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TTN ÇAYANFrom the Department of Urology, University of Mersin School of Medicine, Mersin, Turkey.
| Correspondence to: Dr Selahittin Çayan, Associate Professor of Urology, University of Mersin School of Medicine, Department of Urology, 33079-Mersin, Turkey (e-mail: selcayan{at}mersin.edu.tr). |
| Received for publication December 4, 2008; accepted for publication April 23, 2009. |
The aim of the study was to prospectively investigate the efficacy of
recombinant human follicle-stimulating hormone (rhFSH) in the treatment of
various types of male-factor infertility at a single university hospital. The
study included 61 infertile men receiving rhFSH because of various type of
male infertility. Treatment included 100–150 IU of rhFSH 2–3
times/wk. All men were divided into 4 groups: hypogonadotropic hypogonadism (n
= 21), isolated follicle-stimulating hormone (FSH) deficiency (n = 13),
idiopathic oligoasthenospermia (n = 16) and maturation arrest on testicular
biopsy (n = 11). Total motile sperm count (TMSC), serum FSH level, and
testicular volume were compared before and after treatment in all groups. In
the hypogonadotropic hypogonadism group, spermatozoa appeared in the
ejaculate, with a mean TMSC of 6.67 ± 1.57 million, in 15 of 21
patients (71.4%) who were totally azoospermic before the treatment. In the
isolated FSH deficiency group, TMSC significantly increased from 6.64 ±
3.27 to 32.4 ± 9.09 million after the treatment (P = .003).
TMSC did not significantly increase in the idiopathic oligoasthenospermia
group. Two of the men with maturation arrest (18.1%) had spermatozoa in the
ejaculate after the treatment. rhFSH therapy may be effectively used to
improve sperm parameters in infertile men with hypogonadotropic hypogonadism
and isolated FSH deficiency. In addition, rhFSH may effect some improvement by
either providing sperm in ejaculate or increasing intracytoplasmic sperm
injection success in infertile men with maturation arrest.
Key words: Male infertility, recombinant human FSH, sperm
o
lu
et al, 2001; Çayan et
al, 2002; McLachlan et al,
2007; Meacham et al,
2007). Evaluation of male infertility plays an important role in
approximately 50% of couples (Mosher,
1985; De Kretser,
1997). The aim of the evaluation of men for infertility is to
diagnose correctable pathologies, to detect genetic disease, and also to
diagnose life-threatening disease. It is sometimes not possible to treat men
with idiopathic oligospermia or azoospermia, and these men are referred for
intrauterine insemination, in vitro fertilization (IVF), or intracytoplasmic
sperm injection (ICSI) based on impaired semen quality. However, infertility
has been reported to be on the rise worldwide, and use of assisted
reproductive techniques (ART) is an economic burden. Therefore, the aims of
pathophysiology-specific treatment of male infertility are to achieve
spontaneous pregnancy, to obviate the need for ART, to downstage the level of
ART needed to bypass male-factor infertility, and also to increase pregnancy
rates with ART in those who have achieved unassisted reproduction. Hypogonadotropic hypogonadism includes idiopathic hypogonadotropic hypogonadism, excessive exercise, trauma, stress, Kallmann syndrome, late puberty, and hyperprolactinemia (Nachtigall et al, 1997). Treatment of male hypogonadotropic hypogonadism includes human chorionic gonadotropin (hCG) for 2–3 months initially, and then with the addition of recombinant human follicle-stimulating hormone (rhFSH) for up to 12–18 months (Bouloux et al, 2002, 2003). Spontaneous pregnancies can be achieved with the treatment of hypogonadotropic hypogonadism; however, in those who fail therapy, treatment may increase pregnancy rates with ART (Bakircioglu et al, 2007).
Follicle-stimulating hormone (FSH) plays an important role for the initiation and maintenance of spermatogenesis in men (Nieschlag et al, 1999). rhFSH has been used in the treatment of male infertility, and studies have reported successful results in separate patient groups with limited numbers of patients, including hypogonadotropic hypogonadism, idiopathic infertility, and maturation arrest (Kamischke et al, 1998; Bouloux et al, 2002, 2003; Foresta et al, 2002; Caroppo et al, 2003; Selman et al, 2004, 2006; Bakircioglu et al, 2007). However, no study has investigated the effect of rhFSH in the treatment of various types of male-factor infertility in the same population. Therefore, the aim of this study was to investigate the efficacy of rhFSH in the treatment of various types of male-factor infertility at a single university hospital.
Materials and Methods
This prospective study included 61 infertile men receiving rhFSH because of various types of male-factor infertility. The study was approved by the ethical committee at the University of Mersin School of Medicine. An informed consent was taken from patients. All men were evaluated by a single physician (S.Ç.) at 1 hospital (University of Mersin School of Medicine). All men underwent a detailed history, physical examination, measurement of serum hormone levels, and semen analysis.
Testicular volumes were measured with an ellipsoid orchidometer (Prader orchidometer; ASSI, Westbury, New York) at baseline and after the end of treatment. Mean value of bilateral testicular volume was included for comparison before and after the treatment. Blood samples for hormonal evaluation were taken in the early morning between 8:00 and 10:00 AM. For each patient, hormonal evaluation included measurement of plasma serum FSH, luteinizing hormone (LH), prolactin, and testosterone. In patients with isolated FSH deficiency in the presence of normal LH and testosterone level, if serum FSH level was low in the first measurement, the measurement was repeated to confirm FSH deficiency. Semen samples were collected by masturbation after 2–4 days of sexual abstinence and processed within 1 hour of ejaculation. At baseline, a minimum of 3 specimens were collected, separated by a 2–4 week interval. All semen analyses were performed in the same andrology laboratory according to World Health Organization (1998) criteria (normal sperm concentration >20 million/mL, normal sperm motility >50%). Pretreatment and posttreatment total motile sperm counts (TMSCs; ejaculate volume x concentration x motile fraction) were calculated on all semen analyses. For each patient, the greatest TMSC value was used and compared from pretreatment to posttreatment.
Hypogonadotropic hypogonadism was considered in the presence of undetectable or low level of serum testosterone (normal range, 3.3–9 ng/mL), FSH (normal range, 2.8–8 mIU/mL) and LH (normal range, 3–9 mIU/mL). Isolated FSH deficiency was defined as the presence of <2 mIU/mL serum FSH level. Maturation arrest at the spermatocyte or spermatid level was diagnosed on testicular biopsy or cytology. Idiopathic infertility was considered in the presence of normal testicular volume and gonadotropin level with abnormal semen analysis. All men (n = 61) were treated with 100–150 IU of rhFSH (Puregon; Schering Plough, Kenilworth, New Jersey) 2–3 times/wk. The men with hypogonadotropic hypogonadism initially and additionally received hCG 1500 IU (Pregnyl; Schering Plough) 2–3 times/wk to achieve sufficient serum testosterone level. When men had achieved a serum testosterone level in normal range with approximately 3 months of hCG treatment, rhFSH was added.
All men were divided into 4 groups: hypogonadotropic hypogonadism (n = 21), isolated FSH deficiency (n = 13), idiopathic oligoasthenospermia (n = 16) and maturation arrest on testicular biopsy or cytology (n = 11). Of the men with maturation arrest, 4 were at the spermatocyte level and 7 were at the spermatid level. TMSC, serum hormone levels, and testicular volumes were compared before and after treatment in all groups.
All female partners underwent a basic diagnostic infertility evaluation including a history, physical examination, and pelvic ultrasound. Couples in whom the female partners had a history of gynecologic surgery or ovulatory abnormalities were excluded from the study.
Statistical Analysis
Statistical analysis was performed using paired t tests to compare
pretreatment to posttreatment TMSC, serum hormone levels, and testicular
volumes in individual patients. All data are given as mean ± SD.
Probability values of <.05 were considered significant.
Results
The mean age was 23.19 ± 7.79 years in the hypogonadotropic hypogonadism group, 30.23 ± 7.01 years in the isolated FSH deficiency group, 31.43 ± 7.01 years in the idiopathic oligoasthenospermia group, and 31.09 ± 4.52 years in the maturation arrest group. The mean treatment duration was 13.66 ± 4.77 months in the hypogonadotropic hypogonadism group, 12.11 ± 4.7 months in the isolated FSH deficiency group, 9.56 ± 3.22 months in the idiopathic oligoasthenospermia group, and 7.45 ± 4.5 months in the maturation arrest group.
In all patients, no side effects were observed with the treatment. As shown in the Table, mean FSH level significantly increased in all groups from pretreatment to posttreatment (P = .001 for the hypogonadotropic hypogonadism group, P = .004 for the isolated FSH deficiency group, P = .001 for the idiopathic oligoasthenospermia group, P = .004 for the maturation arrest group). In patients with isolated FSH deficiency, pretreatment LH level was 4.37 ± 0.6 mIU/mL, and posttreatment LH level was 4.23 ± 0.42, revealing no significant difference (P = .744). Pretreatment serum testosterone level was 5.89 ± 0.51 ng/mL, and posttreatment testosterone level was 6.08 ± 0.81 ng/mL, revealing no statistical significance (P = .582).
|
Mean testicular volume significantly increased in the hypogonadotropic hypogonadism group (P = .001), the isolated FSH deficiency group (P = .011), and the maturation arrest group (P = .038); however, mean testicular volume did not change in the idiopathic oligoasthenospermia group (P = .544).
In the hypogonadotropic hypogonadism group, TMSC increased from 0 to 4.77 ± 1.3 million, revealing a significant difference (P = .002). Spermatozoa appeared in the ejaculate, with a mean TMSC of 6.67 ± 1.57 million, in 15 of 21 patients (71.4%) who were totally azoospermic before the treatment, although 6 patients (28.6%) remained azoospermic. Sperm appeared in the ejaculate with a median of 7 months of treatment. Of the patients who were still azoospermic on treatment, 2 had sperm with a testicular sperm extraction (TESE) procedure. In the isolated FSH deficiency group, TMSC significantly increased from 6.64 ± 3.27 to 32.4 ± 9.09 million after the treatment, revealing a significant difference (P = .003). In the idiopathic oligoasthenospermia group, pretreatment TMSC was 2.18 ± 0.74 million, and posttreatment TMSC was 2.51 ± 0.85 million, revealing no statistical significance (P = .095). In the maturation arrest group, posttreatment TMSC was 0.02 ± 0.02 million, whereas all were azoospermic before the treatment, revealing no statistical significance after the treatment (P = .323). However, of the men with maturation arrest, 2 (18.1%) had spermatozoa in the ejaculate and 2 (18.1%) had spermatozoa on TESE, whereas all were azoospermic before the treatment.
Discussion
Efficacy and safety of rhFSH has been well documented in the treatment of hypogonadotropic hypogonadism in men and women. This study is important to include treatment of various types of male-factor infertility with rhFSH. In addition to men with hypogonadotropic hypogonadism, treatment with rhFSH has provided significant improvement in men with isolated FSH deficiency and maturation arrest. Gonadotropins are required for fully normal spermatogenesis. FSH is absolutely necessary to initiate spermatogenesis. FSH may stimulate early events in spermatogenesis, including spermatogonial proliferation and meiosis (Sofitikis et al, 2008). In addition, the administration of FSH had a positive role in sperm cytostructural parameters (Baccetti et al, 1997). FSH in connection with LH/testosterone is also fundamental for the maintenance of quantitatively normal spermatogenesis (Nieschlag et al, 1999).
The induction of spermatogenesis in men with hypogonadotropic hypogonadism
can be successfully achieved using gonadotropins or gonadotropin-releasing
hormone (Bouloux et al, 2002,
2003;
Aydos et al, 2003;
Delemarre-van de Waal, 2004;
Miyagawa et al, 2005;
Bakircioglu et al, 2007).
Gonadotropins include hCG, human menopausal gonadotropin (hMG), and urinary
and recombinant FSH preparations. Full spermatogenesis and pregnancy may not
be achieved in all cases despite prolonged treatment. Fahmy et al
(2004) reported outcomes of
ICSI using testicular sperm in male hypogonadotropic hypogonadism unresponsive
to gonadotropin therapy. In 11 out of 15 patients (73%), after the treatment
of 75 IU hMG 3 times weekly and 5000 IU hCG 1 or 2 times weekly for more than
6 months, sperm could be retrieved from testicular tissue and were used for
ICSI. Treatment of male hypogonadotropic hypogonadism includes hCG 1500 IU 3
times/wk for 2–3 months initially to supply the necessary LH bioactivity
to stimulate the Leydig cells, and then with the addition of rhFSH
100–150 IU 3 times/wk for 12–18 months to stimulate the Sertoli
cells (Bouloux et al, 2002,
2003;
Bakircioglu et al, 2007).
Initial testicular volume before treatment may provide a developmental
perspective of the severity of these syndromes. Long-term administration of
hCG/hMG therapy in men with hypogonadotropic hypogonadism successfully
increased and maintained serum testosterone level and testicular volume
values, and improved sexual dysfunction as well as anejaculation. The
small-testis subset responded poorly in terms of serum testosterone levels and
did not achieve sufficient testicular volume; only 36% of the patients in this
subset showed sperm production. In contrast, 71% of the large-testis subset
showed sperm production (Miyagawa et al,
2005). Bakircioglu et al
(2007) reported results of
gonadotropin therapy in combination with ICSI in 25 men with hypogonadotropic
hypogonadism. All men were treated with hCG twice weekly for 1 month plus 100
IU of rhFSH 3 times a week the following month, until spermatozoa appeared in
the ejaculate. Spontaneous pregnancies were achieved in 4 couples, and 12
pregnancies were achieved with ICSI using ejaculated or testicular
spermatozoa. rhFSH has been shown to be both well tolerated and effective for
the stimulation of spermatogenesis in infertile men. Bouloux et al
(2002) reported that after the
treatment of rhFSH 150–225 IU 3 times weekly for up to 18 months,
spermatogenesis was achieved in 15 of 19 azoospermic patients with 9 months of
median time to initiation of spermatogenesis, 12 achieving a sperm
concentration of 
1.5 million. Treatment was well tolerated, and serum
antibodies to FSH were not detected
(Bouloux et al, 2003). In the
present study, in the hypogonadotropic hypogonadism group, mean serum FSH
value and mean testicular volume increased significantly after the treatment.
TMSC increased significantly from 0 to 4.77 ± 1.3 million. Spermatozoa
appeared in the ejaculate, with a mean TMSC of 6.67 ± 1.57 million, in
15 of 21 patients (71.4%) who were totally azoospermic before the treatment,
although 6 patients (28.6%) remained azoospermic. rhFSH treatment was well
tolerated in our study population, and no side effect was observed with the
treatment.
Isolated FSH deficiency has been reported in infertile men (Berger et al, 2005; Mantovani et al, 2003), and successful results have been obtained with treatment. After 6 months of hMG treatment, spermatogenesis was successfully induced in an azoospermic man with isolated FSH deficiency (Murao et al, 2008). In the present study, TMSC significantly increased from 6.64 ± 3.27 to 32.4 ± 9.09 million after the treatment with rhFSH. In addition, mean serum FSH level and mean testicular volume significantly increased after the treatment. To our knowledge, this is the first study to report outcomes of treatment with rhFSH in infertile men with isolated FSH deficiency.
Use of rhFSH has been reported in the treatment of men with idiopathic infertility. Foresta et al (1998) suggested that rhFSH treatment may be appropriate for oligospermic men who have normal FSH plasma levels and a testicular evaluation characterized by hypospermatogenesis without maturational disturbances. In their recent controlled study, Foresta et al (2002) evaluated 3 months of treatment with rhFSH or no treatment. Treatment with rhFSH at a dose of 50 IU induced no increase in sperm concentration, whereas treatment with rhFSH at a dose of 100 IU induced significant increase in sperm concentration in 11 of 15 patients with hypospermatogenesis on testicular aspiration cytology. Caroppo et al (2003) reported 33 infertile men with idiopathic oligoasthenoteratozoospermia who had failed to conceive after previous ICSI attempts. After the treatment with 150 IU of rhFSH 3 times a week for 3 months, the mean fertilization and pregnancy rates were higher in the treatment group (62.3% and 30.4%, respectively) than in the control group (47.2% and 0, respectively), although no significant difference in the increase of sperm parameters between the 2 groups. Kamischke et al (1998) reported outcomes of treatment with rhFSH for male idiopathic infertility in a randomized, double-blind, placebo-controlled clinical trial. rhFSH did not lead to an improvement of conventional or electron microscope sperm parameters or to an increase in pregnancy rates; however, increased testicular volume and sperm DNA condensation were seen in the treated group compared with the control group. In the present study, in contrast to the study by Kamischke et al (1998), mean testicular volume did not change, although mean FSH level significantly increased after the treatment in the idiopathic oligoasthenospermia group. TMSC did not significantly increase in the idiopathic oligoasthenospermia group, in agreement with the controlled studies published (Kamischke et al, 1998; Foresta et al, 2002). Sperm structure may affect ICSI outcomes, and low fertilization rates may be due to acrosomal dysfunction or disturbed axonemal or DNA integrity, and therefore treatment with rhFSH may promote increased sperm DNA condensation (Kamischke et al, 1998; Sakkas et al, 1998). However, more clinical trials are needed for men with idiopathic infertility to predict subgroups who would respond to rhFSH treatment.
Rescue of spermatogenesis arrest has been reported in azoospermic men after long-term gonadotropin treatment. Selman et al (2006) reported a total of 49 infertile men who failed to produce any mature sperm for an IVF/ICSI cycle, showing maturation arrest at the spermatocyte or spermatid level on testicular biopsy. All men underwent long-term gonadotropin therapy with 75 IU of rhFSH on alternate days for the first 2 months, and then 150 IU on alternate days plus 2000 IU of hCG twice weekly for 4 months. After 6 months of gonadotropin therapy, testicular sperm were found in 11 of 49 patients (22.4%). In the present study, 4 (36.3%) of the 11 men with maturation arrest had spermatozoa either in the ejaculate or on the testicular tissue samples, whereas all were azoospermic before the rhFSH treatment. An azoospermic patient with a Y chromosome microdeletion was treated with recFSH for 6 months, and successful twin pregnancy was obtained with ICSI using ejaculated sperm after the treatment, whereas the patient had no sperm in the ejaculate and maturation arrest on testicular biopsy before the treatment (Selman et al, 2004). These findings suggest that rhFSH treatment may improve spermatogenesis in some azoospermic men with maturation arrest, leading to successful sperm retrieval from either ejaculate or testicular tissue samples for ICSI cycles. Treatment with FSH may also improve the success of testicular sperm retrieval in nonobstructive azoospermic men with normal FSH levels. In the present study, in the maturation arrest group, TMSC increased from 0 to 0.02 ± 0.02 million, revealing no statistical significance, although mean serum FSH level and mean testicular volume significantly increased after the treatment. However, of the men with maturation arrest, 2 (18.1%) had spermatozoa in the ejaculate and 2 (18.1%) had spermatozoa on TESE, whereas all were azoospermic before the treatment. Aydos et al (2003) reported that pure FSH treatment for 3 months increased the quantity of retrieved spermatozoa compared to control values (64% vs 33%). These findings suggest that rhFSH may increase chances of ejaculated sperm and testicular sperm retrieval rate for ICSI in infertile men with maturation arrest. However, further studies including control groups are needed to emphasize the findings.
Conclusions
rhFSH therapy may be effectively used to improve sperm parameters in
infertile men with hypogonadotropic hypogonadism and isolated FSH deficiency.
In addition, rhFSH may effect some improvement by either providing sperm in
ejaculate or increasing ICSI success in infertile men with maturation
arrest.
Footnotes
Previous Presentation: This study was presented in part at the 24th Annual Meeting of the European Society of Human Reproduction and Embryology, July 6–9, 2008, Barcelona, Spain.
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