Medical management of non-obstructive azoospermiaRajeev Kumar

All India Institute of Medical Sciences, Department of Urology, New Delhi, India.

Non-obstructive azoospermia is diagnosed in approximately 10% of infertile men. It represents a failure ofspermatogenesis within the testis and, from a management standpoint, is due to either a lack of appropriatestimulation by gonadotropins or an intrinsic testicular impairment. The former category of patients hashypogonadotropic hypogonadism and benefits from specific hormonal therapy. These men show a remarkablerecovery of spermatogenic function with exogenously administered gonadotropins or gonadotropin-releasinghormone. This category of patients also includes some individuals whose spermatogenic potential has beensuppressed by excess androgens or steroids, and they also benefit from medical management. The other, largercategory of non-obstructive azoospermia consists of men with an intrinsic testicular impairment whereempirical medical therapy yields little benefit. The primary role of medical management in these men is toimprove the quantity and quality of sperm retrieved from their testis for in vitro fertilization. Gonadotropinsand aromatase inhibitors show promise in achieving this end point.

KEYWORDS: Infertility; Drug Therapy; Gonadotropins; Hypogonadism; Aromatase Inhibitors.

Kumar R. Medical management of non-obstructive azoospermia. Clinics. 2013;68(S1):75-79.

Received for publication on February 29, 2012; Accepted for publication on March 2, 2012

E-mail: rajeev02@gmail.com

Tel.: +91-11-26594884

& INTRODUCTION

Non-obstructive azoospermia (NOA) is generally consid-ered a non-medically manageable cause of male infertility.These patients, who constitute up to 10% of all infertile men,have abnormal spermatogenesis as the cause of theirazoospermia. The establishment of in vitro fertilizationusing intracytoplasmic sperm injection (ICSI) as a standardtreatment modality has resulted in a number of these mensuccessfully fathering a child through surgically retrievedsperm from the testis. The challenge, however, is to improvetheir spermatogenic function to enable the appearance ofsperm in their ejaculate or to improve the chances of asuccessful retrieval from the testis for ICSI.

The initial evaluation aims at resolving the followingissues: (1) confirming azoospermia, (2) differentiatingobstructive from non-obstructive etiology, (3) assessing forthe presence of reversible factors and (4) evaluating for thepresence of genetic abnormalities. An elevated follicle-stimulating hormone (FSH) level or an absence of normalspermatogenesis by testicular histology in the presence ofazoospermia is generally considered sufficient evidence of anon-obstructive etiology. The most common reversiblefactors that need to be ruled out include recent exogenous

hormone administration, severe febrile illnesses, chemother-apy/radiation or prolonged antibiotic use.

Hormone analysis forms the cornerstone of the furtherevaluation and management of NOA and serves twoimportant functions. The first function is to identify adistinct subset of men who have hypogonadotropism (lowFSH), in which azoospermia results from an inadequatestimulation of the testis by gonadotropins. The inherentspermatogenic potential of the testis may be partiallyrecoverable, and the management and prognosis of inferti-lity in these men differ from all other subsets. The secondfunction is to predict the success of medical therapy and ofsurgical sperm retrieval. Based on these initial hormonestudies, the two broad categories are hypogonadotropichypogonadism and hypergonadotropic hypogonadism oreugonadism (Table 1). There is considerable overlap in thehormone statuses of men who do not have hypogonado-tropism, with similar etiologies producing a spectrum ofhormonal changes. The American Urological Associationrecommends an estimation of serum FSH and testosteroneas the initial hormonal assessment (1). However, endocrineabnormalities are a rare cause of male infertility and accountfor less than 3% of all cases. Additional hormone analysis,including luteinizing hormone (LH), estradiol and prolactinevaluations, is performed based on the likelihood of theirabnormality and potential impact on management.

& HYPOGONADOTROPIC HYPOGONADISM

Hypogonadotropic hypogonadism (HH) is a condition oflow serum testosterone due to a decrease in the secretion ofFSH and LH from the pituitary gland. HH may becongenital, acquired or idiopathic. The congenital forms

Copyright � 2013 CLINICS – This is an Open Access article distributed underthe terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided theoriginal work is properly cited.

No potential conflict of interest was reported.

DOI: 10.6061/clinics/2013(Sup01)08

REVIEW

75

are classically syndromic, such as Kallmann syndrome,Prader-Willi syndrome and Laurence-Moon syndrome.Acquired HH usually results from the destruction of normalpituitary function following radiotherapy, trauma or apituitary tumor. Another form of acquired HH is due toexcess exogenous steroids or androgens. Hyperprolactinemiamay also cause infertility by inhibiting the hypothalamicsecretion of gonadotropin-releasing hormone (GnRH) andalso through a direct inhibition of the binding of LH to theLeydig cells in the testis.

Congenital hypogonadotropic hypogonadism typicallyoccurs in association with anosmia and is known asKallmann syndrome. It has varying genetic modes oftransmission, including via both sex chromosomal (X-linked) and autosomal abnormalities. Hypogonadismresults in abnormal secondary sexual characteristics, includ-ing gynecomastia, cryptorchidism and micropenis. Theprimary abnormality is decreased GnRH secretion fromthe hypothalamus with consequent low levels of gonado-tropins (FSH and LH) from the pituitary.

Hypogonadotropic hypogonadism is one of the few causesof NOA that have shown a consistent response to medicalmanagement (2,3). Gonadotropin therapy is begun at thetime the patient wishes to father a child, and three to sixmonths of treatment are usually sufficient to inducespermatogenesis (4,5). Therapy is initiated with humanchorionic gonadotropin (hCG) at 2,000 IU subcutaneouslythree times per week or 2,500 IU twice a week andsupplemented with FSH (menopausal, purified or recombi-nant) at 37.5-150 IU three times a week after three to sixmonths. hCG is sufficient to initiate spermatogenesis, butFSH is required to complete the spermiogenesis, particularlyin patients with congenital abnormalities. In one of the largestreported series, Burgues et al. (6) evaluated self-administeredhighly purified follicle-stimulating hormone in 60 men withhypogonadotropic hypogonadism who showed an adequateresponse to an initial hCG therapy. Subjects self-administered150 IU of FSH three times per week and 2,500 IU of hCGtwice a week for at least six months, with non-responderscontinuing treatment for a further period. By the end of thetreatment, 80% of these azoospermic/aspermic men hadsperm in their ejaculate, with a median time to spermpresence of five months. Similar data reported from otherstudies support the specific role of hormone replacementtherapy in these men (7,8).

An alternative method for treating hypogonadotropichypogonadism is with a pulsatile injection of GnRH in

patients with intact pituitary glands. GnRH can beadministered subcutaneously, intravenously or intranasally,but the 2-hour dosing regimen makes the intravenous andintranasal routes impractical. The standard method is 5-20micrograms administered every 2 hours subcutaneously. Ina large cohort of men with idiopathic hypogonadotropichypogonadism (IHH), a bihourly pulsatile administration ofGnRH subcutaneously through an infusion pump for 12-24months resulted in the induction of spermatogenesis in 77%of initially azoospermic men (9). The authors reported amore rapid return of spermatogenesis in men who hadachieved at least partial puberty at the time of initiatingGnRH therapy, with all such subjects responding within sixmonths. GnRH therapy reliably corrected the hypogonad-ism, with a reversal of azoospermia in a majority of the men,but a subset of men may exhibit pituitary resistance oratypical response (10). Other studies have also reported thesuccessful initiation of pregnancy using GnRH therapy(11,12). Pulsatile GnRH therapy is more cumbersome andexpensive than gonadotropin therapy, and this precludes itsroutine use. However, in men with IHH who fail to respondto gonadotropin therapy, GnRH therapy may be an option.GnRH therapy is also not possible in men who do not havefunctional pituitary glands.

Congenital abnormalities are likely to have been noticedearly during adolescence, and a number of these men wouldhave received testosterone therapy near the onset of pubertyto induce the development of secondary sexual character-istics. This prior treatment with testosterone at the time ofpuberty does not interfere with the response to gonado-tropins when attempting a pregnancy. A number of thesemen will produce sperm in their ejaculate but with totalcounts below the reference range. However, these men areoften able to initiate a pregnancy with these low counts (13).Therapeutic interventions may be associated with a sig-nificant delay in the appearance of sperm or achieving asufficient quantity or quality to imitate a spontaneouspregnancy, and some men may benefit from assistedreproduction techniques if an adequate response is notobserved at the end of one year (14,15).

Androgen and steroid excessAndrogen excess through exogenous administration or

pituitary/adrenal or testicular tumors can also lead to thesuppression of spermatogenesis and NOA that is amenableto medical management. This is a form of hypogonadotropichypogonadism, where the excess androgens produce feed-back inhibition on normal pulsatile gonadotropin secretion,and suppression of excess steroids results in the recovery ofspermatogenesis.

Congenital adrenal hyperplasia is a diagnosis of child-hood. However, a number of these men will present as adultswith infertility. Infertility is particularly common in thepresence of associated testicular adrenal rest tumors(TARTs). Exogenous steroid administration results in sup-pression of adrenocorticotropic hormone (ACTH) with aconsequent decrease in the size of the TARTs and the possiblereturn of fertility (16,17). Devoto et al. (18) reported a 29-year-old male with azoospermia and congenital adrenal hyper-plasia with a 21-hydroxylase deficiency who had normalserum hormones but a testicular biopsy suggesting hypogo-nadism. The patient was treated with exogenous corticoster-oids that resulted in normal testicular development,improvement in sperm counts and spontaneous paternity

Table 1 - Non-obstructive azoospermia classification

Hypogonadotropic hypogonadism

N Low FSH, Low LH, Low testosterone

N Congenital: Kallmann syndrome (hypothalamic GnRH deficiency)

N Acquired: Pituitary tumors

Hypergonadotropic hypogonadism/eugonadism

N High/normal FSH, Normal/high LH, Normal/low testosterone

N Congenital: Genetic abnormalities (Chromosomal)

N Acquired:

N Varicocele

N Orchitis

N Gonadotoxins (chemotherapy/radiation)

N Trauma/torsion

N Idiopathic

Drug therapy for NOAKumar R

CLINICS 2013;68(S1):75-79

76

on two occasions. The authors cautioned that hormoneanalysis in these men might not suggest hypogonadismbecause the excess testosterone production from the adrenalsmasks the intra-testicular hypogonadism. A reversal ofazoospermia may depend on the type of steroid used andits dose. Claahsen-van der Grinten (19) noted inadequatesuppression with 30 mg of hydrocortisone but a significantimprovement after changing to an equivalent dose ofdexamethasone in a patient who had azoospermia but wenton to father two children through spontaneous conceptionafter this change. These outcomes have been supported byother reports on the reversal of azoospermia with exogenousdexamethasone treatment (20,21).

Excess androgens present in anabolic steroids or testos-terone itself are potent causes for the suppression ofendogenous hormone production. The initial step in themanagement of these men is the cessation of the use of allsuch hormones. It may take a year or longer for endogenousproduction to return to normal after the cessation ofexogenous therapy. Spermatogenesis may then be sponta-neously restored, or there may then be evidence ofadditional endocrine abnormalities that will need to beaddressed.

& HYPERGONADOTROPIC HYPOGONADISM/EUGONADISM

Aromatase inhibitorsHigh intra-testicular levels of testosterone are necessary

for spermatogenesis. An imbalance between the circulatingtestosterone and estrogen levels has been investigated as apotential therapeutic target in men with NOA. The enzymearomatase, which is present in the adipose tissue, liver,testis and skin, is responsible for converting testosteroneand other androgens to estradiol in men. Estradiol sup-presses pituitary LH and FSH secretion and also directlyinhibits testosterone biosynthesis. This results in an imbal-ance in the testosterone and estradiol (T/E) ratio, whichmay be reversible. Aromatase inhibitors have the potentialto block the conversion of androgens to estradiol. The twotypes of aromatase inhibitors are steroidal (testolactone) andnon-steroidal (anastrozole, letrozole). Both of these groupsof agents have been studied for potential therapeutic roles inNOA.

In 2001, Pavlovich et al. reported one of the first studieson the potential role of low-dose oral testolactone in menwith NOA or severe oligospermia (22), in which 63 men(NOA or sperm density below 10 million/mL) wereevaluated. This study included 43 men with NOA thatwas documented by a testis biopsy. Data from these menwere compared with those from 40 age-matched fertilecontrols. All men underwent a baseline hormone profile,and 45 out of 63 men had a testosterone-to-estradiol ratiobelow the 20th percentile of normal, as determined from thehealthy controls. These 45 men included patients withKlinefelter’s syndrome, chromosomal anomalies, varico-celes, etc. as the cause for NOA. Subjects received 50 to100 mg of oral testolactone twice a day for a mean of fivemonths. Hormone profiles were obtained at one month oftherapy, and the dose of testolactone was increased from 50to 100 mg if the ratios remained low. A semen analysis wasperformed after at least three months of stable drug therapy.The authors reported a decline in estradiol or an increasein testosterone with drug therapy in all patients, with

significant improvements in T/E ratios. However, while theoligospermic men demonstrated significant improvementsin total sperm counts and motility, none of the 12azoospermic men who completed three months of treatmentshowed any return of sperm in the ejaculate.

In a direct comparison between testolactone and anastro-zole, Raman and Schlegel treated 140 men with low T/Eratios with testolactone and/or anastrozole (23). Some menreceived both therapies sequentially; they overlapped in thestudy population. Ultimately, 74 men received 50 to 100 mgof testolactone twice daily for a mean of six months, and 104men received 1 mg of anastrozole daily for a mean of 4.7months. The 12 azoospermic men did not exhibit anyimprovement. Similar to their experience with testolactone,while the T/E ratios improved in all men, none of the 14azoospermic men experienced a return of sperm to theejaculate.

These studies argue against the use of aromataseinhibitors in NOA men. However, there may be a potentialrole in improving the quality or quantity of testicular sperm,thus improving the outcomes of sperm retrieval usingtesticular sperm extraction (TESE) and ICSI. Schiff et al.reported their experience with pretreatment with testolac-tone, hCG and anastrozole in men with non-mosaicKlinefelter’s syndrome prior to TESE/ICSI (24). Amongtheir cohort of 42 men, 36 had low pre-treatment levels oftestosterone. These men received either an aromataseinhibitor alone or in combination with hCG until thetestosterone or T/E ratio normalized. TESE was successfulin all men who received either anastrozole alone or incombination with hCG, while it succeeded in 74% of thosereceiving only testolactone and 54% of those receivingtestolactone and hCG. The authors did not have a controlgroup, and it is difficult to assess the contribution of thepretreatment on the successful outcomes, particularlybecause all six men who did not require pretreatment hadsuccessful outcomes. However, the success rates in thesemen were higher than historical controls. In a more recentupdate of their data, this group identified no significantimpact of the pretreatment on a successful outcome (25).However, they did note an improved outcome if thepretreatment resulted in an improved serum testosteronelevel prior to performing the TESE.

AntiestrogensClomiphene citrate and tamoxifen are non-steroidal anti-

estrogens that have long been used as empirical options in themanagement of idiopathic oligospermia. Clomiphene blocksthe feedback inhibition of estrogen on the pituitary, resultingin increased FSH and LH secretion and a consequent rise intestosterone. There is little scientific evidence in favor of usingclomiphene empirically. However, it continues to be a popularchoice and has been used in men with NOA. Hussein et al.treated 42 men with NOA and either hypospermatogenesis ormaturation arrest based on a biopsy with clomiphene citrate,which was initially 50 mg every alternate day for two weeksand then increased serially until the testosterone levelsreached between 600-800 ng/dL (26). Semen analysis wasperformed at regular intervals, and if azoospermia persistedbeyond six months of treatment, a testis biopsy wasperformed. The results revealed that 64% of the menexperienced a return of sperm in their ejaculate, with spermdensity ranging from 1-16 million/mL. Among those whoremained azoospermic, sperm retrieval for ICSI was successful

CLINICS 2013;68(S1):75-79 Drug therapy for NOAKumar R

77

in all cases. Of note, the authors excluded all men with Sertolicell-only syndrome or a low testicular volume and a mean FSHat baseline of 7.21 mIU/mL. Further, this remains the onlyseries on the successful use of clomiphene in azoospermicmen, and its results have not been replicated by otherinvestigators.

GonadotropinsThe use of gonadotropins to induce the appearance of

sperm in the ejaculate or to increase the success rates ofTESE in men with NOA has been based on the rationalethat high levels of exogenous gonadotropins decrease theendogenous gonadotropin secretion. This in turn allows a‘‘resetting’’ of the FSH and LH receptors in the Leydig andSertoli cells, whose functions then improve (27).

Selman et al. reported a 32-year-old man with Ychromosome microdeletions who received recombinantFSH and hCG before a successful ICSI procedure withejaculated sperm that numbered in the few thousands (28).Similarly, Efesoy et al. reported sperm in the ejaculate of 2of 11 azoospermic men with maturation arrest who weretreated with recombinant FSH (29).

Shiraishi et al. reviewed their data on repeat TESE in menwith NOA who had no sperm retrieved during the firstTESE (30). Of 48 such men with no chromosomal anomaliesand normal serum testosterone levels, 28 received 5,000 IUof hCG three times a week for three months. The men whoseFSH declined significantly received additional recombinantFSH of 150 IU three times a week for two months, while theother men continued to receive hCG until the repeat TESE.Another 20 men in this cohort refused hormonal therapyand underwent a second TESE at a mean of 17 months afterthe first surgery. None of the 48 men experienced a return ofsperm in their ejaculate. However, the second TESE wassuccessful in 21% of men who received hormonal therapy,while it failed in all those who did not. By evaluating a moreselect group of men with normal baseline hormone profiles,testicular volumes and genetic analyses, Selman et al.treated 49 men with rFSH, which was initially at 75 IU onalternate days for two months, followed by 150 IU for twomonths and then an additional 2,000 IU of hCG for twomonths (31). All men remained azoospermic at the end oftreatment; however, while none had mature sperm in thepre-treatment testis biopsy, sperm were found in thebiopsies of 22% men after treatment. Similarly, Ramasamyet al. reported improved outcomes of primary TESEfollowing gonadotropin therapy in men with NOA andKlinefelter’s syndrome (25).

AntioxidantsThe role of antioxidant therapy in male subfertility

continues to be debated. While there is a significant amountof data documenting raised oxidative stress and lowantioxidant capacity in the seminal plasma of infertile menwith abnormal semen parameters, including azoospermia,there is little high-quality evidence in support of usingantioxidants in the treatment of these men (32). This isprimarily because such therapy has not resulted in significantimprovements in pregnancy rates, although statisticallysignificant changes in anti-oxidant capacity and improve-ments in measured seminal parameters have occurred.Furthermore, most of the existing literature involves menwith oligo/asthenospermia and not azoospermia. One of thefew studies using antioxidants on azoospermic men reported

a remarkable improvement in all subjects but was hamperedby a poorly documented methodology (33).

Among men with NOA, gonadotropin therapy forhypogonadotropic hypogonadism is the only specificindication that has universally shown an improvement insemen analysis and pregnancy rates. Gonadotropins (hCGand rFSH) in combination constitute a standard therapy,with GnRH therapy reserved for non-responders. Themedical management of other forms of NOA remainsempirical. Drug therapy with aromatase inhibitors andgonadotropins shows potential promise in improving out-comes in men requiring surgical sperm retrieval, but there islack of level I clinical evidence for this indication.

& REFERENCES

1. American Urological Association. The optimal evaluation of the infertilemale. Accessed February 22, 2012. Available from: http://www.auanet.org/content/media/optimalevaluation2010.pdf.

2. Hoffman AR, Crowley WF. Induction of Puberty in Men by Long-TermPulsatile Administration of Low-Dose Gonadotropin-Releasing Hormone.New Engl J Med. 1982;307(20):1237-41, http://dx.doi.org/10.1056/NEJM198211113072003.

3. Belchetz PE, Plant TM, Nakai Y, Keogh EJ, Knobil E. Hypophysialresponses to continuous and intermittent delivery of hypopthalamicgonadotropin-releasing hormone. Science. 1978;202(4368):631-3, http://dx.doi.org/10.1126/science.100883.

4. Vicari E, Mongioi A, Calogero AE, Moncada ML, Sidoti G, Polosa P, et al.Therapy with human chorionic gonadotrophin alone induces spermato-genesis in men with isolated hypogonadotrophic hypogonadism—long-term follow-up. International journal of andrology. 1992;15(4):320-9,http://dx.doi.org/10.1111/j.1365-2605.1992.tb01131.x.

5. Finkel DM, Phillips JL, Snyder PJ. Stimulation of spermatogenesis bygonadotropins in men with hypogonadotropic hypogonadism.N Engl J Med. 1985;313(11):651-5.

6. Burgues S, Calderon MD. Subcutaneous self-administration of highlypurified follicle stimulating hormone and human chorionic gonadotrophinfor the treatment of male hypogonadotrophic hypogonadism. SpanishCollaborative Group on Male Hypogonadotropic Hypogonadism. HumReprod. 1997;12(5):980-6, http://dx.doi.org/10.1093/humrep/12.5.980.

7. Liu PY, Gebski VJ, Turner L, Conway AJ, Wishart SM, Handelsman DJ.Predicting pregnancy and spermatogenesis by survival analysis duringgonadotrophin treatment of gonadotrophin-deficient infertile men. HumReprod. 2002;17(3):625-33, http://dx.doi.org/10.1093/humrep/17.3.625.

8. Efficacy and safety of highly purified urinary follicle-stimulatinghormone with human chorionic gonadotropin for treating men withisolated hypogonadotropic hypogonadism. European Metrodin HPStudy Group. Fertil Steril. 1998;70(2):256-62.

9. Pitteloud N, Hayes FJ, Dwyer A, Boepple PA, Lee H, Crowley WF, Jr.Predictors of outcome of long-term GnRH therapy in men withidiopathic hypogonadotropic hypogonadism. The Journal of clinicalendocrinology and metabolism. 2002;87(9):4128-36, http://dx.doi.org/10.1210/jc.2002-020518.

10. Sykiotis GP, Hoang XH, Avbelj M, Hayes FJ, Thambundit A, Dwyer A,et al. Congenital idiopathic hypogonadotropic hypogonadism: evidenceof defects in the hypothalamus, pituitary, and testes. J Clin EndocrinolMetab. 2010;95(6):3019-27, http://dx.doi.org/10.1210/jc.2009-2582.

11. Buchter D, Behre HM, Kliesch S, Nieschlag E. Pulsatile GnRH or humanchorionic gonadotropin human menopausal gonadotropin as effectivetreatment for men with hypogonadotropic hypogonadism: a review of 42cases. Eur J Endocrinol. 1998;139(3):298-303.

12. Delemarre-Van de Waal HA. Induction of testicular growth and spermato-genesis by pulsatile, intravenous administration of gonadotrophin-releasinghormone in patients with hypogonadotrophic hypogonadism. ClinEndocrinol (Oxf). 1993;38(5):473-80.

13. Burris AS, Clark RV, Vantman DJ, Sherins RJ. A Low SpermConcentration Does Not Preclude Fertility in Men with IsolatedHypogonadotropic Hypogonadism after Gonadotropin Therapy.Fertility and sterility. 1988;50(2):343-7.

14. Tachiki H, Ito N, Maruta H, Kumamoto Y, Tsukamoto T. Testicularfindings, endocrine features and therapeutic responses of men withacquired hypogonadotropic hypogonadism. International journal ofurology : official journal of the Japanese Urological Association.1998;5(1):80-5, http://dx.doi.org/10.1111/j.1442-2042.1998.tb00244.x.

15. Liu PY, Handelsman DJ. The present and future state of hormonaltreatment for male infertility. Human reproduction update. 2003;9(1):9-23, http://dx.doi.org/10.1093/humupd/dmg002.

Drug therapy for NOAKumar R

CLINICS 2013;68(S1):75-79

78

16. Augarten A, Weissenberg R, Pariente C, Sack J. Reversible maleinfertility in late onset congenital adrenal hyperplasia. J EndocrinolInvest. 1991;14(3):237-40.

17. Tiitinen A, Valimaki M. Primary infertility in 45-year-old man withuntreated 21-hydroxylase deficiency: successful outcome with glucocor-ticoid therapy. The Journal of clinical endocrinology and metabolism.2002;87(6):2442-5, http://dx.doi.org/10.1210/jc.87.6.2442.

18. Devoto CE, Madariaga AM, Fernandez W. [Congenital adrenal hyperpla-sia causing male infertility. Report of one case]. Revista medica de Chile.2011;139(8):1060-5, http://dx.doi.org/10.4067/S0034-98872011000800012.

19. Claahsen-van der Grinten HL, Otten BJ, Sweep FC, Hermus AR.Repeated successful induction of fertility after replacing hydrocortisonewith dexamethasone in a patient with congenital adrenal hyperplasiaand testicular adrenal rest tumors. Fertility and sterility. 2007;88(3):705e5-8.

20. Nicopoullos JD, Ramsay JW, Cassar J. From zero to one hundred millionin six months: the treatment of azoospermia in congenital adrenalhyperplasia. Archives of andrology. 2003;49(4):257-63, http://dx.doi.org/10.1080/713828165.

21. Iwamoto T, Yajima M, Tanaka H, Minagawa N, Osada T. [A case report:reversible male infertility due to congenital adrenal hyperplasia]. NihonHinyokika Gakkai zasshi The japanese journal of urology. 1993;84(11):2031-4.

22. Pavlovich CP, King P, Goldstein M, Schlegel PN. Evidence of a treatableendocrinopathy in infertile men. J Urol. 2001;165(3):837-41.

23. Raman JD, Schlegel PN. Aromatase inhibitors for male infertility. J Urol.2002;167(2 Pt 1):624-9.

24. Schiff JD, Palermo GD, Veeck LL, Goldstein M, Rosenwaks Z, SchlegelPN. Success of testicular sperm extraction [corrected] and intracytoplas-mic sperm injection in men with Klinefelter syndrome. J Clin EndocrinolMetab. 2005;90(11):6263-7, http://dx.doi.org/10.1210/jc.2004-2322.

25. Ramasamy R, Ricci JA, Palermo GD, Gosden LV, Rosenwaks Z, SchlegelPN. Successful fertility treatment for Klinefelter’s syndrome. J Urol.2009;182(3):1108-13.

26. Hussein A, Ozgok Y, Ross L, Niederberger C. Clomiphene administra-tion for cases of nonobstructive azoospermia: a multicenter study.J Androl. 2005;26(6):787-91; discussion 92-3.

27. Foresta C, Bettella A, Spolaore D, Merico M, Rossato M, Ferlin A.Suppression of the high endogenous levels of plasma FSH in infertilemen are associated with improved Sertoli cell function as reflected byelevated levels of plasma inhibin B. Hum Reprod. 2004;19(6):1431-7,http://dx.doi.org/10.1093/humrep/deh255.

28. Selman HA, Cipollone G, Stuppia L, De Santo M, Sterzik K, El-DanasouriI. Gonadotropin treatment of an azoospermic patient with a Y-chromosome microdeletion. Fertility and sterility. 2004;82(1):218-9,http://dx.doi.org/10.1016/j.fertnstert.2003.11.055.

29. Efesoy O, Cayan S, Akbay E. The efficacy of recombinant human follicle-stimulating hormone in the treatment of various types of male-factorinfertility at a single university hospital. J Androl. 2009;30(6):679-84.

30. Shiraishi K, Ohmi C, Shimabukuro T, Matsuyama H. Human chorionicgonadotrophin treatment prior to microdissection testicular spermextraction in non-obstructive azoospermia. Hum Reprod. 2012;27(2):331-9, http://dx.doi.org/10.1093/humrep/der404.

31. Selman H, De Santo M, Sterzik K, Cipollone G, Aragona C, El-DanasouriI. Rescue of spermatogenesis arrest in azoospermic men after long-termgonadotropin treatment. Fertil Steril. 2006;86(2):466-8, http://dx.doi.org/10.1016/j.fertnstert.2005.12.055.

32. Esteves SC, Agarwal A. Novel concepts in male infertility. Int Braz J Urol.2011;37(1):5-15.

33. Singh AK, Tiwari AK, Singh PB, Dwivedi US, Trivedi S, Singh SK, et al.Multivitamin and micronutrient treatment improves semen parametersof azoospermic patients with maturation arrest. Indian J PhysiolPharmacol. 2010;54(2):157-63.

CLINICS 2013;68(S1):75-79 Drug therapy for NOAKumar R

79