Non-obstructive azoospermia (NOA) possesses the properties of lack of sperm in the semen, which portrays a bothersome condition for 5–15% of men in view of spermatogenic failure, which influences around 60% of men whose presentation is infertility and come asking for help [1]. An exhaustive evaluation needs to have the goal of isolating the genetic factors, conditions where treatment is feasible, as well as correlated situations, for instance, hypogonadism [1]. NOA might be caused by various factors resulting in testicular deficiencies, for instance, genetic aberrations, congenital diseases [2,3], gonadotoxin exposure, orchitis, testicular trauma, but many cases remain idiopathic (4). Despite its prevalence, few studies have evaluated the hormonal profile of men with NOA seeking fertility [5].

Men with NOA might display biochemical hypogonadism [5,6], which gets pointed by low circulating levels of total testosterone (T) quantities [8], pointing to concomitant Leydig cell deficiency. In view of testis generates >95% of total T quantities, utilisation of its circulating concentrations is made to determine intratesticular testosterone (ITT) generation. In nonobese men, there is a fair association (r ¼ 0.82) amongst existent circulating T as well as ITT quantities [9], despite ITT are much greater [10]. Intratesticular T play a key part in spermatogenesis, particularly at the time of the final stages of working, via androgen receptors in Sertoli cells, T-quantities based that generates paracrine stimuli for germ cell production [11,12]. In men with NOA illustrating biochemical hypogonadism, there might be diminished ITT [9], quantities plausibly resulting in spermatogenesis. Studies in rodents have displayed that diminished ITT quantities are correlated with disturbed spermatogenesis [13]. In addition, in humans, serum T concentrations apparently have a positive association with sperm retrieval (SR) rates [14].

Nevertheless, the prevalence of hypogonadism in men with NOA is not well demonstrated, in addition to outcomes over the clinical factors correlated with this condition are absent. Furthermore, the assessment of men with azoospermia is to explore chronic physical signs, for instance, gynecomastia, small testis, absence of secondary sexual features, or any kind of hormonal dysbalance, which might be a pointer for any cause of the same [1]. Furthermore, men presenting with simultaneous biochemical hypogonadism, which by definition would be complete testosterone (T) quantities of<300ng/dl, might be pointing to a plausible leydig cell deficiency, pituitary deficiency, or a combination of both [5,6,16]. In men having NOA as well as biochemical hypogonadism, there might be a reduction in intratesticular testosterone (ITT) quantities, which possess the capacity of resulting in dysfunctional spermatogenesis [15]. Achermann et al. [16], evaluated in a study conducted recently in reference to finding the prevalence of biochemical hypogonadism in case of a cohort comprising of 767 successive patients possessing normogonadotropic or hypergonadotropic NOA. It was significantly noticeable significantly that the authors ruled out men presenting with genetically determinable aetiologies of NOA. Furthermore, subsequently, patients were separated into those believed to be eugonadal (19.2%) vis a vis the ones believed to be hypogonadal (80.8%). Utilisation of a cutoff of 350ng/dl for T was done by them. On evaluating the outcomes of the study it got apparent that of the men having biochemical hypogonadism, a considerable proportion possessed the probability of having luteinizing hormone (LH) quantities of <8 IU/L, pointing to secondary hypogonadism (pituitary deficiency), whereas lesser percentage were having the probability of LH>8 IU/L pointing to primary hypogonadism (testicular deficiency) [16]. The median LH quantities for the patients having biochemical hypogonadism were 6.2 IU/L, having an interquartile variation of 5.0-8.09 IU/L pointing that 50% of patients were lying in this variation. Acknowledged the upper boundary of interquartile variation, it would be justifiable to decipher that maximum patients possessed LH quantities<8 IU/L pointing to secondary hypogonadism, there by pituitary deficiency [16]. In reference to this men having secondary hypogonadism are candidates for selective estrogen receptors modulators (SERM) in addition to human chorionic gonadotropins (HCG), while men having primary hypogonadism with greater LH quantities would not be candidates for SERM in addition to HCG, until T: E2 (estradiol) ratio is aberrant (estrogen blockers, would be plausible therapeutic option on isolation of same [6,17]. Actually, a remarkable percentage of men having NOA from the hypogonadal group might have been believed to be candidates for SERM in addition to HCG treatment. Moreover significant variations were observed amongst men having lesser T quantities along with men having eugonadal state. Significantly on one side hypogonadal men possessed substantially significant lesser testicular volume; lesser baseline E, T along with free T in addition to lesser T: E2 ratio [16]. Noticeably Achermann etal. [16], further performed histopathological examination(HPE), which illustrated that patients believed to be hypogonadal possessed greater rates of sertoli cell only syndrome or hypospermatogenesis in contrast to eugonadal patients who revealed spermatogenic maturation arrest more commonly pointing to the existence of germ cells would indicate proper leydig cell working. Moreover, sperm retrieving (SR) rate differed over the groups with greatest amounts were observed amongst men having prevalence of normogonadotropic eugonadal patients at 63.1% [16]. There by Achermann et al [16], had the conclusions drawn that their study illustrated a substantially significant biochemical hypogonadism influencing about 80% of men having NOA. The greater prevalence might be reasoned out by factors for instance testicular volume, E quantities, paternal age, testicular HPE as well as probably ethnicity.

Figure 1: Courtesy ref no-16-Three-dimensional scatterplots show the patient distribution (n = 767) into groups on the basis of FSH (12 IU/L) and T (350 ng/dL) threshold levels. Hypergonadotropic hypogonadal (FSH > 12 IU/L and T < 350 ng/dL), hypergonadotropic eugonadal (FSH > 12 IU/L and T ≥ 350 ng/dL), normogonadotropic hypogonadal (FSH ≤ 12 IU/L and T < 350 ng/dL), and normogonadotropic eugonadal (FSH ≤ 12 IU/L and T ≥ 350 ng/dL). FSH = follicle-stimulating hormone; T = testosterone.

Akin to that other studies have evaluated prevalence of hypogonadism rates in case of men having NOA. For example Bobjer et al. [7], evaluated 65 men having NOA who had illustrated 40% of them displayed lesser T quantities in contrast to threshold of 10nmol/L. Nevertheless, their criteria were inclusive of patients with Klinefelters syndrome as well as other genetic aberrations in case of their cohorts that made comparison of results tough with those of Achermann et al.’s [16] study results. Reifsnyder et al. [6], performed asssessment of influence of preoperative medical therapy over men having NOA who had to get microdissection testicular sperm extraction (mTESE) performed. In their study which was encompassing 736 men having NOA, of which 47% of men were having T quantities <300ng/dl, to start with. Their observations were greater follicle stimulating hormone (FSH) quantities in men having Klinefelters syndrome within the men having lesser T quantities [6]. Furthermore, of men having NOA, testicular spermatozoa got retrieved in 52% [6]. Intriguingly , no significant variations in clinical pregnancy rates, live birth rates ( LBR) or SR rates amongst men having lesser T quantities in contrast to the ones having normal quantities were seen irrespective of if men having lesser T quantities got treatment or not. Additionally, no variations were found in testicular histologies amongst eugonadal in addition to hypogonadal patients [6]. These observations are converse of Achermann et al. [16], results where they showed predominantly sertoli cell only syndrome or hypospermatogenesis in men having hypogonadal NOA, pointing that men having biochemical hypogonadism possessed greater rates of spermatogenic failure in contrast to eugonadal patients having hypogonadal NOA [6].

In view of ITT is key in reference to spermatogenesis apart from tough to detect Pozzi & Ramasamy [18] posited serum 17 hydroxy progesterone(17-OHP) in the form of a dependable biomarker regarding status of ITT [18]. Regarding this the observations of Lima et al. [15], corroborate utilization of 17-OHP in the form of a dependable pointer regarding ITT quantities. Further research over the hypogonadism rates in case of men having NOA need to be taken into account, like 17-OHP in the form of a dependable biomarker in reference to status of ITT along with spermatogenesis. Overall these studies emphasize the requirement of greater exhaustive research regarding the prevalence of properties of the hypogonadal men having NOA. This study by Achermann et al. [16], is significant in view of it being large in addition to homogenous cohort of earlier patients having NOA without genetically determinable etiologies of NOA, might have added bias in the outcomes of the earlier studies. Their work displayed a significant prevalence of hypogonadal NOA, of which 80% of men having NOA illustrating T quantities <350ng/dl. Noticeably, if Achermann et al. [16], had chosen a cut off of 300ng/dl, their observations would have been more in agreement with the hypogonadal rates revealed in earlier studies of men having NOA. With prevalence of biochemical hypogonadism getting well displayed now, concentration of further studies need to be regarding treatment – for instance SERM, estrogen blockers (anastrozole), as well as /or HCG would result in escalation of probability of appearance of sperms in the ejaculate or in SR. Into the observations of Achermann et al. [16], continue to be significant in view of provision of greater insight amongst variations in case of eugonadal in addition to hypogonadal NOA along with propel greater work in this field [18].

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