Understanding the role of cerebellum in early Parkinson's disease: a structural and functional MRI study.

Increasing evidence suggests that the cerebellum may have a role in the pathophysiology of Parkinson's disease (PD). Hence, the scope of this study was to investigate whether there are structural and functional alterations of the cerebellum and whether they correlate with motor and non-motor symptoms in early PD patients. Seventy-six patients with early PD and thirty-one age and sex-matched healthy subjects (HS) were enrolled and underwent a 3 T magnetic resonance imaging (MRI) protocol. The following MRI analyses were performed: (1) volumes of 5 cerebellar regions of interest (sensorimotor and cognitive cerebellum, dentate, interposed, and fastigial nuclei); (2) microstructural integrity of the cerebellar white matter connections (inferior, middle, and superior cerebellar peduncles); (3) functional connectivity at rest of the 5 regions of interest already described in point 1 with the rest of brain. Compared to controls, early PD patients showed a significant decrease in gray matter volume of the dentate, interposed and fastigial nuclei, bilaterally. They also showed abnormal, bilateral white matter microstructural integrity in all 3 cerebellar peduncles. Functional connectivity of the 5 cerebellar regions of interest with several areas in the midbrain, basal ganglia and cerebral cortex was altered. Finally, there was a positive correlation between abnormal functional connectivity of the fastigial nucleus with the volume of the nucleus itself and a negative correlation with axial symptoms severity. Our results showed that structural and functional alterations of the cerebellum are present in PD patients and these changes contribute to the pathophysiology of PD in the early phase.

Effect of chronic bromocriptine treatment on psychological profile of patients with PRL-secreting pituitary adenomas.

Hyperprolactinaemic patients are characterized by an altered psychological profile, positively modified by the administration of dopaminergic drugs. This would suggest that the same neurochemical disorder is responsible for both hyperprolactinaemia and abnormal psychological profile in these patients. To identify depression, anxiety, and aggressiveness, nine women affected by prolactin (PRL)-secreting pituitary adenomas were studied before and after 6 and 12 mo of bromocriptine therapy, by the use of different psychometric tests (Mean Minnesota Multiphasic Personality Inventory [MMPI], State-Trait Anxiety Inventory [STAI], and State and Trait Aggressiveness Scale [STAS]). As a group, the patients did not show any depressive, anxious, or aggressive tendencies. Furthermore, no significant modifications were observed during dopaminergic treatment. Patients bearing PRL adenomas seem to be characterized by a dopaminergic background different from that found in functional hyperprolactinaemia. This hypothesis could explain the different psychological configuration and behavior in response to the administration of dopaminergic compounds.

Luteinizing hormone pulsatility and computer-assisted analysis of sperm features in patients with Hodgkin's disease.

The aim of this work was to characterize further the impairment of the reproductive function reported in untreated male patients with Hodgkin's disease. We evaluated the pattern of luteinizing hormone pulsatility and unconventional sperm features by computer-assisted sperm analysis (CASA) in 20 adult patients affected by biopsy-proven Hodgkin's disease before they were submitted to any therapeutic approach. Changes of luteinizing hormone pulsatility were documented and consisted mainly in an increase in pulse number in comparison with control subjects (P < 0.05). On CASA, 1/3 of the patients showed a reduction in the sperm number but, when motility, velocity and linearity of progression were evaluated, the number of patients with seminal alterations rose to 2/3. Sperm velocity and linearity were already impaired in stages I and II, whereas sperm number was reduced only in stage III. Symptomatic patients, regardless of the stage, showed a significant deterioration of all parameters. Our study supports the view that in Hodgkin's disease, before any treatment, a disorder of the reproductive system is present, both at hypothalamic/hypophysial and the gonadal level, having a pathogenesis that deserves to be elucidated by further study.

Human Sertoli cells in vitro: morphological features and androgen-binding protein secretion.

Sertoli cells play a pivotal role in the regulation of spermatogenesis as they provide the anatomical basis of the blood-testis barrier. In the present paper we report some results of our studies on the ultrastructural features, the responsiveness to FSH, and the ability to secrete androgen-binding protein (ABP) of human Sertoli cells in vitro. The nucleus showed the characteristic foldings of the nuclear membrane, scattered chromatin, and a fibrillar nucleolus. In the cytoplasm Charcot-Boettcher crystals were present and active phagocytic activity was documented by the presence of vacuoles containing lipids and cellular debris. Human Sertoli cells in culture responded to FSH with a maximal rise in cAMP that was approx. 3-fold. This response to FSH is comparable to that reported for the adult rat but lower than that of the immature rat, and suggests that human as well as rat Sertoli cells could have a reduced response to FSH since sexual maturation was achieved. As no evidence has been reported on ABP secretion by human Sertoli cells in culture we evaluated the concentration of this protein in the Sertoli cell spent media. Human Sertoli cells in culture produced ABP and the response to FSH was dose-related. The Kd value of human ABP (hABP) was approx. 7.5 nM, being slightly higher than that of the rat ABP and an order of magnitude different from that of sex hormone-binding globulin (SHBG) present in human plasma. We also measured the association and dissociation rates of dihydrotestosterone-hABP complexes and the Kd/Ka ratio was very close to the value of Kd of the Scatchard analysis. The differences between hABP and SHBG may open the way to the selective measurement of ABP in many conditions of male infertility.

[The effect of neoplastic hyperprolactinemia on bone density]. / Ruolo dell'iperprolattinemia tumorale sulla densità ossea.

In young hyperprolactinaemic patients a reduction of bone mass density is frequently shown. However, until now the real mechanism has not been clarified (a direct role of PRL has been suggested). To better clarify the origin of the bone demineralization during hyperprolactinaemia we evaluated the BMD in a group of 24 proved PRL secreting pituitary adenomas. Based on menstrual characteristics the patients were subdivided in 3 groups: 1) oligomenorrhoea (OM), 2) amenorrhea lasting less than 2 years (AMa), 3) long-lasting amenorrhea (AMb). Twelve women with normal menstrual cycles served as controls. The BMD values at L2-L4 and thighbone levels were significantly reduced in the AMb group with respect to the other subgroups. The results support the hypothesis that BMD reduction in aPRL patients is secondary to hypoestrogenism and to the duration of amenorrhea rather than to hyperprolactinaemia.

Internal medicine and reproduction: male hypogonadism.

Awareness of the complex relation linking reproductive function and other major organ systems has been increasing only recently. We have tried to delineate some recent advances in our knowledge of male reproductive function and its disorders as they relate to Internal Medicine. The regulation of Gn-RH secretion and the influence of Gn-RH on gonadotropin secretion are among the most interesting aspects of hypothalamic-pituitary function. The pulsatile pattern of LH secretion is of particular interest in relation to the influence of gonadotropin secretory pattern on testis response. In this regard oligozoospermia with elevated FSH levels and decreased frequency of LH pulses has been identified. Sertoli cells play an essential role in the control of spermatogenesis. We investigated some features of human Sertoli cell function in vitro. These cells secrete transferrin and ABP, and hABP has an affinity for DHT which is different from that of liver-produced SHBG. Seminal transferrin is closely linked to spermatogenesis in oligozoospermia as well as in azoospermia due to damaged spermatogenesis. As a third point of interest paracrine control of testis function, and especially the paracrine role of endogenous opiates and several growth factors are described. LH pulsatility was studied in several medical and endocrine disorders to investigate their impact on male reproductive function. An altered pattern of LH secretion was found in most of the diseases investigated, and in some instances there were hints of hypothalamic involvement. Finally the negative influence on male reproductive function of several drugs, commonly used in the practice of internal medicine is stressed.

[Alteration of luteinizing hormone pulsatility in patients with arterial hypertension]. / Alterazione della pulsatilità dell'ormone luteinizzante in pazienti affetti da ipertensione arteriosa.

The pattern of luteinizing hormone (LH) secretion in men with mild and moderate hypertension was studied. LH pulsatility was evaluated for eight hours in 14 male patients, who were subdivided into two groups: group A, consisting of 8 patients, whose systolic blood pressure ranged between 180-160 mmHg and the diastolic between 104-95 mmHg; group B, 6 patients whose systolic blood pressure ranged between 220 and 180 mmHg and the diastolic between 115-105 mmHg. Seven healthy adult males were evaluated as a control. The major changes of LH pulsatility in group A included an increased peak width (p < 0.05), increased peak amplitude (p < 0.001) and increased peak area (p < 0.001). In group B the changes followed the same pattern as in group A, but were more pronounced. The number of LH peaks was reduced (p < 0.01), the peak width was increased (p < 0.05), and both peak amplitude and peak area were increased as compared to the control group (p < 0.001). Our study demonstrates that the pattern of LH pulsatility is altered in essential hypertension and the main feature is represented by the prolonged duration of LH peaks and their greater amplitude. The altered pattern of LH secretion is likely to reflect a primary hypothalamic derangement with the gonadotropin releasing hormone (Gn-RH) secreting neurons remaining synchronized for longer times and secreting larger Gn-RH masses than in normal subjects.

Insulin resistance and secretion in polycystic ovarian disease.

In order to verify the relationship between insulin resistance and hyperandrogenism in Polycystic ovary disease (PCOD), circulating levels of insulin in response to oral glucose tolerance test (OGTT) were assessed in 23 PCOD patients and 10 matched control subjects without obesity, acanthosis nigricans and impaired glucose tolerance. In PCOD patients serum total testosterone (T), dehydroepiandrosterone sulfate (DHEA-S), LH and LH/FSH ratio were significantly higher than in control subjects; whereas urinary 17-ketosteroids (17-KS) and glycemic response to OGTT were not different. PCOD patients were clearly hyperinsulinemic before and during OGTT compared to the control group: mean +/- SD basal insulin (Io) (23.4 +/- 10.3 vs 11.3 +/- 4.6 microU/ml, p less than 0.001) and the sums of insulin levels (sigma I) during OGTT (341.4 +/- 148.9 vs 162.2 +/- 56 microU/ml, p less than 0.001). In the two groups serum T, but not DHEA-S, LH, urinary 17-KS and the degree of obesity, was strongly associated with Io (r = 0.458, p less than 0.01) and sigma I (r = 0.419, p less than 0.02), as well as with insulin resistance as assessed by basal (r = 0.425, p less than 0.02) and postglucose challenge (r = 0.384, p less than 0.05) insulin to glucose ratio. These results confirm that the hyperinsulinism and insulin resistance in PCOD is not related to obesity and suggest that the hyperandrogenism may be partially responsible of the observed imbalance in glucose-insulin homeostasis.

Lactate dehydrogenase and malate dehydrogenase of Sertoli cells in rats.

Lactate-dehydrogenase (LDH) and malate-dehydrogenase (MDH) activities and isozyme patterns of maturing Sertoli cells were investigated in cultured cells obtained from 2-5-week-old rats. Both enzymes, and more strikingly LDH, increased between 2 and 3 weeks of age. LDH isozyme complement included all five isozymes and, in the more mature rats, had a shift toward the isoforms rich in subunit. These data are consistent with an increasing production of lactate/pyruvate and with a finer regulation of this production occurring during the maturing of Sertoli cells. Since lactate/pyruvate are important energy substrates for germ cells, the changes of LDH activity and isozyme patterns of maturing Sertoli cells support their nutritional role in the seminiferous epithelium.

Effects of Lonidamine on pituitary-gonadal axis in man.

Lonidamine was given for 3 weeks at the dose of 150 mg three times daily to 6 male cancer patients. Serum follicle-stimulating and luteinizing hormone levels were significantly higher as compared to pretreatment values after 1 and 3 weeks of Lonidamine administration, while testosterone, prolactin, and thyroid-stimulating hormone levels remained unchanged.

Treatment of infertile couples by intrauterine artificial insemination homologous (AIH) of motile sperm collected by swim-up in human serum.

Twenty six couples with long standing infertility were treated by intrauterine AIH. Seminal and/or cervical factors were responsible for negative or poor coital test (PCT); retrograde ejaculation occurred in one case. A highly concentrated motile sperm suspension was obtained by swim-up procedure into fasting human serum and utilized for intrauterine insemination. Timing of ovulation was checked with the aid of ultrasound monitoring of follicular development. Totally, 120 cycles were treated. The pregnancy rate was 23.3%. Intrauterine AIH with motile sperm recovered by swim-up in human serum appears a valuable approach in the treatment of infertile couples with poor PCT as well as in cases of retrograde ejaculation.

Seminal estrone, estrone sulfate, and estradiol-17 beta levels in fertile and infertile males.

The seminal levels of estrone (E1), estrone sulphate (E1S), and estradiol-17 beta (E2) were measured simultaneously after a chromatographic step in the semen samples of 79 men, including fertile volunteers, vasectomized subjects, and patients with oligozoospermia and secretory azoospermia. E1S concentrations in seminal plasma were higher than in serum (with a semen/serum ratio of approximately 2). Seminal E1 and E1S levels in oligozoospermic subjects were significantly decreased compared to controls (p less than 0.02 and p less than 0.03, respectively). The seminal E1S concentration was significantly reduced in azoospermic patients (p less than 0.02) and to a greater extent in vasectomized subjects (p less than 0.001). As seminal E1S is likely to be mainly of testicular origin, the decreased seminal E1S levels in oligoazoospermia are an index of impaired testicular function.

Computer assisted sperm motility analysis.

The CellSoft system was employed to study its reliability in the evaluation of seminal data in fertile and infertile subjects. In addition new motility data were introduced and added to the classic parameters. Various clinical and experimental applications are reported. The system is valid and extremely useful in seminal research. In order to obtain the above mentioned benefits it is necessary for the users to have extensive experience of seminology and computer technology.

Detection of sperm surface related antibodies by indirect immunofluorescence test on sperm suspensions. Indirect IFT on sperm suspensions.

An indirect immunofluorescence test (IIFT) using sperm suspensions was carried out on 20 sera with sperm agglutinins (SA) and on 25 negative controls. IIFT gave results highly correlated with the occurrence of sperm agglutinating activity. Moreover, a relation was found among class of Ig involved in IF reactivity, fluorescent stain pattern and type of sperm agglutinations. In all sera with "mixed" or "tail-tail" sperm agglutinating activity, IgG were involved in IF reactivity; the fluorescent stain constantly appeared in a granular pattern along the sperm tail and most often on the head surface too. In relation to high titres of "head-head" sperm agglutinating activity, IgM were involved in IF reactivity; here the fluorescent stain appeared to be localized on acrosomal surface. The results indicate that indirect IFT on sperm suspensions specifically detects sperm surface related antibodies.

Endothelin-1 stimulates deoxyribonucleic acid synthesis and contraction in testicular peritubular myoid cells.

In the testis, endothelin-1 (ET-1) is produced by Sertoli cells, and it has been proposed to be a paracrine factor participating in the regulation of tubular and interstitial function. The response of purified testicular peritubular myoid cells (TPMC) to ET-1 was investigated in the present study. TPMC expressed a single class of high-affinity receptors that were shown by competitive binding experiments with sarafotoxin-6c to belong to the ETA subtype. The binding of ET-1 to TPMC was followed by rapid internalization of the receptor-ligand complex. ET-1 induced a prompt rise in intracellular Ca2+ concentration that was blunted in Ca(2+)-free medium and in the presence of Mn2+ or of voltage-operated-calcium-channel (VOC) blockers, indicating that both Ca2+ mobilization from intracellular stores and extracellular Ca2+ influx were involved. Thymidine uptake was promoted by ET-1 in a time-dependent manner, and the use of cyclo[D-Asp-L-Pro-D-Val-L-Leu-D-Trp] (BQ123) reduced the incorporation of thymidine. Protein kinase C (PKC) inhibition (100 nM calphostin C) abolished the ET-1 mitogenic effect. ET-1 also promoted TPMC contraction, as evaluated in collagen lattices, in a dose-related manner, with the half-maximal response observed at 1 nM. As in the case of mitogenesis, BQ123 blunted ET-1-induced contraction. PKC inhibition abolished ET-1-induced contraction. These findings indicate that ET-1 promotes DNA synthesis and contraction of TPMC and that both effects are mediated by PKC; they suggest as well that ET-1 may have a physiological role in the interaction between Sertoli cells and TPMC.

Testicular peritubular myoid cells are a target for adrenomedullin.

Adrenomedullin (AM) is a recently cloned vasorelaxing peptide that belongs to the calcitonin gene-related peptide family. AM inhibits the contraction of several types of smooth muscle cells and is present in the testis as well as in many other organs. The authors investigated whether testicular peritubular myoid cells (PMC) possess specific receptors for AM. Binding of AM to PMC was saturable in a time-dependent manner and 125I-AM binding was effectively displaced by cold AM. The study documents that testicular peritubular myoid cells are a target for adrenomedullin and suggests a role for this peptide in the paracrine regulation of the testis.

Ultrastructural changes in the seminiferous tubule wall and intertubular blood vessels in human cryptorchidism.

Biopsy material was obtained from adult men whose both testes had descended into the scrotal sac either spontaneously by use of pharmacologic agents or through surgery at age 7--16 yr, and from undescended testes obtained during orchipexy in men 8--40 yr of age. Testes appeared normal until the 10th yr, when progressive alterations were observed with the onset of puberty and through the adult age both in retained testes and cases of testes that descended through chemical or surgical methods before or after puberty. A thickening of the inner and outer acellular layers of the seminiferous tubule wall was due to an accumulation of collagen fibers and microfibrillar material. The basement membrane was also thickened and appeared as a homogeneous or a multilaminar structure. The intertubular blood vessels presented a thickening of the tunica media and a laminar accumulation of basement-membrane-like material.

[Gonadotropin response to slow infusion of GN-RH in idiopathic ologospermia. Preliminary findings]. / Risposta gonadotropinica all'infusione lenta di GN-RH nella oligospermia idiopatica. Rilievi preliminari.

Gn-RH was administered i.v. to infertile patients presenting with idiopathic oligospermia at a constant rate (0,4 microgram) for 4 h. All the patients showed an increased FSH response, and LH levels higher than normal in both the first and the second peak of response. Our data indicate that an increased pituitary sensitivity and reserve of FSH and LH are present in idiopathic oligospermia, suggesting an involvement of both Leydig cells and seminiferous epithelium in this condition.