Gonad evaluation in male systemic lupus erythematosus

OBJECTIVE: To assess gonad function in male patients with systemic lupus erythematosus (SLE). METHODS: Thirty-five consecutive male patients with SLE according to the criteria of the American College of Rheumatology were prospectively evaluated for demographic and clinical features as well as previous and current treatment. Patients underwent urologic evaluation and testicular Doppler ultrasound. We obtained a hormone profile and performed a semen analysis including morphology and testing for the presence of antisperm antibodies. Patients were compared with 35 age-matched healthy controls. RESULTS: Compared with controls, SLE patients had lower median testicular volumes in both testes, a lower median total sperm count, and a lower median total motile sperm count. The mean sperm volume and percentage of normally formed sperm were lower in SLE patients than in controls. Since all SLE patients had semen alterations, they were further subdivided into 2 groups according to the severity of these abnormalities (group 1, with teratozoospermia [n = 18], and group 2, with azoospermia or teratozoospermia in combination with oligozoospermia and/or asthenozoospermia [n = 17]). The frequency of treatment with intravenous cyclophosphamide (IV CYC) after the first ejaculation was higher in group 2 than in group 1. The median testicular volumes measured by ultrasound in both testicles were lower in group 2 than in group 1. Follicle-stimulating hormone levels were higher in group 2 than in group 1. The overall frequency of antisperm antibodies in SLE patients was 40%. The apparent higher frequency of antisperm antibodies in group 1 than in group 2 did not reach significance. CONCLUSION: SLE patients have a high frequency of sperm abnormalities associated with reduced testicular volume. Postpubertal IV CYC treatment was the major factor in potential permanent damage to the testes.     

Lack of evidence of a genetic origin in the impaired spermatogenesis of a patient cohort with low-grade varicocele

Varicocele is the most common clinical finding in infertile men but controversy continues to surround the utility of its treatment. An increased response of FSH to gonadotrophin-releasing hormone testing has been described in patients with varicocele, while the co-influence of Yq chromosome microdeletions in the infertility associated to this pathology is still under investigation. We studied 30 patients with first- and second-grade varicocele, 15 idiopathic oligozoospermic men and 21 age-matched healthy controls. All subjects underwent testicular Doppler ultrasonography, semen analysis, gonadotrophin-releasing hormone testing and baseline blood sampling for total and free testosterone, PRL, 17beta-estradiol, SHBG evaluation and Yq chromosome analysis. Apart from FSH, no difference in baseline hormonal levels was found between the groups. The patients with varicocele showed both an increased basal (p=0.007) and GnRH-induced FSH response (peak and AUC) (p=0.004) in comparison with the controls, while the idiopathic oligozoospermic men had only higher GnRH-induced FSH AUC (p=0.04). In the varicocele group, FSH peaks after GnRH testing correlated positively with the grade of disease (r=0.42, p=0.02) and negatively with sperm count (r=-0.50, p=0.005) and bilateral testis volume (r=-0.52, p=0.005). Sperm count and sperm motility were similarly significantly reduced both in patients with varicocele and in patients with idiopathic oligozoospermia in comparison with healthy controls. Yq chromosome analysis by sequence-tagged site PCR revealed no microdeletion in the AZF regions in any subject studied. Given the quite small number of subjects studied, our overall findings can only prompt us to suggest a possible causal role of varicocele in the impairment of spermatogenesis in our patients. Furthermore, although a genetic co-influence (i.e. Yq microdeletions) does not seem to be involved in the pathogenesis of infertility in men with varicocele and mild to moderate oligozoospermia, genetic screening seems to be advisable, especially in those patients who present a severe impairment of sperm count, as has been suggested by recent literature data.     

Reproductive hormone studies in three subjects with a Robertsonian translocation

The reproductive hormone function was investigated in three subjects, two brothers and one unrelated patient, with a Robertsonian translocation, who had come to us because of infertility. Basal levels of LH, FSH, testosterone, 17-beta-estradiol and prolactin were repeatedly measured by radioimmunoassays. In addition, clomiphene citrate, synthetic LH-RH, hCG and TRH tests were carried out. Karyotypes complemented by G-banding and C-banding, repeated semen analyses, and testicular biopsies were also obtained. The karyotype of all three subjects was 45, XY-13, -14, +t(13; 14) (p11; q11). Semen analyses showed oligozoospermia, and reduced or reduced/normal sperm motility. In addition, a high percentage of atypical forms was present in all three subjects. Reproductive hormone measurements in our three patients were substantially normal. Only one of the two brothers exhibited slightly low LH and testosterone levels. Both brothers also had elevated estradiol levels. Gonadotropin and testosterone responses to respective provocative stimuli, as well as prolactin elevation following TRH, were normal. In conclusion, the semen abnormalities observed in these three subjects with Robertsonian translocation appear to be responsible for their impaired fertility. However, the reason why some carriers of the same translocation are fertile and some others are subfertile or infertile remains unclear. It might be speculated that an individual genetic variability is responsible for different degrees of spermatogenic failure, accompanied, in more severe cases, also by reproductive hormone disorders.     

Diagnostic value of bioactive FSH in male infertility

Bioactive FSH and immunoreactive FSH were determined in 193 infertile men and in 23 men with proven fertility using the Sertoli cell aromatase bioassay for bioactive FSH measurement and a two-site fluoroimmunoassay for immunoreactive FSH measurement. Overall bioactive and immunoreactive FSH levels correlated well (r = 0.74, p less than 0.001) but were significantly different from fertile men (bioactive FSH: 6.2 +/- 0.3 U/l; immunoreactive FSH: 4.1 +/- 0.4 U/l) in patients with Klinefelter's syndrome (24.1 +/- 6.1; 26.9 +/- 3.0), non-obstructive azoospermia (25.1 +/- 4.3; 22.2 +/- 4.0), maldescended testes (12.5 +/- 4.6; 14.6 +/- 1.6), and patients with severe oligozoospermia (11.9 +/- 1.2; 11.2 +/- 1.0). Infertile men with moderate oligozoospermia (8.9 +/- 1.5; 8.0 +/- 1.1) and normal sperm counts (9.6 +/- 1.1; 7.6 +/- 1.0) had insignificantly elevated bioactive FSH and immunoreactive FSH levels. Bioactive to immunoreactive FSH ratios were significantly reduced in all patient groups except for patients with normal sperm counts when compared with fertile men. A considerable number of patients exhibited elevated immunoreactive FSH concomitant with normal bioactive FSH levels. We conclude that 1. determination of immunoreactive FSH suffices for classification of patients; 2. bioactive to immunoreactive FSH ratios are reduced in infertile men; 3. some men might secrete immunoreactive FSH with reduced bioactivity.     

Testicular function after combination chemotherapy for Hodgkin's disease.

Fertility was estimated by sperm counts and hormone assays in 8 patients treated for Hodgkin's disease with at least 6 courses of combination chemotherapy. This consisted of an alkylator (mechloretamine or cyclophosphamide), a vinca alkaloid (vinblastine or vincristine), procarbazine and prednisone. Azoospermia was found in 7 of the 8 patients on examination 12-29 months after termination of chemotherapy. In 1 patient semen quality improved gradually, and a sperm count of 5 mill/ml was found at 21 months. Serum FSH levels were increased in all but 1 patient who was, nevertheless, azoospermic. The levels of testosterone and LH were generally within normal limits. Thus, the germinal tissue is seriously damaged by this type of chemotherapy. The resulting infertility seems to be complete and of long duration. Partial recovery of spermatogenesis may, however, sometimes take place after prolonged unsustained remission.     

Molecular and clinical characterization of Y chromosome microdeletions in infertile men: a 10-year experience in Italy

CONTEXT: An explosive growth in Y chromosome long arm (Yq) microdeletion testing demand for male infertility occurred in the past few years. However, despite the progresses in the biology of this chromosome, a number of molecular and clinical concerns are not supported by definitive data. OBJECTIVE: The objective was to provide information on the type and prevalence of microdeletions in infertile males, indication for testing, genotype-phenotype correlation, sperm aneuploidies, and genetic counseling. DESIGN AND SETTING: We performed a prospective study from January 1996 to December 2005 in an academic clinic. PATIENTS: We studied 3073 consecutive infertile men, of which 625 were affected by nonobstructive azoospermia and 1372 were affected by severe oligozoospermia. Ninety-nine patients with microdeletions are described here. MAIN OUTCOME MEASURES: Yq microdeletions, seminal analysis, reproductive hormones, testicular cytology/histology, and sperm sex chromosomes aneuploidies were used as outcome measures. RESULTS: The prevalence of microdeletions was 3.2% in unselected infertile men, 8.3% in men with nonobstructive azoospermia, and 5.5% in men with severe oligozoospermia. Only 2 of 99 deletions were found in men with more than 2 million sperm/ml. No clinical data are useful to identify a priori patients with higher risk of Yq microdeletions. Most deletions are of the AZFc-b2/b4 subtype and are associated with variable spermatogenic phenotype, with sperm present in 72% of the cases. Complete AZFa and AZFb (P5/Proximal P1) deletions are associated with Sertoli cell-only syndrome and alterations in spermatocyte maturation, respectively, whereas partial deletions in these regions are associated with milder phenotype and frequent presence of sperm. Men with AZFc-b2/b4 deletions produce a higher percentage of sperm with nullisomy for the sex chromosomes and XY-disomy. CONCLUSIONS: This extensive clinical research expands the knowledge on genotype-phenotype relationships and confirms that the identification of Yq microdeletions has significant diagnostic and prognostic value, adding useful information for genetic counseling in these patients.     

Inhibin B: a marker for the functional state of the seminiferous epithelium in patients with azoospermia factor C microdeletions

Testicular production of inhibin B is believed to be dependent on the presence of germ cells within the seminiferous tubules. However, this association has recently been questioned in patients with deletions of azoospermia factor (AZF) on the Y chromosome. We have addressed this problem in 442 unselected infertile/subfertile patients (excluding obstructive and iatrogenic forms) who were analyzed for Yq microdeletions. AZFc microdeletions were found in 16 patients (3.8% of the total infertile group, but 9% of the subgroup with azoospermia or severe oligozoospermia with sperm concentration <1 x 10(6)/ml). The reproductive hormone profiles in patients with AZFc microdeletions were analyzed and compared with those in infertile patients without microdeletions and those in fertile control individuals. The mean serum inhibin B concentration in the patients with AZFc microdeletions (39.5 +/- 36.0 pg/ml) was significantly lower than that in the group of infertile patients without microdeletions (134.6 +/- 88.5 pg/ml). However, no significant difference was found compared with that in a matched group of infertile patients with comparably low sperm counts (72.6 +/- 75.5 pg/ml). Bilateral testicular biopsies in the AZFc-deleted patients revealed a variable histological pattern suggestive of a progressive depletion of seminiferous epithelium. An association between testicular pathology and the reproductive hormone profile was found; the more severe forms had lower inhibin B and higher FSH levels. Importantly, if Sertoli cell-only tubules were prevalent in the biopsy, inhibin B was invariably undetectable. In patients with bilateral spermatocytic arrest, inhibin B remained within the normal range, which is consistent with a role of spermatocytes in the maintenance of inhibin B secretion. Our data support the view that, in contrast to recently published data, in patients with AZF microdeletions the serum concentration of inhibin B is dependent upon the functional interaction between Sertoli cells and spermatocytes and/or spermatids.     

PULSATILE GnRH-THERAPY IN OLIGOZOOSPERMIC MEN DOES NOT IMPROVE SEMINAL PARAMETERS DESPITE DECREASED FSH LEVELS

In order to evaluate GnRH administration for the treatment of infertile men with elevated serum FSH levels we administered GnRH in pulses via portable electronic infusion pumps initially to seven patients with low sperm counts and high FSH values over 12 weeks and later to nine further patients over 24 weeks who also underwent testicular biopsies. Fifty microlitres containing 5 micrograms GnRH were infused subcutaneously for 1 min every 120 min in the short-term study and every 90 min in the long-term study. Although FSH levels could be lowered in both groups of patients, none showed any improvement in sperm count or other seminal parameters. Therefore, pulsatile GnRH treatment cannot be recommended for therapy of severe oligozoospermia with elevated FSH levels.     

Testicular Function after Combination Chemotherapy for Hodgkin's Disease

Fertility was estimated by sperm counts and hormone assays in 8 patients treated for Hodgkin's disease with at least 6 courses of combination chemotherapy. This consisted of an alkylator (mechloretamine or cyclophosphamide), a vinca alkaloid (vinblastine or vincristine), procarbazine and prednisone. Azoospermia was found in 7 of the 8 patients on examination 12–29 months after termination of chemotherapy. In 1 patient semen quality improved gradually, and a sperm count of 5 mill/ml was found at 21 months. Serum FSH levels were increased in all but 1 patient who was, nevertheless, azoospermic. The levels of testosterone and LH were generally within normal limits. Thus, the germinal tissue is seriously damaged by this type of chemotherapy. The resulting infertility seems to be complete and of long duration. Partial recovery of spermatogenesis may, however, sometimes take place after prolonged unsustained remission.     

Gonadal function in male adolescents and young males with juvenile onset systemic lupus erythematosus

OBJECTIVE: To evaluate gonadal function in male adolescents and young men with juvenile onset systemic lupus erythematosus (SLE). METHODS: Four young men with SLE underwent clinical and laboratory evaluation, testicular ultrasound, follicle stimulating hormone, luteinizing hormone, prolactin, testosterone, and anti-sperm antibody determination. The semen analyses were performed according to the WHO guidelines and Kruger strict criteria. All patients were asked to provide 3 semen samples over a period of 2 months. A new sample was collected 6 months later. RESULTS: The median disease duration was 6.6 years. The median age at initial ejaculation was 13.5 years. All 4 patients had severe disease with renal involvement (WHO class IV or V). The SLICC/ACR damage index at the time of study entry ranged between 0 and 3. The patients' Tanner stage was P5G5; all reported normal erection and libido. Gonadal evaluation by thorough examination of the genitalia and ultrasound was normal. Anti-sperm antibodies were negative in all patients. Only one patient showed high FSH and LH levels. The initial and final semen evaluations of the 4 patients were abnormal (azoospermia, oligoastenoteratospermia, or teratospermia). One patient was receiving azathioprine and 2 were receiving cyclophosphamide at the time of study entry. CONCLUSION: Although these patients had normal sexual activity and normal external genitalia, their fertility was decreased based on the sperm abnormalities. Serial semen analyses in larger study populations will be necessary to clarify the degree and duration of sperm abnormalities in male patients with SLE in general.     

The presence of germ cells in the semen of azoospermic, cryptozoospermic and severe oligozoospermic patients: stringent flow cytometric analysis and correlations with hormonal status

OBJECTIVE: To understand the clinical significance of immature germ cells commonly found in ejaculates with low sperm counts by a novel and stringent flow cytometric quantitative method. PATIENTS/MEASUREMENTS: A total of 65 azoospermic, 38 cryptozoospermic and 42 severe oligozoospermic patients underwent routine hormone and semen analysis. Cells from each ejaculate were stained for DNA and mitochondria and analysed as spermatozoa (HC), round spermatids (1N), primary spermatocytes (4N) or diploid cells (2N). RESULTS: About 90% of HC particles were eliminated as contaminants of the spermatozoa population by the analysis of their laser light scatter pattern and mitochondria staining intensity. Ploidy identification accuracy was improved by selection of singlets and elimination of cell aggregates for analysis. Distribution peaks for HC, 1N and 4N cells were displayed in 53%, 56% and 25% ejaculates, respectively, with prevalence in severe oligozoospermia > cryptozoospermia > azoospermia. 1N cell numbers were correlated with 4N and HC cells. For HC and 1N cells, the number/ejaculate and the incidence of distribution peaks were correlated with serum testosterone levels, and inversely with FSH for HC, 1N and 4N cells, suggesting that the abnormal shedding of 1N and 4N germ cells is the consequence rather than the cause of spermatogenic failure in these patients. Ploidy data bear no association with clinical diagnosis except for Klinefelter patients. CONCLUSION: Whereas incidence of HC cells in azoospermic ejaculates may suggest minimal spermatogenic activity which evades detection by routine semen analysis, the presence of 1N and 4N cells in semen of patients provides noninvasive information about their spermatogenic status.     

A novel mutation (N233K) in the transactivating domain and the N756S mutation in the ligand binding domain of the androgen receptor gene are associated with male infertility*

OBJECTIVE: Resistance to androgens has been suggested as a possible cause of male infertility. This hypothesis is based mainly on binding studies in genital skin fibroblasts but the molecular evidence is sparse. DESIGN: Molecular studies of the androgen receptor gene were performed in 10 azoo- or oligozoospermic men, presenting with clinical signs of low androgen activity-poor virilization and high serum LH despite elevated testosterone levels, but without genital malformations. PATIENTS: Ten men with serum LH >10 IU/l and testosterone >30 nmol/l as well as a low sperm concentration < 20 x 106/ml. MEASUREMENTS: Genomic DNA was prepared from peripheral leucocytes and PCR-amplification of the coding region of androgen receptor was performed, followed by direct sequencing. Identified mutations were reconstructed by site-directed mutagenesis and the functional properties of the mutants were analysed, using transient expression in COS-1 cells and subsequent transactivation assays. Hormone binding assays were performed in genital skin fibroblasts from the patients. RESULTS: Two of the 10 men were shown to have a mutation in the androgen receptor gene. Subject 1, who presented with azoospermia, serum testosterone (T) 50 nmol/l and LH 20 IU/l, had a mutation in exon 1, changing amino acid asparagine 233 to lysine (N233K). In fibroblasts cultured from genital skin, the receptor affinity for 5alpha-dihydrotestosterone (DHT) was normal as compared to healthy controls, but the receptor-hormone complex was thermolabile at 42 degrees C. Subject 2 exhibited severe oligozoospermia and a similar endocrine pattern (T = 50 nmol/l and LH = 25 IU/l). He had a mutation in exon 5 changing asparagine 756 to serine (N756S). The affinity for DHT in cultured genital fibroblasts from this patient was reduced. Transactivation was abnormal for both mutants, N233K reaching 46% and N756S 38% of wild type activity when stimulated with 10 nmol/l DHT. CONCLUSIONS: Androgen receptor mutations may affect sperm production without resulting in genital malformations. Thus, in infertile men with a clinical presentation of poor androgen activity and an endocrine profile compatible with androgen resistance, mutations in the androgen receptor should be taken into consideration.     

Pregnancy in acromegaly: a one-center experience

OBJECTIVE AND DESIGN: The aim of the study was the retrospective evaluation of pregnancy in acromegalic women attending our center. PATIENTS AND METHODS: Six active acromegalic women (30-35-years old, disease duration 5-17 years) underwent seven pregnancies. Four patients had macroadenoma and two microadenoma; four had surgery; and two had been treated primarily with drugs. Before conception, GH and IGF-I were 5.4+/-0.8 and 430+/-58 microg/l respectively. GH (by an assay unable to distinguish pituitary hormone from placental variant), IGF-I, and prolactin (PRL) levels were assessed before conception, every 3 months, and after delivery; visual field and magnetic resonance imaging were performed before delivery in the only patient with macroadenoma not previously operated on and after delivery in all. RESULTS: All the women conceived normally, after discontinuation of medications in five cases and, while on treatment with depot somatostatin analogs in two (discontinued after confirmation of pregnancy). All patients remained off-treatment throughout pregnancy, had uneventful pregnancies, and term delivery. The babies were healthy and normal in length and weight. Breast-feeding was allowed in four cases. During pregnancy, GH levels showed variable changes; IGF-I, notwithstanding the withdrawal of any GH hypersecretion-suppressive treatment, remained close to normal limits in all subjects and returned to pathological levels after delivery; PRL increased physiologically, returning to baseline level after delivery. In one of the two patients primarily treated with drugs, GH levels increased and the tumor regrew throughout pregnancy, although without visual impairment. CONCLUSIONS: Pregnancy in acromegalic women has a normal course leading to a normal delivery, and produces normal babies. GH levels show variable changes, but decrease in most patients. IGF-I levels remain normal without medical treatment.     

Studies on the production rate of estradiol in the testis in male infertility--studies of the predictive values on therapeutic efficacy in patients with oligozoospermia]

It is surmised that studies on the relationship between the endocrinological milieu and therapeutic efficacy in male infertile patients are essential in elucidating the etiology of this disease and devising effective therapeutic methods. The relation between serum gonadotropin level and therapeutic efficacy has already been reported. In the present study, we investigated the basal levels of two sex steroids, i.e., testosterone and estradiol, and the estradiol:testosterone (E2/T) ratio, and also the increases in these parameters after the administration of hCG to human subjects presenting various degrees of testicular dysfunction, e.g., male infertile patients, aged males, Klinefelter's syndrome and hypogonadotropic hypogonadism. Special attention was given to the characteristics of the reserve capacity for secretion of estradiol in male infertile patients. The hCG test was performed on a total 527 subjects, including 65 normal adult males. The reserve capacity for the secretion of estradiol was investigated on the basis of the increasing rate in the serum E2/T ratio. The increasing rate in the serum E2/T ratio was statistically larger in subfertile males, oligozoospermia and azoospermia in comparison with the normal adult males. On the other hand, the aged males did not show any difference from the normal adult males, whereas the results were significantly lower in the male subjects with Klinefelter's syndrome and hypogonadotropic hypogonadism. It was considered that the increase in the serum E2/T ratio is one characteristic of the gonads of male infertile patients. The results of multiple regression analysis showed that the LH level, the pretreatment sperm concentration and the increasing rate in the serum E2/T ratio were important factors determining the increase in the sperm concentration after treatment. Accordingly, for cases of oligozoospermia characterized by an LH level of 13.7mIU/ml or less and a sperm concentration of 5 x 10(6)/ml or more, the relationship between the increasing rate in the serum E2/T ratio and therapeutic efficacy was investigated. It was found that the increasing rate in the serum E2/T ratio was significantly greater in the therapeutically ineffective cases compared with the therapeutically effective cases. On the basis of this finding, it was surmised that the percentage increase in the serum E2/T ratio is one index reflecting testicular function. In addition, for cases of oligozoospermia characterized by an LH level of 13.7mIU/ml or less, a sperm concentration of 5 x 10(6)/ml or more and the increasing rate in the serum E2/T ratio of 4.01 or less, the relationship between the degree of spermatogenesis and therapeutic efficacy was investigated.(ABSTRACT TRUNCATED AT 400 WORDS)     

A clinical trial of 7 alpha-methyl-19-nortestosterone implants for possible use as a long-acting contraceptive for men

Several preparations of testosterone and its esters are being investigated alone or in combination with other gonadotropin-suppressing agents as possible antifertility agents for men. We studied the effectiveness of 7 alpha-methyl-19-nortestosterone (MENT) as an antispermatogenic agent in men. MENT has been shown to be more potent than testosterone and to be resistant to 5 alpha-reduction. For sustained delivery of MENT, we used a system consisting of ethylene vinyl acetate implants containing MENT acetate (Ac), administered subdermally. Thirty-five normal volunteers were recruited in 3 clinics and were randomly assigned to 1 of 3 doses: 1 (12 men), 2 (11 men), or 4 (12 men) MENT Ac implants. The initial average in vitro release rate of MENT Ac from each implant was approximately 400 micro g/day. Implants were inserted subdermally in the medial aspect of the upper arm under local anesthesia. The duration of treatment was initially designed to be 6 months. However, in 2 clinics the duration of treatment was extended to 9 months for the 2-implant group and to 12 months for the 4-implant group. Dose-related increases in serum MENT levels and decreases in testosterone, LH, and FSH levels were observed. Effects on sperm counts were also dose related. None of the subjects in the 1-implant group exhibited oligozoospermia (sperm count, <3 million/ml). Four subjects in the 2-implant group became oligozoospermic, 2 of whom reached azoospermia. Eight subjects in the 4-implant group reached azoospermia, with 1 exhibiting oligozoospermia, whereas 2 were nonresponders. Side effects generally seen with androgen administration, such as increases in erythrocyte count, hematocrit, and hemoglobin and a decrease in SHBG, were also seen in this study and were reversible. Changes in lipid parameters were moderate and transient. Liver enzymes showed small changes. This study demonstrates that MENT Ac, when administered in a sustained release fashion via subdermal implants, can inhibit spermatogenesis over a prolonged period after a single administration and has the potential to be used as a male contraceptive.     

Analysis of sperm aneuploidy in infertile subjects after chemotherapy treatment

The continuing search for a cure for cancer has developed more aggressive therapies that may damage germ cells, leading to clinical disease in offspring of survivors. Standard therapy for the majority of cancer today consists in combinations of high doses of radiation and chemotherapy drugs. We investigated the effect of cancer treatments on the reproductive potential of men. Multicolor fluorescence in situ hybridization has been used to recognize chromosomes X, Y and 8 in sperm of 10 severely oligozoospermic subjects (sperm concentration < 5,000,000/mL) treated for cancer at least 5 years before the beginning of this study. As controls, we analyzed sperm aneuploidies in 20 fertile men (sperm concentration > 20,000,000/mL) and in 20 severe idiopathic oligozoospermic subjects (sperm concentration < 5,000,000/mL). In all subjects, X- and Y-bearing spermatozoa were present in a normal 1:1 ratio; nevertheless the frequency of 24,XY, 24,XX and 24,YY disomic sperm was significantly higher in patients treated for cancer and in idiopathic oligozoospermic subjects with respect to normozoospermic men. These results suggest that the increase in sperm aneuploidies in treated patients cannot be reported directly to precedent chemotherapy, but reflects the alteration of testicular structure, as in the case of severe idiopathic oligozoospermic subjects. With the advent of intra-cytoplasmic sperm injection, it is possible to offer the opportunity to conceive in men affected by severe oligozoospermia but it is also possible, when the spermatozoa of these subjects are used, to pass sex chromosome abnormalities on to the children. We therefore suggest caution before application of an artificial reproductive technique in severe oligozoospermic patients.     

Graves' ophthalmopathy in the absence of elevated free thyroxine and triiodothyronine levels: prevalence, natural history, and thyrotropin receptor antibody levels.

The aims of this study were to (a) determine the prevalence of patients without elevated thyroid hormone levels in Graves' ophthalmopathy (GO) using current generation free thyroid hormone assays, (b) measure the prevalence of thyrotropin receptor antibodies (TRAb) in these cases, and (c) identify possible predictors of hyperthyroidism. Over a 30-month period, 1020 cases of thyroid eye disease were evaluated, of which only 19 (1.9%) met the diagnostic criteria. Ten (1%) had subclinical thyrotoxicosis, 7 (0.7%) were euthyroid, and 2 (0.2%) were hypothyroid as determined by a third-generation thyrotropin (TSH) assay. TRAb levels were measured in 16 of these 19 patients. The prevalence of TRAb varied according to the assay used. Polyethylene glycol-extracted thyroid-stimulating immunoglobulin (PEG-TSI), unfractionated thyroid-stimulating immunoglobulin (uTSI), first-generation porcine TSH-binding inhibitory immunoglobulin (pTBII), and second-generation human TSH-binding inhibitory immunoglobulin (hTBII) assays were positive in 93.8%, 50%, 18.8%, and 81.3% of patients, respectively. TRAb was detected by at least one method in all patients. Patients were followed up for 15 to 45 months. Hyperthyroidism developed in 4 patients (25%). Suppressed TSH levels and elevated TBII were predictors of hyperthyroidism. When sensitive assays are used, the prevalence of GO patients without elevated thyroid hormone levels is extremely low. The sensitivities of assays for TRAb detection differ substantially in these cases. PEG extraction improves the detection rate of TSI (p = 0.02), and hTBII assays improve the detection of TBII in these patients (p = 0.002). The high prevalence of TRAb in such cases supports a role for these antibodies in the pathogenesis of thyroid-associated eye disease.     

Effects of high-dose methotrexate and vincristine on ovarian and testicular functions in patients undergoing postoperative adjuvant treatment of osteosarcoma

We have studied gonadal function in five patients (three men and two women) who received high-dose methotrexate (HD-MTX) alone and in 12 patients (seven men and five women) who received HD-MTX and vincristine (VCR) as postoperative adjuvant therapy for osteosarcoma. Testicular function was assessed by determination of testicular size, sperm concentration, and serum follicle-stimulation hormone (FSH), luteinizing hormone (LH), and testosterone levels while evaluation of ovarian function was based on menstrual history and serum FSH, LH, estradiol, and progesterone levels. The two women who received HD-MTX and all five women who received HD-MTX and VCR had regular cyclic menses not only after therapy but also during treatment. Serum FSH, LH, estradiol, and progesterone levels were normal in all women studied. Among the ten men studied, testicular function was normal in the six patients evaluated initially several months after the completion of therapy. In contrast, severe oligospermia was noted among four men evaluated during and immediately after treatment. From serum samples obtained before, during, and after treatment we have determined that approximately one half of the men who received HD-MTX alone or in combination with VCR develop transient testicular failure associated with a significant increase in serum FSH but not LH levels. Sperm concentration and serum FSH levels then return to normal after completion of chemotherapy.     

Galactorrhea-amenorrhea syndrome: follow-up of forty-five patients after pituitary tumor removal

Forty-five patients with galactorrhea-amenorrhea were followed during a period of 1 to 8 years (mean 3.1) after transsphenoidal prolactinoma removal. The ratios of patients who appear to be cured to the total numbers treated were 20 patients of 27 with grade I tumors; six of 10 with grade II; two of five with grade III; and none with grade IV tumors. Six patients with normal prolactin levels one week postoperatively had relapse later, as did three with normal prolactin levels 2 months postoperatively. A normal prolactin level 6 months postoperatively predicted ultimate cure. The 19 pregnancies that occurred in 15 patients, four with high prolactin levels, were uneventful. Prolactin rose normally with pregnancy and returned to prepregnancy level in all but one patient. Prolactin responses to stimulation tests were blunted for 6 months after successful tumor removal. By 1 year, responses to thyrotropin releasing hormone and metoclopramide tests were returning to normal, although responses to chlorpromazine and hypoglycemia remained blunted. The postoperative inhibition of normal lactotropes for 6 months is suggested. Ultimate cure cannot be determined before 6 months and conception should be deferred until then.     

精索静脉曲张患者血清生殖激素、精子形态、精子活率的变化

目的探讨精索静脉曲张（VC）对生殖激素及精子形态、精子活率的影响。方法检测81例VC所致男性不育患者和18例健康生育男性精液及血清标本,其中不育患者按VC临床分度分为Ⅰ°、Ⅱ°和Ⅲ°组,用放射免疫法测定血清催乳素（PRL）、卵泡刺激素（FSH）、黄体生成素（LH）、睾酮（T）、雌二醇（E2）水平;采用计算机辅助精液分析仪测定精子活率。结果Ⅱ°和Ⅲ°组FSH、LH低于对照组（P〈0．05）;Ⅰ°、Ⅱ°和Ⅲ°组的T、PRL和E2与对照组相比差异无统计学意义（P〉0．05）;Ⅱ°和Ⅲ°组正常形态精子百分率低于对照组（P〈0．05）;VC各组精子活率均低于对照组（P〈0．05）,且Ⅲ。组精子活率低于Ⅰ°和Ⅱ°组（P〈0．05）。结论VC可引起血清生殖激素FSH、LH变化,但VC临床分度对血清生殖激素水平的影响关系不明显。VC能够导致正常形态精子百分率和精子活率下降,VC程度越重,对精液正常形态精子率与活率的影响程度越大。