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Objective: Previous studies on the effects of altered thyroid function on the secretion and metabolism of adrenocortical hormones suggest a degree of adrenocortical hyperactivity in hyperthyroidism. We have previously shown that experimentally-induced hyperthyroidism is associated with significant alterations in pituitary–adrenal responsiveness to synthetic ovine corticotropin-releasing hormone (oCRH) that are contingent upon the duration of the altered thyroid function. The purpose of this study was to assess the time-dependent effects of hyperthyroidism on the functional integrity of the hypothalamic–pituitary–adrenal (HPA) axis by in vivo stimulation of the hypothalamic CRH neuron and adrenal cortex. Methods: The functional integrity of the HPA axis was examined in vivo in sham-thyroidectomized male Sprague-Dawley rats given placebo or in thyroidectomized rats given 50 μg of thyroxine every day for 7 or 60 days. Responses to insulin-induced hypoglycemia and IL-1α stimulation were used to assess the hypothalamic CRH neuron. Adrenocortical reserve was assessed in response to low-dose adrenocorticotropic hormone (ACTH), following suppression of the HPA axis with dexamethasone. Adrenal and thymus tissue weight, in addition to basal plasma ACTH, corticosterone and thyroid indices were also determined. Results: Basal plasma corticosterone and corticosterone binding globulin (CBG) concentrations were significantly increased in short- and long-term hyperthyroid rats, and by 60 days, cerebrospinal fluid (CSF) corticosterone levels were significantly increased. Basal plasma ACTH levels were similar to controls. Although plasma ACTH responses to hypoglycemic stress and IL-1α administration in both short- and long-term hyperthyroidism were normal, corticosterone responses to the ACTH release during the administration of these stimuli were significantly increased. The adrenal reserve was significantly elevated in short-term hyperthyroidsim. Long-term hyperthyroidism, however, was associated with a significant reduction in adrenocortical reserve. A significant increase in adrenal weights and a decrease in thymus weights were observed in both short- and long-term hyperthyroidism. Conclusions: The available data confirms that hyperthyroidism is associated with hypercorticosteronemia, although the locus that is principally affected still remains unclear. Despite the sustained hyperactivity of the HPA axis, long-term experimentally-induced hyperthyroidism is associated with diminished adrenal functional reserve. The alterations in HPA function in states of disturbed thyroid function were found to be somewhat more pronounced as the duration of thyroid dysfunction increased.

BACKGROUND: Patients with oligoasthenoteratozoospermia (OAT) and normal karyotypes have an increased sperm aneuploidy rate. This may be due to an altered intratesticular environment that affects the chromosomal segregation mechanism(s). Alternatively, it may be due to a generalized meiotic and mitotic abnormality. In this case, patients with abnormal spermatogenesis should also have an increased somatic cell aneuploidy rate. To test this hypothesis, we evaluated peripheral leukocyte aneuploidy rate in patients with spermatogenic impairment. METHODS: In all, 38 patients were enrolled, of whom 20 had OAT, 15 non-obstructive azoospermia and three Y chromosome (Yq) microdeletions (AZF). Eight healthy normozoospermic men with proven fertility were recruited as controls. Conventional karyotype analysis, AZF microdeletion evaluation and triple-colour FISH for chromosomes X, Y and 12 were conducted in all patients and controls. A total of 1000 lymphocytes were scored for each patient and control. RESULTS: All patients and controls had a normal karyotype. Sex chromosome aneuploidy rates in peripheral lymphocytes was significantly higher in patients with OAT (0.74 6 0.09%), azoospermia (1.15 6 0.15%) or Yq microdeleted (1.54 6 0.40%), compared with controls (0.15 6 0.03%) (P

BACKGROUND: A large proportion of patients undergoing ICSI have been shown to have an increased sperm aneuploidy rate. This study was undertaken to evaluate the impact of sperm aneuploidy on ICSI outcome. METHODS: To accomplish this, 48 consecutive unselected male patients (median age 34 years) had their sperm aneuploidy rate evaluated in the same swim-up preparation used for ICSI. Chromosomes 8, 12, 18, X and Y were evaluated by fluorescence in-situ hybridization. Patients were divided into two groups (A and B) based on the sperm aneuploidy frequency in their sperm. Group A had values below and group B above the upper limit of normal [1.55%, determined in 14 healthy men (median age 25 years) with normal semen parameters by WHO 1999 criteria (control group)]. RESULTS: Group A consisted of 12 patients (25%) whose sperm aneuploidy rates fell below the cut-off value of the control group (median 1.25%; range 0.85‐1.52). Group B consisted of the remaining 36 patients (75%), who had an elevated sperm aneuploidy rate (median 3.25%; range 1.64‐23.60). Fertilization (93 versus 85%) and cleavage (100 versus 98%) rates were similar for both groups. Group A had significantly higher clinical pregnancy (75 versus 34%; P < 0.001) and implantation (34 versus 13%; P < 0.001) rates compared with group B. In addition, group A had a lower overall miscarriage rate (11.1 versus 38.9%). Other factors that affect pregnancy and implantation, such as patient age and conventional semen parameters, were similar for both groups. CONCLUSION: This study showed that chromosomally abnormal sperm have a negative impact on ICSI outcome.

Background We have recently shown that patients with prostato-vesiculo-epididymitis (PVE) have a greater reactive oxygen species (ROS) overproduction than patients with prostatitis or prostato-vesiculitis. Since this biochemical stress persists even after treatment with antimicrobials, it may relate to an imbalance between pro- and anti-oxidant factors at the epididymal level. Methods To evaluate the effects of antioxidant treatment of patients with PVE, whether in the presence or absence of pro-oxidant factors, abacterial PVE infertile patients with normal ( 1x10(6)/ml, group B, n = 20) seminal white blood cell (WBC) concentrations received carnitines (L-carnitine 1 g and acetyl-carnitine 0.5 g twice/day) for 3 months followed by a wash-out period of 3 months. Semen parameters, ROS production and pregnancy outcome were evaluated before, during and following carnitine treatment. Results Carnitines increased sperm forward motility and viability in group A patients. This was associated with a significant reduction in ROS production which persisted during wash-out. Carnitines increased only the percentage of viable spermatozoa in group B patients. Within 3 months after the discontinuation of carnitines, the rate of spontaneous pregnancy in group A patients was significantly higher than that of group B patients, being 11.7% (4/34) compared with 0%. Conclusion These results indicate that carnitines are only an effective treatment in patients with abacterial PVE and elevated ROS production when seminal WBC concentration is normal.

BACKGROUND: The aim of this study was to evaluate whether treatment with acarbose, an α-glucosidase inhibitor, improved hyperandrogenic symptoms, insulin and androgen serum concentrations in hyperinsulinaemic patients with polycystic ovary syndrome (PCOS). METHODS: 30 hyperinsulinaemic women with PCOS and 15 controls were evaluated. Patients were randomized, using a computer-generated randomization list, into two groups of 15 each and treated with placebo or 300 mg/day of acarbose for three months. Hirsutism and acne/seborrhoea scores, hormonal and sex hormone binding globulin serum concentrations, glycaemia and insulin responses to a standard oral glucose load (75g) were measured in all patients before and after three months of treatment. RESULTS: A significant reduction of the acne/seborrhoea score was observed in patients treated with acarbose and eight of them resumed a regular menstrual rhythm. These clinical improvements were associated with a significant reduction of the insulin response to glucose load, a significant decrease of LH, total testosterone and androstenedione and with a significant increase of sex hormone binding globulin serum concentrations. The serum concentrations of FSH, dehydroepiandrosterone sulphate, prolactin and 17α-hydroxyprogesterone did not change significantly. No clinical, metabolic and hormonal modifications were observed in PCOS patients treated with placebo. CONCLUSIONS: This is the first report showing a reduction of the acne/seborrhoea score in hyperinsulinaemic patients with PCOS treated with acarbose. This improvement was associated with a significant decrease of the insulin response to oral glucose load and of LH and androgen serum concentrations and with a significant rise of sex hormone binding globulin concentration.

BACKGROUND: Men with oligoasthenoteratozoospermia (OAT) frequently undergo intracytoplasmic sperm injection (ICSI) as a treatment for their infertility. However, there is an increased risk of transmitting chromosomal abnormalities to the offspring given that natural selection is bypassed by the use of this technique and patients have an increased rate of sperm aneuploidy which, in addition, may negatively affect ICSI outcome. For this reason, the rate of sperm aneuploidy in unselected patients undergoing ICSI and its impact on ICSI performance have been evaluated. METHODS: Aneuploidy and diploidy were evaluated in spermatozoa separated by swim-up for oocyte injection, using DNA probes for chromosomes 8, 12, 18, X and Y. RESULTS: ICSI patients had sperm aneuploidy and diploidy rates significantly higher than those of 13 normozoospermic men who served as controls. Although the total aneuploidy rate varied considerably between the 18 patients, 15 of them (83%) had values above the upper range of the control group. Eighteen ICSI cycles were performed with an overall fertilization rate of 95% and a pregnancy rate of 39%. The aneuploidy rate of the 11 patients whose wives did not achieve pregnancy was slightly higher than that of pregnant couples, but the difference did not reach statistical significance. However, 10 patients in this group (91%) had a sperm aneuploidy rate well above the upper limit of the controls as compared with two patients in the 'pregnant' group (29%). CONCLUSIONS: This study has shown that unselected patients undergoing ICSI had an elevated sperm aneuploidy rate. Lack of pregnancy was associated with a tendency towards an increased aneuploidy rate; however, pregnancy occurred even in the presence of an elevated sperm aneuploidy rate.

A large proportion of patients with oligoasthenoteratozoospermia (OAT) have an abnormal karyotype and hence they produce aneuploid gametes. However, a normal karyotype does not exclude the chance of having germ cell aneuploidy, since an altered intra-testicular environment not only damages spermatogenesis, but may also disrupt the mechanisms controlling chromosomal segregation during meiosis. Therefore, this study was undertaken to evaluate the rate of aneuploidy in the spermatozoa of selected patients with abnormal sperm parameters. For this purpose, sperm aneuploidy rate for chromosomes 8, 12, 18, X and Y was evaluated by multicolour fluorescence in-situ hybridization (FISH) in nine patients with teratozoospermia alone and 19 OAT patients of presumably testicular origin. Thirteen normozoospermic healthy men served as controls. Patients with teratozoospermia or OAT had significantly greater disomy and diploidy rates compared with controls, whereas the rate of nullisomy was similar. XY disomy was very low in all groups, suggesting that chromosomal non-disjunction occurs mainly during the second meiotic division. Autosome 12 disomy rate was low in both patients and controls. There was a marked variability of total sperm aneuploidy rate in both groups of patients. Sperm aneuploidy rate was negatively correlated with sperm concentration and particularly with the percentage of normal forms. In conclusion, patients with teratozoospermia or OAT have an increased rate of sperm aneuploidy. This increase is similar in both groups, suggesting that teratozoospermia may be the critical sperm parameter associated with aneuploidy.

Experimental evidence suggests a tight relationship between cytokines and the reproductive system. Tumour necrosis factor alpha (TNF alpha), a cytokine produced by activated macrophages and mesenchymal cells, seems to participate in the control of fertility. Therefore, the present study was undertaken to evaluate the concentrations of TNF alpha in the follicular fluid of female patients with immunological infertility, as well as the possible role of this cytokine in follicular development. Concentrations of TNF alpha, 17 beta-oestradiol, progesterone, androstenedione and testosterone were measured in the follicular fluid of patients with immunological infertility and patients with a tubal factor of infertility, who served as a control group. Patients with immunological infertility had significantly higher concentrations of TNF alpha in their follicular fluid compared to the control group. In contrast, oestradiol concentrations were significantly lower in the former group. The intrafollicular concentrations of the other steroids measured did not differ significantly between the two groups. The fertilization rate of ova from follicles included in the study was significantly lower in patients with immunological infertility compared to control subjects (19.1 and 57.1% respectively). In conclusion, this study shows that patients with infertility of immunological origin have increased follicular fluid concentrations of TNF alpha and lower oestradiol concentrations. We speculate that elevated TNF alpha concentrations in the human follicle may negatively influence both ovulation-and fertilization-related events.

This study was undertaken to evaluate the effects of gamma-aminobutyric acid (GABA) and GABAergic agonists and antagonists on sperm kinematic parameters and hyperactivation, evaluated by a computer-assisted semen analysis (CASA) system, and intracellular cAMP content in 22 normozoospermic semen samples. Because of the possible interaction of progesterone with the GABAA receptor, we also evaluated the effects of progesterone on these parameters. GABA increased beat cross frequency, curvilinear velocity (VCL), the percentage of spermatozoa moving with an average path velocity > 10 microns/s (active) and hyperactivation, and decreased linearity and straightness. Bicuculline, a GABAA receptor antagonist, antagonized the effects of GABA on all these parameters except the percentage of active spermatozoa. Muscimol, a GABAA receptor agonist, increased VCL, the percentage of active spermatozoa, and hyperactivation by about the same extent as GABA, suggesting the involvement of the GABAA receptor. However, the GABAB receptor also seems to mediate some of the effects of GABA, because baclofen, a selective agonist for this receptor, increased significantly the percentage of active spermatozoa and hyperactivation. The effect of baclofen on this latter parameter was, however, less pronounced than that obtained with GABA or muscimol. Progesterone had the same effects as GABA on sperm kinematic parameters and hyperactivation and the simultaneous presence of both compounds was not more effective than each single one. GABA and progesterone did not have any effect on intracellular cAMP content. In conclusion, GABA modulated sperm kinematic parameters and increased hyperactivation. These effects have the same magnitude of those produced by progesterone and seem to be mediated mainly by the GABAA receptor. We speculate that GABA may be a physiological regulator of sperm function.

Gonadotropin-releasing hormone analogues (GnRH-A) induce inhibition of testicular function and reduction of serum testosterone (T) in man, but the mechanism involved is still debatable. To elucidate it we studied six patients with hypogonadotropic hypogonadism (HH) in chronic substitution with hCG for correction of androgen deficiency symptoms, and evaluated the effect of addition of GnRH-A to the hCG therapy on plasma levels of T and 17α-hydroxyprogesterone (17 OHP). All patients were treated with 1000 U of hCG im every 3rd day for 24 weeks. After 8 weeks of this regimen, GnRH-A, Buserelin (D-Ser-TBU-EA-LHRH), 200 μg per day sc, was added and given for 8 weeks. After cessation of analogue administration patients were followed for 8 further weeks. The levels of the two steroids did not differ markedly in the pre- and post-GnRH-A period. GnRH-A given for two months did not lower T or 17 OHP levels as in eugonadal men after similar treatment. The median T concentrations during GnRH-A tended to be increased, with plasma values higher (P < 0.025) than the peak values observed during hCG alone. Since administration of Buserelin did not inhibit hCG-sustained steroid levels in these HH patients, it is conceivable that GnRH-A may have lacked a direct inhibitory gonadal effect in such experimental conditions.