Medical treatment prior to micro-TESE

Abstract

Except in cases of hypogonadotropic hypogonadism, the use of medical therapy before microsurgical testicular sperm extraction (micro-TESE) is controversial. In some studies, hormone therapy has been shown to improve the possibility of sperm retrieval during micro-TESE and even lead to the presence of sperm in the ejaculate in some cases, thereby obviating the need for micro-TESE. However, their routine use before micro-TESE in cases of nonobstructive azoospermia (NOA) being associated with hypergonadotropic hypogonadism and eugonadism (normogonadotropic condition) has not been supported with robust evidence. In this review, we discuss different types of medical therapy used before micro-TESE for NOA, their risks and benefits, and the available evidence surrounding their use in this setting.

INTRODUCTION

Nonobstructive azoospermia (NOA) is considered to be the most severe form of male infertility.1,2 It is characterized by the absence of sperm in the semen after centrifugation, resulting from underdeveloped or unproduced cells in the testicles.3 In this condition, seminiferous tubules may present three main patterns: Sertoli cell–only syndrome (SCOS), maturation arrest (MA; at spermatogonia, primary spermatocyte or round spermatid stages), and hypospermatogenesis.1,2 The major causes of primary NOA are abnormal chromosomes (structural and numerical aberrations)4 and Y-chromosome microdeletions.5

Because of the minimal availability of treatment choices, andrologists and fertility specialists encounter substantial challenges in handling NOA. Testicular sperm extraction (TESE) paired with intracytoplasmic sperm injection (ICSI) can be performed on men with NOA to allow them to father biological offspring.3 Even in some cases of SCOS and MA, isolated foci of spermatogenesis may be present; in such cases, sperm can be retrieved using TESE.6

Unfortunately, the reported overall success rate of TESE in men with NOA is only around 50%.7,8,9,10 As a result, if microsurgical TESE (micro-TESE) fails to retrieve sperm, these individuals have limited options, such as using donor sperm or considering adoption. There is hope that incorporating additional medical interventions before micro-TESE may increase the rate of successful sperm retrieval (SSR). This review aims to synthesize data on various medical treatments prior to micro-TESE and to discuss clinical practices to address the needs and challenges of NOA management.

BASIC PHYSIOLOGY OF SPERMATOGENESIS

The hypothalamus orchestrates the pulsatile release of gonadotropin-releasing hormone (GnRH), triggering the anterior pituitary to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH).11 The presence of normal levels of FSH and LH plays a crucial role in initiating spermatogenesis and sustaining elevated levels of intratesticular testosterone (ITT).6,7 However, the exact role of FSH and testosterone in spermatogenesis is not completely understood and remains a matter of debate.12,13,14 FSH is possibly needed for the survival of spermatogonia and spermatocytes and the proliferation of the Sertoli cells, which support the germ cells.12,13,14,15,16 Nonetheless, FSH cannot maintain spermatogenesis beyond the early meiotic stage.12,14 After this stage, testosterone is required to continue spermatogenesis and to maintain the blood–testis barrier, which provides the necessary microenvironment for the developing spermatozoa.12,13,14,17 Both FSH and testosterone are needed for spermatogenesis, and they act in a synergistic and overlapping manner.12,14,18

PATIENT SELECTION FOR MEDICAL TREATMENT PRIOR TO MICRO-TESE

The rationale for using hormone therapy in patients with NOA is that spermatogenesis, if present, is often focal. Hormone therapy can improve the ITT level to stimulate spermatogenesis.19,20 Thus, the aim of medical treatment prior to micro-TESE is to improve the chance of sperm retrieval.20,21,22 Sometimes, medical treatment can lead to the presence of sperm in the ejaculate, thereby obviating the need for micro-TESE.21,22 Because of the limited treatment options, there is an increasing demand for medical therapies prior to ICSI to optimize outcomes for patients with NOA.23 The role played by hormone therapy differs depending on the underlying cause of NOA. The causes are as follows: (1) hypogonadotropic hypogonadism (HH), (2) androgen excess due to exogenous androgens or androgen-secreting tumors, and (3) other causes (hypergonadotropic and normogonadotropic conditions).21

HH

HH is a condition for which medical treatment shows consistent results. Micro-TESE can be avoided in the majority of cases.20,21,24,25,26,27,28 HH is characterized by low serum FSH, LH, and testosterone levels, usually accompanied by atrophic testicles.21,29 The underlying mechanism is inadequate secretion of gonadotropins from the pituitary gland, leading to inadequate testicular stimulation.26 Medical treatment options include gonadotropins and GnRH to stimulate spermatogenesis.25,26

Androgen excess

The second underlying cause of NOA is attributed to excess androgens. In this condition, gonadotropins are suppressed by excess androgens, either from an exogenous source or an endogenous source such as an androgen-secreting tumor.22 This condition is characterized by low FSH and LH levels; however, the circulating testosterone level will be in normal-to-high range.21,22 The first step of the treatment is to stop the exogenous testosterone, which can lead to spontaneous resumption of spermatogenesis within a year.21,24,30 Addition of gonadotropins may accelerate the recovery because they can directly stimulate the spermatogenesis, bypassing the suppressed pituitary gland.26,30,31 Prolonged use of clomiphene citrate also appears to be an effective alternative. Clomiphene blocks estrogen receptors, thereby stimulating the release of gonadotropins from the pituitary (which remains intact).31 In case of congenital adrenal hyperplasia (CAH), the size of the testicular adrenal rest tumors (TARTs) increases because of stimulatory action adrenocorticotropic hormone (ACTH).22,32 Exogenous glucocorticoid therapy suppresses ACTH secretion, thereby reducing the amount of excess androgens secreted by the TARTs and leading to the resumption of spermatogenesis.21,22,32 Therefore, in these cases, micro-TESE can be avoided, and natural conception is possible once spermatogenesis is regained.22

Other causes of NOA

The most controversial area of medical treatment before micro-TESE is for cases of idiopathic NOA.19,20,21,22,26,28,33 Most idiopathic cases have hypergonadotrophic hypogonadism, which is characterized by normal-to-low testosterone and high serum FSH and LH levels, often with small and soft testicles.19,20,21,22,26,28,29,33 Some of these patients can be normogonadotropic.20

Men with hypergonadotropic NOA have elevated gonadotropin levels because of inadequate secretion of testicular androgen.19,20,21,22 However, the activity of endogenous gonadotropin may be diminished as a result of the desensitization of Sertoli and Leydig cells from chronic stimulation by elevated levels of gonadotropins.12,13 Exogenous gonadotropins can elevate serum testosterone level, which provides feedback inhibition on pituitary FSH and LH, leading to the “resetting” of the gonadotropin receptors in the testicles, which in turn promotes spermatogenesis.15,20,21,34 It has been shown that if the desensitization of gonadotropin receptors was reversed using GnRH analogs or exogenous testosterone (“gonadotropin reset”), the response to subsequently administered gonadotropins increased.13,35,36 An alternate mechanism of stimulating spermatogenesis in hypergonadotropic NOA cases is to increase ITT, which is essential for the progression of spermatogenesis.20,34 This forms the basis of using exogenous gonadotropins and other hormonal agents in men with HH.12,17,36

In men who have NOA attributed to normogonadotropic eugonadism, there may be a reduction in negative signaling from testosterone and inhibin B,12 because of changes in Leydig and Sertoli cells. This altered signaling, in turn, alters the pulse, frequency, and amplitude of endogenous gonadotropin secretion and leads to inadequate stimulation of spermatogenesis.14 The presence of immunoreactive gonadotropins in serum does not necessarily indicate biologically active gonadotropins in the system.37 Such individuals can have “relative” or “functional” hypogonadism with reduced action of gonadotropins. This means that normal levels of FSH and testosterone are not sufficient to stimulate the testes.38,39 Overstimulation with exogenous gonadotropins can increase ITT levels, which can stimulate the “good clones” of the spermatogonial population after bypassing the “arrest point”.36,38

There exists a subset of men with normogonadotropic NOA who remain hypogonadal (normal FSH and LH but low testosterone levels).38 This condition can be regarded as mixed hypogonadism, in which the concentration of gonadotropins remains normal, but their action is reduced possibly because of FSH receptor polymorphism.38 This leads to inadequate testosterone production (biochemical hypogonadism) and a low level of ITT, which may affect the progression of spermatogenesis.38 Some of these men may benefit from exogenous gonadotropin therapy, which stimulates ITT and overcomes the testicular hindrance.38

DRUGS USED PRIOR TO MICRO-TESE IN PATIENTS WITH NOA

Gonadotropin therapy

The treatment of male infertility in men with pituitary insufficiency relies on the use of gonadotropins.40 Although semen parameters may not be absolutely normal, these men can father children despite the low sperm counts, and micro-TESE is not usually utilized.26 The minimum duration of therapy for the resumption of spermatogenesis is 6 months. However, in many cases, therapy needs to be continued for 2 years to maximize success.19,25,26 Exogenous gonadotropin replacement therapy can lead to the appearance of sperm in the ejaculate in 60%–80% of cases,19,20,21,22,41,42,43 with some studies demonstrating a success rate of 94%.44 Past studies have shown that approximately 38%–51% of couples seeking this treatment can successfully achieve pregnancy.45,46 However, if no adequate response is observed at the end of 1 year, assisted reproductive technology (ART) should be considered.

Exogenous gonadotropins include human chorionic gonadotropin (hCG), FSH, and human menopausal gonadotropin (hMG).16 Previously, gonadotropins were extracted from urine of postmenopausal women. However, progress in laboratory technology has resulted in the development of purified FSH (pFSH), highly purified FSH (HP-FSH), highly purified recombinant hCG (rhCG), recombinant FSH (rFSH), and recombinant LH (rLH).27 Clinically, no differences in outcomes were observed between HP-FSH and rFSH.47 However, recombinant products have the advantages of having a long half-life (they can be administered once weekly), increased medication compliance, and no risk of virally transmitted diseases or Creutzfeldt–Jakob disease.48

The recommended dose of hCG is typically 1000–2500 international units (IU) per administration. It can be administered via intramuscular or subcutaneous (can be self-administered) injections 2–3 times per week for 6–24 months or more.19,25,26,49,50 Patients should undergo monthly semen analysis during the course of this treatment.26 If there are no signs of spermatogenesis after 6 months, initiation of FSH (in the form of rFSH or hMG) at a dose of 75 IU 2–3 times per week is suggested. If the sperm parameters remain suboptimum after 6 months, the dose can be doubled.26

Unlike HH, the evidence in favor of the use of gonadotropins in patients presenting with other forms of NOA remains inconclusive.20 Past research has shown that if hormone therapy is successful in raising the FSH level to 1.5 times the baseline value and the testosterone levels to 600–800 ng dl⁻¹, a high success rate of micro-TESE can be expected.51 However, the required dose of gonadotropin in such cases may be higher than that for HH cases.25 Unfortunately, there is no clear consensus regarding the optimal dose, duration, or type of gonadotropin therapy in these men.18,52 Most of the studies are of low quality, without a control group or randomization.18 These studies had varying inclusion criteria; some studies included men with genetic abnormalities, while other studies excluded them.18

The use of hCG increases ITT, thereby improving the chance of sperm recovery.12 Also, hCG has been found to reduce the testicular interstitial fibrosis seen in men with hypergonadotropic NOA.53 However, hCG alone may not be sufficient to stimulate spermatogenesis. FSH should be considered because of its important role in the regulation and expression of androgen receptors in Sertoli cells.12 In fact, strong testicular stimulation by FSH has been found to overcome LH or testosterone deficiency.18

In women undergoing ART procedures, regardless of the etiology of infertility, gonadotropins are used to overstimulate the ovaries to obtain an excess number of oocytes.38 It has been hypothesized that this approach could be used in men to overstimulate the testes to improve the yield of spermatozoa.38 Esteves et al.38 supported this hypothesis and suggested the classification of infertile men based on addressing male patients with hypogonadism and/or infertility owing to altered idiopathic testicular function (APHRODITE) criteria. They classified men into different subgroups to determine specific hormonal treatment to improve spermatogenesis.38 This classification was based on clinical history, physical examination, semen parameters, and hormone profile (mainly FSH and testosterone).38 This classification scheme also included men with different types of NOA.38 In 2020, La Vignera et al.47 categorized infertile men with normal gonadotropin levels into 4 groups based on testicular volume (TV) and serum testosterone levels. By using individualized treatment based on these two parameters, the authors observed subsequent improvement in the parameters. Accordingly, hCG or FSH alone or in combination or in a sequential manner was advised (FSH alone for men with normal TV and testosterone; hCG followed by FSH for men with normal TV but low testosterone; FSH and hCG together if both TV and testosterone were low; and FSH followed by hCG for men with low TV but normal testosterone).47 Overall, 40% of the men became normozoospermic after hormone therapy, and the prognosis varied between the different groups (men receiving sequential therapy had better prognosis).47

GnRH

The pulsatile administration of GnRH has been proven to be an effective therapeutic approach for addressing GnRH deficiency in infertile men experiencing HH attributed to inadequate secretion from the hypothalamus, such as in cases of Kallmann syndrome or idiopathic HH.11 GnRH is helpful in such cases because it stimulates the secretion of FSH and LH from the pituitary gland.11 This drug is very effective in inducing spermatogenesis as early as 4 months after starting the therapy, which is significantly quicker compared to gonadotropins.54,55 Pulsatile GnRH therapy induced spermatogenesis in about 85% of patients.56,57,58 These men did not usually require micro-TESE. However, if a man does not have a functional pituitary gland, he will not respond to GnRH therapy.22,25 Pulsatile GnRH therapy does not play a role in idiopathic NOA cases.19,25

The most effective dose for pulsatile GnRH is between 5 μg and 20 µg every 1–2 h delivered via a subcutaneous pump or needle, usually for the long term (until pregnancy is achieved).19,59

Dopamine agonists

Hyperprolactinemia, primarily because of a prolactin-secreting pituitary tumor, can hinder the rhythmic release of GnRH, resulting in hypogonadism and infertility in men.19 Dopamine agonists, including bromocriptine and cabergoline, are recommended for treating both infertility and the pituitary tumor.36 Most men with this condition do not require micro-TESE because the dopamine agonist can restore fertility by normalizing prolactin (thereby preventing the inhibition of GnRH) and shrinking the tumor.19,36 Patients who are unable to attain normal prolactin levels at the maximally tolerated dose of the medication, or those who experience <50% reduction in tumor size and failure to restore fertility, likely exhibit dopamine agonist resistance and are recommended to undergo surgery.60

For cabergoline, a weekly dosage of 0.5–4.5 mg is recommended, and the suggested dosage for bromocriptine is 1–30 mg per day until hyperprolactinemia is corrected.36

Aromatase inhibitors

Testosterone to estradiol (T:E2) ratio is an important factor in men with hypogonadism.21,29,61 Testosterone is converted to estrogen peripherally by the enzyme aromatase, reducing the T:E2 ratio to <10:1 and leading to a low ITT level.19,21,22,29,62 Additionally, heightened levels of estrogen induce the feedback inhibition of pituitary FSH and LH.62 Aromatase inhibitors inhibit the conversion to estradiol at the level of testes and adipose tissue and can therefore improve the T:E2 ratio and increase the ITT and gonadotropin levels.21,61,62 In many cases, aromatase inhibitors can improve the success of micro-TESE by enhancing ITT levels, particularly in obese men with normal or high estrogen level (by inhibiting aromatization in adipose tissues).26,27 Men with hypergonadotrophic hypogonadism and a T:E2 ratio less than 10:1 can benefit from aromatase inhibitors.30,51,63,64 In men with Klinefelter syndrome, aromatase inhibitors were especially found to enhance the success of micro-TESE by improving the T:E2 ratio.65,66 However, the use of aromatase inhibitors in patients with NOA has not been approved by the USA Food and Drug Administration (FDA).28,67

The dosages of commonly used aromatase inhibitors are as follows: 1 mg per day for anastrozole, 2.5 mg per day for letrozole, and 100–200 mg per day for testolactone for 3–6 months.36,68,69,70

Selective estrogen receptor modulators (SERM)

These drugs include clomiphene citrate (CC) and tamoxifen, which block estrogen receptors in the pituitary gland and the hypothalamus, thus counteracting the inhibitory action of estrogen on gonadotropins and stimulating the secretion of FSH and LH.21,50 They are particularly useful in men with low testosterone level but a normal T:E2 ratio.24 CC is not effective if LH levels are already elevated or if the T:E2 ratio is low.30 Data from an existing study have suggested that SERM and aromatase inhibitors may not work well if serum testosterone levels are very low (possibly because these drugs inhibit the action of estrogen, and very low testosterone levels impair the production of estrogen).71 Combined use of aromatase inhibitors and SERM has not been supported by robust evidence.30 If these drugs fail, gonadotropins can also be utilized, which can sometimes be successful.21,22 However, there is limited evidence in favor of the use of SERM in patients with NOA. The use of SERM for male infertility has not been approved by the FDA.28,72,73,74

There is no consensus on the dosage of SERM. The most commonly used doses are 25–100 mg per day for CC and 20–80 mg per day for tamoxifen.36,68 After a minimum of 2 weeks, the CC dose can be titrated according to serum testosterone levels, which should be kept at 600–800 ng dl⁻¹.50,75 The average treatment duration is 3–9 months.50,75

EVIDENCE OF THE EFFECTIVENESS OF MEDICAL TREATMENT BEFORE MICRO-TESE

Treatment before micro-TESE in HH cases

Men with HH not responding to hormone therapy are candidates for micro-TESE. However, there are limited data on the use of TESE in HH cases because natural conception happens in most cases once the sperm parameters improve.43 We identified only two studies on the application of TESE in HH cases. Both of these studies are case series,42,43 indicating a low quality of evidence (Table 1). One study demonstrated a successful testicular sperm recovery rate of 33% in men with HH-resistant medical therapy,42 while the other study found the success rate to be as high as 73% after the first attempt of TESE and 100% in the second attempt after prolonged therapy.43 Therefore, gonadotropin therapy may improve the success of ART, if needed, in patients with HH.42

Table 1.

Studies in this review that evaluated the role of hormone therapy in men with hypogonadotropic hypogonadism undergoing testicular sperm retrieval

Study	Study design	Sample size	Study population	Intervention	Type of sperm retrieval technique	Sperms in the ejaculate (in NOA only)	Rate of testicular sperm retrieval (in NOA only)
Efesoy et al.42 2009	Case series	21 cases of HH (total sample size 61)	Azoospermia with HH	hCG 1500 IU 2–3 times a week until serum testosterone level normal, then added rFSH 100–150 IU of 2–3 times a week for 12.11±4.7 (mean±s.d.) months	cTESE	71.4% cases after median of 7-month treatment	33% (who remained azoospermic despite hormone therapy)
Fahmy et al.43 2004	Case series	15	HH not responding to gonadotropins (remaining azoospermic)	hMG 75 IU thrice weekly and hCG 5000 IU once or twice weekly (titrated with serum testosterone level) for >6 months	cTESE	33% (who continued hormone therapy for another 6 months)	73% during the first cTESE, 100% during the second cTESE (who continued hormone therapy for another 6 months)

cTESE: conventional testicular sperm extraction; rFSH: recombinant follicle-stimulating hormone; hCG: human chorionic gonadotropin; HH: hypogonadotropic hypogonadism; hMG: human menopausal gonadotropin; IU: international unit; NOA: nonobstructive azoospermia; s.d.: standard deviation

Treatment before micro-TESE in other forms of NOA

A meta-analysis found that the chance of SSR was significantly higher for men with normal testosterone levels compared to men with subnormal testosterone levels.12 As a result, optimizing testosterone levels using gonadotropins or other agents in hypogonadal men can improve the SSR rate.12 Similarly, another meta-analysis found that hormone therapy could improve the rate of SSR (odds ratio [OR] = 1.96, 95% confidence interval [CI]: 1.08–3.56; P = 0.03).18 However, the subgroup analysis revealed that the improvement was seen only in men who were normogonadotropic/eugonadal at baseline (OR = 2.13, 95% CI: 1.10–4.14; P = 0.02) but not in hypergonadotropic men (OR = 1.73, 95% CI: 0.44–6.77; P = 0.43).18 The SSR rate was higher (although not statistically significant) in normogonadotropic men compared to the hypergonadotropic counterparts (OR = 1.90, 95% CI: 0.95–3.78; P = 0.07).18 In 2020, Tharakan et al.18 hypothesized that hypergonadotropic NOA is a more severe form of NOA and is associated with serious testicular damage, making the testicles less responsive to hormone therapy. Therefore, it is important to separate hypergonadotropic NOA from normogonadotropic NOA.

We found 18 studies focusing on the role of hormone therapy in hypergonadotropic NOA cases. Of them, only one was a randomized controlled trial (RCT),76 two were retrospective cohort studies;15,77 nine were case–control studies,13,34,35,48,66,69,70,78,79 and six were case series17,61,62,64,80,81 (Table 2). Some studies found that hormone therapy led to the appearance of sperm in the ejaculate,13,15,48,64,76 but others did not concur with this finding.61,62 Some authors found that hormone therapy improved the chance of testicular sperm retrieval,13,15,17,34,48,61,66,69,79,80,81 while others failed to prove this.35,70,77 The main limitations of these studies are their retrospective nature (with only one being an RCT), small sample size, lack of proper control group, and variations in the types of medicines used, dose, treatment duration, and surgical techniques.

Table 2.

Studies in this review that evaluated the role of hormone therapy in men with nonobstructive azoospermia and hypergonadotropic hypogonadism

Study	Study design	Sample size (n)	Study population (of NOA only)	Intervention	Type of sperm retrieval technique	Sperms in the ejaculate (in NOA only)	Rate of testicular sperm retrieval (in NOA only)	Other findings
Alrabeeah et al.77 2021	Retrospective cohort	122 (37 hormone therapy, and 85 control)	NOA	CC 50 mg per day for 3–6 months	Micro-TESE	Not reported	40.5% (CC) versus 45.9% (control group): no significant difference	Taking CC does not increase the SSR rate
Amer et al.79 2020	Case control	40 (20 hormone, and 20 no treatment)	Failed micro-TESE	Testosterone enanthate 250 mg per week for 1 month. Then hCG 5000 IU per week and pure FSH 150 IU thrice weekly were added to testosterone enanthate for next 3 months	Repeat micro-TESE	Not reported	10% (hormone therapy) versus 0 (control)
Cavallini et al.76 2013	RCT	11 NOA (6 hormones, and 5 placebo), total sample size 46	NOA having negative FNAC with T:E2 ratio <10:1	Letrozole 2.5 mg per day for 6 months	NA	100% (letrozole group) versus 0 (placebo)	NA
Hu et al.13 2018	Case–control	35 (25 hormone, and 10 no treatment)	NOA, failed TESE histology, hypospermatogenesis	Goserelin 3.6 mg, 4 weekly for 24 weeks + hCG 2000 IU weekly for 20 weeks + hMG 150 IU twice weekly for 16 weeks	Repeat TESE	4% (hormone therapy) versus 0 (control group)	1% (hormone therapy) versus 0 (control group)
Kato et al.17 2014	Case series	22	Failed micro-TESE (AR index was measured in Sertoli cells)	hCG 5000 IU 3 times a week for 3 months. After 3 months, if serum FSH was high, same hCG was continued for next 1–2 months further. If FSH was <2 mIU l−1, rFSH 150 IU 3 times a week was added to hCG for next 2 months	Repeat micro-TESE	Not reported	18%	AR index increased significantly in men having SSR compared to those with failed retrieval after hormone therapy
Kohn and Herati35 2021	Case–control	22 (9 hormone therapy, and 13 no treatment)	NOA with hypergonadotropic hypogonadism	Testosterone enanthate 500 mg, once weekly or 1000 mg every 2 weeks and hCG 3 times a week, and then increased to 3000 IU 3 times a week (total duration not specified)	Micro-TESE	Not reported	78% (hormone therapy) versus 54% (control): not statistically significant	The “axis reset” may help by improving sensitivity of Sertoli and Leydig cells
Majzoub et al.66 2016	Case–control	Total 43, with 23 cTESE (received no hormone), and 20 micro-TESE (of them, 16 received hormone, and 4 no medical treatment)	NOA with nonmosaic Klinefelter syndrome	In micro-TESE group: anastrozole, 1 mg daily for 6 months (n=10) or CC 25 mg daily, and hCG 5000 IU weekly (n=6)	Micro-TESE and cTESE	Not reported	38% (micro-TESE receiving hormone therapy) versus 0 (micro-TESE not receiving hormone therapy), and 0 (cTESE not receiving hormone therapy)	The highest rate of SSR was seen in men receiving anastrozole (28%)
Pavlovich et al.62 2001	Case series	43 cases of NOA (total sample size 63)	NOA (biopsy done)	Testolactone 50 mg twice daily. If estradiol remains high after 1 month, dose increased to 100 mg twice daily, with mean duration 5 months	NA	0	NA	All treated men had improved T:E2 ratio
Peng et al.15 2022	Retrospective cohort	569 (395 hormone therapy, and 174 no therapy)	NOA with hypergonadotropic hypogonadism	hCG 2000 IU every 2 days for 1 month, then if serum FSH >11.1 IU l−1, hCG was continued; if FSH 0.7–11.1 IU l−1, purified FSH 150 IU every 2 days was added to hCG; with total duration of 3 months	Micro-TESE	7% (gonadotropin) versus 0 (control)	31% (gonadotropin) versus 20% (control): significant difference
Ramasamy et al.69 2009	Case–control	68 (91 attempts of micro-TESE), with 56 hormone therapy, and 12 no medical therapy	NOA with nonmosaic Klinefelter syndrome	Different drugs: anastrozole or testolactone, CC, hCG, and rFSH. Unknown medical regimen in one man	Micro-TESE	Not reported	66% men (68% attempt), no mention of sperm recovery rate in hormone therapy and control group	Men responding to hormone therapy with posttreatment testosterone ≥250 ng dl−1 had a higher sperm recovery than those with testosterone <250 ng dl−1 (77% versus 55%). Men with normal baseline testosterone had the highest rate of SSR
Reifsnyder et al.70 2012	Case–control	736, with 388 of initial testosterone >300 ng dl−1, and 348 of initial testosterone <300 ng dl−1 (307 received hormone, and 41 no treatment)	NOA with initial hormone data available	Medical therapy with anastrozole or testolactone (alone or with hCG) CC or hCG-alone if testosterone level <300 ng dl−1 for 2–3 months Unknown medical regimen in 38 men	Micro-TESE	Not reported	56% (initial testosterone >300 ng dl−1) versus 52% (initial testosterone <300 ng dl−1): no significant difference 51% (receiving hormone therapy) versus 61% (not receiving hormone therapy): no significant difference	Optimizing testosterone level cannot improve SSR rate
Saylam et al.64 2011	Case series	17 cases of NOA (total sample size 27)	NOA with T:E2 ratio<10:1	Letrozole 2.5 mg per day for over 6 months	NA	24%	NA
Sen et al.48 2020	Case–control	24 (12 hormone, and 12 no therapy)	NOA with hypogonadism, FSH normal to marginally high	rhCG 250 µg once weekly for 6 months	Micro-TESE	25% (hormone therapy) versus 0 (control)	66% (hormone therapy) versus 33% (control): significant difference	Sperm recovery happened in rhCG group independent of rise in serum testosterone
Shinjo et al.80 2013	Case series	20	Failed micro-TESE (ITT was measured in testicular fluid during micro-TESE)	hCG 5000 IU 3 times a week for 3 months. If after 3 months serum FSH was high, same hCG was continued for next 1–2 months further. If serum FSH was <2 mIU l−1, rFSH 150 IU 3 times a week was added to hCG for next 2 months	Repeat micro-TESE	Not reported	15%	Men with SSR had lower baseline ITT than those with negative retrieval. hCG significantly improved ITT
Shiraishi et al.34 2012	Case–control	48 (28 hormones, and 20 control)	NOA, previously failed micro-TESE	hCG 5000 IU 3 times a week for 3 months. After 3 months, if serum FSH was high, same hCG was continued for next 1–2 months further; if FSH was <3 mIU l−1, rFSH 150 IU 3 times a week was added to hCG for next 2 months	Repeat micro-TESE	Not reported	21% (receiving hormone therapy) versus 0 (control)	No differences between men received hCG alone and hCG and rFSH both (15.4% versus 26.7%). SSR rate was higher in men with hypospermatogenesis
Shiraishi et al.81 2016	Case series	21	NOA Failed micro-TESE	hCG 5000 IU 3 times a week for 1 month. Then rFSH 150 IU 3 times a week was added to hCG for next 3 months	Repeat micro-TESE	0	10%
Shoshany et al.61 2017	Case series	28 NOA (total sample size 86)	Hypoandrogenic infertility: T <155 ng dl−1 and T:E2 <10 or prior adverse reaction to CC	Anaztrozole 1 mg per day for 4 months	Micro-TESE	0	73%
Sujenthiran et al.78 2019	Case–control	23 (15 hormone, and 8 no treatment)	NOA Klinefelter’s syndrome	CC or hCG+FSH	Micro-TESE	Not reported	40% (hormone therapy) versus 0 (control)

AR: androgen receptor; CC: clomiphene citrate; cTESE: conventional testicular sperm extraction; FNAC: fine-needle aspiration cytology; FSH: follicle-stimulating hormone; hCG: human chorionic gonadotropin; hMG: human menopausal gonadotropin; ITT: intratesticular testosterone; IU: international unit; micro-TESE: microsurgical testicular sperm extraction; NOA: nonobstructive azoospermia; rFSH: recombinant FSH; rhCG: recombinant hCG; RCT: randomized controlled trial; SSR: successful sperm retrieval; T:E2: testosterone to estradiol

We identified nine studies on eugonadal men with NOA. Four were case–control studies,50,52,82,83 and five were case series37,39,42,67,84 (Table 3). Most of the studies reported the beneficial role of hormone therapy in terms of the appearance of sperm in the ejaculate39,42,50,67,83,84 and the improvement in the SSR rate after TESE.37,42,50,82,83 However, two studies found that hormone therapy did not result in the appearance of sperm in the ejaculate,37,82 and another study failed to show any improvement in the SSR rate after hormone therapy.52 The main limitations of these studies are their retrospective nature (no RCTs), small sample size, lack of proper control group, and variations in types of medicines used, their dose, treatment duration, and surgical techniques.

Table 3.

Studies in this review that evaluated the role of hormone therapy in men with normogonadotropic nonobstructive azoospermia

Study	Study design	Sample size (n)	Study population (of NOA only)	Intervention	Type of sperm retrieval technique	Sperms in the ejaculate (in NOA only)	Rate of testicular sperm retrieval (in NOA only)	Other findings
Aydos et al.82 2003	Case–control	108 (63 hormone therapy, and 45 no treatment)	Normal FSH, LH, and testosterone, all having previous cTESE	Purse FSH 75 IU thrice weekly for 3 months	Repeat micro-TESE	0	64% (hormone therapy) versus 33% (control): significant difference	Quality of sperms was also significantly better in men receiving pure FSH
Cavallini et al.67 2011	Case series	4	NOA (2 men had FNA before, showing hypospermatogenesis)	Letrozole 2.5 mg per day for 3 months	NA	100%	NA
Cocci et al.83 2018	Case–control	50 (25 hormone therapy, and 25 control)	Idiopathic NOA	FSH 150 IU 3 times a week for 3 months	cTESE	20% (FSH group) versus 0 (control)	24% (FSH group) versus 12% (control group): significant difference	FSH also improved the fertilization rate
Efesoy et al.42 2009	Case series	11 cases of NOA (total sample size 61)	Maturation arrest on testicular biopsy/cytology	rFSH 100–150 IU 2–3 times a week for 7.45±4.5 (mean±s.d.) months	TESE	18%	18%
Gul52 2016	Case–control	83 (34 hormone therapy, 49 control)	Normogonadotropic NOA	hCG 2500 IU twice weekly for 10–14 weeks	cTESE, if failed micro-TESE in the same session	Not reported	50% (hCG) versus 57% (control): no significant difference	In the hCG group, more men had sperm recovery by cTESE than in control group (but not statistically significant), indicating some positive role of hCG hCG does not affect the fertilization capacity of the sperms
Hussein et al.50 2013	Case–control	612 (496 hormone therapy and 116 control)	NOA	CC 50 mg every 2 or 3 days with target serum FSH 1.5 times initial level and serum testosterone 600–800 ng dl−1 (Group 1: obvious increase in FSH and testosterone with continued CC; Group 2: increased FSH but no or little increase in testosterone, added hCG 5000 IU twice weekly and dose adjusted [as per serum testosterone] along with CC; Group 3: no change in FSH, LH, or testosterone, with stopped CC, added hCG 5000 IU weekly and dose adjusted [as per serum testosterone] and hMG 75 IU weekly and dose adjusted [as per serum FSH]; and Group 4: decrease in testosterone- stopped CC, added hCG + hMG [like group 3]). Maximum duration 9 months	Micro-TESE	11% (hormone therapy) versus 0 (control)	57% (hormone therapy) versus 34% (control): significant difference	No difference between different drugs if FSH, LH, and testosterone levels increase obviously (to the target levels)
Romeo et al.39 2023	Case series	19 cases of NOA (total sample size 194)	Idiopathic NOA	FSH 150 IU 3 times a week for duration of 9.1±7.1 (mean±s.d.) months	NA	42%	NA
Selman et al.37 2006	Case series	49	Normogonadotropic NOA with previous TESE showing no sperms (maturation arrest)	rFSH 75 IU per day, alternate day for 2 months, then rFSH 150 IU per day alternate day in the 3rd month, then 2000 IU per day hCG twice weekly added with rFSH from the 4th to 6th month	Repeat TESE	0	22%
Song and Qian84 2012	Case series	4 cases of NOA (total sample size 12)	Idiopathic NOA	Testosterone undecanoate 80 mg per day plus tamoxifen citrate 20 mg per day for 4 months	NA	100%	NA

CC: clomiphene citrate; cTESE: conventional testicular sperm extraction; FNA: fine needle aspiration; FSH: follicle-stimulating hormone; hCG: human chorionic gonadotropin; hMG: human menopausal gonadotropin; IU: international unit; LH: luteinizing hormone; micro-TESE: microsurgical testicular sperm extraction; NOA: nonobstructive azoospermia; rFSH: recombinant follicle stimulating hormone; s.d.: standard deviation; NA: not available; rFSH: recombinant FSH

In addition to the abovementioned studies, we identified six studies that included both hypergonadotropic and normogonadotropic NOA cases (or did not specify the gonadotropic status of the men included; Table 4). Of these studies, one was a retrospective cohort study,16 and five were case series.75,85,86,87,88 Most studies found hormone therapy to be beneficial either because of the appearance of sperm in the ejaculate75,86,87,88 or because of an increase in the testicular sperm retrieval rate.75,86,88 However, one study found no effect of hormone therapy on sperm production,85 and another study did not find any improvement in the SSR rate after hormone therapy.16 The main limitations are the retrospective nature of most studies (no RCTs) and their small sample size, lack of proper control group, and variations in types of medicines used, dosage, treatment duration, and surgical techniques.

Table 4.

Studies in this review that evaluated the role of hormone therapy in men with hypergonadotropic and normogonadotropic nonobstructive azoospermia

Study	Study design	Sample size (n)	Study population (of NOA only)	Intervention	Type of sperm retrieval technique	Sperms in the ejaculate (in NOA only)	Rate of testicular sperm retrieval (in NOA only)	Other findings
Amer et al.16 2019	Retrospective cohort	1395 (426 hormone therapy, and 969 no treatment)	NOA, different surgeons	CC, hCG, HMG, FSH, testosterone, and aromatase inhibitors in different combinations	Micro-TESE		28% (hormone therapy) versus 32% (control): no significant difference	Rate of SSR similar between normal FSH and high FSH
Hussein et al.75 2005	Case series	42	NOA, previous biopsy showing maturation arrest or hypospermatogenesis	CC: 50 mg per day, alternate day, titrated with serum testosterone maintained at 600–800 ng dl−1. If testosterone <600 ng dl−1, then dose increased by 25 mg alternate day (50 mg or 25 mg alternate day, then 50 mg daily, followed by 50 mg or 75 mg alternate day and finally 75 mg daily). If testosterone >800 ng dl−1, then dose is decreased to 50 mg every 3rd day for 3–9 months	Micro-TESE	64.3%	100%	Testicular histology improved significantly after CC therapy
Kobori et al.87 2015	Case series	26	NOA, previously failed micro-TESE (histopathology showing late maturation arrest)	rFSH 75 IU twice weekly for the 3 months followed by 150 IU twice weekly for next 9 months	NA	19%
Kumar et al.85 1990	Case series	50 cases of NOA (total sample size 79)	NOA	hCG 2000 units twice weekly or CC 50 mg once daily, 25 days in a month for 6 months	NA	0	NA
Laursen et al.88 2022	Case series	8	Idiopathic NOA previous failed TESA (no sperm or nonviable sperm)	rhCG 60 μg twice weekly for all men and dose adjusted according to serum FSH and testosterone levels. If FSH <1.5 IU l−1, added rFSH 150–225 IU twice weekly for >3 months If T:E2 <10:1, tablet anastrozole 1 mg per day. Mean duration for 9 months	Repeat TESA	25%	33%
Moein et al.86 2012	Case series	32	NOA, previously underwent TESE	Tamoxifen for 3 months	Repeat TESE	19%	85%

CC: clomiphene citrate; TESE: testicular sperm extraction; cTESE: conventional TESE; FSH: follicle-stimulating hormone; hCG: human chorionic gonadotropin; hMG: human menopausal gonadotropin; IU: international unit; micro-TESE: microsurgical TESE; NOA: nonobstructive azoospermia; rFSH: recombinant FSH; rhCG: recombinant hCG; SSR: successful sperm retrieval; T:E2: testosterone to estradiol; TESA: testicular sperm aspiration; NA: not available

ROLE OF HORMONE THERAPY AFTER FAILED SPERM RETRIEVAL

We encountered 11 studies focusing on the role of hormone therapies before the second testicular sperm retrieval after a previously failed attempt (Table 5). All the studies showed that hormonal agents (including gonadotropins and tamoxifen) improved the success rate of subsequent SSR, with rates varying between 1% and 100%.13,17,34,37,75,79,80,81,82,86,88 Some studies found that hormone therapy after failed TESE could lead to the appearance of sperm in the ejaculate in 4%–64% of cases.13,75,86,88 However, other studies did not report similar findings.8,37,81 One placebo-controlled RCT showed that letrozole therapy after a failed testicular sperm retrieval attempt resulted in the presence of sperm in the ejaculate of all participants. However, the sample size of this study was small and included only 11 men with NOA.76 The main limitation is that all the studies were retrospective (no RCTs). Five were case–control studies,13,17.34,79,82 and six were case series.37,75,80,81,86,88 Other limitations include differences in surgical techniques and small sample sizes.

Table 5.

Studies in this review that evaluated the role of hormone therapy in men with nonobstructive azoospermia and previously failed testicular sperm retrieval

Study	Study design	Sample size (n)	Study population (of NOA only)	Intervention	Type of sperm retrieval technique	Sperms in the ejaculate (in NOA only)	Rate of testicular sperm retrieval (in NOA only)
Amer et al.79 2020	Case–control	40 (20 hormone, and 20 no treatment)	Failed micro-TESE	Testosterone enanthate 250 mg per week for 1 month. Then hCG 5000 IU per week and pure FSH 150 IU thrice weekly were added to testosterone enanthate for the next 3 months	Repeat micro-TESE	Not reported	10% (hormone therapy) versus 0 (control)
Aydos et al.82 2003	Case–control	108 (63 hormone therapy, and 45 no treatment)	Normal FSH, LH, and testosterone, all having previous cTESE	Purse FSH 75 IU thrice weekly for 3 months	Repeat micro-TESE	0	64% (hormone therapy) versus 33% (control) with significant difference
Hu et al.13 2018	Case–control	35 (25 hormone, with 10 no treatment)	NOA, failed cTESE histology hypospermatogenesis	Goserelin 3.6 mg 4 times weekly for 24 weeks + hCG 2000 IU weekly for 20 weeks + hMG 150 IU twice weekly for 16 weeks	Repeat cTESE	4% (hormone therapy) versus 0 (control group)	1% (hormone therapy) versus 0 (control group)
Hussein et al.75 2005	Case series	42	NOA previous biopsy showing maturation arrest or hypospermatogenesis	CC: 50 mg per day, alternate day, titrated with serum testosterone maintained at 600–800 ng dl−1. If testosterone <600 ng dl−1, then dose increased by 25 mg alternate day (50 mg or 25 mg alternate day, then 50 mg daily, followed by 50 mg or 75 mg alternate day and finally 75 mg daily. If testosterone >800 ng dl−1, then dose decreased to 50 mg every 3rd day for 3–9 months	Micro-TESE	64.3%	100%
Kato et al.17 2014	Case series	22	Failed micro-TESE	hCG 5000 IU 3 times a week for 3 months. After 3 months, if serum FSH was high, same hCG was continued for next 1–2 months further; if FSH was <2 mIU l−1, rFSH 150 IU 3 times a week was added to hCG for next 2 months	Repeat micro-TESE	Not reported	18%
Laursen et al.88 2022	Case series	8	Idiopathic NOA Previous failed TESA (no sperm or nonviable sperm)	rhCG 60 µg twice weekly for all men and dose adjusted according to serum FSH and testosterone level. If FSH <1.5 IU l−1, added rFSH 150–225 IU twice weekly for >3 months If T:E2 <10:1, tablet anastrozole 1 mg per day. Mean duration 9 months	Repeat TESA	25%	33%
Moein et al.86 2012	Case series	32	NOA, previously underwent TESE	Tamoxifen for 3 months	Repeat cTESE	19%	85%
Selman et al.37 2006	Case series	49	Normogonadotropic NOA with previous TESE showing no sperms (maturation arrest)	rFSH 75 IU per day, alternate day for 2 months, then rFSH 150 IU per day alternate day in the 3rd month, then 2000 IU per day hCG twice weekly added with rFSH from the 4th to 6th month	Repeat TESE	0	22%
Shinjo et al.80 2013	Case series	20	Failed micro-TESE	hCG 5000 IU 3 times a week for 3 months. After 3 months, if serum FSH was high, same hCG was continued for next 1–2 months further; if serum FSH was <2 mIU l−1, rFSH 150 IU 3 times a week was added to hCG for next 2 months	Repeat micro-TESE	Not reported	15%
Shiraishi et al.81 2016	Case series	21	NOA Failed micro-TESE	hCG 5000 IU 3 times a week for 1 month. Then rFSH 150 IU 3 times a week was added to hCG for next 3 months	Repeat micro-TESE	0	10%
Shiraishi et al.34 2012	Case–control	48 (28 hormones, and 20 control)	NOA, previously failed micro-TESE	hCG 5000 IU 3 times a week for 3 months. After 3 months, if serum FSH was high, same hCG was continued for next 1–2 months further; if FSH was <3 mIU l−1, rFSH 150 IU 3 times a week was added to hCG for next 2 months	Repeat micro-TESE	Not reported	21% (receiving hormone therapy) versus 0 (control)

CC: clomiphene citrate; cTESE: conventional testicular sperm extraction; FSH: follicle-stimulating hormone; hCG: human chorionic gonadotropin; IU: international unit; micro-TESE: microsurgical testicular sperm extraction; NOA: nonobstructive azoospermia; rFSH: recombinant FSH; rhCG: recombinant hCG; T:E2: testosterone to estradiol; TESA: testicular sperm aspiration; LH: luteinizing hormone; hMG: human menopausal gonadotropin

POTENTIAL RISKS AND CONTRAINDICATIONS ASSOCIATED WITH EACH MEDICAL TREATMENT

The safety profile of most of the abovementioned hormonal drugs in men has not been well established.33

Gonadotropins

Long-term adverse effects of hCG treatment in men are not known, but it is possibly safe40 because most of the reported adverse effects are of mild-to-moderate severity.83 Gynecomastia and breast tenderness are often self-limiting.55 Unlike exogenous testosterone therapy, hCG does not appear to increase the risk of venous thromboembolism (VTE) or polycythemia.71 In few cases, hCG may cause acne, allergy, testicular pain, low libido, hot flashes, and injection site reactions.19,36,55,89 FSH injections are also well tolerated except for injection site reactions in some cases.89 Gonadotropin injections are expensive and require regular administration; therefore, acceptability may be low.30,90 Gonadotropins are contraindicated in men with hormone-dependent tumors, intracranial lesions, and uncontrolled dysfunction of the pituitary, thyroid, and adrenal glands.68

GnRH

GnRH therapy may cause injection site reactions.55,58 The side effects are not as severe as in the case of gonadotropins but include low libido, erectile dysfunction, gynecomastia, and hot flashes.36,55 The utilization of pulsatile GnRH is constrained by factors such as cost, limited availability, the inconvenience associated with carrying a pump, and the necessity for regular subcutaneous needle changes.19,21,22,25,27,58,90 This drug is contraindicated in individuals with hormone-dependent tumors.68

Aromatase inhibitors

There is evidence that some amount of estrogen is required for normal male libido and erection. Therefore, aromatase inhibitors can cause low libido and erectile dysfunction.36,67,90,91 In addition, they can cause nausea, elevated liver enzymes, hot flashes, and headache.90 Prolonged use should be avoided because of the impact on bone mineral density.19,90

SERMs

SERMs can sometimes cause hot flashes, visual disturbances, nausea, headache, and leg cramps.36,92 Sexual side effects of tamoxifen and CC include erectile dysfunction and low libido, which are important to consider because they can reduce the chance of natural conception.20 Rarely, tamoxifen causes VTE, gastrointestinal and cardiovascular side effects, and gynecomastia.30,33,90 VTE is an important concern, particularly in men with Klinefelter syndrome (possibly because of the increased factor VIII synthesis by the extra X chromosome) and those who are obese and smokers.20,36,93 CC appears to be safer than tamoxifen because of significantly less severe side effects. Unlike testosterone, CC does not affect the hematocrit level or prostate-specific antigen. It also does not increase the risk of VTE.90 Approximately 1.5% of men on CC could experience visual disturbances, such as diplopia, photophobia, and blurred vision, which stop after the cessation of the drug.30 CC is contraindicated in men having liver disease and uncontrolled dysfunction of the pituitary, thyroid or adrenal glands.68 In men having risk factors for VTE, tamoxifen is contraindicated.33,90

FINAL THOUGHTS ON EMPIRICAL THERAPIES

The use of micro-TESE followed by ICSI provides an opportunity for men with NOA to have biological offspring. Before surgical extraction, aromatase inhibitors, SERMs, and gonadotropins can be considered for use separately or in combination because they can stimulate spermatogenesis and improve male reproductive health. However, there is limited availability of supporting evidence (level I).22,25,28,38,51,94 Many of the studies included in this review have methodological fallacies, with moderate to high risk of bias; therefore, the results should be interpreted with caution.18,27 Except in the case of patients with HH, there is no definite evidence-based consensus regarding dose, duration, type, and sequence of hormone therapy before micro-TESE to improve the success.20,33,51,68 For achieving successful medical treatment and testicular sperm retrieval, it is mandatory that all the procedures be performed by experienced reproductive urologists in association with experienced embryologists.18

The use of the empirical therapies outlined in this review is not supported by the guidelines published by the European Association of Urology, the National Institute for Health and Clinical Excellence, the American Urology Association, and the American Society for Reproductive Medicine.27,28,40,95 Therefore, hormone therapy before micro-TESE for testicular failure needs further evaluation by good quality RCTs with an adequate sample size.12,18,19,20,33,36,68,70 Despite this, many specialists advise hormone therapy before TESE, presumably because the success rate of TESE has remained static over the last few years.18,68 The type of NOA is also an important determinant of the success of micro-TESE.18 Therefore, correct diagnosis of the cause of NOA (such as HH, genetic problems, or chemotherapy) is important.36 We suggest a possible flowchart for drug intervention before micro-TESE (Figure 1).

Figure 1.

Suggested drug intervention before micro-TESE according to hormonal status. CAH: congenital adrenal hyperplasia; CC: clomiphene citrate; FSH: follicle-stimulating hormone; hCG: human chorionic gonadotropin; GnRH: gonadotropin-releasing hormone; HH: hypogonadotropic hypogonadism; micro-TESE: microsurgical testicular sperm extraction; NOA: nonobstructive azoospermia; SERM: selective estrogen receptor modulator; T:E2: testosterone:estradiol ratio.

Importance of a collaborative approach between the andrologist and the patient

A thorough clinical history evaluation, physical examination, general analytics, serologies, cytogenetic, and genetic analyses, and full endocrinological evaluation should be conducted before advising micro-TESE.21 It is important to keep in mind that the hormonal profiles may sometimes overlap between different types of hypogonadism; therefore, repetition of tests may need to be considered.22,26,29 There have been different recommendations regarding the upper level of FSH (levels between 8 IU l⁻¹ and 12 IU l⁻¹ have been described) that can distinguish between HH and idiopathic hypogonadism.26

Even if there is scope for hormone therapy, the patients should be informed that these therapies will take months to years to achieve the optimum result.26 In some cases, the couples may not want to spend that much time and would prefer to directly try ART.26 The patients should be informed whether the use of hormone therapy in a particular scenario is strongly based on evidence or is purely empirical.19,26 The side effects should also be discussed.20

In special cases, hormone therapy may convert azoospermia to oligospermia, thus avoiding micro-TESE.21 This may not achieve natural conception, but ICSI is certainly possible using ejaculated sperm, reducing the extent of ART.20,21 When this is not possible, hormone therapy may increase the chance of successful sperm retrieval after micro-TESE.21

Economic and logistical challenges

Most of these medicines discussed in this review are off-label for use in men.19,28,33,90,94 The use of gonadotropins in men has been approved by the FDA only for HH cases.19,68,90 At the same time, the cost-effectiveness of this therapy should be considered and compared with that of direct ART.19,28 Therefore, if at all any empirical therapy is to be used before micro-TESE in men with NOA, oral drugs should be considered.30 The use of hCG should be reserved for those who are unable to tolerate oral drugs and are willing to bear the expenses.30

CONCLUSION

Medical therapy plays an effective role in the outcomes of patients with NOA attributed to HH and androgen excess. In such cases, gonadotropin therapy can even lead to natural conception, obviating the need for micro-TESE in most cases. In some cases of hypothalamic dysfunction, pulsatile GnRH therapy can be helpful. In cases of NOA due to HH and eugonadism, hormone therapy has been tried to enhance ITT, thereby improving spermatogenesis. In most cases, this improved spermatogenesis may not lead to the appearance of spermatozoa in the ejaculate but may sometimes improve the chance of sperm retrieval during micro-TESE. Gonadotropin therapy, SERMs, and aromatase inhibitors have been applied in many studies, although robust evidence is lacking. The safety of most of these medications in men with idiopathic NOA has not yet been established. From the patient’s perspective, medical therapy is an attractive option. Therefore, more evidence is required to recommend the routine use of medical therapies prior to micro-TESE in men with NOA.

AUTHOR CONTRIBUTIONS

SD and TSL conducted the literature search and drafted the manuscript. AR and RS participated in planning the design and coordination of the literature search and helped draft the manuscript. AA conceived the study, participated in coordination of the manuscript, and helped with drafting this manuscript. All authors read and approved the final manuscript.

COMPETING INTERESTS

All authors declare no competing interests.