madman
Super Moderator
Fertility Considerations in Hypogonadal Men (2022)
Nikoleta Papanikolaou, MBBS, MRCP, Rong Luo, MBBS, Channa N. Jayasena, MA, Ph.D., MRCP, FRCPath*
INTRODUCTION
Male factors are increasingly recognized to be a causative or contributory factor in approximately 50% of infertile couples.1,2 Hypogonadism may be present in up to 40% of men who present with couple infertility.3 Testosterone is the major androgen-regulating spermatogenesis in men; as a result, men with either primary or secondary hypogonadism may be subfertile because of impaired spermatogenesis. The clinical impact of hypogonadism on fertility potential depends on the timing of its onset (fetal, prepubertal, or postpubertal) and effect on semen parameters. Secondary hypogonadism is one of the few medically treatable causes of male infertility.
Hormonal treatment with gonadotropins, pulsatile gonadotrophin-releasing hormone (GnRH) as well as off-label medications, such as selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AI), has been trialed in men with hypogonadism with various results. Treatment pathways and success rates differ according to the cause of hypogonadism and the time of its onset. Assisted reproductive technologies account for another treatment pathway that has further improved fertility potential of hypogonadal men.
BACKGROUND PHYSIOLOGY
Boys have a surge of GnRH during the first 3 months of life, leading to pulsatile follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion known as “mini-puberty.”4 The increase in serum LH stimulates the Leydig cells to synthesize testosterone, leading to increase in penile length and testicular volume.5 Crucially for fertility, the surge in FSH induces proliferation of immature Sertoli cells (SC) by 5-fold from approximately 260 106 at birth to 1500 106 by 3 months of age.6 These SC begin to express androgen receptors at around 12 months of age in humans.7,8 After 6 months of age, the hypothalamic-pituitary-gonadal (HPG) axis is quiescent, and testosterone levels remain low until puberty.4,6 Reactivation of the HPG axis during puberty stimulates a second wave of SC proliferation, doubling the number of SC to approximately 2900 million.6 By now, the vast majority (87%–95%) of SC express androgen receptors.7 In healthy men, LH pulses stimulated by GnRH pulsatility are generated every 1.5 to 2 hours,9 but this pattern is largely lost in hypogonadotropic hypogonadism (HH).
Testosterone is the major androgen-regulating spermatogenesis in men. It is synthesized by Leydig cells in response to LH and binds to androgen receptors expressed on SC to support spermatogenesis.10,11 The classical testosterone signaling pathway takes 30 to 45 minutes for cellular response.12 Testosterone first diffuses across the plasma membrane to bind with intracellular androgen receptors that are sequestrated by heat shock proteins in the cytoplasm. Binding of testosterone to androgen receptors induces phosphorylation and subsequent homodimerization, and a conformational change in the receptor structure allows recruitment of co-regulators and its nuclear translocation and upregulation and downregulation of target genes transcription.13 The nonclassical pathways of testosterone signaling are much more rapid, occurring within seconds to minutes.14 One pathway involves activation of Src tyrosine kinases, resulting in phosphorylation of epidermal growth factor receptor and consequent activation of the MAP kinase cascade (Raf, MEK, ERK).15 This pathway has been shown to facilitate Sertoli-germ cell attachment and release of mature sperm.15,16
Because of localized production of testosterone within the testes, intratesticular concentrations of testosterone are reported to be 200-fold higher than serum level samples from peripheral venous blood.17,18 Below a critical concentration of testosterone, spermatogenesis becomes impaired.19
Testosterone replacement therapy (TRT) in men with hypogonadism is often used to induce virilization and bolster secondary sexual characteristics as well as to improve libido, bone composition, and bone mineral density.20,21 TRT may be administered enterally, parenterally, and transdermally. TRT does not support spermatogenesis because of its negative feedback on the GnRH and gonadotrophin secretion. In one study, regular administration of exogenous testosterone in 271 healthy fertile men induced azoospermia after a mean of 4 months, whereas restoration of spermatogenesis after cessation of testosterone therapy took 6 months.22 Therefore, testosterone therapy is not recommended in men with hypogonadism who desire fertility in the next 6 to 12 months.23 In addition, there have been concerns regarding persistent suppression of spermatogenesis following discontinuation of TRT.23 A meta-analysis by Rastrelli and colleagues24 reported that previous TRT in men with HH did not have a negative effect on treatment outcomes with gonadotrophins/GnRH fertility induction. Appropriate fertility counseling of men who are being considered for TRT should take place.
SECONDARY HYPOGONADISM OR HYPOGONADOTROPIC HYPOGONADISM
HH is one of the few medically reversible causes of male infertility (Table 1). It is characterized by low or inappropriately normal FSH and or LH; hence, treatment with gonadotrophins or pulsatile GnRH to stimulate gonadotrophins represents a logic approach. Men with congenital hypogonadotropic hypogonadism (CHH) typically present in their adolescence with either partial (25%) or complete absence of puberty (75%).25 Pitteloud and colleagues26 studied 78 men with HH and found that 80% had pulsatile LH activity resulting in absent puberty, whereas 20% had discernible LH pulses, which were either low in frequency or amplitude or both, resulting in partial puberty. There were significantly higher rates of cryptorchidism, microphallus, and severely reduced testicular volume in men with complete compared with partial HH.26 If HH has a postpubertal onset, secondary sexual characteristics, and testicular development are normal. Men with HH usually present with reduced libido, fewer nighttime, and spontaneous erections, decreased sexual activity, and reduced or absent sperm in ejaculate.
Gonadotropins
Human chorionic gonadotropin (hCG) hormone exerts similar actions to LH on Leydig cells. Several studies have shown that hCG can increase the intratesticular testosterone in a dose-dependent manner27,28 and induce spermatogenesis.29 However, hCG monotherapy appears to have inferior results to the combination therapy with FSH in cases where there has been lack of pubertal development and/or history of cryptorchidism. Men with postpubertal onset of HH or some degree of gonadal development are more likely to respond to hCG alone.30 A study by Depenbusch and colleagues31 observed that LH monotherapy could sustain sufficient spermatogenesis for extended periods following initial treatment with either a combination of gonadotrophins or GnRH in a small cohort of 13 patients with idiopathic HH (IHH). A European consensus statement on the treatment of CHH recommends that hCG should be the first-line therapy for patients with some gonadal development (testicular volume >4 mL) and no history of undescended testes and that duration of treatment should be at least for 3 to 6 months before adding FSH.30
FSH induces proliferation and maturation of SC, which support the spermatogenesis process within the testis. In clinical practice, either urine-derived FSH (human menopausal gonadotrophin) or recombinant FSH (rFSH) is commonly used. The safety and efficacy of rFSH have been demonstrated in many studies.32,33 Furthermore, by modifying the glycosylation sites of the rFSG, long-acting FSH analogues have been developed; these long-acting FSH analogues have been shown to be safe and efficacious in women seeking infertility care. Corifollitropin alfa has the same pharmacodynamic profile as the rFSH, but it has a longer half-life,34 reducing the frequency of multiple injections. A small number of studies of long-acting rFSH in men with HH35,36 have shown these preparations to be safe and able to induce greater than 1 million sperm in more than 75% of men with HH, but further studies are warranted before they are established in clinical practice
Combination FSH with hCG hormone stimulation has yielded improved results in producing sperm and promoting fertility compared with hCG alone. Approximately 50% of those remaining azoospermic with LH monotherapy produced greater than 1 X 10 6 sperm when FSH was added.33 FSH is usually added after 3 to 6 months of LH hormone stimulation if LH alone has failed to induce spermatogenesis. Baseline testicular volume and sexual development are important prognostic factors for response to combination gonadotropins therapy.37,38 In addition, body mass index (BMI) has been recognized as a prognostic marker of inducing spermatogenesis with gonadotrophins therapy, with lower BMI being associated with a better response.39 Given the improved outcomes with combination gonadotropins therapy, FSH was evaluated as an adjunct to standard testosterone therapy in an early study aiming to assess spermatogenesis induction and maintenance in HH men without cryptorchidism. Following 24 months of cotreatment, combined treatment with testosterone and FSH failed to show sperm induction; instead, the sperm count decreased even further.40
A meta-analysis of 49 studies by Rastrelli and colleagues24 reported an overall success rate of 75% in achieving at least 1 spermatozoa in the semen from baseline of azoospermia and a mean sperm concentration of 5.92 million/mL after gonadotrophin therapy. Prior therapy with TRT did not affect the outcome of gonadotrophin therapy. Higher success rates were observed with combination therapy of hCG and FSH than with hCG alone; poorer outcomes were noted in men with prepubertal onset of HH.24
Gonadotropin therapy is in general effective in inducing spermatogenesis in men with HH. Several different gonadotropin therapy protocols exist, but insufficient data exist on the relative efficacy of various regimens. The treatment regimens typically include hCG at a dose from 500 to 2500 IU twice or thrice weekly and FSH at a dose from 75 to 150 IU 2 to 3 times weekly.25,41 To date, no randomized prospective trials exist to confirm the best treatment regimen, and these protocols are based on expert opinions.42,43
When gonadotropin therapy fails to induce enough sperm for a couple to conceive naturally, assistive reproductive technologies (ART) can enhance paternity potential in men with HH. A meta-analysis of 709 patients with CHH showed that the rates of fertilization, implantation and live births (72%, 36%, and 40%) did not differ in men with CHH compared with men with other causes of infertility.44 Thus, ART is a rational next step in the management of infertility in men with HH who fail to respond to gonadotrophin treatment.
Pulsatile Gonadotrophin-Releasing Hormone
Pulsatile GnRH represents another approach for managing infertility in men with CHH. Several studies have investigated the efficacy of GnRH treatment, and some studies have compared GnRH treatment with combined gonadotropins treatment.25 However, no head-to-head trials have compared GnRH treatment with combined gonadotropin treatment. GnRH pumps are not widely available, and in many countries, these pumps are available only in research settings. A meta-analysis of 8 studies reported that treatment with GnRH resulted in earlier onset of spermatogenesis compared with gonadotropins treatment in men with CHH, but there were no differences in sperm concentration and pregnancy rate.45 To mimic the pulsatile pattern of release in normal physiology, GnRH is given either intravenously or subcutaneously via a pump. Standard commencement dose is 25 ng/kg per pulse every 2 hours, and the dose is titrated to achieve serum testosterone levels in the normal reference range.25 Duration of GnRH pump therapy normally exceeds 12 months in men with HH. Response to treatment varies according to degree of GnRH deficiency, baseline inhibin B level, and presence of cryptorchidism.46
Another therapeutic regimen that has been evaluated is pulsatile GnRH with rFSH pretreatment.47 This small, open-label study showed that 24 months of GnRH therapy with preceding 6-month rFSH administration had a possible favorable effect on gonadal development, attaining testicular growth, normalizing levels of inhibin B levels, and promoting fertility in patients with CHH compared with 24 months of GnRH therapy alone; however, the 2 regimens did not differ significantly in the final testicular volume, sperm count, time to sperm appearance in the ejaculate, and fertility outcomes.47 The study had a small number of participants (n = 13), and it was not powered to prove superiority of FSH/GnRH group in either sperm count or fertility outcomes.
Pulsatile GnRH is effective in cases with intact pituitary. GnRH appears to have less estrogenic derived side effects, but it has not been found to expedite testicular growth or the presence of sperm in the ejaculate compared with FSH/hCG treatment.48 A mean sperm concentration of 4.27 million/mL was reported following hormonal stimulation with GnRH treatment in men with HH.24 Although these values decreased well below the lower reference limit according to World Health Organization 2010 classification,49 they were sufficient to obtain a pregnancy in 30% to 50% of cases of those who wanted to achieve paternity through both natural conception and assisted reproduction. This is further supported by a previous study that demonstrated that 16% of pregnancies occurred when the mean sperm concentration was less than 1 X 106 million/mL and 71% of pregnancies occurred when the mean sperm concentration was less than 20 X 106 million/mL.50
Selective Estrogen Receptor Modulators
SERMs have been used off-label to treat men with low testosterone. Clomiphene citrate (CC) and tamoxifen are the most commonly used SERM agents. SERMs provide a potential advantage over TRT because they work by inhibiting the negative feedback of estrogen to the hypothalamus/pituitary, resulting in increased gonadotrophin secretion and subsequent testosterone secretion. Many studies have shown an improvement in endogenous testosterone levels in hypogonadal men51–53; however, the improvement in hypogonadal symptoms with SERM treatment has been inconsistent in published studies.51,54,55 Furthermore, these studies included predominantly men with late-onset hypogonadism. The men with congenital or acquired HH secondary to pituitary tumor did not respond to high doses or prolonged course of clomiphene (50 mg twice daily).56 Similarly, Kulin and colleagues57 observed that prepubertal boys, before the maturation of their hypothalamic-pituitary axis, did not respond to CC. Thus, an intact and functioning HPG axis is necessary for the mechanism of action of SERM to activate testicular function.
Common adverse effects of SERMs include headache, visual changes, nausea and vomiting, and mood swings. Clomiphene has been reported to cause gynecomastia, and there have been rare reports showing induced azoospermia.58 Only a few studies have addressed possible side effects after long-term use of clomiphene (>3 years); the long-term side effects appear to be similar to those with short-term use. Given the antiestrogenic effects, there had been concern regarding bone density. Three years of CC usage resulted in improvement of bone mass across all 29 patients who had either normal or reduced bone mineral density at baseline.53 This is explained by the estrogenic agonistic effect on bones. However, this could not be extrapolated for all class drugs, and tamoxifen’s effect on bone density remains questionable.59,60
Aromatase Inhibitors
AI, such as anastrozole, also have been used off-label in hypogonadal men to increase testosterone production. A randomized control trial with 26 hypogonadal men suggested that anastrozole resulted in a significantly larger increase in T/E2 ratio than CC.61 A low T/ E2 ratio has been suggested as a separate endocrine parameter of male infertility.62A few studies observed that treatment of hypogonadal men with low T/E2 ratio with anastrozole resulted in improvement of this ratio, and this correlated with a 3-fold improvement in sperm concentration.63,64 These findings instigated the design of following studies where both anastrozole and CC were administered aiming to tackle the hyperestrogenemia derived from the latter. A retrospective study investigating the efficacy and safety of combination therapy in 51 men with low testosterone concluded that therapy was safe and effective in raising testosterone levels and normalizing estrogen levels and T/E2 ratio.65 However, effect on semen parameters was not reported.
AI’s commonest side effects include headache, gastrointestinal disturbances, hot flushes, and bone pains. In addition, the long-term skeletal safety remains an issue of concern with anastrozole, which has been associated with accelerated bone loss in postmenopausal women with breast cancer.66 Therefore, anastrozole is not routinely used. Last, AI and SERMs have been associated with increased risk of thromboembolic events67; it is unclear if thrombosis risk is higher in comparison to TRT or to baseline risk in an age-matched population.
PRIMARY HYPOGONADISM
The men with primary hypogonadism may be azoospermic (nonobstructive azoospermia [NOA]) or have reduced semen quality. The histopathological finding can vary from absence of germ cells (SC only) to maturation arrest and hypospermatogenesis and is directly linked to the cause of the testicular failure. Historically, the only viable options to paternity in men with azoospermia were sperm donation or adoption. Recent advances in surgical extraction of sperm in some men with NOA along with ART have enabled many men with primary testicular failure to father their own biological children.
There are different surgical methods to retrieve sperm in men with NOA. Conventional testicular sperm extraction (cTESE) involves exposure of the testis through a small incision and the acquisition of multiple biopsies blindly as a means to isolate sperm. Microdissection testicular sperm extraction (mTESE) is performed with the aid of a surgical microscope to identify engorged seminiferous tubules (containing sperm, it is hoped) in situ and to take out a small amount of testicular tissue for sperm extraction68 (Fig. 1). Although mTESE is now considered the gold-standard method for sperm retrieval, a meta-analysis did not show superiority of mTESE over cTESE with regards to sperm recovery.69 TESA (testicular sperm aspiration), which is performed by introducing a needle into the testis and aspirating fluid and tissue, has been shown to be inferior to testicular sperm extraction (TESE).70
Endocrine stimulation is an emerging area with a potential role in the treatment of men with NOA undergoing surgical sperm retrieval (SSR). Although at a first glance it seems counterintuitive to use medications that increase gonadotrophins, there are pathophysiological arguments to support this approach: maximization of intratesticular testosterone, SC desensitization theory.71–73 Low testosterone and T/E2 appear to be implicated in the pathophysiology of NOA.62Also, it has been observed that HCG therapy can increase testosterone production in men with hypergonadotropic hypogonadism.74 SC desensitization theory has emanated from animal studies; SC appear to be less sensitive when chronic stimulation of FSH occurs, resulting in downregulation of testicular gonadotropin receptor binding sites.75 Foresta and colleagues72 demonstrated that in their population of men with high baseline FSH and oligozoospermia, improved SC function was observed in response to FSH therapy following a 4-month period of temporary GnRH blockage. This postulates that SC desensitization can be reversed.72 However, hormonal stimulation as a means to optimize intratesticular testosterone before SSR has only been insufficiently reviewed in small-scale studies, and there is conflicting evidence of whether it increases SSR rates in men with primary testicular failure.73,76,77 Moreover, there is no clear evidence base for drug selection. SERMs and AI are commonly preferred given their oral route of administration and relatively low cost compared with gonadotropins/GnRH therapy. Although some centers use endocrine stimulation to optimize testosterone levels before SSR owing to some reports that showed favorable outcomes,62,74,78,79 because of insufficient data, the practice committee of the American Society for Reproductive Medicine does not support the endocrine stimulation as standard clinical practice.80
Klinefelter syndrome (KS) is a chromosomal disorder typically associated with 47, XXY karyotype or mosaicism (47,XXY/46,XY), and primary testicular failure. Classical KS is characterized by tall stature, eunuchoid body proportions, gynecomastia, small testes, and NOA. Only a minority of men with nonmosaic KS (7%–8%) has been reported to produce few spermatozoa in ejaculate.81,82 Most men with KS (XXY, karyotype) are azoospermic83 and require surgical sperm extraction to achieve fatherhood. A successful rate of SSR using cTESE or mTESE in KS is estimated at 44% to 61%69,84,85; however, the likelihood of live childbirth decreases to approximately 16%.86
It is worth noting that KS is a cause of primary testicular failure, yet with a progressive course. Men with KS are born with spermatogonia, but during puberty, there is an accelerated reduction in germ cells. Sperm have been identified in 70% of ejaculated semen specimens in adolescents with KS aged 12 to 20 years.85 Moreover, adolescents with KS are known to have normal or low normal testosterone levels, whereas exogenous testosterone might further complicate their fertility potential in their adulthood. For those reasons, there is an ongoing discussion about the appropriate time of sperm harvesting and sperm cryopreservation. Isolation of good-quality sperm in the ejaculate and cryopreservation would mitigate the need to undergo invasive TESE in the future. However, sperm cryopreservation at a young age raises issues of emotional immaturity to make such a decision and financial burden for health service or family. Recent studies have not shown improved SSR rates in adolescents versus adults, and a 2017 meta-analysis did not show improved live birth and pregnancy outcomes with frozen versus fresh sperm in 1248 KS patients.86
ASSISTIVE REPRODUCTIVE TECHNOLOGIES/INTRACYTOPLASMIC SPERM INJECTION RISKS
ART have revolutionized the field of couple infertility with more than 7 million children born worldwide with these methods. Intracytoplasmic sperm injection (ICSI), in particular, has overcome to an extent the problem of fertilization in cases with severe oligospermia or azoospermia. ICSI involves the injection of a single sperm directly into a mature oocyte (Fig. 2). However, ART treatments do not come without risks. Although the risks are considered modest, there are a few key factors that may contribute to this relatively higher risk compared with naturally conceived pregnancies: infertility itself, risks associated with culture of embryos and gametes, type of ART, and epigenetic imprinting. A recent study using data from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System registry concluded that ART is associated with increased risks of a major nonchromosomal birth defect, cardiovascular defect, and any defect in singleton children, and chromosomal defects in twins.87 In addition, the use of ICSI further increases this risk, and particularly when male factor infertility is implicated.87 It remains unclear though if one of the aforementioned key factors contributes more to this relative increased risk. There is not enough evidence to consolidate the long-term health risks of ART. Limited data suggest that altered blood pressure and cardiovascular function are more commonly encountered in ART children compared with children born from natural conception. It has also been described as a plausible association between cerebral palsy and ART. To date, no evidence to support increased risks of malignancies exists.88
SUMMARY
Fertility potential of hypogonadal men has been enhanced over the past 40 years. It is of utmost importance that fertility care is delivered by an experienced multidisciplinary team to ensure appropriate investigation, counseling, pharmacologic therapy, and follow-up as well as a timely referral for ART should it be required.
HH represents one of the few medically treatable causes of male infertility. Treatment pathways and success rates differ according to the cause of hypogonadism and the time of onset. Puberty, a crucial milestone in a man’s life, informs the definitive management and response to treatment.89,90 Postpubertal onset, early arrest of puberty, and complete failure of puberty have different fertility induction outcomes listed from more to least favorable. Hormonal treatment with gonadotropins and pulsatile GnRH has a much stronger evidence base in men with HH than SERMs or AI. In addition, hCG with or without FSH and pulsatile GnRH have been shown to be consistently effective in HH, but pulsatile GnRH is less favored in clinical practice mainly because of cumbersomeness and cost. The role for hormonal stimulation in cases with primary hypogonadism remains equivocal: ART with ICSI represents the gold standard of treatment. Modest risks have been reported with ART/ICSI.
Nikoleta Papanikolaou, MBBS, MRCP, Rong Luo, MBBS, Channa N. Jayasena, MA, Ph.D., MRCP, FRCPath*
INTRODUCTION
Male factors are increasingly recognized to be a causative or contributory factor in approximately 50% of infertile couples.1,2 Hypogonadism may be present in up to 40% of men who present with couple infertility.3 Testosterone is the major androgen-regulating spermatogenesis in men; as a result, men with either primary or secondary hypogonadism may be subfertile because of impaired spermatogenesis. The clinical impact of hypogonadism on fertility potential depends on the timing of its onset (fetal, prepubertal, or postpubertal) and effect on semen parameters. Secondary hypogonadism is one of the few medically treatable causes of male infertility.
Hormonal treatment with gonadotropins, pulsatile gonadotrophin-releasing hormone (GnRH) as well as off-label medications, such as selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AI), has been trialed in men with hypogonadism with various results. Treatment pathways and success rates differ according to the cause of hypogonadism and the time of its onset. Assisted reproductive technologies account for another treatment pathway that has further improved fertility potential of hypogonadal men.
BACKGROUND PHYSIOLOGY
Boys have a surge of GnRH during the first 3 months of life, leading to pulsatile follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion known as “mini-puberty.”4 The increase in serum LH stimulates the Leydig cells to synthesize testosterone, leading to increase in penile length and testicular volume.5 Crucially for fertility, the surge in FSH induces proliferation of immature Sertoli cells (SC) by 5-fold from approximately 260 106 at birth to 1500 106 by 3 months of age.6 These SC begin to express androgen receptors at around 12 months of age in humans.7,8 After 6 months of age, the hypothalamic-pituitary-gonadal (HPG) axis is quiescent, and testosterone levels remain low until puberty.4,6 Reactivation of the HPG axis during puberty stimulates a second wave of SC proliferation, doubling the number of SC to approximately 2900 million.6 By now, the vast majority (87%–95%) of SC express androgen receptors.7 In healthy men, LH pulses stimulated by GnRH pulsatility are generated every 1.5 to 2 hours,9 but this pattern is largely lost in hypogonadotropic hypogonadism (HH).
Testosterone is the major androgen-regulating spermatogenesis in men. It is synthesized by Leydig cells in response to LH and binds to androgen receptors expressed on SC to support spermatogenesis.10,11 The classical testosterone signaling pathway takes 30 to 45 minutes for cellular response.12 Testosterone first diffuses across the plasma membrane to bind with intracellular androgen receptors that are sequestrated by heat shock proteins in the cytoplasm. Binding of testosterone to androgen receptors induces phosphorylation and subsequent homodimerization, and a conformational change in the receptor structure allows recruitment of co-regulators and its nuclear translocation and upregulation and downregulation of target genes transcription.13 The nonclassical pathways of testosterone signaling are much more rapid, occurring within seconds to minutes.14 One pathway involves activation of Src tyrosine kinases, resulting in phosphorylation of epidermal growth factor receptor and consequent activation of the MAP kinase cascade (Raf, MEK, ERK).15 This pathway has been shown to facilitate Sertoli-germ cell attachment and release of mature sperm.15,16
Because of localized production of testosterone within the testes, intratesticular concentrations of testosterone are reported to be 200-fold higher than serum level samples from peripheral venous blood.17,18 Below a critical concentration of testosterone, spermatogenesis becomes impaired.19
Testosterone replacement therapy (TRT) in men with hypogonadism is often used to induce virilization and bolster secondary sexual characteristics as well as to improve libido, bone composition, and bone mineral density.20,21 TRT may be administered enterally, parenterally, and transdermally. TRT does not support spermatogenesis because of its negative feedback on the GnRH and gonadotrophin secretion. In one study, regular administration of exogenous testosterone in 271 healthy fertile men induced azoospermia after a mean of 4 months, whereas restoration of spermatogenesis after cessation of testosterone therapy took 6 months.22 Therefore, testosterone therapy is not recommended in men with hypogonadism who desire fertility in the next 6 to 12 months.23 In addition, there have been concerns regarding persistent suppression of spermatogenesis following discontinuation of TRT.23 A meta-analysis by Rastrelli and colleagues24 reported that previous TRT in men with HH did not have a negative effect on treatment outcomes with gonadotrophins/GnRH fertility induction. Appropriate fertility counseling of men who are being considered for TRT should take place.
SECONDARY HYPOGONADISM OR HYPOGONADOTROPIC HYPOGONADISM
HH is one of the few medically reversible causes of male infertility (Table 1). It is characterized by low or inappropriately normal FSH and or LH; hence, treatment with gonadotrophins or pulsatile GnRH to stimulate gonadotrophins represents a logic approach. Men with congenital hypogonadotropic hypogonadism (CHH) typically present in their adolescence with either partial (25%) or complete absence of puberty (75%).25 Pitteloud and colleagues26 studied 78 men with HH and found that 80% had pulsatile LH activity resulting in absent puberty, whereas 20% had discernible LH pulses, which were either low in frequency or amplitude or both, resulting in partial puberty. There were significantly higher rates of cryptorchidism, microphallus, and severely reduced testicular volume in men with complete compared with partial HH.26 If HH has a postpubertal onset, secondary sexual characteristics, and testicular development are normal. Men with HH usually present with reduced libido, fewer nighttime, and spontaneous erections, decreased sexual activity, and reduced or absent sperm in ejaculate.
Gonadotropins
Human chorionic gonadotropin (hCG) hormone exerts similar actions to LH on Leydig cells. Several studies have shown that hCG can increase the intratesticular testosterone in a dose-dependent manner27,28 and induce spermatogenesis.29 However, hCG monotherapy appears to have inferior results to the combination therapy with FSH in cases where there has been lack of pubertal development and/or history of cryptorchidism. Men with postpubertal onset of HH or some degree of gonadal development are more likely to respond to hCG alone.30 A study by Depenbusch and colleagues31 observed that LH monotherapy could sustain sufficient spermatogenesis for extended periods following initial treatment with either a combination of gonadotrophins or GnRH in a small cohort of 13 patients with idiopathic HH (IHH). A European consensus statement on the treatment of CHH recommends that hCG should be the first-line therapy for patients with some gonadal development (testicular volume >4 mL) and no history of undescended testes and that duration of treatment should be at least for 3 to 6 months before adding FSH.30
FSH induces proliferation and maturation of SC, which support the spermatogenesis process within the testis. In clinical practice, either urine-derived FSH (human menopausal gonadotrophin) or recombinant FSH (rFSH) is commonly used. The safety and efficacy of rFSH have been demonstrated in many studies.32,33 Furthermore, by modifying the glycosylation sites of the rFSG, long-acting FSH analogues have been developed; these long-acting FSH analogues have been shown to be safe and efficacious in women seeking infertility care. Corifollitropin alfa has the same pharmacodynamic profile as the rFSH, but it has a longer half-life,34 reducing the frequency of multiple injections. A small number of studies of long-acting rFSH in men with HH35,36 have shown these preparations to be safe and able to induce greater than 1 million sperm in more than 75% of men with HH, but further studies are warranted before they are established in clinical practice
Combination FSH with hCG hormone stimulation has yielded improved results in producing sperm and promoting fertility compared with hCG alone. Approximately 50% of those remaining azoospermic with LH monotherapy produced greater than 1 X 10 6 sperm when FSH was added.33 FSH is usually added after 3 to 6 months of LH hormone stimulation if LH alone has failed to induce spermatogenesis. Baseline testicular volume and sexual development are important prognostic factors for response to combination gonadotropins therapy.37,38 In addition, body mass index (BMI) has been recognized as a prognostic marker of inducing spermatogenesis with gonadotrophins therapy, with lower BMI being associated with a better response.39 Given the improved outcomes with combination gonadotropins therapy, FSH was evaluated as an adjunct to standard testosterone therapy in an early study aiming to assess spermatogenesis induction and maintenance in HH men without cryptorchidism. Following 24 months of cotreatment, combined treatment with testosterone and FSH failed to show sperm induction; instead, the sperm count decreased even further.40
A meta-analysis of 49 studies by Rastrelli and colleagues24 reported an overall success rate of 75% in achieving at least 1 spermatozoa in the semen from baseline of azoospermia and a mean sperm concentration of 5.92 million/mL after gonadotrophin therapy. Prior therapy with TRT did not affect the outcome of gonadotrophin therapy. Higher success rates were observed with combination therapy of hCG and FSH than with hCG alone; poorer outcomes were noted in men with prepubertal onset of HH.24
Gonadotropin therapy is in general effective in inducing spermatogenesis in men with HH. Several different gonadotropin therapy protocols exist, but insufficient data exist on the relative efficacy of various regimens. The treatment regimens typically include hCG at a dose from 500 to 2500 IU twice or thrice weekly and FSH at a dose from 75 to 150 IU 2 to 3 times weekly.25,41 To date, no randomized prospective trials exist to confirm the best treatment regimen, and these protocols are based on expert opinions.42,43
When gonadotropin therapy fails to induce enough sperm for a couple to conceive naturally, assistive reproductive technologies (ART) can enhance paternity potential in men with HH. A meta-analysis of 709 patients with CHH showed that the rates of fertilization, implantation and live births (72%, 36%, and 40%) did not differ in men with CHH compared with men with other causes of infertility.44 Thus, ART is a rational next step in the management of infertility in men with HH who fail to respond to gonadotrophin treatment.
Pulsatile Gonadotrophin-Releasing Hormone
Pulsatile GnRH represents another approach for managing infertility in men with CHH. Several studies have investigated the efficacy of GnRH treatment, and some studies have compared GnRH treatment with combined gonadotropins treatment.25 However, no head-to-head trials have compared GnRH treatment with combined gonadotropin treatment. GnRH pumps are not widely available, and in many countries, these pumps are available only in research settings. A meta-analysis of 8 studies reported that treatment with GnRH resulted in earlier onset of spermatogenesis compared with gonadotropins treatment in men with CHH, but there were no differences in sperm concentration and pregnancy rate.45 To mimic the pulsatile pattern of release in normal physiology, GnRH is given either intravenously or subcutaneously via a pump. Standard commencement dose is 25 ng/kg per pulse every 2 hours, and the dose is titrated to achieve serum testosterone levels in the normal reference range.25 Duration of GnRH pump therapy normally exceeds 12 months in men with HH. Response to treatment varies according to degree of GnRH deficiency, baseline inhibin B level, and presence of cryptorchidism.46
Another therapeutic regimen that has been evaluated is pulsatile GnRH with rFSH pretreatment.47 This small, open-label study showed that 24 months of GnRH therapy with preceding 6-month rFSH administration had a possible favorable effect on gonadal development, attaining testicular growth, normalizing levels of inhibin B levels, and promoting fertility in patients with CHH compared with 24 months of GnRH therapy alone; however, the 2 regimens did not differ significantly in the final testicular volume, sperm count, time to sperm appearance in the ejaculate, and fertility outcomes.47 The study had a small number of participants (n = 13), and it was not powered to prove superiority of FSH/GnRH group in either sperm count or fertility outcomes.
Pulsatile GnRH is effective in cases with intact pituitary. GnRH appears to have less estrogenic derived side effects, but it has not been found to expedite testicular growth or the presence of sperm in the ejaculate compared with FSH/hCG treatment.48 A mean sperm concentration of 4.27 million/mL was reported following hormonal stimulation with GnRH treatment in men with HH.24 Although these values decreased well below the lower reference limit according to World Health Organization 2010 classification,49 they were sufficient to obtain a pregnancy in 30% to 50% of cases of those who wanted to achieve paternity through both natural conception and assisted reproduction. This is further supported by a previous study that demonstrated that 16% of pregnancies occurred when the mean sperm concentration was less than 1 X 106 million/mL and 71% of pregnancies occurred when the mean sperm concentration was less than 20 X 106 million/mL.50
Selective Estrogen Receptor Modulators
SERMs have been used off-label to treat men with low testosterone. Clomiphene citrate (CC) and tamoxifen are the most commonly used SERM agents. SERMs provide a potential advantage over TRT because they work by inhibiting the negative feedback of estrogen to the hypothalamus/pituitary, resulting in increased gonadotrophin secretion and subsequent testosterone secretion. Many studies have shown an improvement in endogenous testosterone levels in hypogonadal men51–53; however, the improvement in hypogonadal symptoms with SERM treatment has been inconsistent in published studies.51,54,55 Furthermore, these studies included predominantly men with late-onset hypogonadism. The men with congenital or acquired HH secondary to pituitary tumor did not respond to high doses or prolonged course of clomiphene (50 mg twice daily).56 Similarly, Kulin and colleagues57 observed that prepubertal boys, before the maturation of their hypothalamic-pituitary axis, did not respond to CC. Thus, an intact and functioning HPG axis is necessary for the mechanism of action of SERM to activate testicular function.
Common adverse effects of SERMs include headache, visual changes, nausea and vomiting, and mood swings. Clomiphene has been reported to cause gynecomastia, and there have been rare reports showing induced azoospermia.58 Only a few studies have addressed possible side effects after long-term use of clomiphene (>3 years); the long-term side effects appear to be similar to those with short-term use. Given the antiestrogenic effects, there had been concern regarding bone density. Three years of CC usage resulted in improvement of bone mass across all 29 patients who had either normal or reduced bone mineral density at baseline.53 This is explained by the estrogenic agonistic effect on bones. However, this could not be extrapolated for all class drugs, and tamoxifen’s effect on bone density remains questionable.59,60
Aromatase Inhibitors
AI, such as anastrozole, also have been used off-label in hypogonadal men to increase testosterone production. A randomized control trial with 26 hypogonadal men suggested that anastrozole resulted in a significantly larger increase in T/E2 ratio than CC.61 A low T/ E2 ratio has been suggested as a separate endocrine parameter of male infertility.62A few studies observed that treatment of hypogonadal men with low T/E2 ratio with anastrozole resulted in improvement of this ratio, and this correlated with a 3-fold improvement in sperm concentration.63,64 These findings instigated the design of following studies where both anastrozole and CC were administered aiming to tackle the hyperestrogenemia derived from the latter. A retrospective study investigating the efficacy and safety of combination therapy in 51 men with low testosterone concluded that therapy was safe and effective in raising testosterone levels and normalizing estrogen levels and T/E2 ratio.65 However, effect on semen parameters was not reported.
AI’s commonest side effects include headache, gastrointestinal disturbances, hot flushes, and bone pains. In addition, the long-term skeletal safety remains an issue of concern with anastrozole, which has been associated with accelerated bone loss in postmenopausal women with breast cancer.66 Therefore, anastrozole is not routinely used. Last, AI and SERMs have been associated with increased risk of thromboembolic events67; it is unclear if thrombosis risk is higher in comparison to TRT or to baseline risk in an age-matched population.
PRIMARY HYPOGONADISM
The men with primary hypogonadism may be azoospermic (nonobstructive azoospermia [NOA]) or have reduced semen quality. The histopathological finding can vary from absence of germ cells (SC only) to maturation arrest and hypospermatogenesis and is directly linked to the cause of the testicular failure. Historically, the only viable options to paternity in men with azoospermia were sperm donation or adoption. Recent advances in surgical extraction of sperm in some men with NOA along with ART have enabled many men with primary testicular failure to father their own biological children.
There are different surgical methods to retrieve sperm in men with NOA. Conventional testicular sperm extraction (cTESE) involves exposure of the testis through a small incision and the acquisition of multiple biopsies blindly as a means to isolate sperm. Microdissection testicular sperm extraction (mTESE) is performed with the aid of a surgical microscope to identify engorged seminiferous tubules (containing sperm, it is hoped) in situ and to take out a small amount of testicular tissue for sperm extraction68 (Fig. 1). Although mTESE is now considered the gold-standard method for sperm retrieval, a meta-analysis did not show superiority of mTESE over cTESE with regards to sperm recovery.69 TESA (testicular sperm aspiration), which is performed by introducing a needle into the testis and aspirating fluid and tissue, has been shown to be inferior to testicular sperm extraction (TESE).70
Endocrine stimulation is an emerging area with a potential role in the treatment of men with NOA undergoing surgical sperm retrieval (SSR). Although at a first glance it seems counterintuitive to use medications that increase gonadotrophins, there are pathophysiological arguments to support this approach: maximization of intratesticular testosterone, SC desensitization theory.71–73 Low testosterone and T/E2 appear to be implicated in the pathophysiology of NOA.62Also, it has been observed that HCG therapy can increase testosterone production in men with hypergonadotropic hypogonadism.74 SC desensitization theory has emanated from animal studies; SC appear to be less sensitive when chronic stimulation of FSH occurs, resulting in downregulation of testicular gonadotropin receptor binding sites.75 Foresta and colleagues72 demonstrated that in their population of men with high baseline FSH and oligozoospermia, improved SC function was observed in response to FSH therapy following a 4-month period of temporary GnRH blockage. This postulates that SC desensitization can be reversed.72 However, hormonal stimulation as a means to optimize intratesticular testosterone before SSR has only been insufficiently reviewed in small-scale studies, and there is conflicting evidence of whether it increases SSR rates in men with primary testicular failure.73,76,77 Moreover, there is no clear evidence base for drug selection. SERMs and AI are commonly preferred given their oral route of administration and relatively low cost compared with gonadotropins/GnRH therapy. Although some centers use endocrine stimulation to optimize testosterone levels before SSR owing to some reports that showed favorable outcomes,62,74,78,79 because of insufficient data, the practice committee of the American Society for Reproductive Medicine does not support the endocrine stimulation as standard clinical practice.80
Klinefelter syndrome (KS) is a chromosomal disorder typically associated with 47, XXY karyotype or mosaicism (47,XXY/46,XY), and primary testicular failure. Classical KS is characterized by tall stature, eunuchoid body proportions, gynecomastia, small testes, and NOA. Only a minority of men with nonmosaic KS (7%–8%) has been reported to produce few spermatozoa in ejaculate.81,82 Most men with KS (XXY, karyotype) are azoospermic83 and require surgical sperm extraction to achieve fatherhood. A successful rate of SSR using cTESE or mTESE in KS is estimated at 44% to 61%69,84,85; however, the likelihood of live childbirth decreases to approximately 16%.86
It is worth noting that KS is a cause of primary testicular failure, yet with a progressive course. Men with KS are born with spermatogonia, but during puberty, there is an accelerated reduction in germ cells. Sperm have been identified in 70% of ejaculated semen specimens in adolescents with KS aged 12 to 20 years.85 Moreover, adolescents with KS are known to have normal or low normal testosterone levels, whereas exogenous testosterone might further complicate their fertility potential in their adulthood. For those reasons, there is an ongoing discussion about the appropriate time of sperm harvesting and sperm cryopreservation. Isolation of good-quality sperm in the ejaculate and cryopreservation would mitigate the need to undergo invasive TESE in the future. However, sperm cryopreservation at a young age raises issues of emotional immaturity to make such a decision and financial burden for health service or family. Recent studies have not shown improved SSR rates in adolescents versus adults, and a 2017 meta-analysis did not show improved live birth and pregnancy outcomes with frozen versus fresh sperm in 1248 KS patients.86
ASSISTIVE REPRODUCTIVE TECHNOLOGIES/INTRACYTOPLASMIC SPERM INJECTION RISKS
ART have revolutionized the field of couple infertility with more than 7 million children born worldwide with these methods. Intracytoplasmic sperm injection (ICSI), in particular, has overcome to an extent the problem of fertilization in cases with severe oligospermia or azoospermia. ICSI involves the injection of a single sperm directly into a mature oocyte (Fig. 2). However, ART treatments do not come without risks. Although the risks are considered modest, there are a few key factors that may contribute to this relatively higher risk compared with naturally conceived pregnancies: infertility itself, risks associated with culture of embryos and gametes, type of ART, and epigenetic imprinting. A recent study using data from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System registry concluded that ART is associated with increased risks of a major nonchromosomal birth defect, cardiovascular defect, and any defect in singleton children, and chromosomal defects in twins.87 In addition, the use of ICSI further increases this risk, and particularly when male factor infertility is implicated.87 It remains unclear though if one of the aforementioned key factors contributes more to this relative increased risk. There is not enough evidence to consolidate the long-term health risks of ART. Limited data suggest that altered blood pressure and cardiovascular function are more commonly encountered in ART children compared with children born from natural conception. It has also been described as a plausible association between cerebral palsy and ART. To date, no evidence to support increased risks of malignancies exists.88
SUMMARY
Fertility potential of hypogonadal men has been enhanced over the past 40 years. It is of utmost importance that fertility care is delivered by an experienced multidisciplinary team to ensure appropriate investigation, counseling, pharmacologic therapy, and follow-up as well as a timely referral for ART should it be required.
HH represents one of the few medically treatable causes of male infertility. Treatment pathways and success rates differ according to the cause of hypogonadism and the time of onset. Puberty, a crucial milestone in a man’s life, informs the definitive management and response to treatment.89,90 Postpubertal onset, early arrest of puberty, and complete failure of puberty have different fertility induction outcomes listed from more to least favorable. Hormonal treatment with gonadotropins and pulsatile GnRH has a much stronger evidence base in men with HH than SERMs or AI. In addition, hCG with or without FSH and pulsatile GnRH have been shown to be consistently effective in HH, but pulsatile GnRH is less favored in clinical practice mainly because of cumbersomeness and cost. The role for hormonal stimulation in cases with primary hypogonadism remains equivocal: ART with ICSI represents the gold standard of treatment. Modest risks have been reported with ART/ICSI.
