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From the * Department of Endocrinology, The Royal
Free Hospital, London, United Kingdom;
Institute of Reproductive Medicine of the
University, Münster, Germany; Prince
Henry's Institute of Medical Research, Clayton, Australia;
Rikshospitalet, Copenhagen, Denmark;||
Department of Endocrinology, Manchester Royal
Infirmary, University of Manchester, United Kingdom;¶
ANZAC Research Institute, Sydney, Australia;#
Royal Women's Hospital, Melbourne University,
Melbourne, Australia; 1 Fertility Centre, Scanian
Andrology Centre, Malmö, Sweden; 2 Department of
Andrology, Concord Hospital, University of Sydney, Sydney, Australia; and3
NV Organon, Oss, The Netherlands.
| Correspondence to: Gerrit Voortman, NV Organon, Clinical Development Department, PO Box 20, 5340 BH, Oss, The Netherlands (e-mail: gerrit.voortman{at}organon.com). |
| Received for publication November 4, 2002; accepted for publication January 23, 2003. |
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Abstract |
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Key words: Follistim, gonadotrophin deficiency, male infertility, testis
Treatment in this study occurred in 2 phases. Since hCG alone is sufficient to induce spermatogenesis in some patients, hCG was initially given to normalize testosterone levels. Subjects who were still azoospermic after this first phase were treated with a combination of both hCG and recombinant FSH (recFSH). Both gonadotropins were injected subcutaneously, providing a more convenient method than the intramuscular route of administration, which was common practice in the past. The efficacy and tolerability of recFSH, in combination with hCG, for the induction of spermatogenesis was studied using 2 treatment regimens (225 IU 2 times a week and 150 IU 3 times a week), resulting in an equal weekly dose of 450 IU.
The objective of this study was to investigate the efficacy and safety of recFSH in combination with hCG for initiation or improvement (or both) of spermatogenesis in hypogonadotropic hypogonadal men.
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Materials and Methods |
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Subjects were first treated with subcutaneous (SC) hCG (Pregnyl, Organon, Oss, The Netherlands) twice a week for a period of 16 weeks. Treatment was started with 1500 IU hCG twice weekly. In case of insufficient response after 8 weeks, as assessed by serum testosterone levels, the dose was increased to 3000 IU twice weekly. Eligible subjects (ie, those with normalized testosterone levels and still azoospermic) were randomized into 2 different treatment schedules of SC-injected recFSH (Puregon, Organon, Oss, The Netherlands), either 225 IU twice weekly (group A) or 150 IU recFSH 3 times a week (group B) for 48 weeks. In the phase of combined gonadotropin treatment, hCG injections continued twice weekly at the same dose level as was used during the hCG-alone phase. recFSH and hCG were always given as separate injections. At screening, after the hCG-only phase and at fixed time points during the study, testicular volumes were assessed and blood and semen samples were taken for hormonal measurements and determinations of semen characteristics, respectively. Injection sites were monitored to assess the local tolerance of injection of recFSH and hCG. For safety reasons, standard blood chemistry and urinalysis were performed. Since recFSH is produced by a CHO cell line transfected with the human genes for FSH, the potential presence of antibodies against FSH or CHO cell-derived proteins in serum was determined.
Inclusion criteria were subjects between the ages of 18 and 60, body mass index less than or equal to 35 kg/m2, azoospermia, low circulating levels of gonadotropins (FSH and LH ≤2 IU/L and testosterone ≤6 nmol/L), presence of scrotal testes, adequate replacement of other pituitary hormones (if applicable), good general physical and mental health, and ability and willingness to comply with the protocol and to give written informed consent. Exclusion criteria were testicular pathology of clinical importance, including vasectomy; any serious disease affecting testicular function; and presence of clinically relevant abnormalities of blood chemistry, hematology, or urinalysis. Furthermore, previous treatment within various time periods preceding the start of the study with FSH (6 months), gonadotropin-releasing hormone (GnRH) (6 months), hCG (3 months), or testosterone undecanoate (2 weeks), or treatment with injectable testosterone preparations (6 weeks) was prohibited. Other exclusion criteria were hypophysectomy within a period of 6 months before the start of this study, past or present oncological treatment, diabetes mellitus, untreated hyperprolactinemia, use of drugs known to impair testicular function, history of alcohol and drug abuse, and administration of investigational drugs within 90 days before study.
Hormonal Measurements
The hCG-alone phase and combined gonadotropin treatment period comprised a
total of 64 weeks. On the first day of weeks 1, 8, and 16 of the hCG-alone
phase (before each hCG injection), and on the first day of weeks 17, 22, and
every 6 weeks thereafter in the combined gonadotropin treatment period (before
the first recFSH injection of that particular week) and at the final visit
(scheduled in week 65), blood samples were collected for the assessment of
FSH, hCG, testosterone (T), estradiol (E2), sex hormone-binding
globulin (SHBG), and inhibin B. Inhibin B serum concentrations were analyzed
centrally by NV Organon's Department of Drug Metabolism and Kinetics, Oss, The
Netherlands, using a validated enzyme immunoassay (EIA) kit (Instruchemie,
Hilversum, The Netherlands). Serum FSH, LH, hCG, T, E2, and SHBG
concentrations were determined centrally by ABL, Assen, The Netherlands, using
kits for time-resolved fluoroimmunoassays (Delfia, Wallac Oy, Turku,
Finland).
Blood Chemistry/Hematology, Urinalysis, Physical and Andrological
Examination, and Vital Signs
At screening, in week 16 and every 12 weeks during the combined
gonadotropin treatment period, routine blood chemistry, hematology,
urinalysis, and physical and andrological examinations were performed, as well
as measurements of body weight, height, blood pressure, and heart rate.
Determination of Antibodies Against FSH or CHO Cell-Derived
Proteins
All antibody determinations were performed centrally by NV Organon's
Department of Drug Metabolism and Kinetics. The presence of anti-FSH
antibodies was investigated in blood samples collected at screening at week 22
and every 6 weeks thereafter up to and including week 64 and at the final
visit scheduled at week 65 with a validated radio-immunoassay using purified
FSH as a standard. Anti-CHO IgG and anti-CHO IgE antibodies in human serum
were determined with a validated EIA.
Semen Analysis and Determination of Testicular Volume
Semen was collected for analysis of sperm concentration, motility, and
morphology on the first day of weeks 8, 16, 22, and every 6 weeks thereafter
up to and including week 64 after a minimum of 3 days of abstinence. Sperm
concentrations were measured locally at each study center according to the WHO
manual (1992). For exploratory
reasons, mean sperm concentrations were statistically compared between the
treatment groups using the two-sample Student's t test, assuming
unequal variances.
Testicular volume was assessed according to a similar time schedule with an additional assessment at the final visit in week 65 using orchidometry or ultrasonography.
Local Tolerance
The local tolerance of the subcutaneous route of administration was
assessed by filling in diary cards. The maximal intensity of redness, itching,
swelling, pain, and bruising experienced during the preceding period after the
last injection was scored as none, mild, moderate, or severe. The hCG and
recFSH injection sites were monitored separately.
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Results |
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A total of 11 subjects were diagnosed as idiopathic hypogonadotropic hypogonadal, 15 subjects presented with Kallmann syndrome, and in 4 subjects other causes for their hypogonadotropic hypogonadal condition were found. Eleven subjects (7 in group A and 4 in group B) presented with a history of either unilateral or bilateral maldescended testes, often also referred to as cryptorchidism. For all subjects without maldescended testes the baseline (ie, before starting combination therapy) FSH serum concentration was 1.1 (SD 0.3) and for subjects with maldescended testes baseline FSH serum concentration was 1.2 (SD 0.3) IU/L.
Several men received previous treatment with GnRH or gonadotropins or both. A total of 8 men were treatment naïve (5 in group A and 3 in group B). For one man in group A, no data were available (see Table 2).
Induction of Spermatogenesis
Fourteen (47%) subjects reached a sperm concentration of at least 1 x
106/mL at one of their assessments after a median treatment time of
165 days (approximately 5.5 months), ranging from 25 to 327 days.
In Figure 1, the mean sperm concentrations are given for the treatment groups. In this figure the standard deviations are not given because they are very large and, in combination with the logarithmic ordinate, make the figure rather confusing. Although the response in group B seems slightly lower than in group A, the onset of spermatogenesis and the results at the end of treatment are comparable and no statistically significant differences (P > .05) were found between the treatment groups. The abstinence time was recorded; the median abstinence time calculated over all samples was 4 and 3 days for groups A and B, respectively.
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Sperm concentrations of 20 x 106/mL or higher, regarded by the WHO as the lower limit of the normal range (WHO, 1992), were reached by 3 subjects. The mean sperm count, over all subjects, exceeded a value of 1x 106/mL after combined gonadotropin treatment for 28 weeks. A total of 10 (33%) men remained completely azoospermic, 5 (33%) in group A and 5 (33%) in group B.
The subject population was comprised of a relatively large subgroup of men with a history of unilateral or bilateral maldescended testes. Therefore, in Figure 2 the development of spermatogenesis is depicted for men with and without maldescended testes. In men without a history of maldescended testes, the mean sperm count exceeded 1 x 106/mL between weeks 22 and 28. Thirteen of the 19 men without a history of maldescended testes (68%) showed an increase in sperm concentration.
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Except for one individual (subject ID 17), the induction of spermatogenesis in the group with a history of maldescended testes was much slower. Although subject 17 was diagnosed as having bilateral maldescended testes, this subject reached sperm concentrations of 39.5 x 106/mL. To show the influence of this high value on the total group of men with maldescended testes, a third curve is given in Figure 2, representing all men with maldescended testes with the exception of subject 17. In the group of men without a history of maldescended testes, 7 subjects showed an increase in sperm concentration to ≥1 x 106/mL over at least 4 assessments.
At the end of the combined gonadotropin treatment period, an overall mean fraction of 35% (SD 25%) of progressive sperm cells (total of rapid and slow progressive cells) was reached and the overall mean percentage of morphologically normal sperm cells was 24% (SD 16%).
Testicular Size
Over the whole combined gonadotropin treatment period consisting of 48
weeks, for both treatment groups mean testicular volume increased from 5.5 (SD
2.8) and 5.9 (SD 3.2) mL to 11.7 (SD 6.5) and 12.3 (SD 6.5) mL, for left and
right testicle, respectively. Although group A started with a higher
testicular volume, the relative increase was the same in both groups. Subjects
with a history of maldescended testes had a lower starting testicular volume,
but subjects with or without a history of maldescended testes showed the same
relative increase in testicular volume.
There was a clear relation between the initial testicular volume and the time needed for first sperm cells to appear in the ejaculate. The relation was identical for both treatment groups (Figure 3).
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Hormonal Responses
During the hCG-alone phase of 16 weeks, mean serum T levels increased from
1.08 and 1.22 ng/mL to 6.26 and 4.52 ng/mL in groups A and B, respectively.
During the treatment period with combined hCG and recFSH, mean serum T levels
showed a minor increase (Figure
4). Although the variability in T levels was high, the mean T
levels in group A were consistently higher than in group B. This difference
was already present before combined gonadotropin treatment and is therefore
not related to the different treatment regimens with recFSH.
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The mean inhibin B levels remained fairly constant during the hCG-alone phase but showed a gradual increase during combined gonadotropin treatment (Figure 5A). After an initial increase, the mean serum FSH concentration reached a steady state. At the end of treatment, group A had slightly higher FSH levels but variability was also high (Figure 5B). Overall mean serum levels of SHBG remained fairly constant and E2 levels showed a trend toward higher levels over the treatment period (Figure 5C and D).
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Safety
Two subjects (4.1%) in the hCG-alone phase and 2 subjects (6.7%) in the
combined gonadotropin treatment period reported one serious adverse event
(SAE) each. The SAEs included one case each of hyperglycemia, gynecomastia,
pilonidal cyst, and hemorrhoids. All 4 subjects recovered. Nine subjects
experienced at least one adverse event (AE) classified as ``related to
treatment'' (3 [6.1%] in the hCG-alone phase, six [20%] during combined
gonadotropin treatment). In the hCG-alone phase, 1 subject discontinued
because of an aggravated depression, whereas no subjects discontinued because
of AEs in the period of combined gonadotropin treatment. Among the
drug-related AEs, there were 2 cases of acne, injection site reaction, and
injection site pain, and single cases of varicose veins, gynecomastia, and a
dermoid cyst. With regard to laboratory values and vital signs, no clinically
relevant findings were observed. The local tolerance data were comparable
between the 2 treatment groups. The mean percentage of days without pain for
the Puregon injection calculated for all subjects in the combined gonadotropin
treatment period was 76% for subjects in group A and 91% for subjects in group
B. Mostly mild pain was reported. For itching, bruising, swelling, and
redness, some mild cases were reported and a few moderate and severe cases.
Itching was only experienced in group A on an average of 8% of all treatment
days. Bruising was seen in both treatment groups, on an average of 13% and
14.4% of all treatment days in groups A and B, respectively. Swelling of the
injection site occurred on an average of 11.8% and 0.3% of the treatment days.
Redness occurred approximately 9% of the treatment days in both groups.
Antibodies against FSH or CHO cell-derived proteins were not present.
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Discussion |
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Treatment of hypogonadotropic hypogonadism may be initiated for 2 purposes: induction of fertility or androgenization (Burger et al, 1981). Combinations of hCG and FSH have been successful in the treatment of hypogonadotropic hypogonadism. In the past, combinations of hCG and hMG were used (Gayral et al, 1975; Kuhenuri, 1976, Finkel et al, 1985; Ley and Leonard, 1985; Saal et al, 1991; Jones and Darne, 1993; Kirk et al, 1994; Kung et al, 1994; Büchter et al, 1998; Bouvattier et al, 1999). More recently, studies with highly purified and recombinant FSH have been performed (Burgués et al, 1997; European Metrodin HP study group, 1998; Liu et al, 1999).
Recombinant products such as Puregon have an improved purity compared with urinary preparations. A pharmacokinetic-pharmacodynamic study in men with hypogonadotropic hypogonadism showed that Puregon is well tolerated and shows dose-linear serum FSH levels (Mannaerts et al, 1996). In addition, a case report supported that recFSH in combination with hCG was effective in stimulation of testicular function in a hypogonadotropic hypogonadal man (Kliesch et al, 1995).
In the present study, 14 of 30 men reached sperm concentrations ≥1 x 106/mL. This is slightly lower than reported in some other studies (Burgués et al, 1997; European Metrodin HP Study Group, 1998; Liu et al, 1999). This may be explained by difference in duration of treatment. In this study, treatment duration was 48 weeks (11 months), whereas 18 months or more were reported in other studies. Also, different dosage schemes comprising daily injections were described (Jones and Darne, 1993). Furthermore, our subject population included a relatively large number of men with a history of maldescended testes (37%), which is regarded as a less favorable condition for positive therapeutic outcome (Finkel et al, 1985; Kirk et al, 1994; Bouvattier et al, 1999). Subjects with a history of maldescended testes may also require longer treatment in comparison with subjects without this preexisting condition. All subjects, except one, reaching normal or nearly normal values for sperm concentration were in the group of men without a history of maldescended testes. The mean time of 22–28 weeks required for sperm concentrations to reach levels of at least 1 x 106/mL is comparable with or even shorter than that in other studies (Kliesch et al, 1994; Burgués et al, 1997; Büchter et al, 1998; European Metrodin HP Study Group, 1998; Liu et al, 1999). By the end of the study, most patients did not reach a normal sperm concentration (lower limit 20 x 106/mL, according to WHO limits), although this is not a prerequisite for fertility in this population (Finkel et al, 1985; Ley and Leonard, 1985; Burris et al, 1988; Burris et al, 1988; Kliesch et al, 1994).
It should be noted that this study was not designed as a dose-finding study. The treatment regimens applied have been used for decades already in clinical practice. Only very few studies have applied higher weekly doses than 450 IU of FSH (Gayral et al, 1975; Saal et al, 1991, Jones and Darnes, 1993; Kirk et al, 1994). Since these studies included different populations concerning hypothalamic or pituitary disorders and maldescended testes, different treatment regimens for hCG, different treatment durations, and different definitions of efficacy, it is difficult to assess the effect of higher FSH doses. Therefore the applied doses and regimens from past studies and the present study do not necessarily have to be at the top of the dose response curve.
Apart from the concentration of sperm cells, motility and morphology are regarded as critical factors for fertility (Rogers et al, 1983; Zamboni, 1992; Bonde et al, 1998). The mean values for sperm motility were within the range normally obtained after gonadotropin therapy (Burris et al, 1988,Burris et al, 1988). In the present study, an overall mean fraction of 35% (SD 25%) of progressive sperm cells (total of rapid and slow progressive cells) was reached at the end of treatment. According to WHO criteria (WHO, 1992), the lower limit of normal motility is 50%. Several studies involving intrauterine insemination, however, report a value of 30% of progressive motility as a good prognostic factor for positive outcome (Dickey et al, 1999). The overall mean percentage of normal morphology at the end of treatment in this study was 24% (SD 16%), which is slightly lower than the value of 30% that is regarded as the lower limit for normal sperm morphology by the WHO.
Consistent with data in the literature, a clear relation between the initial testicular volume and the treatment time required for sperm to appear in the ejaculate was found (Burris et al, 1988; Burris et al, 1988; Büchter et al, 1998; Liu et al, 2002).
Testicular volume progressively increased during treatment. As expected, mean T levels showed a sharp increase during the hCG-alone phase. In the combined gonadotropin treatment period, only minor or no changes in T levels were found. The fact that group A showed consistently higher T levels than group B may be explained by the higher initial testicular volume in this group.
For inhibin B, a strong increase to values seen in normozoospermic men was observed (Andersson et al, 1998; Mahmoud et al, 1998; Foresta et al, 1999; Kamischke et al, 2001). Inhibin B is produced by the testis and is a measure for Sertoli cell function (Anderson et al, 1997). Since it is known that FSH is the principal stimulus for the secretion of testicular inhibin B, this increase also indicates the efficacy of the recFSH treatment.
Since no differences were seen in local tolerance scores between the 2 treatment schemes, it can be concluded that both regimens are equally well tolerated by patients. As for convenience, patients may have a preference for a treatment scheme with 2 injections per week instead of 3 injections per week.
In conclusion, recFSH induced spermatogenesis effectively in many hypogonadotropic hypogonadal men by weekly administration of 3 x 150 IU or 2 x 225 IU, the latter being most convenient for the patient. Long-term treatment with recFSH was safe and well tolerated and antibodies against FSH or CHO cell-derived proteins were not detected.
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Acknowledgments |
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References |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Andersson AM, Muller J, Skakkebaek NE. Different roles of
prepubertal and postpubertal germ cells and Sertoli cells in the regulation of
serum inhibin B levels. J Clin Endocrinol Metab.1998; 83:4451
–4458.
Bonde JPE, Ernst E, Jensen TK, et al. Relation between semen quality and fertility: a population-based study of 430 first-pregnancy planners. Lancet.1998; 352:1172 –1177.[Medline]
Bouvattier C, Tauber M, Jouret B, Chaussain J-L, Rochiccioli P. Gonadotropin treatment of hypogonadotropic hypogonadal adolescents. J Pediatr Endocrinol Metab.1999; 12:339 –344.
Büchter D, Behre HM, Kliesch S, Nieschlag E. Pulsatile GnRH or human chorionic gonadotropin/human menopausal gonadotropin as effective treatment for men with hypogonadotropic hypogonadism: a review of 42 cases. Eur J Endocrinol.1998; 139:298 –303.[Abstract]
Burger HG, de Kretser DM, Hudson B, Wilson JD. Effects of preceding androgen therapy on testicular response to human pituitary gonadotrophin (HPG) in hypogonadotrophic hypogonadism (HH): a study of three patients. Fertil Steril.1981; 35:64 –68.[Medline]
Burgués S, Calderón MD, and the Spanish Collaborative Group on Male Hypogonadotropic Hypogonadism. Subcutaneous self-administration of highly purified follicle stimulating hormone and human chorionic gonadotrophin for the treatment of male hypogonadotrophic hypogonadism. Hum Reprod.1997; 12:980 –986.
Burris AS, Clark RV, Vantman DJ, Sherins RJ. A low sperm concentration does not preclude fertility in men with isolated hypergonadotropic hypogonadism after gonadotropin therapy. Fertil Steril. 1988;50:343 –347.[Medline]
Burris AS, Rodbard HW, Winters SJ, Sherins RJ. Gonadotropin therapy in men with isolated hypogonadotropic hypogonadism: the response to human chorionic gonadotropin is predicted by initial testicular size. J Clin Endocrinol Metab.1988; 66:1144 –1151.[Abstract]
Crowley WF Jr, Jameson JL. Clinical counterpoint: gonadotropin-releasing hormone deficiency: perspectives from clinical investigation. Endocr Rev.1992; 13:635 –640.[Medline]
Dickey RP, Pyrzak R, Lu PY, Taylor SN, Rye PH. Comparison of the sperm quality necessary for successful intrauterine insemination with World Health Organization threshold values for normal sperm. Fertil Steril. 1999;71:684 –689.[Medline]
European Metrodin HP Study Group. Efficacy and safety of highly purified urinary follicle-stimulating hormone with human chorionic gonadotropin for treating men with isolated hypogonadotropic hypogonadism. Fertil Steril.1998; 70:256 –262.[Medline]
Finkel DM, Phillips JL, Snyder PJ. Stimulation of spermatogenesis by gonadotropins in men with hypogonadotropic hypogonadism. N Engl J Med. 1985;313:651 –655.[Abstract]
Foresta C, Bettella A, Petraglia F, Pistorello M, Luisi S, Rossato M. Inhibin B levels in azoospermic subjects with cytologically characterized testicular pathology. Clin Endocrinol.1999; 50:695 –701.[Medline]
Gayral MN, Millet D, Mandelbaum J, Serfaty D, Netter A. Male hypogonadotropic hypogonadism. Successful treatment of sterility with hMG + hCG. Ann Endocrinol (Paris).1975; 36:227 –241.[Medline]
Jones TH, Darne JF. Self-administered subcutaneous human menopausal gonadotrophin for the stimulation of testicular growth and the initiation of spermatogenesis in hypogonadotrophic hypogonadism. Clin Endocrinol. 1993;38:203 –208.[Medline]
Kamischke A, Simoni M, Schrameyer K, Lerchl A, Nieschlag E. Is inhibin B a pharmacodynamic parameter for FSH in normal men? Eur J Endocrinol. 2001;144:629 –637.[Abstract]
Kirk JMW, Savage MO, Grant DB, Bouloux P-MG, Besser GM. Gonadal function and response to human chorionic and menopausal gonadotrophin therapy in male patients with idiopathic hypogonadotrophic hypogonadism. Clin Endocrinol.1994; 41:57 –63.[Medline]
Kliesch S, Behre HM, Nieschlag E. High efficacy of gonadotropin or
pulsatile gonadotropin-releasing hormone treatment in hypogonadotropic
hypogonadal men. Eur J Endocrinol.1994; 131:347
–354.
Kliesch S, Behre HM, Nieschlag E. Recombinant human follicle-stimulating hormone and human chorionic gonadotropin for induction of spermatogenesis in a hypogonadotropic male. Fertil Steril. 1995;63:1326 –1328.[Medline]
Kuhenuri D. Kombinierte Humegon-Pregnyl-Therapie bei Fertilitätsstörungen des Mannes. Schweiz Rundsch Medizin Praxis. 1976;65:722 –724.
Kung AWC, Zhong YY, Lam KSL, Wang C. Induction of spermatogenesis with gonadotrophins in Chinese men with hypogonadotrophic hypogonadism. Int J Androl.1994; 17:241 –247.[Medline]
Ley SB, Leonard JM. Male hypogonadotropic hypogonadism: factors influencing response to human chorionic gonadotropin and human menopausal gonadotropin, including prior exogenous androgens. J Clin Endocrinol Metab. 1985;61:746 –752.[Abstract]
Liu PY, Turner L, Rushford D, McDonald J, Gordon Baker HW, Conway
AJ, Handelsman DJ. Efficacy and safety of recombinant human follicle
stimulating hormone (Gonal-F) with urinary human chorionic gonadotrophin for
induction of spermatogenesis and fertility in gonadotrophin-deficient men.
Hum Reprod.1999; 14:1540
–1545.
Liu PY, Gebski VJ, Turner L, Conway AJ, Wishart SM, Handelsman DJ.
Predicting pregnancy and spermatogenesis by survival analysis during
gonadotropin treatment of gonadotropin deficient infertile men. Hum
Reprod. 2002;17:625
–633.
Mahmoud AM, Comhaire FH, Depuydt CE. The clinical and biological significance of serum inhibins in subfertile men. Reprod Toxicol. 1998;12:591 –599.[Medline]
Mannaerts B, Fauser B, Lahlou N, Harlin J, Shoham Z, Coelingh Bennink H, Bouchard P. Serum hormone concentrations during treatment with multiple rising doses of recombinant follicle stimulating hormone (Puregon) in men with hypogonadotropic hypogonadism. Fertil Steril.1996; 65:406 –410.[Medline]
Rogers BJ, Bentwood BJ, van Campen H, Helmbrecht G, Soderdahl D,
Hale RW. Sperm morphology assessment as an indicator of human fertility
capacity. J Androl.1983; 4:119
.
Saal W, Happ J, Cordes U, Baum RP, Schmidt M. Subcutaneous gonadotropin therapy in male patients with hypogonadotropic hypogonadism. Fertil Steril.1991; 56:319 –324.[Medline]
Whitcomb RW, Crowley WF Jr. Diagnosis and treatment of isolated gonadotropin-releasing hormone deficiency in men. Clinical Review 4. J Clin Endocrinol Metab.1990; 70:3 –7.[Medline]
WHO Special Programme of Research, Development and Research Training in Human Reproduction. Laboratory Manual for the Examination of Human Semen and Semen-Cervical Mucus Interaction. 3rd ed. Cambridge, United Kingdom: Cambridge University Press;1992 .
Zamboni L. Sperm structure and its relevance to infertility. Arch Pathol Lab Med.1992; 116:325 –344.[Medline]
Zitzmann M, Nieschlag E. Hormone substitution in male hypogonadism. Mol Cell Endocrinol.2000; 161:73 –88.[Medline]
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