Content uploaded by Kulvinder kochar kaur
Author content
All content in this area was uploaded by Kulvinder kochar kaur on Mar 12, 2019
Content may be subject to copyright.
Journal of Pediatrics & Neonatal Biology
Volume 4 | Issue 1 | 1 of 8
J Pediatr Neonatal Biol, 2019
An Update on Aetiopathology, Various Genetic Causes and Management of Delayed
Puberty-A Minireview
Review Article
Kulvinder Kaur1*, Gautam Allahbadia2 and Mandeep Singh3
1Dr Kulvinder Kaur Centre for Human Reproduction, 721, G.T.B.
Nagar Jalandhar, Punjab, India
2
Scientic Director Ex-Rotunda-A Centre for Human reproduction,
672,Kalpak Garden,Perry Cross Road, Near Otter’s Club, Bandra
(W)-400040 Mumbai, India
3
Consultant Neurologist, Swami Satyanand Hospital near Nawi
Kachehri, Baradri, Ladowali road, Jalandhar, Punjab, India
*Corresponding author
Kulvinder Kaur, Dr kulvinder Kaur Centre for Human Reproduction, 721,
G.T.B. Nagar, Jalandhar, India. Tel: 91-181-4613422, E-mail: kulvinder.dr@
gmail.com
Submitted: 02 Dec 2018; Accepted: 10 Dec 2018; Published: 16 Mar 2019
Keywords: Delayed Puberty; hypogonadotropic hypogonadism;
kisspeptin; CDP; sex steroid treatment; gonadotropins.
Introduction
Puberty involves a complicated physical along with psychological
process which ends in development of reproductive capacity.
For puberty to occur there is need for hypothalamic neurons to
get activated required for increasing pulsatile GnRH secretion,
along with activation of the gene networks which bring about this
activation ,that have been dened clearly now. That there is an
increase in excitatory and reduction of inhibitory inputs along with
glial secretory factors like TGF-α and prostaglandin, which leads
to the activation of the gonadotropic axis at the onset of puberty
[1-3]. GnRH synthesis begins very early in fetal life in case of boys
while 2years in girls. This early neonatal period is also labeled as
minipuberty, while gonadotropic axis quietens down after this.
At what time the puberty actually gets initiated varies with some
heritable factors along with racial and ethnic factors and occurs
with the reactivation of GnRH Scretion from the hypothalamus,
determined by genetic, nutritional, ethnic along with environmental
factors [2]. Delayed puberty is dened as the absence of physical
signs of puberty by the age >=2SD beyond the population mean ,a
statistical denition which is necessary in view of the incomplete
understanding by us regarding how the timing of puberty is dene
[4]. One can classify the late onset of pubety into 3 subgroups
i) Hypogonadotropic hypogonadism (HH) ii) hypergonadotropic
hypogonadism and iii) constitutional delay of puberty(CDP) [5].
The causes of delayed puberty (DP) may be congenital or acquired,
of which CDP constitutes the commonest cause of DP among boys,
though the nal diagnosis can only be made by elimination of other
causes (Figure1).
ISSN: 2573 - 9611
Abstract
Delayed Puberty (DP), especially in boys, is a common presentation in paediatrics. By denition DP is dened as
the presentation of clinical signs of puberty 2-2.5SD later than in the normal population. With the recent advances
in understanding of the neuroendocrine, genetic and environmental factors controlling pubertal development it has
become easier to understand the pathophysiology of DP. The discovery of kisspeptin signaling through its receptor
identied neuroendocrine mechanisms controlling the gonadotropin releasing hormone (GnRH) pulse generator
at the onset of puberty. Genetic mechanisms from single gene mutations to single nucleotide polymorphisms
associated with DP are being identied. Environmental factors, including nutritional factors, besides endocrine
disruptors, have been associated with the secular trends and abnormal timing of puberty. Inspite of these advances,
the main question remains how to differentiate DP associated with underlying pathology of hypogonadism from
constitutional delay in growth and puberty (CDP) that remains challenging as biochemical tests do not always
discriminate the 2.The diagnostic accuracies of newer investigations which include the 36-hour luteininzing
hormone releasing hormone(LHRH) tests, GnRH agonist tests, antimullerian hormone and inhibin B, need further
evaluation. Sex hormone replacement remains the main therapy that is available for DP, whose choice is based on
clinical practice and the availability of the various sex steroid preparations. Spontaneous reversal of hypogonadism
has been reported in boys having idiopathic hypogonadotropic hypogonadism following sex steroid treatment,
which highlights the importance of reassessment at the end of pubertal induction .Novel therapies having a more
physiological bases like gonadotropins or kisspeptin agonists are getting investigated for the management of
hypogonadotropic hypogonadism. A careful assessment and knowledge of the normal physiology remains the
mainstay of managing patients with DP.
www.opastonline.com
J Pediatr Neonatal Biol, 2019 Volume 4 | Issue 1 | 2 of 8
www.opastonline.com
Figure 1: Gene network implicated in gonadotropic axis activation.
Kisspeptin neurons located in the arcuate nucleus of the hypothalamus
stimulate GnRH neurons. In yellow, the factors involved in GnRH
neuron migration from the olfactory placodes; in red, hypothalamic
excitatory and inhibitory neurotransmitters and neuropeptides; in
blue, hormones and other factors from the gonadotropic axis at the
pituitary level, and in green, peripheral and environmental cues
inuencing GnRH secretion.
How to diagnose DP
As discussed earlier DP by denition is the absence of enlargement
of testis in boys /breast development in girls at an age which is 2-2.5
SD later than their population mean. Although in Europe it is the age
13 years in girls and 14 yrs in boys decided to be the guideline for the
need for further examination. But these don’t consider the differences
racial and ethnic groups or a recent trend of earlier pubertal onset
seen in United States along with other developed countries [6-16 of
zhu]. One needs to examine for pubertal development both clinically
and biochemically
Medical History
A detailed medical, family history along with lifestyle factors
history (like exercise, nutritional level, developmental along with
any psychological problems) needs to be accounted. Details of birth
and pregnancy like (icterus, neonatal hypoglycaemia), childhood
growth patterns, along with any surgical or medical treatments are
needed. An account of any family history of pubertal delay, parental
size along with age at which onset of puberty occurred, any infertility
or anosmia [4] along with history of any chronic autoimmune or
endocrine diseases need to be taken. If there is any possible acquired
hypogonadism, signs of intracranial hypertension might be present
and need to be looked for.
Physical Examination
One needs to measure weight and height. Breast examination and
tanner staging needs to be done Tanner stage 2indicates onset of
pubertal development with breast development in girls and in boys
a testicular volume>4ml in boys. Further an analyses of dimorphic
features like those present in turners syndrome or klinefelters
syndrome, presence of any operative scars if any, cryptorchidism /
undescended testis, micropenis, gynaecomastia, sense of smell status
and signs of any acquired disease.
Investigations
One has to make the diagnosis of hypogonadism and further how
it is caused –whether there is a primary cause or some central
pathology is involved needs to be ascertained. Despite various
tests involved still it has been very difcult to differentiate patients
having CDP from those having idiopathic hypogonadotropic
hypogonadism [17 reviewed in kkk]. Till date the achievement of
pubertal development by the age of 16-18yrs remains the golden
standard for making a DD of CDP against HH [5]. Though having
a family history of delayed puberty gives a strong suggestion of
CDP, the problem lies in that patients having CDP may be found in
pedigrees of those having isolated HH [18].
Hormonal levels
The basal FSH along with LH levels are low as is following GnRH
injections in pts with HH or CDP but increased in those having
hypergonadotropic hypogonadism. On an injection of 0.1mg GnRH,
pubertal onset gets characterized by LH/FSH Rtio >1. Testosterone
(T) levels in boys are >0.5ng/ml at pubertal onset and estradiol in
girls being <10ng/ml before puberty increase to >40ng/ml. Both
levels of inhibin and antimullerian hormne (AMH) might be of used
in separating CDP from HH, as in prepubertal boys inhibin B>35pg/
ml and AMH>110pmol/l are more commonly seen in CDP than in
hypogonadism [19, 20]. Other pituitary deciencies can be ruled out
by measuring IGF-1, T4, TSH and cortisol, and GH. [21] (Figure2,3)
Bone Age-One encounters a bone age of <11yrs in girls or <13yrs
in boys with growth failure in CDP. If bone age is >11yrsin girls
or >13yrs in boys it needs further tests to rule out hypogonadism.
Pelvic Ultrasound-In case of ovarian volume >2ml and uterus >35mm
implies that puberty is imminent [22]. In hypergonadotropic
hypogonadism, one might nd small or absent gonads, and testis
in males probably located intra abdominally.
Volume 4 | Issue 1 | 3 of 8
J Pediatr Neonatal Biol, 2019 www.opastonline.com
Karyotype
This is needed in case of hypergonadotropic hypogonadism, if
patients history doesn’t explain the gonadal pathology and if any
dysmorphic feauture which suggest Turners or Kinefelters are seen.
Brain Magnetic Resonance Imaging (MRI)-If any gonadotropin
deciency is met with MRI stands as the best tests to rule out organic
pituitary or hypothalamic disease. Very important is measuring the
pituitary and pituitary stalk. One encounters agenesis of olfactory
bulbs in case of Kallmann Syndrome (KS).
Molecular Studies
A genetic analysis is warranted in patients having hypogonadism,
with a normal karyotype and if possibly other clinical features of
syndromic hypogonadism are present. On testing if genes that are
involved in pubertal diseases are normal one can do other genetic
analyses which are being used in research presently. Exomic
sequencing may nd mutations in genes which are representative
of new cases of hypogonadism [23]. In case siblings are also affected
with similar hypogonadism phenotypes, genetic variants having
a single nucleotide polymorphism is found more commonly in
patients having hypogonadism and is said to be associated with the
disease [24], and one needs to mark the region of the genome which
inuences the risk of disease.
Puberty Timing
Variations are seen in initiation and end of puberty in boys and girls,
girls show signs of puberty before boys [25]. Recent advances in onset
of puberty obtained through study of genetic determinants of normal
puberty. Different neurotransmitters along with neuropeptides in the
hypothalamic arcuate nucleus have been found to be of importance
to reactivate the gonadotropic axis. Of these if there are loss of
function mutations in genes that encode for neuropeptides like
kisspeptin (Kp) or neurokinin B (TAC3) or their receptors (KISS1
or TAC3R respectively) =>hypogonadism [26, 27]. In case of sheep,
neurokinin B is expressed by the same neurons which manufacture
Kp [28]. In man these neurons are present in the arcuate nucleus
(in infundibular nucleus),that has an important role in the pulsatile
GnRH release [29]. In case of mice an increased activity of a tumor
related gene network in the hypothalamus has been observed at the
pubertal onset of female mice and its suggested that it participates
in the reactivation of the gonadotropic axis [30]. Also pubertal onset
might depend on epigenetic factors and complex regulation by LIN
28 protein has been seen [31].
Two neurotransmitters like GABA and glutamate control the
excitability of GnRH neurons, directly with GABA causing inhibition
and glutamate stimulation [32]. This balance between GABAergic
inhibitory and glutamatergic excitatory inputs of Gn RH neurons gets
modied at puberty, shifting towards activation. There is different
involvement of the opioid peptides along with action of different
peptides at various receptor subtypes making it complex which
act to inhibit GnRH secretion either directly or indirectly [23,33].
Neuropeptides RFamides, both RFRP1 and RFRP3 act on GnRH
neurons through the GPR 47 receptor [34]. Peripheral hormones
like leptin are also implicated in the regulation of GnRH network.
Another causative factor has been found in heterozygous activating
germline mutations seen in rat sarcoma-mitogen–activated protein
kinase (RAS-MAPK) pathway genes, which lead to developmental
disorders like RAS opathes like Noonan Syndrome, Costello and
cranio facio-cutaneous syndromes. The RAS-MAPK pathway plays
a central role in signal transduction from extracellular stimuli to the
intracellular environment. These RASopathies are usually associated
with delayed puberty although occasional cases of precocious
puberty has been dened making it difcult to ascertain role of
RAS-MAPK genes in the development of puberty [35van]. Thus if
any of the above factors get disrupted it modies the onset of puberty.
Etiopathology
Hypergonadotropic Hypogonadism
Increased FSH/LH suggest a primary gonadal deficit with
Hypergonadotropic Hypogonadism being either congenital or
acquired. Any history of previous surgery or disease affecting the
gonads helps in focusing on the diagnosis that is generally easy
in cases of delayed puberty where gonadal pathology is present.
Klinefelters syndrome (46XXY) is the commonest cause of
Hypergonadotropic Hypogonadism which is very often related
to Turners Syndrome in girls .This diagnosis gets conrmed by
karyotyping.
Hypogonadotropic Hypogonadism
The diagnosis of HH in boys is done based on the low plasma
testosterone concentrations that are associated with low LH and
FSH (both basal along with following Gn RH injection) as well as
at age 14 years when a testicular volume is found to be <4ml. As far
as girls are concerned one proposes HH when plasma gonadotropins
are normal or low, with any lack of pubertal sign as by the age of
13yrs. Certain inltrative or infectious lesions of the pituitary (like
histiocytosis or tumors), any medications (like GnRH analogs), brain
J Pediatr Neonatal Biol, 2019 Volume 4 | Issue 1 | 4 of 8
www.opastonline.com
trauma or radiation may=>acquired HH. If the HH gets corrected
following the reversal of pathology it implies that pathology is
the causative factor. This is mainly important in patients having
hypercortisolism, renal failure, celiac disease and malnutrition,
with especial emphasis on anorexia nervosa that is the major cause
of HH among girls.
In case of isolated gonadotropin deciency, congenital hypogonadism
may or may not be associated with anosmia.
On detailed analysis of families having knowledge ,it was
demonstrated that in cases of normosmic HH, which is a monogenic
mendelian disease there is an involvement of 6 genes namely
GnRH1[36,37], Gn RH R[26,38-,39], KISS1R [40-41], KISS1
[42,43] reviewed in kkk] TAC3 and its receptor TAC3R [44,]. Animal
model studies have given a better understanding regarding the role of
these factors in the gonadotropic axis [33, 44]. [17 reviewed in kkk].
Kalmann’s syndrome (KS) has variable clinical presentations, having
an X linked along with autosomal dominant and recessive causes
which have different penetrance. There may be coexisting renal
anomalies along with synkinesia. Its prevalence is 1/8000 men, and
that in women is ve times lower. On MRI, aplasia or hypoplasia of
the olfactory bulbs, which are associated with defective migration
of GnRH neurons through the cribriform plate [45].
Genes implicated in causation of KS are the 8 genes that are involved
in the olfactory bulb development. Initially inactivating mutations
were described in the KAL1 gene (that encodes anosmin1) that
is located on X chromosome [46,47], subsequently on autosomal
genes which included Fibroblast growth factor receptor FGFR1/
KAL, broblast growth factor8 (FGF8), [48-50, prokineticin2
(PROK2/Kal4), PROKR2/Kal 3[51-56], reviewed in ref 57, nasal
embryonic LHRH factor (NELF) [58], WD repeat containing protein
11(WDR11) [59] and Semaphorin 3 A(SEMA3A) and SEMA7 [60-
62], CHD7, [63-65], TSHZ1, AXL, HESX1[66-69].
Further 5 new genes of the FGF8/FGFR1 network in which mutations
were present in pts suffering from HH was reported by Miraoui etal
[70 alrady reviewed in17]. Roughly FGFR1 mutations are present in
10% of patients having idiopathic HH. The same FGFR1 mutations
might present with severe hypogonadism or reversible phenotypes
[71, 72].
HH might be syndromic and also part of the HH developmental
anomalies of GnRH neurons. Also there might be an association with
other pituitary deciencies and hence one needs to rule out tumoral
pathology along with inltrative diseases which need to be ruled
out. If there are various decits present during the neonatal period
or infancy a classication of congenital panhypopituitarism is made.
Both combined or multiple pituitary hormone deciencies might
get acquired during childhood. One performs the genetic testing
for known monogenic or digenic causes of HH in the 2nd phase
of testing. Yet, that an overlap is present between KS, combined
pituitary deciency and septooptic dysplasia has been reported,
hence pituitary function needs to be reexamined if any doubt is
present [73].
Constiutional Delay of Puberty (CDP)
Important fact to note is that the initial cause of pubertal delay in boys
is represented by CDP (idiopathic) that might be difcult to separate
from other congenital or acquired types of HH. This is a diagnosis
conrmed by exclusion if puberty onset occurs spontaneously. These
are healthy girls and boys reaching puberty spontaneously by the age
of 13yrs and 14 yrs respectively. There is delay in puberty, growth
along with bone maturation. Thus to diagnose this, slow growth
for age, but within the prepubertal range, with other siblings with
constitutional delay of growth and puberty and a normal physical
examination with normal olfaction are required [4,74,75]. A family
history of delayed puberty is seen in half of the CDP cases, that
strongly suggests CDP [74, 75]. But patients having CDP may be also
seen in pedigrees of families of isolated HH. In most cases the rst
signs of sexual maturation occur within 1year after gonadotropin and
testosterone or E2 concentrations begin to increase spontaneously
[76]. Mostly the 1st signs of sexual maturation occur within 1year
after LH rises >2u/l in 3
rd
generation assays after administration
of LHRH or within 1year of gonadotropin and testosterone or E2
concentrations begin to rise spontaneously [76]. Mostly patients with
CDP consult initially for short stature instead of delayed puberty. It
is much more common in boys comparable to girls since pubertal
growth does not occur and they remain small compared to other
children of the same age. They have delayed epiphysis maturation.
A 2nd important point is that the physical sign is a relatively short
upper body segment which is seen after 9 years of age with growth
delay [77]. Important is to rule out any chronic illness or intense
exercise that can =>growth and pubertal delay.
If no criteria for any suspected disease, careful monitoring and a
brain MRI is required in teenagers having gonadotropin deciency.
Since there is a dilemma whether self limited delayed puberty (DP)
is benign or is associated with long term effects and on role of
giving sex steroids in these pts Zhu et al reviewed the literature and
found that CDP may be both harmful and have protective effects on
different adult health outcomes. Especially, height and bone mineral
density have been observed to be compromised in some studies of
adults having a history of DP. DP might also negatively affect adult
pshychosocial functioning and educational achievement, besides
which individuals having history of DP carry a risk of metabolic and
cardiovascular disorders. While in contrast, history of DP seems to
be protective for breast and endometrial cancer in women and for
testicular cancer in men. Although most studies of adult outcomes of
self limited DP have been in small series with signicant variability
in outcome measures and study criteria. Thus more future research
is needed to ll the gaps in our knowledge [78].
Environmental factors
Recent trends of early puberty reects how modern environment
has changed. One of the reasons is global warming. Besides that
endocrine disruptors play a part, but besides that the family context
and psychological development during pre adult life are important
inuences in transition between childhood and puberty, possibly
via epigenetic changes [79].
Treatment principles
2 important aims are to make sure full pubertal development occurs
and that reproductive capacity is achieved.
Treatment for Pubertal Development
Cause of hypogonadism found have to be treated if possible
following which pubertal development will take a normal course
following treatment of underlying disease. Pituitary tumors need
treatment before initiating hormonal replacement for correcting
J Pediatr Neonatal Biol, 2019 Volume 4 | Issue 1 | 5 of 8
www.opastonline.com
delayed puberty. For other causes aim is to make sure full pubertal
development, associated with growth acceleration, development of
sexual feautures, optimal bone mass is achieved along with normal
sexual activity.
Before starting replacement therapy, it is important to differentiate
hypogonadism from CDP, for which a short term test with low dos
sex steroids will induce the growth spurt, that will be sustained in
CDP. Low doses do not inuence the nal height. In boys use of
low doses of T (50mg i/m every 4weeks) for 6 months or classic
protocols with low doses of anabolic steroids like oxandrolone
(1.5-2.5mg/day for 6 mths) have been used. In girls low doses of
estrogen (2-5µg/day of ethinyl estradiol or equivalent transcutaneous
estrogen doses-5µg/kg body weight of 17β estradiol for 6 months [4,
77]. T in males and eatrogens and estrogen-progestogen in girls are
given in gradually increasing doses. In girls E2,is the commonest
replacement via oral or cutaneous administration. Patches have fewer
secondary effects, as the estrogen do not pass into the liver. In CDP
no treatment should start before 13 years or a bone age of 12yrs.
No international consensus, but usually E2 is given at the dose of
2-6µg/kg(1/12th to1/4th of patch of 25µg/day (6 months to 1year)
[1]. When hypogonadism is present, low doses are given initially-
0.3mg of estrogen or 5µg/kg body weight daily of E2 or one eighth
of transdermal patch of 25µg, which is increased progressively
between 0.3and 0.6mg or 1/8
th
-1/4
th
patch every 6 mths or 2-3yr
still dose of 2mg E2/day or 10µg/kg/day is reached [4]. Following
2yrs of treatment, progesterone is given to induce cycles-2mg/
day of E2 from day 1 to 21and P from day 10 to day 21. Estrogen
progestin pills can also be used. Bone age, ultrasonography and
monitoring of the evolution of pubertal clinical feautures, growth
and estrogen tolerance should be done every 6 mths. Lipid levels,
glycaemia and liver enzyme levels are assessed before starting
treatment. In boys CDP is treated when the delay has psychological
consequences .This replacement therapy needs to start when bone
age is 12-13years.Treatment entails an i/m injection of the ester of
T (enanthate, cypionate or propionate) every 4 weeks beginning
at 50mg and increasing to 100mg during 6mths-1year. T patches
prevent abrupt increase of T at treatment onset. One needs clinical
monitoring every 6mths. In both cases, if no responses is observed
after 1year hypogonadism should be taken into account.
Treatment with gonadotropins (subcutaneous weekly multi-LH or
HCG and FSH or recombinant GnRH or pump) is used in adulthood
for specic treatment of infertility In HH [80], but it can be used
to induce puberty [81]. Here an increase in testicular volume is
observed. Reviewing the possible benets of neonatal gonadotropin
treatments in males with congenital HH, Bouvattier [82] found that
pulstile GnRH could be effective to help in orchidopexy a surgery
on a small testis would be more difcult. But these treatments are
more complex and expensive with compliance problems.
Fertility Treatment
On diagnosis of hypogonadism during adulthood, the aim of
treatment for most young men and women is there desire for fertility,
which needs hormonal therapy. Men having hypergonadotropin
hypogonadism don’t respond to this hormonal therapy since
primarily the disease is caused by testicular dysfunction. T enanthate
is given to reverse signs and symptoms of hypogonadism. In HH,
GnRH and gonadotropin therapies remain the best way of treating
men who have a desire for fertility. Therapy with HCG alone 1000-
2500IU twice a week for 8-12weeks, increases testosterone and
sometimes induces spermatogenesis, or combined with recombinant
FSH (75-150IU thrice a week) to stimulate sperm production along
with T levels. Subcutaneous GnRH administration with a pump
(100-400ng/kg every2h in the abdominal subcutaneous tissue if
available) during 4mths can also restore fertility in HH. Although
semen sperm concentration usually remains below the normal range.
Hence treatment is required for 6-12 mths, that is essential to restore
spermatogenesis. Since this is costly all patients might not afford it
[83, 84]. Recently Kp agonists have been tried in some cases having
KISS1/KISS1R mutations [43, 85] although not available in every
country. Although NKB is not effective it being downstream of KISS,
KP agonists are also effective in TAC3/TAC3R mutations [86-88].
Conclusions
Diagnosis of hypogonadism is based on when clinical feautures
appear, that depends on when hypogonadism starts. In case of
congenital delayed puberty, degree to which the child gets affected
is related to when during fetal life the gonadotropic axis gets affected
[5]. If there is inuence early in utero, it results in more severe
defects, which possibly explains why there are severe, moderate
and even reversible forms of DP [5]. GnRH deciency occurring
during fetal life is accompanied by cryptorchidism and micropenis.
In Case of GnRH deciency starting in infancy, before puberty or
after, infertility, lack of libido, gynaecomastia and low bone density
are the common presenting feautures, but in these testis and penile
size may be normal and them having secondary sex characters.
Thus it may be difcult to diagnose in children if no feautures are
seen in the newborn. In adults., hypogoadism, might be post pubertal
or partial with hormone levels during GnRH test, AMH and inhibin
conrming the diagnosis. MRI has importance in the diagnosis of
secondary hypogonadism and in KS. One needs specic therapy in
hypogonadiem, which depends on when to treat. In CDP, if treatment
is to be done needs consideration.
With the advances in puberty research one has received a greater
insight into initiation of puberty through studying different genetic
diseases, along with populations having normal puberty, besides
animal studies. This initiation of puberty occurs because of post natal
hypothalamic maturation=>increased secretion of hypothalamic
Gn RH neurons. This involves a complex gene network. With the
identication of new monogenic diseases, new members of the
network are getting identied. Genotyping and epigenetic study
might further help for nding the status of the complex neuronal
hypothalamic network. With these methods one might be able to
understand the potential problems in the gonadotropic axis even
before puberty gets initiated. Further research is needed to get
answers for these queries.
References
1. Ankarberg Lindgren C, Elfving M, Wikland KA, Nirjavaara T
(2001) Nocturnal application of transdermal estradiol patches
produce levels of estradiolthat mimic those seen at the onset
of spontaneous puberty in girls. J Clin Endocrinol Metab 86:
3039-3044.
2.
Palmert MR, Boepple BA (2001) Variation in the timing of
puberty: clinical spectrum and genetic unvestigations. J Clin
Endocrinol Metab 86: 2364-2368.
3.
Palmert MR, Dunkel L (2012) Clinical Practice.Delayed
Puberty. N Engl J Med 366: 443-453.
4. Ojeda SR, Lomniczi A, Sardau US (2008) Glial-gonadotropin
J Pediatr Neonatal Biol, 2019 Volume 4 | Issue 1 | 6 of 8
www.opastonline.com
hormone (GnRH) neurons interaction s in the median eminence
and the control of GnRH secretion.J Neuroendocrinol 20: 732-
742.
5. Rey RA, Crimpson RP, Gottlieb S, Pasqualini T, Knobiovvits
P et al. (2013) Male hypogonadism: an extended classication
based on a developmental, endocrine, physiology based
approach. Andrology 1: 3-16.
6.
Marcia E Herman-Giddens, Eric J Slora, Richard C Wasserman,
Carlos J Bourdony, Manju V Bhapkar et al. (1997) Secondary
sexual characters and menses in young girls seen in ofce
practice:a study from the Pediatric Researchin Ofce Settings
network. Pediatrics 99: 505-512.
7. Liu YX, Wickland KA, Karlberg J (2000) New reference for
the age at childhood onset of growth and secular trend in the
timing of puberty in Swedish.Acta Pediatrics 89: 637-643.
8. Sun SS, Schubert CM, Chumlea WC, Alex F Roche, Howard
E Kulin et al. (2002) National estimates of the timing of sexual
maturation and racial differences among US children. Pediatrics
110: 911-919.
9. Wu T, Mendola P, Buck GM (2002) Ethnic differences in the
presence of secondary sex characteristics and menarche mong
US girls :the 3rd National Health and Nutrition Examination
Survey 1988-1994. Pediatrics 110: 752-757.
10.
Anderson SE, Must A (2005) Interpreting the continued decline
in the average ag at menarche: results from two national
representative surveys of US girls studied 10yrs apart. J Pediatr
147: 753-760.
11.
Susman EJ, Houts RM, Steinberg L, Jay Belsky, Elizabeth
Cauffman et al. (2010) Eunice Child Care Research Network.
Longitidinal development if secondary sexual characteristics
in girls and boys between 91/2and 151/2 years. Arch Pediatr
Adolesc Med 164: 166-173.
12.
Goldstein JR (2011) A secular trend toward earlier male sexual
maturity: evidence from shifting ages of male adult young asilt
mortality. PLoS One 6: 14826.
13. Ma HM, Chen SK, Chen RM, Zhu C, Xiong F et al. (2011)
Pubertal study group of the Society of Paediatric Endicrinology
and Genetic Disease .Chinese Medical Association Pubertal
timing in urban Chinese boys. Int JAndrol 34: 433-445.
14.
Monteilh C, Kieszak S, Flanders WD, Maisonet M, Rubin C et
al. (2011) Timing of maturation and predictors of Tanner stage
transitions in boys enrolled in a contemporary British cohort.
Paediatr Perinat Epidemiol 25: 75-87.
15.
Herman-Giddens ME, Steffes J, Harris D, Slora E, Hussey M et
al. (2012) Secondary sexual characteristics in boys :data from
the Pediatric Research in Ofce Setting Networks. Pediatrics
130:1058-1068.
16. Biro FM, Greenspan LC, Galvez MP, Pinney SM, Teitelbaum
S et al. (2013) Onset of breast development in a longitudical
cohort. 132: 1019-1027.
17.
Kulvinder Kochar Kaur, Allahbadia GN, Mandeep Singh (2016)
Idiopathic Hypogonadotropic Hypogonadism-An Update on
the Aetiopathogenesis, Management of IHH in Both Males and
Females-An Exhaustive Review-Advances in Sexual Med 6: 4.
18.
BhagvathB, Podolsky RH, Ozata M, Bolu E, Bick DP et al.
(2006) Clinical and molecular characterization of a large sample
of patients with hypogonadotropic hypogonadism. Fertil Steril
85: 706-713.
19. Coutant R, Biette-Demeneux E, Bovattier C, Bouhours-Nouet
N, Gatelais F et al. (2010) Baseline inhibinB and antimullerian
hormone measurements for diagnosis of hypogonadotropic
hypogonadism in boys with delayed puberty. J Clin Endocrinol
Metab 95: 5225-5232.
20.
HeroM, Tommiska K, Laitinen EM, Sipila I, Puhakka L et
al. (2012) Curculating antimullerian hormonelevels in boys
decline during early puberty and correspond with inhibin B.
Fertil Steril 97: 1242-1247.
21. Young J (2012) Approach to the male patient with Congenital
Hypogonadotropic Hypogonadism.J Clin Endocrinol Metab
97: 707-718.
22. Stanhope R, Adams I, Jacobs HS, Brook CG (1985) Ovarian
ultrasound assessment in normal children, idiopathicprecocious
puberty and during low dose gonadotropin releasing hormone
treatment in hypogonadotropic hypogonadism. Arch Dis Child
60:116-119.
23.
Margolin DH, Kousi M, Chan YM, Lim FY, Schmahmann ID et
al (2013) Ataxia,dementia and hypogonadotropic hypogonadism
disordered ubiquitination. N Engl J Med 368:1992-2003.
24. WehkalampiK, Widen E, Laine T, Palotie A, Dunkel L (2008)
Associartion of the timing of puberty with a chromosome 2
locus . J Clin Endocrinol Metab 93: 4833-4839.
25.
Sisk CL, Foster DL (2004) The neural basis of puberty and
adolescence. Nat Naurosci 7:1040-1047.
26.
Karges B, Karges W, De Roux N (2003) Clincal and molecular
genetics of the human GnRH receptor Hum Reprod Update 9:
523-530.
27.
Guran T, Tolhurst G, Bereket A, Rocha N, Porter K et al. (2009)
Hypogonadotropic hypogonadism due to a novel missense
mutation in the rst extracellular loop of the neurokininB
receptor. J Clin Endocrinol Metab 94: 3633-3639.
28.
Goodman RL, Lehman MN, Smith JT, Coolen LM, De Oliveira
CV et al. (2007) Kisspeptin neurons in the arcuate nucleus of the
ewe express both dynorphun And neurokinin B. Endocrinology
148: 5752-5760.
29.
Plant TM, Moosy J, Hess DL, Nakai Y, Mc Cormack IT et
al. (1979) further studies on the effect of lesions in the rostral
hypothalamus on gonadotropin secretion in the female rhesus
monkey (Macaica mulatta) Endocrinology 105: 465-473.
30. Roth CL, Mastronardi C, Lomniczi A, Wright H, Cabrera R et
al. (2007) Expession of a tumor related gene network increases
in the mammalian hypothalamus at the time of female puberty.
Endocrinology 148: 5147-5161.
31.
Sangiao- Alvarello S, Manfrfredi-Lozano M, Ruiz-Pino F,
Navarro VM, Sanchez Garrido MA et al. (2013) Changes in
the hypothalamic expression of the LIN 28/let7system and
related micro RNA’s during post natal maturation and after
experimental manipulations of puberty.Endocrinology154:
942-955.
32.
Ojeda SRUH (2007) Puberty in the rat. New York, Raven Press.
33.
Navarro VM, Gottsch ML, Chavkin C, Okamura H, Clifon DK
et al. (2009) Regulation of gonadotropin releasing hormone
secretion by kisspeptin/dynorphin /neurokininB neurons in
the arcuate nucleus of the mouse. J Neurosci 29: 11859-11866.
34.
Ducret E, Anderson GM, Herbison AE (2009) R famide relared
peptide 3, a mammalian gonadotropin-inhinbitory hormone
ortholog regulates gonadotropin releasing hormone neuron
ring in the mouse. Endocrinology 150: 2799-804.
35.
Van der Kaay DC, Levine BS, Doyle D, Londono RM, Palmert
MR (2016) RAS opathiesassociated with delayed puberty; Are
they Associated with Precocious Puberty Too?Paediatrics 58:
J Pediatr Neonatal Biol, 2019 Volume 4 | Issue 1 | 7 of 8
www.opastonline.com
201660182.
36.
Bouligard J, Ghervan C, Tello JA, Brailly-Tabard S, Salenave S
et al. (2009) Isolated familial hypogonadotropic hypogonadism
ana a GnRH 1 mutation. N Engl J Med 360: 2742-274.
37.
Chan YM, de Guillebon A, Lang-Muritano M, Plummer
L, Cerrato et al. (2009) GnRH 1 mutations in patients with
idiopathic hypogonadotropic hypogonadism . Proc Natl Acad
Sci USA 106:11703-11708.
38.
Tello JA, Newton CL, Bouligard J, Guiochon-Mantel A, Millar
RP et al. (2012) congenital hypogonadotropic hypogonadism
due to GnRH receptor mutations in three brothers reveal sires
affecting conformation and coupling.PLoS One 7: 38456.
39. Sykiotis GP, Plummer L, Hughes VA, Au M, Durrani S et al.
(2010) Oligogenic basis of isolated gonadotropin –releasing
hormone deciency.Proc Natl Acad Sci USA 107:15140-15144.
40. de Roux N, Genin E, Carel JC, Matsuda F, CusSainJL et al.
(2003) Hypogonadotropic hypogonadism due to loss of function
of the KiSS1 derived peptide receptor GPR54. Proc Natl Acad
Sci USA100:10972-10976.
41. Pallais JC, Bo-Abbas Y, Pitteloud N, Crowley WF, Seminara
SB (2006) Neuroendocrine, gonadal, placental, and obstetric
phenotypes in patients with IHH and mutations in the G-protein
coupled receptor,GPR54.Molecular and Cellular Endocrinology
255: 70-77.
42.
Topaloglu AK, Tello JA, Kotan LD, Ozbek MN, Yilmaz MB et
al. (2012) Inactivating KISS1 mutations and hypogonadotropic
hypogonadism. N Engl J Med 366: 629-635.
43. Kochar Kaur K, Allahbadia GN, Singh M (2012) Kisspeptins
in human reproduction-future therapeutic potentials. J Assist
Reprid Genet 29: 999-1011.
44.
Topaloglu AK, Reimann F, Guclu M,Yalin AS,Kotani LD et al.
(2009) TAC3 and TACR3 mutations in familial hypogonadotropic
hypogonadism reveal a key role for neurokinin B in the central
control of reproduction. Nat Genet 41: 354-358.
45. Dode C, Hardelin P (2009) Kallmann Syndrome. Eur J Hum
Genet17:139-146.
46. Franco B, Guioli S, Pragliola A, Incern B, Bardoni B et al. A
gene deleted in Kallmann’s syndrome shares homology with
neural cell adhesion and axonal path-nding molecules. Nature
353: 529-536.
47.
Legouis R, Hardelin JP, Levilliers J, Claverie JM, Compain
S et al. (1991) The candidate gene for the X linked Kallmann
syndrome encodes a protein related to adhesion molecules.
Cell 67: 423-435.
48. Dode C, Levilliers J, Dupont JM, De PaepeA, Le Du N et al.
(2003) Loss of function mutations in FGFR1 cause autosomal
dominant Kallmanns syndrome.Nat Genet 33: 463-465.
49. Falardeau J, Chung WC, Beenken A, Raivio T, Plummer EF
et al. (2008) Decreased FGF8 signaling causes deciency of
gonadotropin releasing hormone in humans and mice. J Clin
Endocrinol Metab 118: 2822-2831.
50. Pitteloud N, Acierno Jr JS, Meysing A, Eliseenkova AV, Ma
J et al. (2006) Mutations in broblast growth factor receptor
1 causes both Kallmann syndrome and normosmic idiopathic
hypogonadotropic hypogonadism.Proc Natl Acad Sci USA
103: 6281-6286.
51.
Dode C, Teixeira L Levvilliers J, Fouveaut C, Bouchard P,
Kottler ML et al. (2006) Kalmann syndrome; mutations in
the genes encoding prokineticin 2 and prokineticin receptor 2
PLoS Gene 2: 175.
52.
Pitteloud N, Zhang C, Pognatelli D, LiJD, Raivio T et al.
(2007) Loss of function mutation in the prokineticin 2
gene causes Kallmann syndromeand normosmic idiopathic
hypogonadotropic hypogonadism.Proc Natl Acad Sci USA
104:17447-17452.
53.
Cole LW, Sidis Y, Zhang C, Quinton R, Plummer L et al. (2008)
Mutations in prokineticin 2 and prokineticin receptor2 genes in
human gonadotropin –releasing hormone deciency:molecular
genetics and clinical apectrum.L Clin Endocrinol Metab 93:
3551-3559.
54. Leroy C, Fouveaut C, Leclercq S, Jacquemont S, Boullay HD
et al. (2008) Biallelic mutations in the prokineticin gene in
two sporadic case of of Kallmann syndrome.Eur J Hum Genet
16: 865-868.
55.
Abreu AP, Trarbach EB, de CastroM, Frade Costa EM, Versiani
B et al. (2008) Loss of function mutations in the genes encoding
prokineticin 2 or prokineticin receptor 2 cause autosomal
recessive Kallmann syndrome. J Clin Endocrinol Metab 93:
4113-4118.
56. Sarfati J, Guiochon -Mantel A, Rondard P, Arnulf L, Garcio-
Pinero A et al. (2010) A comparative phenotypic study of
Kallmann syndrome patients carrying monoallelic and biallelic
mutations in the prokineticin 2 or prokineticin receptor 2genes.J
Clin Endocrinol Metab 85: 659-669.
57.
Kochar Kaur K, AllahbadiaGN, Singh M (2013) an update
on the role of prokineticins in human reproduction-potential
therapeutic applications.O J Gen 3: 1-15.
58. Miura K, Acierno JS Jr, Seminara SB (2004) Characterization
of the human nasalembryonic LHRH factor gene,NELF,and
a mutation screening among 65 patients with idiopathic
hypogonadotropic hypogonadism. J Hum Genet 49: 265-268.
59. Kim HG, Ahn JW, Kurth I, UllmannR, Kim HT et al. (2010)
WDR11,a WD protein that interacts with transcription
factor EMX1, is mutated in idiopathic hypogonadotropic
hypogonadism and Kallmann syndrome, Am J Hum Genet
87: 465-479.
60.
Hanchate NK, Giacobini P, Lhullier P, Prakash J, Espy C et
al. (2012) SEMA 3A, a gene involved in axonal pathnding,
is mutated in some patients with Kallmann syndrome. PLoS
Genet 8: 1002896.
61. Cariboni A, Davidson K, Rakic S, Maggi R, Parnavelas JG et
al. (2011) Defective gonadotropin releasing hormone neuron
migration in mice lacking SEMA3A signaling through NRP1
and NRP2: Implicationsfor the aetiology of hypogonadotropic
hypogonadism. Hum Mol Genet 20: 336-344.
62.
Kansakoski J, Fagerholm R, LaitinenEM, Vaaralahti K,
Hackman P et al. (2014) Mutation screening of SEMA 3A
and SEMA7A in patients with congenital hypogonadotropic
hypogonadism. Pediatr Res 75: 641-644.
63.
Ogata T, Fujiwara I, OgawaF, Sato N, UdakaT et al. (2006)
Kallmann syndrome phenotype in a female patient with
CHARGE syndrome and CHD7 mutation.Endocr J 53: 741-743.
64. Jongmans MC, van Ravenswaaij-Arts CM, Pitteloud N, Ogata
T, Sato N et al. (2009) CHD7 mutations in patients initially
diagnosed with Kallmann syndrome-the clinical overlap with
CHARGE syndrome. Clin Genet 75: 65-71.
65. Kim HG, Kurth I, Lan F, Meliciani I, Wenzel W et al. (2008)
Mutations in CHD7 ,encoding a chromatin remodeling protein
,causes idiopathic hypogonadotropic hypogonadism and
Kallmann syndrome. Am J Hum Genet 83: 511-519.
66. Ragancokoya D, Rocca E, Oonk AMM, Schultz H, Rohde E
et al. (2014) TSHZ1-dependent gene regulation is essential
Copyright: ©2019 Kulvinder Kaur, et al. is is an open-access article
distributed under the terms of the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are credited.
J Pediatr Neonatal Biol, 2019 Volume 4 | Issue 1 | 8 of 8
www.opastonline.com
for olfactory bulb development and olfaction. J Clin Invest
124:1224-1227.
67. Salian-Mehta S, Xu M, Knox AJ, Plummer AL, Slavov D et
al. (2014) Functional consequences of AXL Sequence Variants
in HypogonadotropicHypogonadism. J Clin Endocrinol Metab
99: 1452-60.
68. Newbern K, Natrajan N, Goo-Kim H, Chorich LP, Halvorson
LM et al. (2013) Identication of HESX1 mutations in Kallmann
syndrome. Fert Steril 99: 1831-37.
69.
Niederberger C (2014) RE: Identication of HESX1 mutations
in Kallmanns Syndrome. J Urol 191:1081.
70.
Miraoui H, Dwyer AA, Sykiotis GP, Plummer L, Chung W
et al. (2013) Mutations in FGF17,IL17RD,DUSP6,SPRY4
and FLRT3 Are iudentird in indiciduals wirh congenital
hypogonadotropic hypogonadism. Am J Hum Genet 92:725-
743.
71.
Villaneuva C, DeRoux N (2010) FGFR1 mutations in Kallmann
Syndrome.Front Horm Res 39:51-61.
72.
Pitteloud N, AcernoJS Jr, Meysing AU, Dwyer AA, Hayes FJ, et
al. (2005) Reversible Kallmann Syndrome, delayed puberty, and
isolated anosmia, occurring in a single family with mutations in
the broblast growth factor receptor I gene. J Clin Endocrinol
Metab. 90:1317-1322.
73. Raivio T, Avbeli M, McCabe MJ, Romero DJ, Swyer AA et al.
(2012) J Clin Endocrinol Metab 97: 694-699.
74.
Sedmeyer IL, Hirschhorn JN, Palmert MR (2002) Pedigree
analysis of constitutional delay of growth and maturation:
determination of familial aggregation and inheritance patterns.
J Clin Endocrinol Metab 87: 5581-5586.
75. Wehkalampi K, Widen E, Laine T, Palotie A, Dunkel I (2008)
Patterns of inheritance of constitutional delay of growth and
puberty in families of adolescent girls and boys referred to
specialist pediatric care. J Clin Endocrinol Metab 93: 723-728.
76.
Grumbach MM,Styne DM (1998) Williams Text Book of
Endocrinology, ed 9, Philadelphoa Saunders pp1550-1551.
77.
Traggert C, Stanhope R (2003) Disorders of pubertal
development. Best Pract Res Clin Obstet Gynacol 17: 41-56.
78.
Zhu J, Chan YM (2017) Adult consequences of self limited
daelayed Puberty. Paediatrics 139: 20163177.
79.
Hochberg Z, Belsky J (2013) Evo-devo of human
adolescence:beyond disease models of early puberty. BMC
Med 11:113.
80.
Fraietta R, Zylberstejn DS, Esteves SC (2013) Hypogonadotropic
hypogonadism revisited. Clinics 68: 81-88.
81.
Raivio T, Wikstrom M, Dunkel L (2007) Treatment of
gonadotropin decient boys with recombinant human FSH:long
term observation and outcome. Eur J Endocrinol 156:105-111.
82.
Bouvatter C, Maione L, Bouligaard J, Dode C, Guiochon Mantel
A et al. (2012) Neonatalgonadotropin therapy in male congenital
Hypogonadotropic hypogonadism.Nat Rev Endocrinol 8: 172-
182.
83.
ZitzmannM, Nieschlag E (2000) Hormone substitution on male
hypogonadism.Mol Cell Endocrinol 161: 73-88.
84. Han TS, Bouloux PM (2010) what is the optimal therapy for
young males with Hypogonadotropic hypogonadism.Clin
Endocrinol 72: 731-737.
85.
George JT, Veldhius JD, Roseweir AK, Newton CL, Fasccenda
E et al. (2011) Kisspeptin 10 is a potent stimulator of LH
&increase pulse frequencty in men. J Clin Endocrinol Metab
96:1228-1236.
86.
George JT, Seminara SB (2012) Kisspeptin and the hypothamic
control of reproduction: Lessons from the Human. Endocrinology
153: 5130-5136.
87. Young J, George JT, Tello JA, Francou B, Bouligard J et al.
(2013) Kisspeptin restores pulsatile LH secretion in patients
with NKB signaling deciencies. Neuroendocrinology 97:
193-202.
88. Villaneuva C, Argente J (2014) Pathology or normal variant:
what constitutes a Delay in Puberty? Horm Res Paediatr 82:
213-221.
