What is the optimal therapy for young males with hypogonadotropic hypogonadism?

Summary

Hypogonadotropic hypogonadism (HH), consequent to congenital or acquired disorders of the hypothalamic–pituitary axis, presents as absent/delayed/arrested sexual maturation and infertility. Optimal management includes: (a) confirmation of the diagnosis and prognosis, (b) timing and choice of therapeutic intervention and (c) consideration of future fertility prospects. Therapy is usually initiated with testosterone to induce development of secondary sexual characteristics, taking the patient (often diagnosed late) through puberty. Monitoring of the impact of the condition on long-term health and psychosocial function is necessary. Treatment is likely to be life-long, requiring regular monitoring for its optimization and avoidance of adverse responses. Induction of spermatogenesis requires either pulsatile gonadotropin releasing hormone (GnRH) or gonadotropin administration. Gonadotropins can be self-administered subcutaneously and are not inferior to the more costly GnRH. ‘Reversible genetic hypogonadotropic hypogonadism’ is a recently described entity which has implications for the long-term management of patients with HH.

Introduction

Hypogonadotropic hypogonadism (HH) may result from either absent or inadequate hypothalamic gonadotropin-releasing hormone (GnRH) secretion or failure of pituitary gonadotropin secretion. HH is characterized by androgen deficiency and absent/delayed or arrested pubertal sexual maturation. Congenital abnormalities leading to HH are usually because of diminished GnRH secretion, occurring in isolation (idiopathic, IHH) or in association with anosmia/hyposmia (Kallmann syndrome, KS), or as part of multiple pituitary hormone deficiencies. Most presentations of isolated HH are idiopathic, with defects identified to date in more than ten separate genetic loci (Table 1), accounting for monogenic and occasionally oligogenic presentations in about 30% of cases.¹ Multiple modes of inheritance have been described. Acquired HH most frequently results from structural lesions of the hypothalamic–pituitary axis or haemochromatosis (Table 1).

Table 1.   Aetiology of congenital and acquired hypogonadotropic hypogonadism

Congenital hypogonadotropic hypogonadism
Monogenic/oligogenic mutations associated with anosmia, hyposmia or euosmia	Monogenic/oligogenic mutations associated with euosmia
Anosmin 1 (KAL1)	Kisspeptin (KISS)
Fibroblast growth factor 8 (FGF8)	G-protein coupled receptor 54 (GPR54 or KISS1R) Leptin (LEP)
Fibroblast growth factor receptor 1 (FGFR1)
Prokineticin 2 (PROK2) Prokineticin receptor 2 (PROKR2) Nasal embryonic LHRH factor (NELF) Heparan sulphate 6 ‘O’ sulphotransferase 2 (HS6ST2)	Leptin receptor (LEPR)
	Luteinising hormone β subunit (LHβ) Prohormone convertase 1 (PC1) Gonadotropin releasing hormone 1 (GNRH1) Gonadotropin releasing hormone receptor (GNRHR) Tachikinin 3 (TAC3) Tachikinin receptor 3 (TACR3) Dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X chromosome, gene 1 (DAX1)
Defective transcription factor genes of pituitary differentiation causing combined pituitary hormone deficiency
Pituitary-specific positive transcription factor 1 (POU1F1)
Homeobox protein prophet of Pit-1 (PROP1)
Homeobox expressed in ES cells 1 (HESX1)
LIM/homeobox protein Lhx3 (LHX3)
Transcription factor SOX-3 (SOX3)
Congenital hypogonadism associated with other central nervous disorders
CHARGE (coloboma, heart defect, choanal atresia, growth retardation, ear abnormalities) syndrome
Gordon Holmes spinocerebellar ataxia syndrome
Laurence–Moon–Bardet–Biedl syndrome
Möbius syndrome
Prader–Willi syndrome
Rud syndrome
Acquired hypogonadotropic hypogonadism (associated with multiple pituitary hormone deficiencies)
Tumour: Pituitary adenomas (multiple endocrine neoplasm type 1, prolactinoma), residual cell tumours (craniopharyngiomas, epidermoid tumours, Rathke’s pouch cysts), gamete tumours (germinomas, teratomas, dysgerminomas), metastases
Infiltrative: Haemochromatosis, sarcoidosis, Langerhans cell histiocytosis (histiocytosis-X), lymphocytic hypophysitis
Infection: Tuberculosis, HIV/AIDS, syphilis, fungus
Trauma: Contusion, skull fracture, pituitary stalk transection, hypophysectomy
Vascular: Ischaemia, Sheehan’s syndrome, pituitary apoplexy
Illness: Diabetes mellitus, nephrotic syndrome, obesity, primary hypothyroidism, critical illness, sickle cell disease, thalassaemia, alcoholism
Medical use and misuse: Glucocorticoids, radiation, anabolic steroids, narcotics
Stress: Excessive exercise, mental stress, severe dieting (anorexia nervosa/bulimia), malnourishment

Congenital male HH caused by GnRH deficiency is associated with full sexual differentiation at birth, since early testosterone production (12–20 weeks of gestation) is stimulated by placental human chorionic gonadotropin (hCG). Patients lack two significant intrinsic GnRH surges: the first, at the late foetal/early neonatal period (lasting up to 6 months of age, and regarded essential for Leydig and Sertoli cell proliferation, testicular growth and scrotal descent), the second at puberty, responsible for secondary sexual development and reproductive maturity. HH is diagnosed by the demonstration of a low serum testosterone in association with inappropriately low or absent circulating luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations in the absence of acute/chronic illness, severe obesity and hyperprolactinaemic states. It is important to distinguish between simple pubertal delay and true idiopathic HH.

Induction of secondary sexual characteristics using testosterone replacement – general considerations

Testosterone has pleiotropic actions, and the adult testes produce about 5–7 mg of testosterone daily. In many tissues, testosterone is a prohormone, and can be aromatized to oestradiol (important for bone), or 5α-reduced to dihydrotestosterone (DHT; skin, prostate). Dose-dependency of various androgen-dependent processes appears to be different in different individuals (vide infra). A clinically robust biological marker of androgen action is lacking however, and this together with the complexities of diurnal, pulsatile and cirannual rhythms of testosterone, render the achievement of truly physiological testosterone levels and its metabolites (DHT and oestradiol) a significant therapeutic challenge.

Although testosterone concentrations at the lower end of the normal range can normalize sexual function in men, the concentrations to fully correct low bone mineral density (BMD), muscle mass and haemoglobin are higher. Replacement doses to improve metabolic effects on the one hand (e.g. on lipids and insulin resistance) and avoidance of unwanted effects on the other (polycythaemia and mood swings) may necessitate individual dose titration. Because of the above considerations, restoration of serum testosterone levels, on average, into the mid-reference range (15–20 nmol/l) remains the pragmatic goal of therapy in most individuals.² Clinical markers include: (1) restoration of sexual function (desire, frequency of erections, frequency of morning erections, masturbation, and penetrative intercourse), (2) secondary sexual characteristics, (3) energy levels and sense of wellbeing. Men newly started on therapy in their 20s and 30s often find it difficult to cope with their new found sexuality, the sense of having ‘missed out’, and may require counselling. Men with HH also lack the FSH necessary for spermatogenesis, and fertility is often an issue in later life. The following case scenarios illustrate some of the clinical challenge of managing IHH patients through the different age groups.

Case 1

A 2-month-old boy, born to a known KAL1 gene mutation carrier responsible for X-linked KS in the maternal uncle, presents with bilateral inguinal testes. He is shown to have the mutation.

Should he have early testicular stimulation with hCG?  Gonadotropin treatment during the first year of life has been shown to result in maturation of spermatogonia³ and increased serum testosterone.⁴ However, a number of potential adverse effects, which may compromise future spermatogenesis, have been reported in those treated with hCG prior to orchiopexy, including apoptotic changes in the germ cells and inflammatory changes in the testes, not seen in orchiopexy alone.⁵ It appears that smaller testes are more severely affected. On the basis of current evidence, early intervention to mimic the gonadotropic surge in the first 6 months of life is therefore not indicated.

Timing and optimum management of induction of testicular descent  GnRH or hCG therapy is effective in inducing descent of retractile testes, but has a poor overall efficacy (<20%) in high-lying undescended testes.⁶ By contrast, orchiopexy has a much greater success rate of 95%.⁷ Testes had to be brought down into the cooler scrotal environment early, to maximize future spermatogenesis potential and testicular expansion,⁷ and to reduce the likelihood of future neoplasm development. There is consensus that this had to be performed before the age of two.⁷ Earlier intervention must be weighed against the risk of vascular pedicle damage to the testes.

How should puberty be initiated and by what means?  The aim of testosterone replacement therapy (TRT) is to mimic the normal cadence of puberty. We recommend injectable i.m. testosterone as first line treatment between 12 and 13 years of age, as the dose can be easily adjusted to match requirements at different stages of pubertal development to avoid mistimed epiphyseal plate closure on the one hand and persistently reduced BMD on the other. A long-acting ester (Testosterone Enanthate or Cypionate) at 50–75 mg/month is used initially and escalated gradually every 6 months to 100–150 mg/month before changing to 3 weekly 250 mg dosage after 3–4 years. Alternatively, oral testosterone undecanoate 40 mg can be given with the evening meal, and gradually titrated upwards every 6 months to a maximum dose of 80 mg tds after 2–3 years. This preparation has a short half-life and must be taken with food for satisfactory absorption, and has a tendency to be 5α-reduced to DHT in the gut. Other non-injectable forms of TRT include a transdermal gel (1% testosterone strength: Testogel^®, Bayer Schering Pharma AG, Leverkusen, Germany, Testim^®, Auxilium Pharmaceuticals, Malvern, Pennsylvania, USA, 50–100 mg of testosterone in 5–10 g of gel daily or the metered-dose gel formulation of 2% testosterone strength: Tostran^®, ProStrakan, Galashiels, UK, 60–80 mg of testosterone in 3–4 g of gel applied daily. This higher strength formulation is indicated for men over 18 years). If Testogel is used, the starting dose had to be around one-third of a 50-mg satchet daily for the first year, and gradually increasing by one-third of a satchet daily every year to a final dose of 50 mg daily in the third year, preferably self-applied at bedtime, while avoiding potential cross-contamination. Other available preparations include the transdermal patch (Andropatch^®, GlaxoSmithKline, Brentford, UK, 2.5 mg daily), but these come as adult doses and experience with their use is limited in adolescent practice. Their use is also associated with a high incidence of local skin reaction. None of these preparations has been licensed for induction of puberty in the UK. By contrast, in the adult, transdermal systems provide testosterone pharmacokinetics that most closely mimic natural diurnal variation in testosterone concentrations and are convenient when changing from the i.m. route at late puberty to adult replacement therapy.

What is the likely impact of undescended testes on future fertility?  A randomized study has shown that testicular growth was greater in earlier (at 9-months-old) than in later orchiopexy (at 3 years-old).⁸ The earlier orchiopexy is performed, the greater subsequent quality and quantity of spermatogenesis,⁹ suggesting capacity for recovery is lost if the testes are left outside the scrotum too long. Lee and Coughlin¹⁰ compared fertility outcome after orchiopexy in a group of men with unilateral vs. bilateral cryptorchidism. Paternity rates were significantly lower following orchiopexy among formerly bilaterally cryptorchid men (65%) compared with unilateral cryptorchidism (90%; P < 0.001) and control men (93%; P < 0.001). The bilateral group also had significantly lower sperm density and inhibin B levels, and higher gonadotropin levels than the unilateral and control groups, reflecting significant germ cell damage.

How should treatment be monitored and when are adult doses warranted?  Patients had to have a physical assessment with full auxology three-monthly during puberty induction, and dosages adjusted to respect the cadence of normal puberty, in order to prevent premature epiphyseal fusion arising from excessive TRT. Once adequate virilization is induced and final expected adult height achieved, any form of TRT can be used, including Nebido^®, Bayer Schering Pharma AG, Leverkusen, Germany (the loading dose comprises two separate 1 g i.m. injections given 6 weeks apart and subsequent maintenance dose of 12 weekly injections). Subcutaneous implantation of 0.8–1.2 g of testosterone twice a year may also be considered, but this requires a minor surgical procedure, with around 10% risk of extrusion, infection, local fibrosis and scar formation.

Case 2

A 18-year-old has shown only modest pubertal development. He is euosmic, has an unbroken voice, eunuchoid segments and 4 cc testes with penis stage 1. His morning testosterone is 0.1 nmol/l, LH 0.1 U/l and FSH 0.1 U/l.

What additional investigations are warranted?  Although the differential diagnosis includes severe pubertal delay, other anterior pituitary hormones including prolactin (PRL), thyroid-stimulating hormone (TSH), insulin-like growth factor 1 (IGF-1) and cortisol had to be measured to exclude multiple defects, and magnetic resonance imaging (MRI) undertaken if appropriate. In addition, ferritin or transferrin saturation and angiotensin converting enzyme are measured to exclude haemochromatosis and sarcoidosis, respectively. If HH is suspected, a prolonged GnRH stimulation test (100 μg followed by 500 μg i.v.) may be helpful; in hypothalamic GnRH deficiency, LH and FSH gradually appear after the 500 μg GnRH administration, whereas in pituitary causes (e.g. secondary to GNRHR1 mutations or pituitary disease), persistent hypo-responsiveness occurs. A hand X-ray will determine the bone age and dual energy X-ray absorptiometry scan can assess BMD. Genotyping for known monogenic causes of HH is at present a research procedure, but may be warranted where there is a positive family history. If performed, it had to be accompanied by genetic counselling.

Is MRI indicated in the presence of isolated HH?  MRI is helpful in identifying space-occupying lesions in the hypothalamic–pituitary region as well as infiltrative disorders. Evidence of hypoplastic/aplastic olfactory bulbs and hypoplastic anterior pituitary is pathognomonic of KS (Fig. 1) although the condition can be present even in the presence of ‘normal’ olfactory bulbs. The diagnostic yield from pituitary MRI in euosmic individuals with isolated HH is poor however.¹¹

Figure 1.  Magnetic resonance imaging of the brain in patients with KS and IHH. (a) Coronal T1-weighted image of a male with KS showing abnormal angulated olfactory sulci (black arrows) and normal olfactory bulbs (white arrows). (b) Axial T1-weighted image of the same patient showing normal olfactory sulci (white arrows). (c) Coronal T1-weighted image of a female with IHH showing normal olfactory bulbs (large arrows) and sulci (small arrows). (d) Coronal T1-weighted image of a female with KS showing absent olfactory bulbs with shallow olfactory sulci (arrows). (Images reproduced from Quinton et al.¹¹ with permission from the Endocrine Society).

Is there an advantage to starting hCG rather than i.m./transcutaneous testosterone?  Quite apart from its reproductive implications, the psychosocial impact of small testes can be considerable, particularly if the patient becomes sexually active. Testosterone therapy does not change testicular volume (TV) whereas hCG gradually augments TVs to a more satisfactory although suboptimal 6–8 cc volume. Further enlargement necessitates adjunctive FSH preparations. Although FSH therapy is expensive and usually reserved for spermatogenesis induction, adjunctive FSH therapy solely to enlarge TV had to be considered in individual cases where the psychological impact of small testes is particularly severe. The safety profile of ultra-longterm hCG therapy is, however not established at present and TRT may therefore be most appropriate.

What is the impact of over-treatment with testosterone/hCG on DHT and oestradiol and how is it managed?  Testosterone over-replacement or Leydig cell androgen over-production in response to hCG stimulation results in excessive serum testosterone levels and consequently, elevated serum levels of DHT and oestradiol via 5α-reductase and aromatase respectively.

Dihydrotestosterone is ten times more potent at the androgen receptor (AR) than testosterone, and in excess, contributes to polycythaemia, acne and seborrhoea, capital hair loss and prostate enlargement (Table 2). There may a be genetic susceptibility to some of these adverse effects, e.g. carriers of short CAG repeat lengths of the AR gene are more androgen sensitive and require lower replacement.¹² Polycythaemia, as evidenced by a raised haematocrit (>55%), had to prompt reduction in testosterone dosage by about 25%. Occasionally, regular venesection is required to correct polycythaemia which does not respond to dosage adjustment.

Table 2.   Monitoring of adverse effects of testosterone

Clinical ascertainment

Breast tenderness/enlargement

Acne and oiliness of skin

Symptoms of sleep apnoea

Symptoms of benign prostate hypertrophy

Mood, aggression, hypersexuality

Haematological and biochemical measurements

Haemoglobin/haematocrit

Prostate specific antigen

Fasting lipids

Gynaecomastia occurs in up to a third of patients on gonadotropins¹³ or testosterone,¹⁴ and usually (although not invariably) occurs during of supraphysiological replacement doses. Gynaecomastia results from excessive peripheral aromatization of testosterone by adipose tissue, especially in the breast. The risk and severity of gynaecomastia can be reversed by adjusting the dose of testosterone or hCG as appropriate. In cases where breast tissue is highly sensitive to oestrogen action, despite oestradiol levels within reference limits, addition of aromatase inhibitor (e.g. anastrozole 1 mg/day) or an oestrogen antagonist (e.g. tamoxifen 20 mg/day) may reverse gynaecomastia if administered early.¹⁵ Long-term treatment with these agents cannot be countenanced and severe gynaecomastia resistant to medical therapy usually requires surgery.

How should the prostate be monitored?  Digital examination of the prostate is essential especially if prostatic and lower urinary tract symptoms are present in the over 45-year group.¹⁶ TRT of hypogonadal men will increase prostatic volume, but provided TRT is physiological, the enlargement is no greater than that of eugonadal age-matched controls.¹⁷ Similarly, TRT does not appear to significantly increase PSA.¹⁸ The evidence for an excess incidence of prostate cancer during TRT is inconclusive¹⁹ and prostate cancer rarely, if ever, occurs in young men.¹⁸ However if urinary/prostatic symptoms occur or PSA levels rise to more than double or above 4 μg/l, a urological referral is mandated for fuller investigations.¹⁶ Monitoring of other adverse effects of testosterone had to be performed routinely (Table 2), and will influence both the choice of type and dosage of testosterone administered.

Could this presentation represent very late onset puberty (i.e. extreme pubertal delay)?  Spontaneous reversal of HH was initially observed in a proportion of non-compliant patients. Subsequently, about 10% of idiopathic HH have been shown to achieve sustained reversal of hypogonadism after treatment discontinuation,²⁰ although relapses can also occur. One possibility is that testosterone may promote GnRH neuronal maturation, but in many cases extreme delayed puberty cannot be totally excluded. We therefore recommend that while on testosterone treatment, TVs are assessed serially; spontaneous enlargement (gonadarche) had to prompt interruption of treatment and testosterone/gonadotropins re-measured off treatment. Indeed, a routine trial of discontinuation of hormonal therapy for 3–6 months to assess reversibility of HH may be advisable after puberty is complete.

Case 3

A 32-year-old teacher has been on TRT for IHH and anosmia (KS) since the age of 14. He has been stabilized on 250 mg i.m. testosterone 3 weekly. He now wishes to consider fertility. He has no history of cryptorchidism. TVs are 4 cc bilaterally.

How should spermatogenesis be induced and what doses of gonadotropins are needed?  To stimulate testosterone synthesis, widen the seminiferous tubules and increase the number of primary spermatocytes, hCG (e.g. Pregnyl^®, Organon, Oss, The Netherlands) at a starting dose of 1500 IU s.c. twice weekly is used. Whilst this is effective in most patients, some patients require greater stimulation by doses of up to 10,000 IU twice weekly to generate normal testosterone levels. Treatment with hCG alone occasionally may result in semen production in those with larger pre-treatment testes (>8 cc) and no history of cryptorchidism, probably reflecting incomplete FSH deficiency. If severe oligospermia or aspermia persists after 3–4 months of hCG, 150–225 IU of FSH (e.g. Menopur^®, Ferring Pharmaceuticals, Saint-Prex, Switzerland) s.c. or i.m. three times weekly for 6–24 months is indicated, incurring an additional treatment cost of ∼£5000 per annum. Alternatively, the addition of recombinant human FSH taken subcutaneously at 150 IU thrice a week may prove successful.^21,22 Combination of hCG and FSH therapy for 6–24 months results in testicular growth in almost all and spermatogenesis in 80–95% of patients without undescended testes.^22–26 Although traditionally administered by the i.m. route, gonadotropins are equally effective when given subcutaneously enabling significantly increased patient compliance. Local allergic reactions occasionally occur but tend to be mild, and treatment rarely needs to be interrupted.

Although growth hormone (GH) may have a direct effect on Leydig cells (based on the evidence of delayed puberty commonly seen in patients with isolated GH deficiency), and recombinant human GH may augment Leydig cell response to hCG,²⁷ there is little evidence showing GH treatment results in improved spermatogenesis outcome.

What sperm concentration is likely to result in pregnancy and what are his fertility prospects?  Factors predicting successful outcomes include larger baseline testicular size and absence of cryptorchidism,^21,28 prior history of sexual maturation and no prior androgen therapy.²⁹ Although most patients will only achieve sperm counts below the reference range with smaller than normal TVs, those who reach sperm concentrations of 0.5–1.5 million/ml can be surprising fertile, and pregnancy rates in the range of 50–80% can be anticipated for those with sperm concentrations of 5 million/ml.²⁶ While spermatogenesis can be initiated even in patients with TV below 3 cc, it tends to take longer.³⁰ In any case, assisted reproductive technologies are now available to poor responders. From a practical point of view, it is therefore advisable to commence induction 6–12 months prior to a planned conception, whether ‘natural’ or by in vitro fertilization or intracytoplasmic sperm injection (ICSI).³¹ Facilities had to be made available for sperm storage in good responders who are contemplating adding to their family. Genetic counselling may be needed prior to spermatogenesis induction.

Is there an advantage to using pulsatile GnRH therapy?  Programmable portable infusion pumps (e.g. Zyklomat pump, Ferring GmbH, Kiel, Germany) can be used to provide pulses of s.c. GnRH into the abdominal wall. The frequency of administration is every 2 h, and a starting dose of 5 μg per pulse is generally used with increments of 2 μg every 4 weeks until physiology LH and FSH concentrations are attained. Serum testosterone concentrations are monitored in 6–8 weeks in most cases. Testosterone will increase significantly within 3–6 months, and sperm appear in the ejaculate from 18 to 139 weeks.³²

Although there is some evidence that GnRH therapy may stimulate testicular growth at a faster rate than gonadotropins,³³ most studies have shown no advantage of GnRH over gonadotropin therapy in achieving final TV, onset of spermatogenesis, sperm counts or pregnancy rates.^26,34 Thus the choice of hCG/FSH or pulsatile GnRH regimen will depend on according to the patient’s preference and to pharmacoeconomic factors. However, GnRH therapy is unlicensed and available only in few specialized tertiary centres. The costs of the delivery equipment and drug exceed £5000 per annum. The inconvenience of being permanently attached to the pump with a subcutaneous dispensing system, the need to rotate the infusion site to prevent potential infection, and interference with patient lifestyle represent additional potential disadvantages.

When should stimulation treatment be stopped?  Once pregnancy is achieved, therapy had to continue until at least the second trimester when miscarriage is less likely. Spermatogenesis induced by the combination of hCG and FSH or GnRH can occasionally be maintained with hCG alone, enabling subsequent pregnancies to be achieved.³⁵ If a long delay is likely to occur before a subsequent pregnancy, a long-acting i.m. testosterone ester is desirable (e.g. Nebido), and advice on contraception had to be given as spermatogenesis may persist after cessation of gonadotropin therapy. Sperm storage for subsequent use in intra-uterine insemination or ICSI also had to be offered, and makes economic sense. Spermatogenesis can be re-initiated with hCG in some cases.

Should antenatal diagnosis of the unborn child be considered?  Genetic testing may be indicated if the individual belongs to a pedigree with HH or where HH occurs with a recognizable syndrome. Genetic counselling is advisable prior to testing.

Case 4

A 28-year-old man with known haemochromatosis, is referred because of sexual malfunction. He has little secondary sexual hair and 5 cc testes with a normal phallus. Ferritin is 2600 μg/l. His LH is 0.4 U/l, FSH 0.3 U/l and testosterone 1.2 nmol/l, SHBG 98 nmol/l.

How should his hypogonadism be treated?  In haemochromatosis, hypogonadism arises from damage to the hypothalamic–pituitary axis through iron deposition. Iron tends to damage the hypothalamus before being deposited in the pituitary and testes.³⁶ Treatment options had to consider whether both restoration of sexual function and fertility are required. General well-being and psychosocial aspects also had to be considered. In a patient with haemochromatosis who wishes to achieve sexual function, 50 mg of daily Testogel or Testim would be appropriate, as dose adjustment is easily achievable. Physiological concentrations can usually be achieved using 0.5–2 sachets per day. Gonadotropins are used if fertility is required, although testosterone production and spermatogenesis may be suboptimal if significant iron damage has occurred. Spermatogenesis can be initiated with hCG alone if FSH secretion remains intact. This may occur when the condition is at an early stage.

What are his prospects for reversal of hypogonadism with venesection?  Venesection prevents further damage to the pituitary and testes from iron deposition. Repeated venesection to normalize ferritin levels can reverse hypogonadism in some patients with iron deposition particularly in those below 40 years old.^37,38

Conclusions

Optimal management of young HH males requires elucidation of the underlying aetiology, and genetic tests are now available to detect mutations within key candidate genes in the hypothalamic–pituitary axis. Investigation may also lead to detection of structural abnormalities in the hypothalamic–pituitary region but this usually occurs when multiple pituitary hormone deficiencies are present. The choice of therapeutic intervention is based on the individual’s requirement. Puberty is induced by low i.m. doses of testosterone initially, followed by upward titration to reproduce the natural cadence of pubertal development. Fertility is induced by hCG and FSH preparations or pulsatile GnRH. Regular monitoring of the impact of the condition on long-term health and psychosocial function is necessary. Treatment with TRT is likely to be life-long, requiring regular monitoring for its optimization and avoidance of adverse responses. A small subset of patients may have a reversible phenotype, and this may enable withdrawal of therapy in up to 10% of cases.

Acknowledgements

We are grateful for helpful comments from Dr B Khoo, Miss J Kisalu and Dr S Janmohamed (Centre for Neuroendocrinology, Royal Free Hospital, London).