madman
Super Moderator
Abstract: Hormonal stimulation of spermatogenesis prior to surgery has been tested by some authors to maximize the sperm retrieval yield in patients with nonobstructive azoospermia. Although the rationale of such an approach is theoretically sound, studies have provided conflicting results, and there are unmet questions that need to be addressed. In the present narrative review, we reviewed the current knowledge about the hormonal control of spermatogenesis, the relationship between presurgical serum hormone levels and sperm retrieval rates, and the results of studies investigating the effect of hormonal treatments prior to microdissection testicular sperm extraction. We pooled the available data about sperm retrieval rate in patients with low vs. normal testosterone levels and found that patients with normal testosterone levels had a significantly higher chance of successful sperm retrieval compared to those with subnormal T levels (OR 1.63, 95% CI 1.08–2.45, p = 0.02). These data suggest that hormonal treatment may be justified in patients with hypogonadism; On the other hand, the available evidence is insufficient to recommend hormonal therapy as standard clinical practice to improve the sperm retrieval rate in patients with nonobstructive azoospermia.
1. Introduction
Azoospermia, defined as the absence of sperm in the ejaculate, affects about 10–15% of infertile men, and in about two-thirds of cases is due to severe spermatogenic dysfunction [1]: such a clinical condition is termed nonobstructive azoospermia (NOA) to differentiate it from the less severe (in terms of spermatogenesis impairment) form of azoospermia due to obstruction of the seminal tract. Men with NOA may still have residual focal areas of spermatogenesis that could enable them to father children genetically of their own if mature sperm are surgically retrieved and used for intracytoplasmic sperm injection (ICSI): however, sperm retrieval is successful in up to 58% of cases, even when the most effective surgical technique, namely, microdissection testicular sperm extraction (microTESE), is used [2]. Among the strategies sought to maximize the sperm retrieval yield, hormonal stimulation of spermatogenesis prior to surgery has been tested by several authors. Although the rationale of such an approach is theoretically sound, studies in the field have provided conflicting results so that the beneficial effect of hormonal optimization of spermatogenesis is yet to be demonstrated. The present narrative review is intended to discuss the evidence in the field and to offer some points for reflection for further studies. To provide unbiased results and avoid the possible impact of less effective surgical procedure on the sperm retrieval rates, only studies evaluating patients undergoing the gold-standard surgical technique for sperm retrieval (micro-TESE) [2] have been included in the present review.
2. Hormonal Control of Spermatogenesis
*Both FSH and testosterone are, therefore, required to promote full spermatogenesis; in addition, both hormones have synergistic effects upon spermatogenesis. FSH regulates transcripts required for normal testicular function, including StAR gene, which is essential for steroid synthesis [14], and stimulates the Sertoli cell production of androgen binding globulin, which helps maintain a high T concentration within the testes.
3. Relationship between Serum Hormones Levels and Sperm Retrieval
4. Hormonal Treatment before Micro-TESE
5. Unmet Needs and Future Directions
The management of patients with NOA is to a large extent knowledge-based. Thanks to the evidence produced by the literature of the past 20 years, we know with a good approximation that about 57–60% of patients with NOA may be successful in having their testicular sperm retrieved, what clinical conditions are predictive of SSR, that SRR may vary significantly according to testis histology and that micro-TESE provides better results in terms of SRR compared to the other available surgical techniques [61]. What we do not know, due to the inconclusive data provided by the literature, is whether and how should we treat these patients before surgery to maximize the chance of sperm retrieval.
The pooled estimation of studies reporting the SRRs in patients with subnormal T compared to those with normal T levels (Figure 1) suggests that optimization of serum T levels may be indicated in hypogonadal men before micro-TESE, since it may improve the SRR. However, due to the demonstrated poor relationship between serum and intratesticular T levels [17], and to the relatively low ITT required for spermatogenesis [16], the target serum T levels to be achieved to improve spermatogenesis is not clear. Relevantly, two large sample studies [34,57] reported similar SRRs despite significantly different post-treatment T levels (230 vs. 600–800 ng/dL). To improve our knowledge in this field, it could be helpful to identify serum biomarkers that could reliably predict ITT levels and serve for post-treatment ITT levels monitoring. In this perspective, the demonstration that serum 17 OHP and INSL3 levels are, to some extent, related to ITT levels, which may pave the way for a new line of research. In addition, the possible predictive role of bioactive T level (computed by the formula (Bio T= free T + albumin-bound T)) on SRR would deserve further studies.
Optimization of testosterone and, possibly, ITT levels, may require also FSH, since the expression of AR on Sertoli cells increases following FSH stimulation but not with hCG [53]. In addition, since FSH is essential to promote spermatogonial proliferation in men with NOA [51], many authors added FSH to hCG or CC when falling serum FSH levels were observed following hormonal treatment (Table 2). Interestingly, although the feasibility of FSH as treatment of infertile men with oligozoospermia has been investigated by many studies, with a recent one, even proposing that possible responders to FSH treatment may be identified by means of epigenetic biomarkers [62], very few studies sought to evaluate the effect of FSH alone to improve the chance of SRR in patients with NOA. Indeed, the finding that FSH may maintain spermatogenesis independently from testosterone, as found in transgenic male mice with activating FSHR mutation that enabled strong FSH activation, may prompt further studies on high dose FSH treatment of men with NOA.
Although we know with a good approximation the chance of SSR in men with different testis histology, we need more data to establish whether a specific histological pattern may be considered an indication or a contraindication to hormonal treatment. It would be helpful, therefore, for further studies in this field to report the response to hormonal treatment as stratified by testis histology. It is reminded here that, to obtain reliable testis histology pictures, the fragments of seminiferous tubules sent to the pathologist should be representative of the predominant tissue as observed at high magnification during micro-TESE.
In conclusion, to establish whether hormonal treatment may be of help in improving the reproductive potential of men with NOA, it is of the utmost importance to design studies with a large sample size and well-defined entry criteria and outcome measures: in this view, collaborative multicentric studies could provide valuable data. The actual evidence is insufficient to support the indiscriminate use of hormonal treatment prior to surgery in patients with NOA.
1. Introduction
Azoospermia, defined as the absence of sperm in the ejaculate, affects about 10–15% of infertile men, and in about two-thirds of cases is due to severe spermatogenic dysfunction [1]: such a clinical condition is termed nonobstructive azoospermia (NOA) to differentiate it from the less severe (in terms of spermatogenesis impairment) form of azoospermia due to obstruction of the seminal tract. Men with NOA may still have residual focal areas of spermatogenesis that could enable them to father children genetically of their own if mature sperm are surgically retrieved and used for intracytoplasmic sperm injection (ICSI): however, sperm retrieval is successful in up to 58% of cases, even when the most effective surgical technique, namely, microdissection testicular sperm extraction (microTESE), is used [2]. Among the strategies sought to maximize the sperm retrieval yield, hormonal stimulation of spermatogenesis prior to surgery has been tested by several authors. Although the rationale of such an approach is theoretically sound, studies in the field have provided conflicting results so that the beneficial effect of hormonal optimization of spermatogenesis is yet to be demonstrated. The present narrative review is intended to discuss the evidence in the field and to offer some points for reflection for further studies. To provide unbiased results and avoid the possible impact of less effective surgical procedure on the sperm retrieval rates, only studies evaluating patients undergoing the gold-standard surgical technique for sperm retrieval (micro-TESE) [2] have been included in the present review.
2. Hormonal Control of Spermatogenesis
*Both FSH and testosterone are, therefore, required to promote full spermatogenesis; in addition, both hormones have synergistic effects upon spermatogenesis. FSH regulates transcripts required for normal testicular function, including StAR gene, which is essential for steroid synthesis [14], and stimulates the Sertoli cell production of androgen binding globulin, which helps maintain a high T concentration within the testes.
3. Relationship between Serum Hormones Levels and Sperm Retrieval
4. Hormonal Treatment before Micro-TESE
5. Unmet Needs and Future Directions
The management of patients with NOA is to a large extent knowledge-based. Thanks to the evidence produced by the literature of the past 20 years, we know with a good approximation that about 57–60% of patients with NOA may be successful in having their testicular sperm retrieved, what clinical conditions are predictive of SSR, that SRR may vary significantly according to testis histology and that micro-TESE provides better results in terms of SRR compared to the other available surgical techniques [61]. What we do not know, due to the inconclusive data provided by the literature, is whether and how should we treat these patients before surgery to maximize the chance of sperm retrieval.
The pooled estimation of studies reporting the SRRs in patients with subnormal T compared to those with normal T levels (Figure 1) suggests that optimization of serum T levels may be indicated in hypogonadal men before micro-TESE, since it may improve the SRR. However, due to the demonstrated poor relationship between serum and intratesticular T levels [17], and to the relatively low ITT required for spermatogenesis [16], the target serum T levels to be achieved to improve spermatogenesis is not clear. Relevantly, two large sample studies [34,57] reported similar SRRs despite significantly different post-treatment T levels (230 vs. 600–800 ng/dL). To improve our knowledge in this field, it could be helpful to identify serum biomarkers that could reliably predict ITT levels and serve for post-treatment ITT levels monitoring. In this perspective, the demonstration that serum 17 OHP and INSL3 levels are, to some extent, related to ITT levels, which may pave the way for a new line of research. In addition, the possible predictive role of bioactive T level (computed by the formula (Bio T= free T + albumin-bound T)) on SRR would deserve further studies.
Optimization of testosterone and, possibly, ITT levels, may require also FSH, since the expression of AR on Sertoli cells increases following FSH stimulation but not with hCG [53]. In addition, since FSH is essential to promote spermatogonial proliferation in men with NOA [51], many authors added FSH to hCG or CC when falling serum FSH levels were observed following hormonal treatment (Table 2). Interestingly, although the feasibility of FSH as treatment of infertile men with oligozoospermia has been investigated by many studies, with a recent one, even proposing that possible responders to FSH treatment may be identified by means of epigenetic biomarkers [62], very few studies sought to evaluate the effect of FSH alone to improve the chance of SRR in patients with NOA. Indeed, the finding that FSH may maintain spermatogenesis independently from testosterone, as found in transgenic male mice with activating FSHR mutation that enabled strong FSH activation, may prompt further studies on high dose FSH treatment of men with NOA.
Although we know with a good approximation the chance of SSR in men with different testis histology, we need more data to establish whether a specific histological pattern may be considered an indication or a contraindication to hormonal treatment. It would be helpful, therefore, for further studies in this field to report the response to hormonal treatment as stratified by testis histology. It is reminded here that, to obtain reliable testis histology pictures, the fragments of seminiferous tubules sent to the pathologist should be representative of the predominant tissue as observed at high magnification during micro-TESE.
In conclusion, to establish whether hormonal treatment may be of help in improving the reproductive potential of men with NOA, it is of the utmost importance to design studies with a large sample size and well-defined entry criteria and outcome measures: in this view, collaborative multicentric studies could provide valuable data. The actual evidence is insufficient to support the indiscriminate use of hormonal treatment prior to surgery in patients with NOA.
Last edited:
