potential  later in adult life .

Another significant   clinical importance of MiniPuberty is that it gives a  window of chance to promote the finding of children with Congenital GnRH deficiency ,who would show  abnormally low T,LH, as well as     FSH  amounts on measurement,thus giving a benefit  of a definitive prepubertal diagnosis  as well as   signposting  them to preplanned  pubertal induction with sex hormones at the median age  of pubertal onset  instead of expectant treatment followed earlier.

5.Avoidance of Delay in Pubertal Induction  by Early Diagnosis

Thus Early life Diagnosis of   CHH aids in structuring the long time monitoring  as well as    therapy plans along with  seeing to it that counselling  as well as   psychological support  to patients as well as  family  are given.Once patients  reach early adolescence,age –related Pubertal Induction   therapy   will   see to it  that secondary  sex characteristics  form  as it does in peers[15],thus preventing the delay  which has been usually found by most CHH men.Thus uncertainties gets to the least along with removing the fear as well as   anxiety.

5.2Advantage  of Early Diagnosis in Escalating the Chance of Fertility

Early Diagnosis of boys  presenting with CHH could probably  give a  chance to maximize fertility potential. Though longterm   GnRH therapy or gonadotropins combinations are efficacious  for most CHH men in inducing spermatogenesis, sperm results usually remain suboptimal[35,49,50].Further ,about a third  with severe CHH continue to be azoospermic  despite  prolonged   gonadotropins combinations  as well as  monotherapy with HCG has continued to be not efficacious to our disappointment.

Clinical Features (that corroborate with longtime   severe  GnRH deficiency  minipuberty)which forecast poor treatment response;like total absence of puberty on presentation,ii) cryptorchidism(particularly if bilateral);low serum I_B amount(pointing depleted sertoli cells) as well as  prepubertal   testicular volume(pointing depleted   germ as well as    sertoli cells as well as   seminiferous tubules ) [35,49].Conversely CHH men  presenting with partial  GnRH deficiency (testicular volume ≥4ml)give a much better response  to   gonadotropins   combinations, with about 80%  attaining sperms in the ejaculate [51].

Hence  men presenting with  complete   CHH ,need the maximum utilization of  germ as well as  sertoli cells proliferation  as well as   growth of   seminiferous tubules by delivery of  recombinant follicle stimulating hormone before the HCG  gets introduced to avoid  premature maturation of depleted pool of sertoli cells under the action of  intratesticular T.

FSH- monotherapy in children  as well as adolescents  with HH of prepubertal –onset showed its effectiveness  in aiding in testicular growth  as well as  circulating   I_B amounts [52]. Especially there was a good spermatogenesis response in a subgroup of adolescents having CHH where FSH priming was done prior to  the combining with HCG caused a success in inducing spermatogenesis in ¾ patients [52].

Potential advantage  of unopposed   FSH- therapy  was evaluated further in a randomized ,open label  trial of 13 treatment  naïve  adult CHH  men possessing prepubertal   testis(<4ml)[53].7 men were   randomized to recombinant FSH-pretreatment x4mths  prior to  giving a 24 mth GnRH-  therapy  protocol.At the time of FSH-only  phase , testicular volume  doubled   as well as   circulating   I_B amounts  escalated to adult  amounts, as well as  all patients   in this  arm formed sperms  in ejaculate on GnRH-  therapy   as compared to 4/6 men  in the 24mths GnRH-  only arm.Further trends towards > testicular volume,  as well as   >sperm counts  along with shorter time  to the 1^st look of sperms in the ejaculate in the FSH- therapy   pre treatment    group was observed.

Hence the advantage  of  FSH-priming  as well as   potential harmful action of premature HCG would be significant  to tell the clinicians  on the selection of   treatment   would be markedly aided in timely diagnosing.

5.3 Potential of neonatal  gonadotropins therapy for further enhancing outcomes

Getting insight into the key role of Mini –Puberty in the formation of external genitalia as well as    sertoli cells proliferation  as well as    future effect on  future fertility the possibility as well as    advantage  of bringing about the   physiological   hormonal   milieu in male CHH infants has been evaluated.

The 1^st report that was published  was that  a boy  presenting with   CHH with   micropenis   who was administered  short term  recombinant LH as well as   FSH from the age of 7.9-13.7mths, the penile length  enhanced successfully  by 50% as well as    the testicular volume almost tripled  by the end of treatment   [54]. Another publication of 2 male infants ,one  case each of  Combined pituitary   hormone deficiency (CPHD) as well as    CHH,6mths of   gonadotropins   combinations therapy  was delivered via a subcutaneous  pump infusion  started at age 8 as well as 20wks respectively ,caused a 4 times escalation of   penile length  as well as      testicular volume [55]. Even later ,3-6mths of continuous subcutaneous    infusion   of recombinant human gonadotropins in 5 male infants [4CHH ,1CPHD] gave  various fold escalation of  I_B amounts  , testicular volume as well as   T liberation [56[.

Other than these good effects  with of   gonadotropins   combinations therapy at infancy ,it could further aid in  managing   undescended testis . Cryptorchidism is there  in about 50% of boys with severe  CHH[25],being an independent  anticipating factor  for infertility .If  orchidopexy  is delayed it correlates with marked decrease  in germ cells [57], and usual recommendations are there that surgery be done by 1 yr of life[58].Nevertheless ,small testis  causes difficulty in surgical manipulation  as well as    would lead to extra risk  of testicular damage  as well as    tissue loss [59,60].By delivering a period of presurgical  gonadotropins, aids in escalation of   testicular volume which helps in the procedure.

Actually there is data coming that spontaneous descent  might get successfully stimulated by gonadotropins therapy in infants  having central hypogonadism,thus avoid the requirement of surgery .In 8 infants having maldescended testis  secondary to hypogonadototropic  hypogonadism[[5CHH ,3CPHD] ,infusion of gonadotropins stimulated full  testicular descent  in 6 boys with partial descent in 2 boys ,so that  only 1 required   orchidopexy almost a yr later  due to reascent of the testis[61].In another combination of  recombinant LH as well as   FSH in the 1^st 6mths  of life successfully  stimulated spontaneous  descent of the testis in 2 to 4 bilateral Cryptorchid CHH /CPHD boys [56].

Thus short term neonal gonadotropins therapy in confirmed cases of hypogonadototropic  hypogonadism seems to be efficacious  in replicating the actions of mini puberty,by correction of ,micropenis ,facilitation of testicular growth  in view of sertoli cells expansion as well as   stimulating spontaneous  testicular descent   of malpositioned testis.Significant  , treatment   was well tolerated  in all cases documented.Though definitive proof is still absent ,the chances of early  hormonal replacement in CHH  boys  in escalating sexual   as well as    reproductive function in adult life  is worth serious evaluation,and   give input for larger clinical trials .

This was exemplified by the study of Papadimitriou  etal.,in which Neonates or infants ,all having  bilateral cryptorchidism  in intraabdominal/inguinal  place as well as  micropenis  with  no neonatal  male minipuberty,got daily subcutaneous  injections of Pergoviris(recombinant LH/FSH 75/150 IU for 3mths  as part of the REMAP (REplacement of  MAle  mini Puberty) study where 10yr follow up was attempted .By the end of therapy ,median LH/FSH ,both undetectable  prior to therapy ,went upto high normal levels  of 4.45 IU/L as well as  supranormal  levels  83 IU/L,respectively ,median inhibin –B as well as  antimullerian hormone(AMH)  levels enhanced from below normal (27.8and 1.54ng/mL, respectively) to normal values (365 as well as  150ng/mL, respectively),median testosterone escalated  from just detected (0.02ng/Ml) to normal values(3.3ng.mL).Stretched penile length  enhanced from a median of 2  to 3.8cm .During treatment all testes descended  to the scrotal position (by the end of 1^st mth  in 3 cases ,the 2^nd mth in 4 patients  and the 3^rd in 3 patients  )measuring 1.5ml  and ,looking normal sonographically .Extra  therapy with testosterone enanthate  was administered to these infants.In 2 infants ,one of 2 testes  regressed  in the low inguinal area;both infants  got successful treatment surgically .Following 1 to 10yrs  of follow up ,all testes  are still in scrotal position ,having slightly regressed in size .Hence the proposed regimen simulates  male minipuberty  and treats successfully  infants presenting with micropenis as well as   cryptorchidism  along with restoration of sertoli as well as  leydig cell function  as per Papadimitriou[62].Hence from this it is quiet clear that early identification  of CHH as well as isolated sertoli cell dysfunction  needs to be identified in prepubertal as well as   transition age .

Legend for Figure 1

Courtesy ref no-74-Summary of reproductive hormone changes during early life in healthy boys. Fetal gonadotrophins surge at mid-gestation, then decline and are low or undetectable in cord blood, owing to the inhibitory effect of placental estrogens. Immediately after birth, LH transiently increases by around 10-fold, followed by a testosterone peak, which lasts 12–24 h. A few days after birth, gonadotropins surge again. LH peaks between the 2nd and the 10th week of life and then gradually decreases, reaching the low prepubertal values by 6 months of age. FSH drops to the prepubertal range within the 4th month of life. Both at mid-gestation and during minipuberty, LH predominates over FSH.

 Legend for  Figure 2

Courtesy ref no-74-Summary of reproductive hormone changes during early life in healthy girls. Fetal gonadotrophins peak at mid-gestation. Overall gonadotropin levels are higher than in males. During fetal life placental and fetal estrogens overlap. Cord blood LH and FSH are low or undetectable, due to the inhibitory feed-back induced by placental estrogens. There are no peaks of LH or estrogens immediately after birth. Starting from the 2nd week, gonadotropins increase and stimulate estradiol secretion that remains high (although fluctuating) until at least the 6th month. LH declines at the same time as in boys, while FSH remains stably high up to 3 or 4 years of age. Both at mid-gestation and during minipuberty, FSH predominates over LH.

5.4 Proposed Method  for Enhancing Finding the male infants with severe CHH

 This phase of   minipuberty gives an extraordinary  useful window  to confirm or deny the diagnosis of congenital hypogonadism with a simple  biochemical analysis  without the requirement of complicated dynamic  examination.In a cohort of CPHD male infants (mainly presenting with hypoglycaemia),presence of low LH as well as   FSH and T amounts reliably picked up  concomitant hypogonadototropic  hypogonadism in 14/15 infants with genitalia anomalies ,while all other boys with normal  genitalia  showed intact   P-G axis function[63].This is in marked contrast with  the  method of   differential   diagnosis   of   CHH from CDGP in adolescence.But unlike CPHD,neonates with CHH without Cryptorchidism especially  if  bilateral or correlated with micropenis ,so that proper  examination can be done[27,58].Actually the presence of  red flag markers  need more tests  for ruling out    such possibility.

The other problem is  trying to evaluate the  < obvious gonadotropin  well as    T  results  in the male infants .Of significantly ,normative values  of various significant  reproductive  hormone reports during minipuberty   –that are LH ,FSH and T(both via radioimmunoassay(RIA) as  well as    tandem spectrometry ),AMH well as    I_Bamount have been calculated via a large cohort of healthy  Danish infants  where  result amounts above  the cutoff levels  extensions formed   lower than adult ranges –could be taken as the intact HPT axis function ,while if equivocal biochemical outcomes  which lay below  the  cutoff levels   might require testing again.Moreover expanding the screening panel well as    include AMH well as    I_Bamount could improve the confidence of diagnostic ability.Critically this study  also showed  that the different  sex hormone peak just prior  to 3.5mth of age ,pointing that diagnostic acumen would be best if analysis is done at this time.

5.5 Potenial screening indicator-Bilateral  Cryptorchidism

Although routine screening for minipuberty is not practical ,a targeted approach examining infants  when suspicious signs of   CHH,would be cost effective.Of the Clinical Features -correlated Bilateral  Cryptorchidism is especially  significantly  in view of its >prevalence  with severe GnRH-   deficiency  which has both prognostic as well as    therapeutic significance[15,16,26].

Though  Cryptorchidism is a common  congenital urogenital anomaly  in newborns ,many would undergo spontaneous  descent without hypogonadism /other organic problems.Results from earlier studies demonstrated that the prevalence  of  Bilateral  Cryptorchidism reduces markedly from 1.66 to 4.54% at time of birth  to 0.09-0.66% by 3-12 mths of age[64-66].Additionally spontaneous descent  is not likely  to occur  beyond 3mths postnatal [67],that coincides with the anticipated  minipuberty,that makes it an ideal time for assessing reproductive  hormones in boys having continuing  Bilateral  Cryptorchidism.Further although non-CHH   Cryptorchidism might also show hormones anomalies,they tend to have > FSH ,similar  T as  well as    little < I_Bamount as compared to healthy infants ,that are separate  from the biochemical  pattern anticipated in CHH  male infants[68].

Hence evaluating  male infants[ with Bilateral  Cryptorchidism with/without micropenis  at 3 mths of age  for absent minipuberty could aid in an appropriate approach  for aiding in early  CHH diagnosis .  Utilizing British birth data  as an e.g of mathematic  evaluation

i)with an average  male live birth rate(LBR) of 390,070/annum in Britain[69]-among 26 of 88  boys born every yr  could be afflicted  by  CHH(on the basis of anticipated prevalence  of 1 in 4415-15,000).

ii)Conversely , Bilateral  Cryptorchidism could involve among 6475-17 ,702(54%)of all boys  at birth ,irrespective  of the presence of CHH.Of these among 4 as  well as    30 infants could possess underlying   CHH(as Bilateral  Cryptorchidism involves 13,9-34.5% of CHH population),hence representing 0.02-0,46% of all Bilateral  Cryptorchidism boys at birth.

iii)by 3mths of age following  spontaneous testicular descent anticipated in most of non –CHH infants ,the total number of infants with Bilateral  Cryptorchidism would be anticipated to reduce considerably  to among 351 as  well as   2,574(0.09-0.66%).

iv)Since spontaneous testicular descent   is not anticipated in CHH  involved infants,they now represent  the >%age  of all potentially Bilateral  Cryptorchidism boys ;0.16-8.55%(as compared to  0.02-0,46% at birth).Thus screening  at 3mths of age  seems to be the most cost effective by preventing  tests for maximum   number  of infants  without persistent Bilateral  Cryptorchidism

On the basis of this posit ,probably 1 in 11-12 male  infants with persistent Bilateral  Cryptorchidism at 3mths of age  could have underlying CHH.Significantly  this calculation corraborates  the observations  from a historical surgical patient    series  that had been treated with orchidopexy.Here in 98   patients  examined for probable  underlying endocrine etiology for Cryptorchidism,2 were seen to have CHH in adult life  as  well as     both of them  had Bilateral undescended testis [70],that represented 6.1%(2/33)of all individuals  with Bilateral  Cryptorchidism in the series.

Yet is needs emphasis that no literature is there pointing that CHH screening in infants  has been systematically  evaluated by any research group,hence remains a working concept  which is in early exploratory time.Future long multicentric  research is essential for any screening method that tries to get early diagnosis  of this rare disorder  as  well as    effectiveness as  well as    safety of hormonal therapy  in CHH  infants .Protocols need to be developed  with adult as  well as    paediatric  endocrinologists  to make sure that these children  are put in a structured follow up  as  well as    transitional programme ,hence ensuring that  no body gets a victim  of the breakthrough of the health system.

6.A Little about Pre- pubertal Acquired Hypogonadotropic hypogonadism

Pubertal failure  in male adolescents  with known  history of acquired hypopituitarism  usually prevents the  diagnostic testing for CHH,thus allowing Pubertal induction  therapy to get planned around 12yrs of age ,with gradual escalation of T dose  prior to reaching adult replacement dose in approximately 3yrs [21].Significantly  in view of preserved minipuberty , normal sertoli cell proliferation  is anticipated in early childhood ,testicular maldescent  is most propably not going to take place[52].Hence these individuals  usually  have more optimism  regarding fertility,with higher spermatogenic response to gonadotrophin therapy[71],until testicular tissue  has been affected by previous  gonadotoxic treatment.To allow a timely identification of isolated tubulopathy and sertoli cell dysfunction, the investigation  should start in the prepubertal age and the transition phase[72]. The latter is the moment of transition from  the   pediatrician to the family doctor and hence one can avoid development of male infertility[reviewed in ref [73].

7. Conclusions

Early  finding of CHH  via finding the  absence minipuberty can potentially  manipulate the patients  experience via  aiding in timely treatment at various phases of life.This can be achieved in a male  utilizing a systematic approach by isolation of male infants  with markers of CHH   especially Bilateral  Cryptorchidism,so that biochemical investigations can be done  in the narrow diagnostic  window called the minipuberty. Bizzari  and Cappa showed the difference in hormonal changes during  minipuberty in male and female infants with in utero changes in their hormones [74].

     Neonatal gonadotropins therapy   seems to be of advantage  in rectifying micropenis   as  well as   bilateral  cryptorchidism.In adolescents age proper pubertal induction  is the basic target ,and a small course of FSH monotherapy  needs to be  tried to maximize the fertility potential.Close  cooperation among paediatric  care providers   as  well as    adult endocrinologists  would make sure  that these patients   have a smooth transition to adulthood ,at the time  aim of therapy  should   shift towards fertility induction  as  well as   longterm androgen replacement therapy .Equally significant  are the psychological  aupport a as  well as   genetic counselling  needs to be  given  along  the way for empowering the patients   ,for coping with the situation.Rarely once kisspeptins are in use smoothly they can be tried in those with Kisspeptin or its receptor deficiency [6]  .