CLASSIC REVERSIBLE AAS-INDUCED HYPOGONADOTROPHIC HYPOGONADISM
Infertility after AAS abuse commonlypresents as oligozoospermia or azoospermia,associated with abnormalities in spermmotility and morphology [8]. According tomost reports, sperm quality tends to recoverspontaneously within 4–12 months afterdiscontinuation [9]. However, the negativeeffect on semen quality may persist forlonger periods. A hypogonadotrophichypogonadism state is induced,characterized by decreased serumtestosterone concentrations, testicularatrophy and impaired spermatogenesis[10]. These effects result from thenegative feedback of androgens onthe hypothalamic-pituitary axis, andpossibly from local suppressive effectsof exogenous androgens on the testis.FSH and luteinizing hormone (LH)concentrations are typically low. Inaddition, during AAS use, serum androgenconcentrations may be supraphysiologicallyhigh, but the hypogonadotrophic statelowers the intratesticular testosteroneconcentrations required to maintain normalspermatogenesis. The management ofAAS-induced male infertility has also beenextensively reported. Simple discontinuationof AAS use may lead to fertility recovery in acertain proportion of male users [10], butthere is little literature and considerabledisagreement regarding the management ofsuch cases. Patients may also be activelytreated, in a manner similar to that usedfor other forms of hypogonadotropichypogonadism infertility, requiring theinduction of spermatogenesis withgonadotropins or gonadotropin analogues,including i.m. injections of hCG, humanmenopausal gonadotropin (hMG) or evenrecombinant FSH. The use of hCG alone, or incombination with hMG, has been reported tobe a successful treatment for this group ofpatients [11]. Fertility restoration has beenreported, even in situations of persistentazoospermia up to 5 years after AASdiscontinuation so AAS-associated maleinfertility may be treatable because of itsendocrine nature. Considering the prevalenceof AAS abuse and the favourable results aftertreatment, it is reasonable to consider itduring the infertility consultation.
Histopathlogy
Experiments in animal models mainly reportAAS-induced Leydig cell alterations, butcellular morphology anomalies have also beenreported [12]. The decrease in this populationof cells is accompanied by low testosteroneand LH levels in all papers reviewed, especiallyin those papers reporting on adult animalmodels. Immunohistochemical findingshave suggested decreased steroidogenesisin testicular tissue, hence spermatogenesiswas considered unchanged by some otherauthors. Nethertheless, specific end-stagespermatogenesis impairment, with a lackof advanced forms of spermatids, has beendescribed [13]. After AAS discontinuation,Leydig cells tend to proliferate but remainbelow the regular counts, even after longerperiods [14]. Clearly, long-lasting, or possiblypersistent effects of AAS use cannot be ruledout.
Impact on semen quality
The use of a combination of hCG and steroidsis a common practice among AAS users. Thegoal is to avoid the impact of LH suppressionafter long-term AAS administration,which may lead to a persistent state ofhypogonadism and low-quality semen.Restoration of spermatogenesis has beendescribed; however more abnormal andhypokinetic spermatozoa are found, evenafter hCG ‘post-cycle’ use, showing apotential for persistent alterations after thediscontinuation of AAS use [15].
Apoptosis
Apoptosis has been reported to play animportant role in the regulation of germcell populations in the adult testis. Recently,the correlation between apoptosis andhigh AAS doses and exercises has beenexperimentally assessed in animal models.Shokri et al. report a significant increasein the rate of apoptosis after nandroloneadministration, an increase clearly amplifiedby physical exercise [16]. Shokri et al. alsoreport an evident impairment in semen qualityamong the same set of individuals, in the sameconditions. Testicular histopathologicalevaluation according to Johnsen’s method[17] has also been performed, revealing lowquality spermatogenesis.
Aneuploidies and ultrastructural changesin spermatozoa
The innovative use of both transmissionelectron microscopy and fluorescence in situhybridization (FISH) has recently beenreported in an AAS user sperm sample,searching for genetic and ultrastructuralconsequences of steroid abuse. Immaturity,necrosis and apoptosis were assessed, anda high percentage of structurally normalspermatozoa were found, which showed theabsence of a correlation between AAS andultrastructural sperm changes. In contrast tothese findings, FISH sperm analysis revealedXY and chromosomes 1 and 9 disomies,suggesting anomalies in the meiotic processand genetic damage among AAS users [18].An overview of the effects of AAS use on malefertility is presented in Table 2 [9–18].
[8] Dohle GR, Smit M, Weber RF.Androgens and male fertility. World J Urol2003; 21: 341–59 Turek PJ, Williams RH, Gilbaugh JH III,Lipshultz LI. The reversibility of anabolicsteroid-induced azoospermia. J Urol 1995;153: 1628–3010 Gazvani MR, Buckett W, Luckas MJ,Aird IA, Hipkin LJ, Lewis-Jones DI.Conservative management ofTABLE 2 Overview of effects of AASs on male fertilityEffect analysed Reference Study design OutcomeDrug-induced hypogonadotropichypogonadism (HH)Turek et al. 1995
[9] Case report Complete reversion of persistent azoospermia after hCG treatment (2000–3000 IU three times a week for 4 months). It is recommended that therapybe started after a 6-month period of unsuccessful conservativemanagement. Pregnancy was achieved after treatment.Gazvani et al. 1997
[10] Case report Four cases of AAS-induced HH and azoospermia were managed in aconservative fashion. Hormonal and seminal parameters were restored and3/4 achieved pregnancy. Up to 10 months were required for restoration ofsemen quality.Menon 2003
[11] Case report AAS-induced azoospermia (persistent after 1 year of discontinuation of steroiduse) was reversed with hCG (10 000 UI twice a week) and hMG (75 UI daily)for 3 months. Pregnancy was achieved.Semen quality Karila et al. 2004
Semen quality Karila et al. 2004
[15] RetrospectiveseriesA total of 18 subjects were evaluated after AAS + hCG use. Transient HH wasshown, with severe oligozoospermia. hCG therapy could restorespermatogenesis, but was positively correlated with morphologicalabnormalities in sperm after treatment.Sperm apoptosis Shokri et al. 2009
[16] Experimental Caspase-3 assay and terminal deoxynucleotidyl transferase enzyme-mediateddUTP nick end labelling were used to assess germ cell apoptosis after AAStherapy, and it was found to be significantly high. A decrease in germ celllayers and in semen quality were also found.Testicular histology Feinberg et al. 1996
[12] Experimental Leydig cell depletion and irregularly shaped Leydig cells were found during AASadministration. After discontinuation, Leydig cells increased in number,staying below the baseline even after long periods.Grokett et al. 1992
[13] Experimental End-stage spermatogenesis impairment resulted from AAS therapy; the mostadvanced stages of spermatids and mature sperm were lacking.Nagata et al. 1999
[14] Experimental Leydig cell depletion and arrest of advanced spermatogenesis were found.Immunopositive cells for inhibin and steroidogenesis enzymes decreased inthe testicular interstitial compartment.Sperm aneuploidies and meioticsegregationMoretti et al. 2007
[18] Case report The FISH technique was used after spermatogenesis recovery, resulting in ahigher frequency of XY disomy (segregation anomaly at the first meioticdivision), and chromosomes 1 and 9 disomies.Sperm ultra-structure Moretti et al.
[18] Case report After AAS discontinuation, spermatogenesis was induced with r-FSH (150 IUon alternate days) plus hCG (100 UI twice a week) for 6 months.Azoospermia was reversed and pregnancy was achieved. Sperm immaturity,necrosis and apoptosis were assessed through transmission electronmicroscopy. Ultra-structural sperm changes were not significantly high.
Guilherme Leme de Souza* and Jorge Hallak†
*Department of Urology, Sao Paulo State Military Police Hospital, and †Division of Urology and PathologyDepartment, Reproductive Toxicology Unit, Hospital das Clinicas, University of Sao Paulo Medical School, Sao Paulo,Brazil
Infertility after AAS abuse commonlypresents as oligozoospermia or azoospermia,associated with abnormalities in spermmotility and morphology [8]. According tomost reports, sperm quality tends to recoverspontaneously within 4–12 months afterdiscontinuation [9]. However, the negativeeffect on semen quality may persist forlonger periods. A hypogonadotrophichypogonadism state is induced,characterized by decreased serumtestosterone concentrations, testicularatrophy and impaired spermatogenesis[10]. These effects result from thenegative feedback of androgens onthe hypothalamic-pituitary axis, andpossibly from local suppressive effectsof exogenous androgens on the testis.FSH and luteinizing hormone (LH)concentrations are typically low. Inaddition, during AAS use, serum androgenconcentrations may be supraphysiologicallyhigh, but the hypogonadotrophic statelowers the intratesticular testosteroneconcentrations required to maintain normalspermatogenesis. The management ofAAS-induced male infertility has also beenextensively reported. Simple discontinuationof AAS use may lead to fertility recovery in acertain proportion of male users [10], butthere is little literature and considerabledisagreement regarding the management ofsuch cases. Patients may also be activelytreated, in a manner similar to that usedfor other forms of hypogonadotropichypogonadism infertility, requiring theinduction of spermatogenesis withgonadotropins or gonadotropin analogues,including i.m. injections of hCG, humanmenopausal gonadotropin (hMG) or evenrecombinant FSH. The use of hCG alone, or incombination with hMG, has been reported tobe a successful treatment for this group ofpatients [11]. Fertility restoration has beenreported, even in situations of persistentazoospermia up to 5 years after AASdiscontinuation so AAS-associated maleinfertility may be treatable because of itsendocrine nature. Considering the prevalenceof AAS abuse and the favourable results aftertreatment, it is reasonable to consider itduring the infertility consultation.
Histopathlogy
Experiments in animal models mainly reportAAS-induced Leydig cell alterations, butcellular morphology anomalies have also beenreported [12]. The decrease in this populationof cells is accompanied by low testosteroneand LH levels in all papers reviewed, especiallyin those papers reporting on adult animalmodels. Immunohistochemical findingshave suggested decreased steroidogenesisin testicular tissue, hence spermatogenesiswas considered unchanged by some otherauthors. Nethertheless, specific end-stagespermatogenesis impairment, with a lackof advanced forms of spermatids, has beendescribed [13]. After AAS discontinuation,Leydig cells tend to proliferate but remainbelow the regular counts, even after longerperiods [14]. Clearly, long-lasting, or possiblypersistent effects of AAS use cannot be ruledout.
Impact on semen quality
The use of a combination of hCG and steroidsis a common practice among AAS users. Thegoal is to avoid the impact of LH suppressionafter long-term AAS administration,which may lead to a persistent state ofhypogonadism and low-quality semen.Restoration of spermatogenesis has beendescribed; however more abnormal andhypokinetic spermatozoa are found, evenafter hCG ‘post-cycle’ use, showing apotential for persistent alterations after thediscontinuation of AAS use [15].
Apoptosis
Apoptosis has been reported to play animportant role in the regulation of germcell populations in the adult testis. Recently,the correlation between apoptosis andhigh AAS doses and exercises has beenexperimentally assessed in animal models.Shokri et al. report a significant increasein the rate of apoptosis after nandroloneadministration, an increase clearly amplifiedby physical exercise [16]. Shokri et al. alsoreport an evident impairment in semen qualityamong the same set of individuals, in the sameconditions. Testicular histopathologicalevaluation according to Johnsen’s method[17] has also been performed, revealing lowquality spermatogenesis.
Aneuploidies and ultrastructural changesin spermatozoa
The innovative use of both transmissionelectron microscopy and fluorescence in situhybridization (FISH) has recently beenreported in an AAS user sperm sample,searching for genetic and ultrastructuralconsequences of steroid abuse. Immaturity,necrosis and apoptosis were assessed, anda high percentage of structurally normalspermatozoa were found, which showed theabsence of a correlation between AAS andultrastructural sperm changes. In contrast tothese findings, FISH sperm analysis revealedXY and chromosomes 1 and 9 disomies,suggesting anomalies in the meiotic processand genetic damage among AAS users [18].An overview of the effects of AAS use on malefertility is presented in Table 2 [9–18].
[8] Dohle GR, Smit M, Weber RF.Androgens and male fertility. World J Urol2003; 21: 341–59 Turek PJ, Williams RH, Gilbaugh JH III,Lipshultz LI. The reversibility of anabolicsteroid-induced azoospermia. J Urol 1995;153: 1628–3010 Gazvani MR, Buckett W, Luckas MJ,Aird IA, Hipkin LJ, Lewis-Jones DI.Conservative management ofTABLE 2 Overview of effects of AASs on male fertilityEffect analysed Reference Study design OutcomeDrug-induced hypogonadotropichypogonadism (HH)Turek et al. 1995
[9] Case report Complete reversion of persistent azoospermia after hCG treatment (2000–3000 IU three times a week for 4 months). It is recommended that therapybe started after a 6-month period of unsuccessful conservativemanagement. Pregnancy was achieved after treatment.Gazvani et al. 1997
[10] Case report Four cases of AAS-induced HH and azoospermia were managed in aconservative fashion. Hormonal and seminal parameters were restored and3/4 achieved pregnancy. Up to 10 months were required for restoration ofsemen quality.Menon 2003
[11] Case report AAS-induced azoospermia (persistent after 1 year of discontinuation of steroiduse) was reversed with hCG (10 000 UI twice a week) and hMG (75 UI daily)for 3 months. Pregnancy was achieved.Semen quality Karila et al. 2004
Semen quality Karila et al. 2004
[15] RetrospectiveseriesA total of 18 subjects were evaluated after AAS + hCG use. Transient HH wasshown, with severe oligozoospermia. hCG therapy could restorespermatogenesis, but was positively correlated with morphologicalabnormalities in sperm after treatment.Sperm apoptosis Shokri et al. 2009
[16] Experimental Caspase-3 assay and terminal deoxynucleotidyl transferase enzyme-mediateddUTP nick end labelling were used to assess germ cell apoptosis after AAStherapy, and it was found to be significantly high. A decrease in germ celllayers and in semen quality were also found.Testicular histology Feinberg et al. 1996
[12] Experimental Leydig cell depletion and irregularly shaped Leydig cells were found during AASadministration. After discontinuation, Leydig cells increased in number,staying below the baseline even after long periods.Grokett et al. 1992
[13] Experimental End-stage spermatogenesis impairment resulted from AAS therapy; the mostadvanced stages of spermatids and mature sperm were lacking.Nagata et al. 1999
[14] Experimental Leydig cell depletion and arrest of advanced spermatogenesis were found.Immunopositive cells for inhibin and steroidogenesis enzymes decreased inthe testicular interstitial compartment.Sperm aneuploidies and meioticsegregationMoretti et al. 2007
[18] Case report The FISH technique was used after spermatogenesis recovery, resulting in ahigher frequency of XY disomy (segregation anomaly at the first meioticdivision), and chromosomes 1 and 9 disomies.Sperm ultra-structure Moretti et al.
[18] Case report After AAS discontinuation, spermatogenesis was induced with r-FSH (150 IUon alternate days) plus hCG (100 UI twice a week) for 6 months.Azoospermia was reversed and pregnancy was achieved. Sperm immaturity,necrosis and apoptosis were assessed through transmission electronmicroscopy. Ultra-structural sperm changes were not significantly high.
Guilherme Leme de Souza* and Jorge Hallak†
*Department of Urology, Sao Paulo State Military Police Hospital, and †Division of Urology and PathologyDepartment, Reproductive Toxicology Unit, Hospital das Clinicas, University of Sao Paulo Medical School, Sao Paulo,Brazil
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