Clinical and social characteristics of Korean men with Klinefelter syndrome

Authors

  • Chong Won Bak,

    1. Department of Andrology, Center for Reproductive Medicine
    2. Center for Prostate, Zaii Urological Institute, Zaii Medical Center
    3. Genetics Laboratory
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  • Jae Sang Byun,

    1. Department of Andrology, Center for Reproductive Medicine
    2. Center for Prostate, Zaii Urological Institute, Zaii Medical Center
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  • Jee Han Lee,

    1. Department of Andrology, Center for Reproductive Medicine
    2. Center for Prostate, Zaii Urological Institute, Zaii Medical Center
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  • Ji Hye Park,

    1. Fertility Center, CHA Gangnam Medical Center, CHA University, Seoul, Korea
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  • Kyung-Ah Lee,

    1. Fertility Center, CHA Gangnam Medical Center, CHA University, Seoul, Korea
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  • Sung Han Shim

    Corresponding author
    1. Genetics Laboratory
    2. Fertility Center, CHA Gangnam Medical Center, CHA University, Seoul, Korea
      Sung Han Shim Ph.D., Genetics Laboratory, Fertility Center, CHA Gangnam Medical Center, CHA University, 606-13 Yeoksam 1-dong, Gangnam-Gu, Seoul 135-081, Korea. Email: shshim@cha.ac.kr
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Sung Han Shim Ph.D., Genetics Laboratory, Fertility Center, CHA Gangnam Medical Center, CHA University, 606-13 Yeoksam 1-dong, Gangnam-Gu, Seoul 135-081, Korea. Email: shshim@cha.ac.kr

Abstract

Objectives:  To investigate the characteristics of Klinefelter syndrome in a consecutive series of men consulting for sexual as well as fertility problems in Korea.

Methods:  A total of 179 men with non-mosaic 47,XXY Klinefelter syndrome of the 1876 azoospermic males who visited the fertility center of our university hospital between January 2002 and January 2010 were included in this analysis. Their semen characteristics, hormone profiles, size of the prostate gland, and education level were assessed and compared with an age-matched control group of 218 fertile males. Additionally, a histological evaluation was carried out.

Results:  Prostate size, testicular volume, semen volume and symptom severity showed statistically significant differences in both groups (P < 0.0001). As the severity of signs and symptoms worsened, the education level decreased. Each degree of signs and symptoms was associated with a different level of education, as well as with significant differences in the level of testosterone and testicular volume (P < 0.05). Spearman's correlation coefficient showed the severity of signs and symptoms was associated with testosterone (P < 0.0001).

Conclusions:  Testosterone has the strongest negative association with the severity of signs and symptoms in patients with Klinefelter syndrome. It influences the reproductive capacity, as well as the manifested signs and symptoms of hypogonadism. Furthermore, it is also associated with various aspects of life in these patients.

Abbreviations & Acronyms
AMS =

Aging Males' Symptoms

KS =

Klinefelter syndrome

FSH =

follicle stimulating hormone

GY =

gynecomastia

KEDI =

Korean Educational Development Institute

LH =

luteinizing hormone

PRL =

prolactin

S&S =

signs and symptoms

TESE =

testicular sperm extraction

T =

testosterone

TRUS =

transrectal ultrasonography

Introduction

KS is the most common sex chromosome disorder, with an estimated frequency of 1:400 to 1:1000 live deliveries.1–3 According to its original description, KS is characterized by GY, tall stature with eunuchoid body proportions, small testes, sterility and hypergonadotropic hypogonadism.4 It is generally reported that low libido and erectile dysfunction are present in KS, which is also a major cause of infertility resulting from azoospermia in men with high levels of gonadotropins (FSH and LH) and low normal levels of T.5,6 Most Klinefelter boys enter puberty at the expected time with an initial growth of the testes and increasing levels of serum T. However, degeneration of the testes and development of the classical features of KS accelerate around this time.7,8 Some KS patients show all of the classic signs of this disorder, whereas others, because of the wide variability in clinical expression, lack many of these features; nevertheless, almost all men with KS share and suffer from fertility problems. Hence, a variety of S&S begin to emerge at different stages of development, and varying degrees of the symptoms are influenced by hormonal imbalances. The aim of the present study was to analyze the prevalence and frequency of certain KS signs and symptoms in Korea and, hence, to investigate correlations and evaluate the pituitary–gonadal axis in these patients compared with age-matched controls through the measurement of various signs and symptoms, and, hence, education level, in relation to a series of hormones.

Methods

Site

The evaluation site comprised the Fertility Center, the Department of Genetics and the Andrology Unit of Gangnam Medical Center, CHA University located in Seoul, Korea. The present study was approved by the local hospital ethics committee.

Participants

Of the 1876 azoospermic males who visited our university hospital during the 8-year period between January 2002 and January 2010, 187 men (9.97%) with KS were initially identified after chromosomal evaluation of all of the men with azoospermia. Eight KS men with mosaicism (4.3%) were excluded from the study population; thus, 179 men with non-mosaic 47,XXY KS were finally enrolled in the study – all the 187 men were diagnosed with KS for the first time on presenting for fertility or andrological investigations. Participants gave written informed consent and completed a demographic form while waiting. Those who agreed to provide additional information about level of education and performance at school were assessed during either baseline and/or return visits to andrologists. Of the 179 patients, 41 (22.9%) visited our Andrology Unit because of various symptoms related to androgen deficiency, such as decreased libido, erectile dysfunction or reduced amount of ejaculation, whereas 138 patients (77.1%) visited the Fertility Center because of fertility problems.

Controls

Of the 218 fertile men who served as the control group, six men (2.78%) consulted for andrological reasons, such as loss of hair and decreased performance at work; 212 men (97.22%) came to our hospital for a pre-marriage check-up, for general consultation or for a routine fertility work-up. Only men with no signs or previous history of andrological diseases, such as cryptorchidism, hypospadia or varicocele, were included. Exclusion criteria included any underlying diseases, previous history of genitourinary tract infection, exposure to gonadotoxin, surgery of the genitourinary tract, an insufficient sexual abstinence period and more than 3 months of any medical therapy.

S&S, semen analysis and prostate volume

Measurement of S&S was based on the AMS rating scale, which was categorized into five groups: none, mild, moderate, severe and extremely severe, after 17 questions. One more question about the presence of GY comprised the last 18th question of our questionnaire. All the participants answered the questionnaires and underwent physical examination to differentiate GY from lipomastia. GY was also classified into the very severe degree, as GY was the least detected form in the study group and those who showed GY also complained of at least moderate symptoms. Semen samples were obtained after abstaining from sexual activity for the minimum period of 48 h and were analyzed using the guidelines put forth by the World Health Organization criteria (fourth edition, 1999). The size of the prostate gland was measured on TRUS in 89 men with KS and 107 controls. TESE was microscopically carried out on the KS men who provided additional informed consent, comprising just 21 patients.

Education level

With the exception of 13 patients who refused to participate in this segment of the study, 141 of 154 men (91.6%) with different S&S disclosed their education level. It would seem important to verify that the socioeconomic status of the families of patients and controls was similar. Authors selected another approach that analyzed the educational status of the siblings.

Statistical analysis

All statistical analyses were carried out using a commercially available software program (sas Enterprise Guide 4.1; SAS Institute, Cary, NC, USA). Independent t-test and χ2-test or Fisher's exact test were utilized to investigate statistical significances of characteristics between KS and the control (Table 1). anova was used to evaluate the significance of the variation in symptom severity in relation to the levels of various hormones (Table 2). Spearman's correlation coefficient was utilized to evaluate the association of hormone levels with symptom severity. Statistical significance was defined as P < 0.05.

Table 1.  Characteristics of the study participants
CharacteristicKS (n = 179)Control (n = 218)P-value
  • Independent t-test,

  • χ2-test or Fisher's exact test. Plus-minus values are means ± SD.

Age (years)32.85 ± 3.52 (27.0–42.0)33.64 ± 4.51 (23.0–41.0)0.14
Married171 (95.5%)207 (94.9%)0.7889
Spouse age, if married (years)28.91 ± 3.52 (21.0–36.0)29.85 ± 3.69 (23.0–42.0)0.8416
Physical characteristics   
 Height (cm)177.1 ± 6.2 (165.0–191.0)172.9 ± 5.3 (150.0–186.0)<0.0001
 Weight (kg)75.93 ± 11.59 (45.0–102.0)75.47 ± 9.86 (53.0–105.0)0.3708
 BMI (kg/m2)24.18 ± 3.51 (15.6–33.0)24.81 ± 3.00 (18.5−34.8)0.0479
 Testicular volume (cc)2.24 ± 1.61 (1.0–7.0)17.07 ± 4.57 (9.0–25.0)<0.0001
 Prostate volume (cc)15.81 ± 3.16 (12.0–20.5)24.91 ± 2.75 (18.0–33.5)<0.0001
 Semen volume (mL)1.68 ± 1.41 (0.01–6.4)2.72 ± 1.21 (0.3–7.4)<0.0001
 Symptom severity, n (%)  <0.0001
  None16 (10.39%)190 (87.96%)
  Mild37 (24.03%)20 (9.26%)
  Moderate43 (27.91%)6 (2.78%)
  Severe51 (33.12%)0 (0.00%)
  Extremely severe7 (4.55%)0 (0.00%)
Education level   
 Patients, n (%)(n = 154)(n = 216)<0.0001
  Graduate school2 (1.3%)15 (6.94%)
  University22 (14.3%)149 (68.98%)
  Vocational college47 (30.5%)36 (16.67%)
  Senior high59 (38.3%)16 (7.41%)
  Junior high24 (15.6%)0 (0.00%)
 Siblings, n (%)(n = 104)(n = 175)0.2713
  Graduate school6 (5.77%)10 (5.71%)
  University70 (67.31%)115 (65.71%)
  Vocational college19 (18.27%)35 (20.00%)
  Senior high9 (8.65%)15 (8.57%)
  Junior high0 (0.00%)0 (0.00%)
Table 2.  Characteristics of the patients according to the severity of andrological signs and symptoms
CharacteristicNone (n = 16)Mild (n = 37)Moderate (n = 43)Severe (n = 51)Very severe (n = 7)P-value
  • anova was utilized for statistical analysis to elucidate the relationship between hormone levels and the degree of signs and symptoms. The severity was assessed with AMS rating scale. Extremely severe grade included GY. Plus-minus values are mean ± SD.

Age (years)33.57 ± 2.1632.17 ± 1.9332.86 ± 2.2732.53 ± 1.6932.39 ± 2.510.3166
FSH (mIU/mL)39.85 ± 8.6736.55 ± 12.9438.51 ± 13.9535.71 ± 12.3338.97 ± 5.760.2788
LH (mIU/mL)17.44 ± 6.5215.61 ± 5.6518.72 ± 9.8215.03 ± 6.414.67 ± 7.480.1258
PRL (ng/mL)10.06 ± 5.5410.05 ± 7.3310.44 ± 10.2510.48 ± 8.078.10 ± 4.670.9737
T (ng/mL)3.80 ± 1.002.32 ± 1.112.37 ± 1.391.23 ± 0.690.31 ± 0.21<0.0001
BMI (kg/m2)22.35 ± 3.0623.89 ± 3.1824.35 ± 3.4124.83 ± 3.2624.58 ± 4.720.0985
Testicular volume (cc)2.42 ± 2.512.68 ± 1.312.27 ± 1.771.84 ± 1.091.79 ± 1.22<0.0001
Prostate volume (cc)15.62 ± 4.9215.27 ± 2.2317.91 ± 4.3916.43 ± 5.1715.19 ± 4.230.6533

Results

Patient characteristics

The clinical characteristics and sociodemographics of the study cohort of 179 men with non-mosaic KS compared with 218 age-matched controls are summarized in Table 1. S&S were categorized into five groups: none, mild, moderate, severe and very severe. No men in the control group complained of severe and very severe S&S. The level of education, as well as height, testicular volume, size of the prostate gland size, semen volume and symptom severity showed statistically significant differences between the men with KS and the controls.

S&S, TRUS and histology

Table 2 shows the variable degree of S&S in KS men in relation to the levels of various hormones. All men with GY presented other symptoms that were of moderate and severe grade of complaints. While testicular volume was decreased according to the severity of S&S (P < 0.0001), prostate size was not related to the S&S (P = 0.6533). Measured S&S were not adjusted for age, because there were no differences in age (P = 0.3166). As seen in Table 2, there was a trend for the level of T to decrease with the increasing severity of S&S (P < 0.0001). Spearman's correlation coefficient showed T had the strongest and negative association with the severity of S&S (rho = –0.61379, P < 0.0001) among evaluated hormones; that is, as the level of T was reduced, the degree of S&S became severe. FSH and LH also had a weak negative correlation with the degree of S&S (rho = –0.18802, P = 0.0169 and –0.15854, P = 0.0452, respectively), whereas PRL showed statistically no significant relationship (rho = –0.61379, P = 0.8052). In total, 94 of 104 siblings of men with KS (90.4%) showed no S&S, whereas 10 complained of mild grade S&S. The size of the prostate gland on TRUS was significantly different between the KS and controls (15.81 ± 3.16 vs 24.91 ± 2.75 cc, P < 0.0001). Three men with KS (3/89, 3.37%) showed the atrophied/underdeveloped seminal vesicle on TRUS, whereas none of the controls showed the atrophy. A total of 21 men with KS underwent TESE, and not a single man produced testicular sperm and, hence, after histological evaluation, showed no other histological results than Sertoli cell only syndrome with Leydig cell hyperplasia. All the 21 patients were older than 36 years-of-age (36.0–42.0) and their FSH levels were more than 33.5 mIU/mL with T of less than 0.9 ng/mL.

Education level

Education level is summarized in Table 3 according to the degree of S&S. No KS men with severe or very severe complaints completed tertiary qualifications, in contrast to those with no symptoms, 86% of whom attended tertiary education. A total of 90.4% of siblings of men with KS complained of no S&S. With regard to the educational status of siblings, there were no statistical differences between the patients and controls, whereas significant differences were present between the men with KS and their siblings (P < 0.0001). According to the KEDI, between 51.4% and 68.0% of secondary school graduates entered tertiary education between the years 1995 and 2000, when the study participants joined college or a higher level of education (KEDI, 2010).

Table 3.  Characteristics of KS men according to the severity of signs and symptoms in relation to education level and school performance
CharacteristicNone (n = 16)Mild (n = 37)Moderate (n = 43)Severe (n = 51)Very severe (n = 7)
Patients who answered (n = 14)Patients who answered (n = 36)Patients who answered (n = 36)Patients who answered (n = 47)Patients who answered (n = 6)
T (ng/mL)3.80 ± 1.002.32 ± 1.112.37 ± 1.391.23 ± 0.690.31 ± 0.21
Education level (n = 141)     
 Graduate school1 (7.14%)0 (0.00%)1 (2.63%)0 (0.00%)0 (0.00%)
 University4 (28.57%)7 (19.44%)4 (11.11%)2 (4.26%)0 (0.00%)
 Vocational college7 (50.00%)13 (36.11%)14 (36.84%)10 (21.28%)0 (0.00%)
 Senior high2 (14.29%)12 (33.33%)12 (31.58%)24 (51.06%)4 (66.67%)
 Junior high0 (0.00%)4 (11.11%)4 (10.53%)11 (23.40%)2 (33.33%)
 n = 94n = 9n = 1n = 0n = 0
Education level of siblings (n = 104)
 Graduate school 3 (31.91%)3 (33.33%)0 (0.00%)0 (0.00%)0 (0.00%)
 University66 (70.21%)4 (44.44%)0 (0.00%)0 (0.00%)0 (0.00%)
 Vocational college16 (17.02%)2 (22.22%)1 (100.00%)0 (0.00%)0 (0.00%)
 Senior high9 (9.57%)0 (0.00%)0 (0.00%)0 (0.00%)0 (0.00%)

Discussion

Currently, it is well recognized that Klinefelter's original description of the syndrome is too limited, because the condition can manifest a broad spectrum of phenotypes, professions, incomes and socioeconomic statuses.2 It is known that levels of T in the serum of adults with KS are in the low-to-normal range, and that serum gonadotropin levels are subsequently elevated; this is in accordance with the present results.2,4,8 As already described in many literature, men with KS in the present study were significantly taller than controls (177.1 ± 6.2 vs 172.9 ± 5.3 cm, P < 0.0001). Androgens influence the growth hormone axis only after aromatization into estrogens.9 Hence, estradiol is probably the principal hormone that stimulates the pubertal growth spurt in boys and girls. According to a recent study, accelerated growth is apparent during pubertal maturation before any biochemical evidence of impaired testicular function.10 The prostate gland is known to be responsible for 15% of semen volume.11 As shown by Watanabe et al., it is clearly shown that the size of the prostate gland of men with KS is significantly smaller than that of controls (P < 0.0001),12 and mainly responsible for the noticeable difference in semen volume (1.68 ± 1.41 vs 2.72 ± 1.21, P < 0.0001). Atrophy and/or underdevelopment of the seminal vesicle was often discovered in the unilateral or bilateral absence of the vas deferens.13 It is well known that semen volume is significantly smaller in men with KS, as shown in the present results.14 The same authors also showed that small semen volume supports the notion of 47,XXY patients being androgen insufficient, despite having serum testosterone levels within the normal range. However, the present results show that Korean men with KS recorded a semen volume of 1.68 ± 1.41 mL (mean ± SD) with a median of 1.01 mL, whereas a T level of 0.94 ± 1.33 with the median value of 2.04 ng/mL, which is below the normal range (2.45 to 18.36 ng/mL), was shown. According to a previous study, seven out of 84 patients (8.3%) produced sperm in the ejaculate and nine out of 24 patients (37.5%) had successful sperm recovery in TESE,15 and two out of 40 patients (5%) had sperm in the ejaculate.14 In the present cases, all of the study cohort produced not a single spermatozoan. Several recent studies reported high success rates of up to 50% from testicular sperm retrieval in Klinefelter patients, unlike the present result where not a single men with non-mosaic KS visiting our center produced testicular sperm.16–18 Degeneration of the seminiferous tubules in 47,XXY males is a well-described phenomenon. It begins in the fetus, progresses through infancy and accelerates dramatically at the time of puberty with complete hyalinization of the seminiferous tubules, although a few tubules with spermatogenesis might be present in adult life.

With regard to men with KS in Korea in the past, the sperm retrieval rate of the patients with mosaic and non-mosaic KS was 54.5% and 16%, respectively.19 According to their data, age, and the level of FSH and T were shown to be 31.2 ± 1.9 years, 34.9 ± 10.4 mIU/mL and 2.8 ± 0.9 ng/mL in men with testicular sperm, whereas KS males without testicular sperm recorded 32.3 ± 3.4 years, 35.4 ± 13.1 mIU/mL and 2.2 ± 1.4 ng/mL, in contrast to our data that showed 34.0 ± 4.7 years, 39.03 ± 16.33 mIU/mL and 1.88 ± 1.02 ng/mL. In accordance with another study, the present results clearly present the fact that men with KS should undergo evaluation well in advance of planning to have their own babies, preferentially before 31 years at the latest, as fecundity dramatically reduces with aging between 31 years and 34 years, according to the present results.20 Another study also reported that TESE or testicular sperm aspiration should be carried out before the critical age of 32 years.21 Cut-off of 30.5 years-of-age had a sensitivity of 78% and a specificity of 48% for successful sperm retrieval.22 There is also an increased risk for postsurgical androgen insufficiency in addition to the endogenous descent of testosterone production over the age of 40 years.2 Testicular biopsy was carried out in just 21 men and was followed by histological evaluation after hematoxylin–eosin stain. The low number of patients (21/179) that chose to undergo testicular biopsy could be explained by fear that harm could be done to their already small testicles. The present findings are concordant with evidence presented in previous reports, which showed that micronodules of Leydig cells with impaired function are also associated with increased LH/T ratios.23,24 It is also well known that biopsies of prepubertal KS boys show preservation of the seminiferous tubules with reduced numbers of germ cells, and Sertoli and Leydig cells with normal appearance. In contrast, the testes of adult KS males are characterized by extensive fibrosis and hyalinization of the seminiferous tubules, and hyperplasia of the interstitium; however, the tubules might show residual foci of spermatogenesis.25 Many hypotheses regarding the underlying mechanism of the depletion of the germ cells in Klinefelter males have been reported, and include insufficient supranumerary X-chromosome inactivation, Leydig cell insufficiency and disturbed regulation of apoptosis of Sertoli and Leydig cells.18 It is widely known that GY is common among KS patients, to some extent, in approximately one-third of KS cases. According to the present study, just seven of 161 (4.4%) patients showed a detectable S&S of GY. All patients, however, had spontaneous puberty. Why such a low percentage of KS cases in Korea show GY and a higher prevalence of osteoporosis is an enigma that remains to be resolved. We, the authors, consent to the idea that all men with GY complained of decreased libido and sexual dissatisfaction because these could be a psychosocial consequence of breast development itself. GY was also present more commonly among KS patients with failed testicular sperm extraction.16 The results of the present study suggest that S&S become more severe as LC function diminishes, as represented by the level of T, which was shown to possess the strongest and negative association with the severity of S&S (rho = –0.61379, P < 0.0001). The sexual dysfunction present in KS is not apparently associated with the syndrome, but is caused by the underlying hypogonadal state.26,27 Hypogonadism might be associated with physical discomfort, but it is believed that most of the complaints and physical discomfort in relation to hypogonadism disappear after a period of appropriate androgen replacement.28

The present study clearly showed that men with KS achieved a lower level of education than their siblings, as well as controls (P < 0.0001). The fact that 15.6% of men with KS in Korea completed just 9 years of education shows more interest and assistance are required both at school and at home. As the level of T declines, S&S become severe and, hence, the level of education is also affected. The reason why those men with a severe degree of S&S achieved a lower educational level could not be explained by a single factor, but a variety of biopsychosocial interactions, such as the appearance of GY during school years might hinder boys with KS from active interactions with peer groups and, hence, they become withdrawn. The cognitive profile in KS is characterized by extreme variability.28 With regard to education level associated with KS, in accordance with the present results, recent studies have shown that individuals with sex chromosome trisomies had marked difficulties in speech and language, motor skills, and educational achievement and, hence, they had impairments in basic psychophysiological mechanisms in the area of visuo-motor control and sensory gating.29,30 It is important to remember that the diagnosis and therapy of andrological diseases interact with two biological functions – fertility and sexuality – that are more sensitive to psychological, educational, cultural, religious and social factors than any other body function.31 An early diagnosis is useful in order to plan different types of rehabilitation, where the need is documented.28 According to a previous study, KS patients who were diagnosed prenatally developed learning and language disabilities in a lower proportion than patients diagnosed by chance.32 Improvements were reported in various parameters of physical and emotional well-being with a systematic replacement therapy.33 The motor performance might also become better with the replacement therapy.34 However, clinicians/physicians should remember that, with regard to bone mineral density, testosterone replacement therapy does not always restore bone density in KS patients.35 Another recent study on quality of life of KS patients showed that they frequently report psychological or physical discomfort that is not relieved by adequate androgen treatment.36 The treatment strategy depends on the age of the patient and the goals of therapy (restoration of fertility and/or production and maintenance of virilization).28 However, the optimal testosterone regimen for patients with KS is still to be established.37 We, the authors, consent to the idea that the potential benefits of testosterone therapy on cognition should be evaluated prospectively28 before a consensus is made and a guideline is established. KS has an effect on normal development, growth, social interactions, bone structure, and sexual and reproductive function, thus a multidisciplinary approach to men with KS is important in providing state-of-the-art care to children and men with KS.5 The major limitation of the present study WAS the selection bias of the study cohort. The studies that have found GY to be a common feature amongst KS patients include those diagnosed across all age groups. Those individuals that are diagnosed as adults through fertility investigations might represent a milder phenotype than those diagnosed at younger ages.

In summary, the present study showed that the level of testosterone definitely affects the manifestation of various S&S, thereby influencing education level. Reproductive fecundity, brain functions and behavior depend on the coordinated functions of organs located along the hypothalamo–pituitary–gonadal tract axis. Treatment of KS men usually consists of testosterone replacement therapy to correct the androgen deficiency, not only to secure proper masculine development of sexual characteristics and prevent the long-term deleterious consequences of hypogonadism, but also to secure a better quality of life by providing KS men with increased chances of achieving a higher education level, an important factor determining socioeconomic status. However, testosterone replacement therapy should not be started on men desiring to father children that are yet to undergo TESE or micro-TESE.

Acknowledgments

We express our gratitude to Professor Niels E Skakkebaek and Dr Lise Aksglaede at the Department of Growth and Reproduction, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark, for their valuable advice and help. Our sincere thanks to Ms Eun Suk An and Ms Yon-Wan Han for her helpful comments and excellent assistance. This study was supported by a grant from the Korea Healthcare Technology R&D Project, Ministry of Health, Welfare & Family affairs, Republic of Korea (A084923).

Conflict of interest

None declared.

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