Chronic migraine: current concepts and ongoing treatments.

Migraine is an episodic painful disorder occasionally developing into a chronic form. Such disorder represents one of the most common neurological diseases in clinical practice. Chronicization is often accompanied by the appearance of acute drugs overuse. Chronic migraine (CM) constitutes migraine's natural evolution in its chronic form and involves headache frequency of 15 days/month, with features similar to those of migraine attacks. Medication Overuse Headache (MOH) has been defined as a headache present on > or = 15 days/month, with regular overuse for > 3 months of one or more drugs used for acute and/or symptomatic headache management. Subtypes of MOH attributed to different medications were delineated. Misuse of ergots, triptans, opioids or combination analgesics on > or = 10 days/month was required to make the diagnosis of MOH, while > or = 15 days/month were needed for simple analgesic-overuse headache. CM's low prevalence produces an extremely high disability grade. Therefore, special attention should be paid to both control and reduction of risk factors which might favour the migraine chronicization process and/or the outbreak of MOH. In MOH sufferers, the only treatment of choice is represented by drug withdrawal. Successful detoxification is necessary to ensure improvement in the headache status when treating patients who overuse acute medications. Different procedures have been suggested for withdrawal namely at home, at the hospital, with or without the use of steroids, with re-prophylaxis performed immediately or at the end of the washout period. At the moment we have not a total agreement whether prophylactic treatment should be started before, during, or after discontinuation of the overuse drug. Both drugs have been approved for CM treatment in view of their well-defined resistance to previous prophylaxis drugs. Recently, the PREEMPT clinical program has confirmed onabotulinumtoxinA as an effective, safe, and well-tolerated prophylactic treatment for adults with CM.

Male osteoporosis.

Osteoporosis is a worldwide major public health problem, defined as "a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fractures". Osteoporosis is diagnosed by bone mineral density measurement (T-score of -2.5 or below) also in men. However, most of the studies carried out in the last decade focused on pathogenesis, diagnosis and treatment of osteoporosis in women. In spite of this, recent epidemiological and observational studies have shown that osteoporosis in men is an increasingly important clinical issue. In part because the world population is aging, it is likely that the total number of hip fractures in men in 2025 will be similar to current estimates in women. Furthermore 25-33% of men in some populations will sustain osteoporotic fractures in their lifetime. Nevertheless, male osteoporosis is still underdiagnosed and further studies are required to clarify the pathogenesis and find out the right therapy. Prevention and early diagnosis are, nowadays, the best ways of treatment.

New frontiers in the treatment of male sterility.

Male factor responsibility in couple infertility has been exponentially increasing in recent years, due both to improved diagnostic techniques and to the important role of lesive factors, mainly environmental, on reproductive male function. Therefore, male infertility therapy is one of the most challenging topics of modern clinical medicine. Unfortunately, however, 30% of cases of male infertility must still be classified as "idiopathic." In these cases, no "causal" treatments can be used but only empiric treatments. These are lacking of an etiopathogenetic basis, and often result from theoretical concepts without a proven statistical effectiveness. These facts have somehow allowed the explosive development of the assisted reproduction techniques (ART). Andrologist's therapeutic strategies have so changed and are no longer aimed, as in the past, to achieve an increase in the spermatozoa number, but rather to improve the "quality" of semen, that is, the "fertility potential."

Androgens and penile erection: evidence for a direct relationship between free testosterone and cavernous vasodilation in men with erectile dysfunction.

OBJECTIVE: Androgens are essential in the maintenance of nitric oxide-mediated erectile activity in the rat. The objective of the present study was to investigate the role of androgens in regulating trabecular smooth muscle relaxation in the corpus cavernosum in response to vasoactive challenge in men with erectile dysfunction (ED). DESIGN: Retrospective, double-blind correlation analyses. PATIENTS: Fifty-two impotent patients without confounding risk factors for ED were obtained from a total of 250 undergoing diagnostic evaluation. MEASUREMENTS: All patients had dynamic colour duplex ultrasound (D-CDU) and hormonal evaluation for LH, total and free testosterone, SHBG and oestradiol. RESULTS: Based upon D-CDU results patients were diagnosed as having arteriogenic (AR, n = 18; mean age 51) or corporeal venocclusive (CVO, n = 13; mean age 49) ED; in other patients (n = 21, mean age 43) a diagnosis of psychogenic (P)-ED was made by comprehensive psychogenic testing and confirmed by normal D-CDU results. AR and CVO patients had altered compliance of cavernous arteries recorded by D-CDU [20-25% lower resistive index (RI) than patients with psychogenic ED], and lower free testosterone (FT) levels than psychogenic patients [42.3 +/-3.5 SE and 49.3+/-5.2 vs. 75.2+/-7.6 pmol/l, respectively; P<0.01]. More important, in all patients there was a strong direct correlation between resistive index values and FT levels (r = 0.47, P = 0.002); the relationship was maintained also when adjusted for age, SHBG and oestradiol (r = 0.37, P = 0.02). CONCLUSIONS: These results indicate that in men with erectile dysfunction low free testosterone may correlate independently of age with the impaired relaxation of cavernous endothelial and corporeal smooth muscle cells to a vasoactive challenge. These findings give clinical support to the experimental knowledge of the importance of androgens in regulating smooth muscle function in the penis.

Dazl protein expression in adult rat testis is up-regulated at meiosis and not hormonally regulated.

The Y-chromosomal DAZ (deleted in azoospermia) gene and the autosomal Dazl (deleted in azoospermia-like) gene are two crucial factors for the achievement and maintenance of spermatogenesis. Whereas Y-chromosomal DAZ is present in certain primates, it is lacking in rodents and other species. We have investigated the expression of Dazl protein during spermatogenesis in the adult rat testis using immunohistochemistry. Dazl immunoreactivity was found predominantly in the cytosol of primary pachytene spermatocytes. A weaker but clearly detectable signal was present in intermediate and B spermatogonia and in early spermatocytes from preleptotene to zygotene. The highest expression patterns were observed between stages IV and VIII during the spermatogenic cycle when spermatocytes prepare for the first meiotic division. Specific staining could also be observed in step 11-19 elongating spermatids in the acrosome region. Treatment for 42 days with a potent GnRH-antagonist abolished gonadotrophin secretion and led to a regressed testis, lacking most of the advanced germ cell types such as spermatids but still bearing spermatogonia and spermatocytes. No difference in staining pattern for Dazl protein was observed in GnRH antagonist-treated rats despite the lack of gonadotrophins and substantial impairment of the spermatogenic process, indicating that Dazl expression is clearly hormone-independent. The localization and level of Dazl expression suggests an important role in the regulation of the first meiotic stages of spermatogenesis. The hormone independent onset of expression points to an autonomous cell-cycle event in which Dazl seems to be essential for the entry into meiosis. The presence of Dazl in the acrosome region of elongating spermatids might reflect an unknown role of Dazl as a morphogenetic factor during spermiogenesis.

The Old World monkey DAZ (Deleted in AZoospermia) gene yields insights into the evolution of the DAZ gene cluster on the human Y chromosome.

The DAZ gene cluster on the human Y chromosome is a candidate for the Azoospermia Factor (AZFc). According to the current evolutionary model, the DAZ cluster derived from the autosomal homolog DAZL1 through duplications and rearrangements and is confined to Old World monkeys, apes and humans. To study functional and evolutionary aspects of this gene family we have isolated from a cynomolgus (Old World) monkey testis cDNA library the Y chromosomal cynDAZ and the autosomal cynDAZL1 cDNA. cynDAZL1 contains one DAZ repeat and displays high homology to human DAZL1. cynDAZ comprises 11 repeats, each consisting of exons 7 and 8, whereas the human DAZ cDNA repeat units contain predominantly exon 7. Genomic studies revealed the same amplific- ation events of a 2.4 kb genomic unit encompassing exons 7 and 8 in both species, indicating that after splitting of the two lineages, in the human mainly exon 8 was converted to a pseudoexon by splice site mutations. The structural features of cynDAZ reveal a more detailed model for the sequence of events leading to the present form of human DAZ. Thus, in a monkey species DAZ is present in a form more ancestral than that of the human. Studies on the immunolocalization of cynDAZ / DAZL1 in cynomolgus monkey testis revealed a biphasic expression pattern with proteins being detectable in A-pale to B-spermatogonia, late spermatocytes and spermatids, but not in early spermatocytes and late spermatids. In contrast, in the marmoset monkey, an animal lacking DAZ, DAZL1 protein was only expressed in late spermatocytes and early spermatids. These findings point to an additional function of cynDAZ / cynDAZL1 during spermato- genesis in the Old World monkey not needed in the New World monkey.

[Pharmacology of male sexual dysfunction]. / Farmacologia delle disfunzioni sessuali maschili.

The understanding of pharmacology of impotence has shown a steady improvement over the last 15 years which has resulted in a better appreciation of the neurovascular mechanisms of the erectile process especially at the level of the corpora cavernosa; however, central mechanisms which control libido and erection are not yet completely elucidated. Frequent diseases most commonly encountered in elderly patients--i.e. diabetes, hypertension, atherosclerosis, depression, etc--represent a frequent cause of erectile dysfunction (ED) and are treated with medications that can interfere with sexual functioning at the central and/or peripheral level. Antidepressants, including the tricyclics and the monoamine oxidase inhibitors, have been implicated in ED, decreased libido, and impaired ejaculation. Most antihypertensives have been associated with some erectile impairment, but diuretics seem to have little effect on erectile function. The calcium channel blockers and ACE inhibitors are associated with a low incidence of ED. Sympatholytic antihypertensives seldom cause importence but can cause retrograde ejaculation because of the relaxation of the smooth muscles in the prostatic urethra and bladder neck. The most commonly prescription drugs that can affect sexual function are briefly discussed and an integrated pharmacological approach to the patient with drug-induced ED is proposed.

Analysis of Yq microdeletions in infertile males by PCR and DNA hybridization techniques.

Defects in spermatogenesis have been found associated with deletions of different portions of Y chromosome long arm (Yq), suggesting the presence of the azoospermia factor in the control of spermatogenesis. We studied 67 men with idiopathic azoospermia and severe oligozoospermia, cytogenetically normal, for the presence of microdeletions on Yq chromosome. By using polymerase chain reaction (PCR) and Southern blotting techniques we analysed the AZFa, AZFb and AZFc loci on Yq, where deletions have been associated with defects in spermatogenesis. Deletions of a portion of the Y chromosome were detected in five patients. Four of these patients shared deletions in distal Yq11 interval 6, including the DAZ gene, while one patient lacked loci in the proximal Yq11. Testicular histology of two patients bearing distal Yq11 deletions showed two different spermatogenic defects including Sertoli cell-only (SCO) syndrome and maturation arrest, while the patient with microdeletions in the proximal Yq11 showed a SCO phenotype.

[Azoospermia and genetic mutations: implications for the methods of in vitro fertilization]. / Azoospermie e mutazioni geniche: implicazioni nelle tecniche di procreazione assistita.

Much evidence suggests the fundamental role of the Y chromosome during spermatogenesis. Especially, a gene on the long arm (localized in a portion of the chromosome called Yq11), the AZF (azoospermic factor), is necessary for the achievement and the maintenance of the spermatogenetic process. In fact mutations and deletions in this part of the chromosome inevitably cause severe oligozoospermia or azoospermia. Furthermore other genes on the short arm seem to have a role during spermatogenesis: they are called ZFY (zink finger Y, which encodes a DNA binding protein) and TSPY (expressed in the spermatids nuclei); but the function of these genes is still uncertain, since at this moment no deletions or mutations have been found at this level. Further genes only recently cloned include the CREM (cAMP-responsive element modulator), whose mutation causes azoospermia with a spermatidic arrest in the mouse, and the complex c-kit/Steel-factor. The latter is essential for spermatogonial proliferation and differentiation, so that an alteration at this level can determine spermatogonial arrest or the absence of germinal cells with the presence of Sertoli cells only (Sertoli cells only syndrome). In contrast with AZF, both the CREM gene and c-kit/Steel-factor genes are autosomal (chromosome 10 for the CREM, 4 for c-kit, 1 for Steel-factor, respectively). Several genes may be involved in the spermatogenetic process, but their role, excepting for AZF, is still unclear.

Anxiety-induced failure in erectile response to intracorporeal prostaglandin-E1 in non-organic male impotence: a new diagnostic approach.

Intracavernous injection (ICI) of prostaglandin-E1 (PGE1) is used widely as the first diagnostic test in the study of erectile dysfunction. However, a lack of full erection after a maximal dose is frequent. As well as vascular incompetence, this may be due to stress-induced changes, related to the ICI procedure. The aim of this study was to investigate the influence of emotional disturbances on erectile response to ICI in impotent patients. Initially, 24 young men with non-organic impotence (age 34.6 +/- 1.5 years; mean +/- SEM) were selected and randomized single-blind to pharmacoerection with PGE1 alone (20 micrograms/mL) or a mixture (cocktail) containing 20 micrograms PGE1 plus an alpha-adrenergic receptor blocker, phentolamine (Phe, 0.5 mg/mL). Additional studies were also performed double-blind on 10 men with non-organic impotence (age 37.6 +/- 1.2 years) utilizing higher PGE1 dosages for ICI (25 micrograms/mL alone or in combination with Phe, 0.5 mg/mL). After a 7-day interval, all subjects were crossed-over to receive the alternative treatment. The presence of emotional disturbances was assessed in all patients by the administration of rapid tests (Stai-X1 and Stai-X1r for state-anxiety before and after ICI, respectively; Stai-X2 for trait-anxiety; Zung-test for depression) at the first and at the remaining (Stai-X1 and Stai-X1r) ICI sessions. ICI with 20 and 25 micrograms/mL PGE1 led to a comparable percentage of patients who reported a valid-for-intromission (VFI) erection (63 and 60%, respectively). In contrast, use of the cocktails significantly increased the percentage of subjects with a VFI (87 and 90% of the total number of patients tested, respectively; p < 0.05). Moreover, a strong inverse correlation between state-anxiety scores (Stai-X1) and the erectile response to ICI with 20 and 25 micrograms PGE1 was found (r = -0.69, p < 0.001); such a correlation was not present in patients who underwent ICI with the cocktails. Two cases of prolonged erection occurred (one after 20 micrograms PGE1 and the other after 20 micrograms PGE1 plus Phe) which were reversed promptly by the intracavernous injection of metharaminol. It is concluded that the lack of a full erectile response after ICI with PGE1 can be related to the presence of a high 'state-anxiety' in the patients. In such patients, a VFI erectile response can be induced by the administration of a cocktail test-dose.