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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References

1. Boehm U, Bouloux PM, Dattani MT, de Roux N, Dodé C, Dunkel L, et al. Expert consensus document:

European consensus statement on congenital hypogonadotropic hypogonadism -pathogenesis,

diagnosis and treatment. Nature Reviews Endocrinology 2015; 11: 547-564.

2. Mitchell AL, Dwyer AA, Pitteloud N & Quinton R. Genetic basis and variable phenotypic expression of

Kallmann syndrome: towards a unifying theory. Trends in Endocrinology & Metabolism 2011; 22: 249-

258.

3. Pitteloud N, Hayes FJ, Boepple PA, DeCruz S, Seminara SB, MacLaughlin DT, et al. The role of prior

pubertal development, biochemical markers of testicular maturation, and genetics in elucidating the

phenotypic heterogeneity of idiopathic hypogonadotropic hypogonadism. Journal of Clinical

Endocrinology & Metabolism 2002; 87: 152-160.

4. Spratt DI, Carr DB, Merriam GR, Scully RE, Rao PN, Crowley WF Jr. J Clin Endocrinol Metab. 1987

Feb;64(2):283-91. The spectrum of abnormal patterns of gonadotropin-releasing hormone secretion in

men with idiopathic hypogonadotropic hypogonadism: clinical and laboratory correlations.

5. Kuiri-Hanninen T, Sankilampi U & Dunkel L. Activation of the hypothalamic-pituitary-gonadal axis in

infancy: mini-puberty. Hormone Research in Paediatrics 2014; 82: 73-80.

6. Varimo T, Hero M, Laitinen EM, Miettinen PJ, Tommiska J, Känsäkoski J et al. Childhood growth in boys

with congenital hypogonadotropic hypogonadism. Pediatric Research 2015 Dec 31. [Epub ahead of

print].

7. Grinspon RP, Ropelato MG, Gottlieb S, Keselman A, Martínez A, Ballerini MG, et al. Male

hypogonadism: an extended classification based on a developmental, endocrine physiology-based

approach. Andrology 2013; 1: 3-16.

8. Russell LD1, Ren HP, Sinha Hikim I, Schulze W, Sinha Hikim AP. A comparative study in twelve

mammalian species of volume densities, volumes, and numerical densities of selected testis

components, emphasizing those related to the Sertoli cell. American Journal of Anatomy 1990; 188: 21-

30.

9. Orth JM, Gunsalus GL & Lamperti AA. Evidence from Sertoli cell-depleted rats indicates that spermatid

number in adults depends on numbers of Sertoli cells produced during perinatal development.

Endocrinology 1988; 122: 787-794.

10. Sharpe RM, Turner KJ, McKinnell C, Groome NP, Atanassova N, Millar MR, et al. Inhibin B levels in

plasma of the male rat from birth to adulthood: effect of experimental manipulation of Sertoli cell number.

Journal of Andrology 1999; 20: 94-101.

11. Boepple PA, Hayes FJ, Dwyer AA, Raivio T, Lee H, Crowley WF Jr & Pitteloud N. Relative roles of

inhibin B and sex steroids in the negative feedback regulation of follicle-stimulating hormone in men

across the full spectrum of seminiferous epithelium function. Journal of Clinical Endocrinology &

Metabolism 2008; 93: 1809-1814

12. Young J1, Rey R, Couzinet B, Chanson P, Josso N, Schaison G. Antimullerian hormone in patients with

hypogonadotropic hypogonadism. Journal of Clinical Endocrinology & Metabolism 1999; 84: 2696-2699.

8

217

218219220221222223224225226227228229230231232233234235236237238239240241242243244245246247248249250251252253254

13. Hero M1, Tommiska J, Vaaralahti K, Laitinen EM, Sipilä I, Puhakka L et al. Circulating antimullerian

hormone levels in boys decline during early puberty and correlate with inhibin B. Fertility & Sterility 2012;

97: 1242-1247.

14. Rey RA, Musse M, Venara M & Chemes HE. Ontogeny of the androgen receptor expression in the fetal

and postnatal testis: its relevance on Sertoli cell maturation and the onset of adult spermatogenesis.

Microscopy Research & Technique 2009; 72: 787-795.

15. Valeri C, Schteingart HF, Rey RA. The prepubertal testis: biomarkers and functions. Current Opinion in

Endocrinology, Diabetes & Obesity 2013; 20: 224-33.16.

16. Grumbach MM. A window of opportunity: the diagnosis of gonadotropin deficiency in the male infant.

Journal of Clinical Endocrinology & Metabolism 2005; 90: 3122-3127.

17. Kaplan JD, Bernstein JA, Kwan A, Hudgins L. Clues to an early diagnosis of Kallmann syndrome. Am J

Med Genet A. 2010 Nov;152A(11):2796-801.

18. Sarfati J, Bouvattier C, Bry-Gauillard H, Cartes A, Bouligand J, Young J. Kallmann syndrome with

FGFR1 and KAL1 mutations detected during fetal life. Orphanet J Rare Dis. 2015 Jun 9;10:71.

19. Harrington J1, Palmert MR. Clinical review: Distinguishing constitutional delay of growth and puberty

from isolated hypogonadotropic hypogonadism: critical appraisal of available diagnostic tests. J Clin

Endocrinol Metab. 2012 Sep;97(9):3056-67.

20. Quinton R, Duke VM, Robertson A, Kirk JM, Matfin G, de Zoysa PA et al. Idiopathic gonadotrophin

deficiency: genetic questions addressed through phenotypic characterisation. Clinical Endocrinology

2001; 55: 163-174.

21. Dwyer AA, Quinton R, Pitteloud N, Morin D. Psychosexual development in men with congenital

hypogonadotropic hypogonadism on long-term treatment: a mixed methods study. Sex Med. 2015

Mar;3(1):32-41.

22. Dwyer AA, Quinton R, Morin D, Pitteloud N. Identifying the unmet health needs of patients with

congenital hypogonadotropic hypogonadism using a web-based needs assessment: implications for

online interventions and peer-to-peer support. Orphanet J Rare Dis. 2014 Jun 11;9:83.

23. Varimo T, Hero M, Laitinen EM, Sintonen H, Raivio T. Health-related quality of life in male patients with

congenital hypogonadotropic hypogonadism. Clin Endocrinol (Oxf). 2015 Jul;83(1):141-3.

24. Mann DR, Gould KG, Collins DC & Wallen K. 1989 Blockade of neonatal activation of the pituitary-

testicular axis: effect on peripubertal luteinizing hormone and testosterone secretion and on testicular

development in male monkeys. Journal of Clinical Endocrinology & Metabolism 68: 600-607.

25. Pitteloud N, Hayes FJ, Dwyer A, Boepple PA, Lee H, Crowley WF Jr. Predictors of outcome of long-term

GnRH therapy in men with idiopathic hypogonadotropic hypogonadism. Journal of Clinical

Endocrinology & Metabolism 2002; 87: 4128-4136.

26. Miyagawa Y, Tsujimura A, Matsumiya K, Takao T, Tohda A, Koga M et al. Outcome of gonadotropin

therapy for male hypogonadotropic hypogonadism at university affiliated male infertility centers: a 30-

year retrospective study. Journal of Urology 2005; 173: 2072-2075.

9

255256257258259260261262263264265266267268269270271272273274275276277278279280281282283284285286287288289290291

27. Muller J & Skakkebaek NE. Quantification of germ cells and seminiferous tubules by stereological

examination of testicles from 50 boys who suffered from sudden death. International Journal of

Andrology 1983; 6: 143-156.

28. Boyar RM, Rosenfeld RS, Kapen S, Finkelstein JW, Roffwarg HP, Weitzman ED et al. Human puberty.

Simultaneous augmented secretion of luteinizing hormone and testosterone during sleep. Journal of

Clinical Investigation 1974; 54: 609-618.

29. Pitteloud N, Dwyer AA, DeCruz S, Lee H, Boepple PA, Crowley WF Jr, Hayes FJ. The relative role of

gonadal sex steroids and gonadotropin-releasing hormone pulse frequency in the regulation of follicle-

stimulating hormone secretion in men. J Clin Endocrinol Metab. 2008 Jul;93(7):2686-92.

30. Matsumoto AM, Karpas AE & Bremner WJ. Chronic human chorionic gonadotropin administration in

normal men: evidence that follicle-stimulating hormone is necessary for the maintenance of

quantitatively normal spermatogenesis in man. Journal of Clinical Endocrinology & Metabolism 1986; 62:

1184-1192.

31. Finkel DM, Phillips JL & Snyder PJ. Stimulation of spermatogenesis by gonadotropins in men with

hypogonadotropic hypogonadism. New England Journal of Medicine 1985; 313: 651-655.

32. Ley SB & Leonard JM. Male hypogonadotropic hypogonadism: factors influencing response to human

chorionic gonadotropin and human menopausal gonadotropin, including prior exogenous androgens.

Journal of Clinical Endocrinology & Metabolism 1985; 61: 746-752.

33. Kirk JMW, Savage MO, Grant DB, et al. Gonadal function and response to human chorionic and

menopausal gonadotrophin therapy in male patients with idiopathic hypogonadotrophic hypogonadism.

Clinical Endocrinology 1994; 41: 57-63.

34. Dwyer AA, Raivio T & Pitteloud N. Gonadotrophin replacement for induction of fertility in hypogonadal

men. Best Practice & Research: Clinical Endocrinology & Metabolism. 2015; 29: 91-103.

35. Bouvattier C1, Maione L, Bouligand J, Dodé C, Guiochon-Mantel A, Young J. Neonatal gonadotropin

therapy in male congenital hypogonadotropic hypogonadism. Nature Reviews Endocrinology 2012; 8:

172-182.

36. Main KM, Schmidt IM, Toppari J, Skakkebaek NE. Early postnatal treatment of hypogonadotropic

hypogonadism with recombinant human FSH and LH. European Journal of Endocrinology. 2002;

146:75-79.

37. Bougnères P, François M, Pantalone L, Rodrigue D, Bouvattier C, Demesteere E et al. Effects of an

early postnatal treatment of hypogonadotropic hypogonadism with a continuous subcutaneous infusion

of recombinant follicle-stimulating hormone and luteinizing hormone. J Clin Endocrinol Metab. 2008

Jun;93(6):2202-5.

38. Rastrelli G1, Corona G, Mannucci E, Maggi M. Factors affecting spermatogenesis upon gonadotropin-

replacement therapy: a meta-analytic study. Andrology. 2014 Nov;2(6):794-808.

39. Liu PY, Baker HW, Jayadev V, Zacharin M, Conway AJ, Handelsman DJ. Induction of spermatogenesis

and fertility during gonadotropin treatment of gonadotropin-deficient infertile men: predictors of fertility

outcome. J Clin Endocrinol Metab. 2009 Mar;94(3):801-8.

10

292293294295296297298299300301302303304305306307308309310311312313314315316317318319320321322323324325326327328329

40. Raivio T1, Wikström AM, Dunkel L. Treatment of gonadotropin-deficient boys with recombinant human

FSH: long-term observation and outcome. Eur J Endocrinol. 2007 Jan;156(1):105-11.

41. Dwyer AA, Sykiotis GP, Hayes FJ, Boepple PA, Lee H, Loughlin KR et al. Trial of recombinant follicle-

stimulating hormone pretreatment for GnRH-induced fertility in patients with congenital

hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2013 Nov;98(11):E1790-5.

42. Biers SM & Malone PS. A critical appraisal of the evidence for improved fertility indices in undescended

testes after gonadotrophin-releasing hormone therapy and orchidopexy. Journal of Pediatric Urology

2010; 6: 239-246.

43. Docampo MJ1, Hadziselimovic F. Molecular Pathology of Cryptorchidism-Induced Infertility. Sex Dev.

2015;9(5):269-78.

44. Tomboc M1, Lee PA, Mitwally MF, Schneck FX, Bellinger M, Witchel SF. Insulin-like 3/relaxin-like factor

gene mutations are associated with cryptorchidism. J Clin Endocrinol Metab. 2000 Nov;85(11):4013-8.

45. Henna MR, Del Nero RG, Sampaio CZ, Atallah AN, Schettini ST, Castro AA, Soares BG. Hormonal

cryptorchidism therapy: systematic review with metanalysis of randomized clinical trials. mPediatr Surg

Int. 2004 May;20(5):357-9.

46. Li T, Gao L, Chen P, Bu S, Cao D, Yang 6, Wei Q. A systematic review and meta-analysis of

comparative studies assessing the efficacy of luteinizing hormone-releasing hormone therapy for

children with cryptorchidism. Int Urol Nephrol. 2016 Feb 22.

47. Abacı A, Çatlı G, Anık A, Böber E. Epidemiology, classification and management of undescended

testes: does medication have value in its treatment? J Clin Res Pediatr Endocrinol. 2013;5(2):65-72

48. Santhakumar A, Miller M, Quinton R. 2013 Pubertal Induction in adult males with isolated

hypogonadotropic hypogonadism using long-acting intramuscular testosterone undecanoate 1g depot

(Nebido). Clinical Endocrinology 2013; 80: 155-157.

49. Deruyve Y, Vanderschueren D, Van der Aa F. Outcome of microdissection TESE compared with

conventional TESE in non-obstructive azoospermia: a systematic review. Andrology. 2014; 2: 20-24

50. Ramasamy R, Lin K ,Godsen LV, Rosenwaks Z, Palermo GD, Schlegel PN. High serum FSH levels in

men with non obstructive azoopsermia does not affect success of microdissection testicular sperm

extraction. Fertil Steril. 2009; 92: 590-93

51. Fromantin M, Gineste J, Didier A & Rouvier J. Les impubérisms et les hypogonadisms à l'incorporation.

Étude statistique. Problèmes Actuels d'Endocrinologie et de Nutrition 1973; 16: 179-199.

52. Chan E, Wayne C, Nasr A & FRCSC for Canadian Association of Pediatric Surgeon Evidence-Based

Resource. Ideal timing of orchidopexy: a systematic review. Pediatric Surgery International 2014; 30: 87-

97.

53. Kollin C1, Stukenborg JB, Nurmio M, Sundqvist E, Gustafsson T, Söder O, et al. Boys with undescended

testes: endocrine, volumetric and morphometric studies on testicular function before and after

orchidopexy at nine months or three years of age. Journal of Clinical Endocrinology & Metabolism 2012;

97: 4588-4595.

54. Trsinar B & Muravec UR. Fertility potential after unilateral and bilateral orchidopexy for cryptorchidism.

World Journal of Urology 2009; 27: 513-519.

11

330331332333334335336337338339340341342343344345346347348349350351352353354355356357358359360361362363364365366367368

55. Coughlin MT1, O'Leary LA, Songer NJ, Bellinger MF, LaPorte RE, Lee PA. Paternity after unilateral

cryptorchidism: a controlled study. Pediatrics 1996; 98: 676-679.

56. Ritzén EM1, Bergh A, Bjerknes R, Christiansen P, Cortes D, Haugen SE, et al. Nordic consensus on

treatment of undescended testes. Acta Paediatrica 2007; 96: 638-643.

57. Chan E, Wayne C, Nasr A. FRCSC for Canadian Association of Pediatric Surgeon Evidence-Based

Resource. Ideal timing of orchiopexy: a systematic review. Pediatr Surg Int. 2014.

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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