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Caroppo, E. Nonobstructive Azoospermia. Encyclopedia. Available online: https://encyclopedia.pub/entry/7046 (accessed on 18 June 2024).
Caroppo E. Nonobstructive Azoospermia. Encyclopedia. Available at: https://encyclopedia.pub/entry/7046. Accessed June 18, 2024.
Caroppo, Ettore. "Nonobstructive Azoospermia" Encyclopedia, https://encyclopedia.pub/entry/7046 (accessed June 18, 2024).
Caroppo, E. (2021, February 04). Nonobstructive Azoospermia. In Encyclopedia. https://encyclopedia.pub/entry/7046
Caroppo, Ettore. "Nonobstructive Azoospermia." Encyclopedia. Web. 04 February, 2021.
Nonobstructive Azoospermia
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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 study, we reviewed the current knowledge about the hormonal control of spermatogenesis, the relationship between presurgical serum hormones levels and sperm retrieval rates, and the results of studies investigating the effect of hormonal treatments prior to microdissection testicular sperm extraction.

nonobstructive azoospermia micro-TESE FSH treatment hormonal treatment testosterone level

1. Introduction

Azoospermia, defined as the absence of sperm in the ejaculate, affects about 10–15% of infertile men, and in about two-third 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 (micro-TESE), 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.

2. Hormonal Control of Spermatogenesis

The role of follicle-stimulating hormone (FSH) in the modulation of spermatogenesis has been a matter of debate since a study on five men with inactivating mutation of the FSH receptor (FSHR) gene showed that none was azoospermic and that two had children [3]. This finding prompted some researchers to hypothesize that FSH was not necessary for spermatogenesis, but the finding that men with inactivating mutations in FSH beta subunit were completely azoospermic [3] challenged that hypothesis. Further studies clarified that the mutant FSHR is not completely inactive [4], so that a residual FSH action could be able to promote spermatogenesis and that mutations in the FSH gene are more severe than those of the FSHR [5].

Studies in mice lacking FSH (FSHKO) or FSHR (FSHRKO) clearly demonstrated that FSH is required to increase the number of spermatogonia and spermatocytes [6] and that FSH treatment was found to increase spermatogonial and spermatocyte number in hypophysectomized or gonadotropin-releasing hormone (GnRH)-immunized adult rats [7]. FSH acts also as a survival factor for spermatogonia, since acute FSH suppression induces spermatogonial apoptosis [8] and is required to stimulate the prenatal and prepubertal proliferation of Sertoli cell, an effect which is totally independent from luteinizing hormone (LH) action, as demonstrated in hypogonadal LH receptor null mice [9], as well as from testosterone action, as demonstrated in mice lacking Sertoli cell androgen receptor (SCARKO) and FSHR, which had a Sertoli cell number comparable to that of FSHRKO mice [6]. In the absence of FSH or FSHR, the Sertoli cell number is decreased by about 30–45% in comparison to normal testicular development: since the Sertoli cell is able to support a certain number of germ cells, the number of Sertoli cells determines the quantity of sperm produced. This may explain why FSHRKO mice present with complete spermatogenesis, but the amount of germ cells is lower than in wild-type animals [6].

Studies in men with congenital hypogonadotropic hypogonadism suggest that pretreatment with FSH alone prior to combined gonadotropin treatment enhances spermatogenesis [10]. However, FSH alone is not able to promote spermatogenesis beyond the pachytene spermatocytes: a recent study on SCARKO mice demonstrated that Sertoli cell androgen receptor (AR) signaling is required for the survival of meiotic prophase spermatocytes, since SCARKO mice exhibited loss of meiotic germ cells and failure of surviving spermatocytes to progress. Early meiotic prophase events are not dependent upon androgen signaling, therefore, chromosome synapsis and recombination occurred normally in surviving spermatocytes that entered meiotic prophase; however, SCARKO pachytene spermatocytes were found to acquire aberrant transcriptomic attributes (leptotene or zygotene transcriptome state) and failed to progress to subsequent transcriptomic signatures [11].

FSH alone has been also found to maintain spermatogenesis independently from testosterone; this is the case of transgenic male mice with activating FSHR mutation that enabled strong FSH activation (cAMP response > 10-fold above basal). Use of the antiandrogen flutamide to interfere the binding of androgens to the AR had no effect on spermatogenesis [12].

In normal conditions, however, testosterone signaling is required for spermatogenesis to proceed beyond meiosis. Testosterone signaling contributes also to maintaining tight junctions between adjacent Sertoli cells (essential for the blood-testis barrier) and a specialized environment for germ cells, mainly through its modulation of micro-RNAs that target genes essential for cell junction restructuring and Sertoli-germ cell adhesion. The absence of T results in disruption of blood–testis barrier, premature detachment of developing spermatid germ cells from Sertoli cells, and block of the release of mature spermatozoa from Sertoli cells, with consequent germ cells phagocytosis by Sertoli cells [13].

Testosterone (T) is produced by Leydig cells in response to LH, and mediates its effects by the AR expressed by the Sertoli cells via classical and nonclassical pathways. In the classical (genomic) pathway, T diffuses through the plasma membrane and interacts with AR and the complex T/AR translocates to the nucleus to bind to androgen response elements (AREs) in gene promoter regions and regulates gene transcription, while in the nonclassical (nongenomic) pathway, T/AR rapidly phosphorylates the SRC kinase, resulting in the stimulation of the epithelial growth factor (EGF) receptor and the fast (within 1 min) activation of MAP-kinase cascade and the CREB transcription factor, with a resulting sustained (for at least 12 h) increased protein phosphorylation and long-term gene expression changes that are mediated by increased kinase activity [14]. Both pathways are essential for spermatogenesis: a study performed on testis explants of male Sprague Dawley rats containing intact seminiferous tubules and accompanying interstitial cells, using inhibitors to specifically block each pathway in vitro, demonstrated that both pathways are able to activate transcription of the Sertoli cell-specific Rhox5 mRNA, which is dramatically upregulated in the presence of T in vivo, and that activation of either T signaling pathway in Sertoli cells can differentially modulate germ cells gene expression [14].

It has been classically demonstrated that intratesticular testosterone (ITT) concentration are much higher (50–100-fold) than circulating levels, however, spermatogenesis may be maintained by very low ITT concentration: mice with inactivation of the LH receptor (LuRKO mice) had intact spermatogenesis despite very low ITT levels (2% of control level), but administration of the antiandrogen flutamide halted sperm maturation at the round spermatid stage [15]. In addition, a more recent study demonstrated that spermatogenesis in LuRKO mice could be normalized with exogenous testosterone that achieved a serum T concentration comparable to that of WT mice, but an ITT level less than 1.5% of the WT concentration [16]. The relationship between serum and intratesticular T levels is, therefore, far to have been clearly established, so that further studies are needed.

It has been proposed that testosterone alone could induce complete spermatogenesis without the need of FSH action; indeed, subcutaneous testosterone supplementation in male mice with hypogonadotropic hypogonadism due to Kiss1 knockout was able to restore serum and intratesticular testosterone levels, promote testicular descent, and induce complete spermatogenesis from spermatocytes to elongated spermatids, but the resultant testicular weight reached only 40% of wild-type controls, similarly to what was found in hypogonadal or GnRH KO mice treated with testosterone supplementation. [17]. Such a quantitative deficit of spermatogenesis is likely to be due to the lack of FSH.

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 [13], and stimulates the Sertoli cell production of androgen binding globulin, which helps maintain a high T concentration within the testes. On the other hand, testosterone is thought to modulate the oligosaccharide complexity of pituitary FSH; castration induces changes in the oligosaccharide composition of pituitary FSH both in prepubertal and adult animals, and administration of flutamide, able to interfere the binding of androgens to the AR both peripherally and at hypothalamic-pituitary level, lead to a predominance of circulating FSH glycosylation variants bearing incomplete oligosaccharides [18]. Administration of testosterone enanthate to pubertal patients does not modify the serum FSH levels, but lead to a significant increase in the proportion of FSH bearing complex oligosaccharides [19].

3. Hormonal Treatment before Micro-TESE

Administration of exogenous gonadotropins has been classically found to be effective in restoring spermatogenesis in azoospermic men with hypogonadotropic hypogonadism. Consequently, hormonal treatment in men with NOA has been pursued with the aim of improving spermatogenesis before surgery, despite these patients may display high FSH and LH levels. It has been demonstrated, in fact, that in these patients Leydig cells respond to high dose hCG stimulation with increased amounts of testosterone production, even under a hypergonadotropic condition [20]. The authors demonstrated that patients with NOA display an altered gonadotrophin pulse amplitude and hypothesized that this weak endogenous gonadotrophin activity could be due to the desensitization of target cells (e.g., Sertoli and Leydig cells). Indeed, other studies demonstrated that men with NOA display abnormalities in gonadotropins pulse frequency and amplitude [21], however, these findings are presumably the consequence of an altered hypothalamus–pituitary–gonadal axis due to reduced testosterone and inhibin B feedback signaling, rather than to desensitization of target cells. As a matter of fact, it has demonstrated that desensitization of Sertoli cells does not occur, but hormonal responsiveness during FSH treatment is preserved, thanks to FSH receptor recycling [22]. Consequently, it may be hypothesized that at least a subset of men with NOA, e.g., those with subnormal T serum levels and inhibin B levels may have an altered endogenous gonadotropin secretion that justifies the use of exogenous gonadotropins or selective estrogen receptors modulators (SERMs) like CC.

Indeed, Shinjo et al. [23] found that hCG treatment significantly increased the ITT levels in patients with NOA; although ITT did not differ among those with SSR or sperm retrieval failure (SRF), men with SSR had significantly lower basal ITT levels compared to men who experienced SRF. This may reinforce the hypothesis that hormonal stimulation is required for men with subnormal T levels to optimize the sperm recovery. However, the administration of hCG alone, although being effective in improving SSR, may be not sufficient to promote spermatogenesis in men with NOA; in the same study, only men who received FSH had an increased spermatogonial proliferating cell nuclear antigen (PCNA) expression, a protein involved in nucleotide excision repair mechanisms prominently expressed in the nuclei of mitotic active spermatogonia, which has been proposed as a marker of normally active spermatogonia [24]. Furthermore, it has been demonstrated that the expression of AR on Sertoli cells increased following FSH plus hCG stimulation rather than after hCG alone [25], supporting the previous demonstration about the role of FSH in regulating Sertoli cell AR expression [26].

The results of the few studies available in this field, however, are not fully able to demonstrate a beneficial effect of hormonal treatment on the SRR in men with NOA. As displayed in Table 2, five studies [27][28][29][30][31] were carried in NOA men who underwent micro-TESE for the first time, while four [20][23][25][32] enrolled men undergoing salvage micro-TESE. The first two studies evaluated a well-selected cohort of patients, e.g., normogonadotropic men [28] and men with well-defined testis histology (MA and HYPO) [29], therefore, their results have poor generalizability, while the results of Amer and coworkers [31] are weakened by the relatively low overall SRR (32,2%), probably due to differences in skill and experience among the 15 urologists who performed micro-TESE. The two largest sample studies [27][30] provided conflicting results, i.e., in the study of Reifsnyder et al. [27], SRR did not differed among men with subnormal T levels receiving hormonal treatment (N = 307) or no treatment (N = 41), while in the study of Hussein et al. [30], SRR was significantly higher in men receiving hormonal treatment (N = 496) compared to those receiving no treatment (N = 112), and 10.9% of treated patients had sperm in the ejaculate after treatment. It has to be remarked that the post-treatment T levels differed significantly among studies, since in the study of Reifsnyder, 82% of treated patients responded to hormonal treatment with a serum T level of at least 250 ng, while in the study of Hussein, treatment was titrated to reach a target T level of 600–800 ng/dL; still, the SRR in the study of Reifsnyder in both treated and untreated patients (51 and 61%, respectively) was comparable to that obtained by patients undergoing hormonal treatment in the study of Hussein, while the SRR of untreated patients in this latter study was too low compared to the average SRR reported by studies in the micro-TESE setting.

Table 2. Hormonal treatment and successful sperm retrieval (SSR) in patients with NOA undergoing micro-TESE.

Study Patients Characteristics Treatment Results
[28] 108 men. 16 with SCO. 36 with focal SCO. 19 with MA. 37 with HYPO. All had serum FSH level below 8 mIU/mL 63 men received FSH 75 IU 3 times/week. 45 received no treatment SSR 64% (40/63) in FSH treated and 33% (15/45) in controls (p < 0.01)
SCO 2/7 (28% controls) vs. 4/9 (44% treated) p = NS
FSCO 4/16 (25%) vs. 13/20 (65% treated) (p < 0.01)
MA 3/8 (37%) vs. 5/11 (45% treated) p = NS
HYPO 6/14 (42%) vs. 18/23 (78% treated) p < 0.05
[29] 42 men with MA (42.9%) and HYPO (57.1%) CC 25–75 mg/day to achieve T 600–800 ng/dL (study target) 27/42 (64.3%) had sperm in the ejaculate; SSR 100% (15/15)
[27] 348 out of 736 patients had subnormal T.
307 out of 348 received hormonal therapy. 41 (12%) received no treatment
348 (47%) with low T (<300) and 388 with normal T (>300).
307 out of 348 (88%) were treated with hormonal therapy. 41 (12%) were not treated.
SSR in 52% of patients with low T and in 56% of patients with normal T.
SSR 51% in treated vs. 61% in untreated
[20] 48 men with failed micro-TESE 28 hCG/hCG plus FSH if FSH levels decreased during treatment. 20 received no treatment.
T did not differ among groups
Sperm retrieval 21% (treatment) vs. 0 (no treatment).
[30] 608 men 496 received CC, then hCG, and, eventually, hMG according to their response to CC, while 112 received no treatment. Target T level = 600–800 ng/dL 10.9% of patients had sperm in the ejaculate; SSR was 57% in treated and 33% in controls
[23] 20 men with failed micro-TESE hCG followed by FSH if serum FSH < 2 SSR 3/20 (15%). T did not differ among patients with SSR and SRF
Spermatogonial PCNA expression increased in patients receiving FSH
Patients with SSR had significantly lower basal ITT compared to those with SRF. Post-treatment ITT increased in all patients
[25] 22 men with failed micro-TESE All received hCG 5000 3 times a week; 12 patients received also FSH 150 thrice/week since FSH level dropped below 2 SSR 4/22 (18%). A significant increase in the AR index was observed in 12 patients receiving FSH + hCG. AR index was significantly higher in men with SSR compared to SRF. T levels did not correlate with AR index
[31] 1395 patients evaluated by different surgeons SSR 450/1395 (32.2%)
Hormonal therapy (CC or hCG or HMG or FSH or T or AI combination of drugs) in 426 patients
SSR was 27.6% (118/426) in treated vs. 31.7% (308/969) in untreated.
No data about T levels in treated vs. untreated.
[32] 40 men with failed micro-TESE. 20 received testosterone for 1 month. then FSH plus testosterone, while 20 received no treatment SSR in salvage micro-TESE was 10% in treated vs. 0 in controls.
No data about T levels in treated vs. untreated.

FSCO, focal Sertoli cell only syndrome; HYPO, hypospermatogenesis; ITT, intratesticular testosterone level; MA, maturation arrest; PCNA, proliferating cell nuclear antigen; NA, not applicable; SCO, Sertoli cell only syndrome; SRF, sperm retrieval failure; SSR, successful sperm retrieval.

On the other hand, the two out of four studies evaluating the results of salvage micro-TESE in treated vs. untreated patients [20][32] agreed in demonstrating the beneficial effect of hormonal treatment on SRR, however, the small number of subjects (48 treated vs. 40 untreated overall) does not allow to draw firm conclusions about that.

Another indication to hormonal treatment in men with NOA has been proposed to be their testicular histological pattern. Kato and coworkers observed that men with early MA had a lower AR index compared to those with late MA [25]; indeed, SCARKO mice have been found to display pachytene spermatocytes with aberrant transcriptomic attributes (leptotene or zygotene transcriptome state) that fail to progress to subsequent transcriptomic signatures [11]. Based on these results, Shiraishi hypothesized that only patients with late MA may respond to hormonal treatment [20]. Indeed, Aydos and coworkers did not observe improvements in SRR in patients with early MA undergoing hormonal treatment [28]. Other groups demonstrated that men with MA or HYPO respond to hormonal treatment with either the appearance of sperm in the ejaculate [30] or with improved SSR [29] even in the case of salvage micro-TESE [23]. However, also in this case, larger sample size studies are needed to confirm these findings.

The results of the available studies, although promising, are insufficient to recommend the hormonal treatment for every patient with NOA before surgery. Therefore, as stated by the recent AUA/ASRM guidelines on the diagnosis and management of infertility in men [33], patients with NOA should be informed of the limited data supporting pharmacologic prior to surgical intervention (Conditional Recommendation; Evidence Level; Grade C).

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