Infertility affects approximately 15% of couples, and male factors contribute to roughly half of cases. Advances in assisted reproductive technologies (ARTs) now provide men with primary (testicular) infertility with treatment options. Notably, secondary infertility is one of the few forms of infertility that can be treated hormonally. This brief overview examines the induction of spermatogenesis in men with gonadotrophin deficiency.

Sperm development requires the co-ordinated endocrine action of follicle-stimulating hormone (FSH) and testosterone. FSH is crucial for seminiferous tubule development, inducing spermatogenesis in the testes and maintaining fertility. Luteinising hormone (LH) induces testosterone secretion from the interstitial Leydig cells.

Although testosterone circulates at nanomolar concentrations in the bloodstream, levels are 100-fold higher (i.e. micromolar) in the testes and testosterone acts in a paracrine manner to support spermatogenesis. Thus, men with secondary infertility (i.e. hypogonadotrophic hypogonadism) who lack adequate endogenous FSH/LH can receive hormone replacement to induce fertility. Importantly, exogenous testosterone will not adequately support spermatogenesis in men with gonadotrophin deficiency. Furthermore, in normal men, exogenous testosterone will inhibit spermatogenesis through suppression of endogenous LH and FSH secretion.

PREDICTORS OF OUTCOME

Whereas females have already achieved their lifetime supply of oocytes before birth, males require three distinct phases of testicular maturation to develop and sustain spermatogenesis. The first wave of testicular development begins in utero, with placental human chorionic gonadotrophin (hCG)-induced testosterone secretion (from 7 weeks of gestation). This is followed by gonadotrophin-releasing hormone-stimulated pituitary LH and FSH secretion during ‘minipuberty’ (during the first 4–6 months of life). It is completed in adolescence with the onset of puberty.

The minipuberty is a critical event for future fertility. This is a proliferative period and serum hormones reach near-adult levels. Notably, while erections may be noted on nappy changing, spermatogenesis does not occur at this point, as Sertoli cells do not express the androgen receptor until much later (around 5 years of age).

Males with absent minipuberty (i.e. in Kallmann syndrome or combined pituitary hormone deficiency) are characterised by 50% prevalence of maldescended testes (cryptorchidism), with or without micropenis, and these patients typically do not have any subsequent spontaneous pubertal development in adolescence.

Several important predictors of outcome have been identified to date. Key factors adversely affecting fertility outcomes include smaller testicular volume (TV) and history of cryptorchidism. Gonadotrophin-deficient men with some spontaneous pubertal development (i.e. TV>4ml) respond better to gonadotrophin treatment and typically develop sperm within 6 months. Patients with severe gonadotrophin deficiency (i.e. TV<4ml and surgically corrected cryptorchidism) are less likely to ever develop sperm in the ejaculate.

MONO- OR COMBINED GONADOTROPHIN THERAPY

Men with deficient LH and FSH secretion – hypogonadotrophic hypogonadism – have a hormonally treatable form of infertility. This, uniquely, can potentially be addressed solely in the endocrine clinic. However, it is good practice to engage with local fertility services at an early stage, in order to identify and address possible female partner subfertility, as well as to access ARTs as needed, if gonadotrophin therapy does not achieve optimal results (e.g. in vitro fertilisation (IVF), intracytoplasmic sperm injection (ICSI) or microdissection with testicular sperm extraction (micro-TESE)). Additionally, if treatment is successful, men may wish to cryopreserve sperm (by banking) prior to stopping gonadotrophin therapy.

Even prolonged hCG monotherapy rarely achieves useful spermatogenesis in men with congenital hypogonadotrophic hypogonadism (CHH), so it is pointless deferring FSH therapy until after an arbitrary period of hCG-monotherapy. However, men with HH acquired after completion of puberty (e.g. following treatment of pituitary tumours) have a much better prognosis, and fertility can often be restored with hCG monotherapy. The very short half-life of recombinant LH precludes a clinically useful role in therapeutics. Hence, hCG is used to stimulate Leydig cells, with stable serum testosterone levels achievable through subcutaneous injection two or three times per week.

Should serum oestradiol begin to rise above the male range, the hCG dose will need to be reduced to mitigate the risk of developing gynaecomastia. Treatment should target normal serum testosterone levels in trough blood samples taken just prior to injection, while monitoring haemoglobin/haematocrit and possible gynaecomastia.

If monotherapy is unsuccessful, FSH can be added. It is available in ‘pure’ recombinant form, or isomolar with LH as human menopausal gonadotrophin, with either being suitable for spermatogenesis induction in males. Stable serum FSH levels are achievable through thrice-weekly subcutaneous injection (or new long-acting FSH analogue every 10–14 days).

Urinary-derived gonadotrophins are much cheaper than their recombinant counterparts. Unfortunately, supply for urinary-derived gonadotrophins is becoming ever more precarious, which threatens the provision of spermatogenesis induction in the NHS. It is really important to get more uniform access to these specialist medications that are so important to affected couples.

Approximately 75% (CI 69–81%) of men with hypogonadotrophic hypogonadism will develop sperm in their ejaculate following mono- or combined gonadotrophin therapy. However, men with smaller TV (<4ml) do not have the same outcomes and their treatment requires a different approach.

 

SEQUENTIAL GONADOTROPHIN THERAPY

For men with severe LH/FSH deficiency, combined gonadotrophin treatment has been the traditional approach to fertility induction. More recently, a sequential approach has been used in gonadotrophin-deficient men to recreate the events of early puberty and maximise fertility potential.

In this approach, FSH ‘priming’ is achieved by FSH monotherapy for 2–4 months. This recapitulates the rise in FSH early in puberty that is critical for proliferation of Sertoli and germ cells. The addition of hCG induces testosterone secretion and Sertoli cell maturation.

Initial reports show promising results even for those men with prepubertal testes and cryptorchidism (i.e. negative predictors of outcome). However, a large international multicentre trial is needed to definitively determine the optimal treatment (i.e. combined versus sequential gonadotrophin treatment) for the most severely affected men.

In summary, men with hypogonadotrophic hypogonadism have a treatable form of infertility. The majority of men can produce sperm in the ejaculate with appropriate, tailored treatment based on predictors of outcome. It is worthwhile noting that many men will not achieve normal sperm counts by the World Health Organization standard, yet low sperm count does not preclude fertility in these men. Such patients should be appropriately counselled on fertility chances and be monitored by endocrinologists who are experienced in using gonadotrophin regimens.

Channa Jayasena, Imperial College London

Du Soon Swee, Newcastle upon Tyne Hospitals and University

Andrew Dwyer, Boston College, MA, USA

Richard Quinton, Newcastle upon Tyne Hospitals and University

FURTHER READING

Boehm U et al. 2015 Nature Reviews Endocrinology 11 547–564.

Dwyer AA et al. 2015 Best Practice & Research: Clinical Endocrinology & Metabolism 29 91–103.

Dwyer AA et al. 2016 Minerva Endocrinologica 41 188–195.

Jones TH & Quinton R 2013 In Oxford Endocrinology Library: Testosterone Deficiency in Men (Ed TH Jones), ch 5, pp. 83–88. Oxford: Oxford University Press.

Rastrelli G et al. 2014 Andrology 2 794–808.