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Congenital hypogonadotropic hypogonadism: implications of absent mini-puberty.
Authors: Dr Andrew A. Dwyer, Dr Channa N. Jayasena & Dr Richard Quinton
AAD: Endocrinology, Diabetes and Metabolism Service of the Centre Hospitalier Universitaire Vaudois, and the
University of Lausanne Institute of Higher Education and Research in Healthcare, Route de al Corniche 10,
1010 Lausanne, Switzerland.
andrew.dwyer@chuv.ch
Tel: +41 (0)21 314 59 46
Fax: +41 021 314 06 30
CNJ: Section of Investigative Medicine, Imperial College London Faculty of Medicine, Hammersmith Hospital,
Du Cane Road, London, UK
c.jayasena@imperial.ac.uk
Tel: +44 208 383 3242
RQ: Endocrine Research Group, Institute of Genetic Medicine, Newcastle University and Endocrine Unit,
Newcastle-upon-Tyne Hospitals, UK
richard.quinton@ncl.ac.uk
Tel: +44 191 282 4635
Fax: +44 191 282 0129
Corresponding Author: Dr Richard Quinton
Endocrine Unit
Royal Victoria Infirmary
Newcastle-upon-Tyne
NE1 4LP
UK
Word count: 2326
Tables: 2
Figures: 0
Conflicts of interest: none declared.
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Abstract
The phenomenon known as “mini-puberty” refers to activation of the neonatal hypothalamo-pituitary axis causing
serum concentrations of gonadotrophins and Testosterone (T) to approach adult male levels. This early neonatal
period is a key proliferative window for testicular germ cells and immature Sertoli cells. Although failure to
spontaneously initiate (adolescent) puberty is the most evident consequence of a defective gonadotrophin
releasing hormone (GnRH) neurosecretory network, absent mini-puberty is also likely to have a major impact on
the reproductive phenotype of men with congenital hypogonadotrophic hypogonadism (CHH). Furthermore, the
phase of male mini-puberty represents a key window-of-opportunity to identify congenital GnRH deficiency
(either isolated CHH, or as part of combined pituitary hormone deficiency) in childhood. Among male neonates
exhibiting “red flag” indicators for CHH (i.e. maldescended testes with or without cryptorchidism) a single serum
sample (between 4-8 weeks of life) can pinpoint congenital GnRH deficiency far more rapidly and with much
greater accuracy than dynamic tests performed in later childhood or adolescence. Potential consequences for
missing absent mini-puberty in a male neonate include the lack of monitoring of pubertal progression / lack of
progression, and the missed opportunity for early therapeutic intervention. This article will review our current
understanding of the mechanisms and clinical consequences of mini-puberty. Furthermore, evidence for the
optimal clinical management of patients with absent mini-puberty will be discussed.
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Introduction
Men with congenital hypogonadotrophic hypogonadism (CHH) typically present in adolescence or early
adulthood with absent, or incomplete puberty and lack of testicular development. They have a treatable form of
infertility that is amenable to hormone replacement therapy1,2. As CHH is clinically and genetically
heterogeneous, the phenotype at presentation is influenced by the severity of the underlying deficiency of
gonadotrophin-releasing hormone (GnRH). Complete GnRH deficiency in males is frequently characterised by
neonatal cryptorchidism and/or micropenis and a presumptive (or occasionally definitive) diagnosis is sometimes
made at that point. Such patients invariably exhibit absent pubertal development (TV < 4mL) in adolescence
consistent with complete GnRH deficiency. However, around one third of CHH cases have partial GnRH
deficiency with normal penile development and testicular descent at birth, and some degree of spontaneous
testicular development during adolescence (TV > 4 mL)3. Moreover, detailed phenotyping studies demonstrate
these men have varying degrees of GnRH-induced LH secretion4.
Notably, the activity and pattern of GnRH secretion change across normal human development, with the fetal
hypothalamic-pituitary-gonadal (HPG) axis first becoming active during the third trimester and remaining active
during the first few months of postnatal life. Activation of the neonatal HPG axis causes serum concentrations of
LH, FSH and Testosterone (T) to approach adult male levels, which is a phenomenon known as “mini-puberty” 5.
Interestingly, a retrospective study of childhood growth charts in 36 Finnish and Danish CHH men found
evidence of a modest deceleration in linear growth rate between the ages of 3 to 6 months, which the authors
postulated might reflect early androgen deficiency; however final adult height did not differ from mid-parental
predictions6.
The gonadotrophins exert differential effects on the compartments of the testes. Broadly, LH stimulates
maturation of the interstitial Leydig cells that secrete T, along with glycoprotein mediators such as insulin-like
factor 3 (INSL3). Intra-testicular T, in concert with FSH, acts on the seminiferous tubules to induce and maintain
spermatogenesis. The physiologic role of INSL3 remains unclear, though it is a marker of Leydig cell activity
and may have anti-apoptotic effects on germ cells7.
FSH is essential for development of the tubular compartment, where spermatogenesis occurs. FSH stimulates
the proliferation of immature Sertoli cells that secrete inhibin B and AMH. The FSH-induced proliferation of
immature Sertoli cells has far-reaching effects on fertility potential, with Sertoli cells supporting a species-specific
number of germ cells8 and determining final seminiferous tubule length9-10. As seminiferous tubules account for
approximately 90% of testicular volume (TV) the size of the testes is a critical indicator of fertility potential.
Inhibin B secreted by mature Sertoli cells is important for negative feedback on FSH in adults 11. AMH is
secreted by immature Sertoli cells and is down-regulated by T, and thus is highest in early puberty and
decreases with rising serum T levels12,13.
Importantly, Sertoli cells do not express the androgen receptor until age 5 years 14; therefore, mini-puberty, the
testes do not mature and spermatogenesis is not initiated during mini-puberty despite the associated high levels
of intra-testicular T. The early neonatal period is thus a key proliferative window for germ cells and immature
Sertoli cells15. Although failure to spontaneously initiate puberty is the most evident consequence of a defective
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GnRH neurosecretory network, the absence of mini-puberty is also likely to have a major impact on the
reproductive phenotype of men with CHH.
Missed opportunities in relation to absent mini-puberty in CHH males
Diagnostics
The phase of male mini-puberty represents a key window-of-opportunity to identify congenital GnRH deficiency
(either isolated CHH, or as part of combined pituitary hormone deficiency) in childhood16,17. While reports of
early diagnosis are relatively scarce, in certain situations diagnosis can even be made during fetal life 18. Among
male neonates exhibiting “red flag” indicators for CHH (i.e. maldescended testes with or without crypotrochidism)
a single serum sample (between 4-8 weeks of life) can pinpoint congenital GnRH deficiency far more rapidly and
with much greater accuracy than dynamic tests performed in later childhood or adolescence16,19. Indeed,
hormonal profiling during mini-puberty can offer greater diagnostic specificity than genetic studies in predicting
the adult phenotype, unless the patient harbours a mutation in ANOS1 (formerly KAL1) which is almost 100%
predictive of Kallmann syndrome (KS) phenotype . Although CHH is a rare disease, necessarily without a clear
reproductive phenotype in childhood, certain “red flag” features, most of them clinically ascertainable at birth, can
identify infants at sufficiently high-risk of having CHH to justify a simple biochemical screening test (Table 1).
In a large retrospective series, around ½ of CHH males were found to have at least one undescended testis at
birth, and ⅓ of these affected patients hadd bilateral disease20. Of those who had undergone bilateral
orchidopexy, only ⅓ had also been referred to Paediatric Endocrinology for further evaluation and none were
tested for absent mini-puberty. Among the majority who were not referred for evaluation, a significant number
came to medical attention with absent puberty much later in adult life20. Importantly, late diagnosis can have
dramatic impact not only on bone and metabolic health but also has significant repercussions on psychosexual
development and wellbeing21-23 Therefore, when the opportunity to identify CHH during mini-puberty is missed,
one can program active monitoring of pubertal status (and presence/absence of spontaneous testicular
development) in early adolescence to facilitate a more timely diagnosis and initiation of appropriate hormonal
treatment. This targeted, active monitoring is preferable to a passively waiting for patients to (hopefully) seek
medical attention during later life if puberty does not commence spontaenously. Unfortunately, despite our
understanding of the mini-puberty, there does not seem to be a discernible trend towards improved neonatal
ascertainment of CHH risk in recent decades.
Potential adverse outcomes of missed absent mini-puberty fall into two broad categories. First, as alluded to
above, the missed opportunity for serial assessment and monitoring of pubertal progression (or lack thereof) is
diminished or lost and the child may be lost to follow-up without a firm plan in place for age-appropriate
induction of puberty as needed. The exact consequences of this will vary, depending on patient- and family-
related factors as well as the quality and accessibility of the healthcare system. Table 2 illustrates the range of
clinical outcomes that we have observed in this context. Second, there is also a missed opportunity for early
therapeutic intervention. This conceivably could be performed either as part of a multi-centre randomised trial
with long-term follow-up, or undertaken pragmatically by experienced clinicians on the basis of “first principles” of
reproductive endocrine physiology.
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Therapeutic opportunities
Numerous studies have highlighted the markedly increased prevalence of cryptorchidism among CHH men with
absent testicular development (i.e. severe GnRH deficiency), underscoring the crucial role of mini-puberty during
the final stages of testicular descent and in anchoring the testes securely within the scrotum. Indeed, primate
studies utilizing long-acting GnRH analogs to suppress mini-puberty have demonstrated subsequent impairment
of testicular maturation24. Sexual (penile) development occurs much earlier in fetal development, so while
micropenis can be observed in CHH (resulting from absent endogenous GnRH secretion in the 3 rd trimester),
hypospadias is not seen25,26. Spermatogenesis requires the coordinated action of FSH and endogenous
testosterone (T) on the testes. Although the HPG axis appears quiescent during childhood, data from primate
and human autopsies reveal progressive, albeit subtle, testicular growth during this period27. The onset of
puberty is marked by sleep-entrained, GnRH-induced pulsatile LH secretion28 and these low-frequency,
nocturnal pulses initially favour FSH secretion over LH29. The resulting increases in serum gonadotrophin and T
levels progressively extend to the waking hours, culminating in sexual maturity and reproductive capacity.
Cryptorchidism, especially if bilateral, is a key adverse prognostic factor for fertility in CHH 30-33, but even in its
absence, men with severe GnRH deficiency (who lack the beneficial stimulatory effects of mini-puberty) often do
not achieve normal TV and semen quality with either gonadotrophin replacement or pulsatile GnRH therapy34.
Although definitive evidence is presently lacking, short-term combined gonadotrophin therapy (FSH+LH) in boys
with absent mini-puberty can stimulate normal levels of T, inhibin B and AMH, and offers the possibility of
affecting several outcomes35-37. First, such an approach is an effective alternative to exogenous T therapy for
correcting micropenis. Second, such hormonal treatment may be critical for priming the testes creating a more
favourable milieu (i.e. inhibin B secretion, germ cell proliferation, testicular growth)with the potential to enhance
the subsequent response to combined gonadotrophin (or pulsatile GnRH) therapy in adult life. (Even with
gonadotrophin replacement or GnRH pump therapy, only 60-75% of men with severe GnRH deficiency (lacking
mini-puberty)- achieve sperm in the ejaculate38. Further, those that do often do not achieve normal TV and
semen quality25,39. A plausible approach to maximizing fertility potential in the most severe cases of GnRH
deficiency has been to attempt to re-create the hormonal milieu of mini-puberty to spur Sertoli cell and germ cell
proliferation in adulthood34. In fact priming with unopposed FSH prior to inducing maturation (with either hCG or
pulsatile GnRH) has beneficial effects in terms of increased serum inhibin B, increased testicular volume and
spermatogenesis40,41. The effect of FSH pre-treatment holds promise for such severe CHH cases, yet further
work is needed to conclusively demonstrate superiority of a sequential treatment approach and to assess such
an approach on patients with a history of maldescended testes.
Gonadotrophin treatment may play an additional role facilitating (or even obviating) the surgical management of
undescended testes. Generally, the smaller the TV, the more challenging the surgical approach to orchiopexy
and the greater the chance of damaging the testis. Hence, any intervention that promotes testicular enlargement
could reduce surgical complication rates42. Importantly, our understanding of the molecular basis of isolated
cryptorchidism continues to grow, and emerging data linking mutations in both the EGR4 /Piwi pathway and the
insulin-like 3/ relaxin-like factor pathway support the notion that impaired mini-puberty is the likely culprit for the
azoospermia resulting from cryptorchidism43,44.Indeed, past numerous investigators have examined the role of
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neoadjuvant therapy (hCG or GnRH) in unselected cryptorchid males (45,46). However, despite apparent
success in individual patients, the possibility of unrelated spontaneous descent of retractile testes cannot be
excluded in the absence of randomisation and, overall, there does not appear to be a sufficiently powerful effect
to justify routine clinical use. However, targeted neonatal treatment for cryptorchid boys with absent mini-
puberty (CHH) might reveal a far higher non-surgical success rate47. One example comes from a case of a 17
year-old male with CHH whose urologist had requested pre-operative combined gonadotropin treatment
(FSH+hCG) with the aim of enlarging the high-inguinal testis prior to orchiopexy yet surgical intervention was not
necessary as gonadotrophin-induced testicular descent occurred with hormonal treatment alone48.
Microsurgical testicular sperm retrieval (mTESE) has recently emerged as a therapeutic approach for men with
CHH with or without a history of orchidopexy, who respond poorly to gonadotrophin replacement or GnRH pump
therapy49,50. In such patients who are usually azoospermic or severe oligospermic, the numbers of sperm are
insufficient to perform assisted reproductive technology (ART) approaches such as introcytoplasmic sperm
injection (ICSI). mTESE allows the identification and microdissection of individual tubules appearing to be
engorged with spermatogenesis in situ. Dissected tubules examined introperatively for sperm using light
microscopy by an assistant, then are either sent to an andrological laboratory for cryopreservation prior to future
ART, or are used to fertilise fresh eggs collected during the same day from the female partner (i.e. a
synchronous ART cycle).
Obstacles for establishing targeted neonatal screening for CHH + cryptorchidism
Whereas the prevalence of CHH has been estimated to be 0.025%51, testicular maldescent is approximately
100-fold more prevalent, affecting approximately 2-5% of full-term neonates52. When the testes have not
descended by the end of the first year, the impact on germ cell survival and long term fertility can be dramatic,
particularly in cases of higher-lying bilateral maldescended testes53. Men with a history of bilateral
cryptorchidism have lower serum inhibin B levels, smaller TV, as well as lower sperm counts54 and they are six-
times more likely to be infertile compared to men with unilateral cryptorchidism or normally descended testes55.
This likely reflects a combination of factors, including thermal- and surgical trauma-effects, intrinsic non-
endocrine defects of testicular function, and, potentially, impaired underlying HPG axis. A study that compared
TV and number of germ cell and Sertoli cells in males who underwent orchidopexy at 9 months versus at 3 years
of age, found strong evidence favouring earlier intervention53. Accordingly, surgical intervention is currently
recommended between 6 months and 1 year of age56,57.
Maldescended testes are more common in preterm male infants and delayed yet spontaneous testicular descent
subsequently occurs (typically within the first 6-months of life) in approximately 75% of cryptorchid male infants.
Thus, it can be problematic to accurately distinguish retractile testes (requiring no intervention) from true
cryptorchidism. Traditionally, the paediatric surgical instinct is understandably to defer formal assessment of
cryptorchid neonates with a view to avoiding unnecessary orchidopexy. However, this means the mini-puberty
window is missed. It seems reasonable to us that an early systematic approach by a multidisciplinary team
involving neonatologists, paediatric endocrinologists and paediatric surgeons would be an effective means to
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assess such cases (especially when mal-desended tesets are accompanied by micropenis) as this critical period
can have far reaching consequences on future fertility, health and wellbeing.
Discussion
Men with CHH who have severe GnRH deficiency lack the important stimulatory effects of the mini-puberty and
have poorer outcomes to treatment in terms of testicular volume and spermatogenesis. Given that
cryptorchidism and absent mini-puberty have such dramatic and long-lasting effects, early detection is
paramount. Thus, we propose that, for male neonates presenting with bilateral cryptorchidism with or without
micropenis have a multidisciplinary team consultation. However, in the absence of an established, systematic
approach, we provide an algorithm that could be followed to facilitate detection of infants with absent mini
puberty (Figure 1). Early diagnosis and timely care may help ameliorate the long-term consequences of absent
mini-puberty. Without neonatal diagnosis, management of such cases requires serial monitoring to identify
cases as early as possible (in late childhood/ early adolescence) to minimize health impact of hypogonadism and
maximize psychological wellbeing.
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375376
377
Table 1: “Red Flag” signs raising the suspicion of congenital hypogonadotropic hypogonadism (CHH)
Strong indicators of absent male mini-puberty (at birth / during neonatal life):
o micropenis
o bilateral cryptorchidism
o absent erections on nappy-change (this may be reported by parents who have an older son)
Presence of non-reproductive CHH-associated phenotypes:
o cleft lip and/or palate (apparent at birth)
o syndactyly, or other anomaly of digits (apparent at birth)
o anosmia (usually not evident until age 6-8 years)
Family history of CHH, including offspring of CHH patients resulting from fertility-inducing treatment (risk
apparent even pre-conception).
13
378
379
380
381
382
383
384
385
386
387
388389390
Table 2: Clinical examples of CHH presentation following a missed opportunity for early diagnosis in mini-puberty (listed from most to lease desirable)
1. Serial follow-up by Paediatric Endocrinology due to clinical suspicion and, when no evidence of
endogenous puberty by age 13 years, testosterone replacement is initiated. CHH formally confirmed
later followed brief treatment wash-out.
2. Lost to follow-up in childhood, referred back to Paediatric Endocrinology when no evidence of
endogenous puberty is observed by age 13 years, testosterone replacement given. CHH confirmed
later.
3. Presents with absent puberty in his late teens, referred for endocrine evaluation, diagnosed with CHH
and given testosterone replacement.
4. Presents with absent puberty in his late teens/early 20s, referred to Endocrinology and diagnosed with
CHH, but inappropriately treated with low-dose intermittent testosterone treatment (e.g. testosterone
enanthate 50mg IM monthly per paediatric protocols for constitutional delay of puberty), fails to fully
develop secondary sexual characteristics as he does not receive appropriate physiologically-dosed
pubertal-induction.
5. Presents with absent puberty in his late teens/early 20s, but misdiagnosed with constitutional delay, not
offered treatment and told to just be patient and await onset of endogenous puberty.
6. Presents later in adult life with absent puberty, sexual dysfunction, infertility, anaemia, or
gynaecomastia, diagnosed with CHH and given testosterone replacement.
7. Presents in middle/old age with gynaecomastia, anaemia, osteoporosis, or muscle weakness/fatigue,
diagnosed with CHH and given testosterone replacement.
8. Presents in middle/old age with osteoporosis and treated with bisphosphonate.
14
391392
393
394
395396397
398399400
401402
403404405406407
408409
410411
412413
414
415
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