Management of hypertensive emergencies: a practical approach.

Background: Acute increases of high blood pressure values, usually described as 'hypertensive crises', 'hypertensive urgencies' or 'hypertensive emergencies', are common causes of patients' presentation to emergency departments. Owing to the lack of ad hoc randomized clinical trials, current recommendations/suggestions for treatment of these patients are not evidenced-based and, therefore, the management of acute increases of blood pressure values represent a clinical challenge. However, an improved understanding of the underlying pathophysiology has changed radically the approach to management of the patients presenting with these conditions in recent years. Accordingly, it has been proposed to abandon the terms 'hypertensive crises' and 'hypertensive urgencies', and restrict the focus to 'hypertensive emergencies'. Aims and Methods: Starting from these premises, we aimed at systematically review all available studies (years 2010-2020) to garner information on the current management of hypertensive emergencies, in order to develop a novel symptoms- and evidence-based streamlined algorithm for the assessment and treatment of these patients.Results and Conclusions: In this educational review we proposed the BARKH-based algorithm for a quick identification of hypertensive emergencies and associated acute organ damage, to allow the patients with hypertensive emergencies to receive immediate treatment in a proper setting.

Modern Management of Hypertensive Emergencies.

Acute increases of blood pressure values are common causes of patients' presentation to emergency departments, and their management represents a clinical challenge. They are usually described as 'hypertensive crises', 'hypertensive urgencies', terms that should be abandoned because they are misleading and inappropriate according to a recent task force of the European Society of Cardiology, which recommended to focus only on 'hypertensive emergencies'. The latter can be esasily identified by using the Brain, Arteries, Retina, Kidney, and/or Heart (BARKH) strategy as herein described. Although current guidelines recommendations/suggestions for treatment of these patients are not evidence-based, owing to the lack of randomized clinical trials, improved understanding of the underlying pathophysiology has changed the approach to management of the patients presenting with hypertensive emergencies in recent years. Starting from these premises and a systematic review of the available studies graded by their quality, using the AHA class of recommendation/level of evidence grading, whenever possible, we herein present a novel a streamlined symptoms- and evidence-based algorithm for the assessment and management of patients with hypertensive emergencies.

Genetic abnormalities among severely oligospermic men who are candidates for intracytoplasmic sperm injection.

Recent reports suggest that children born after intracytoplasmic sperm injection performed for male factor infertility are at increased risk of congenital malformations and chromosome aberrations. To explain these observations, we hypothesized that infertile men may be more likely than fertile men to have genetic abnormalities. We studied 750 severely oligozoospermic men (sperm count <5 million/ml) who were candidates for intracytoplasmic sperm injection, and 303 fertile men. We analyzed the peripheral blood karyotype, the Y chromosome long arm for detection of microdeletions in the azoospermia factors, and mutations in the cystic fibrosis gene and the androgen receptor gene. We also analyzed sperm for chromosome aneuploidies among the 421 men who subsequently entered the in vitro fertilization program. A total of 104 genetic abnormalities were diagnosed, corresponding to a frequency of 13.9% (104 of 750). Chromosomal aberrations were present in 5.6% (42 of 750) of infertile men and 0.3% of controls (one of 295), and they were in most cases alterations of the sex chromosomes. Y chromosome long-arm microdeletions were detected in 6.0% (45 of 750) of infertile men and most frequently included the azoospermia factor c, whereas no cases were found in controls (zero of 210). Mutations in the cystic fibrosis gene were diagnosed in 1.2% (nine of 750) of infertile men and 1.0% of controls (three of 303), and mutations in the androgen receptor gene were found in 1.1% (eight of 750) of infertile men and none of the 188 controls. Sperm sex chromosome aneuploidies were increased in men with karyotype anomalies and Y chromosome microdeletions as well as in subjects without constitutional genetic abnormalities. This study shows that the frequency of genetic alterations is increased among men with severe spermatogenic impairment. Genetic tests and genetic counseling should therefore be considered in oligozoospermic men who are candidates for intracytoplasmic sperm injection.

Androgen receptor gene CAG and GGC repeat lengths in cryptorchidism.

OBJECTIVE: Cryptorchidism is the most common congenital birth defect in male children, and accumulating evidence suggests that genetic abnormalities may be associated with it. The androgen receptor has two polymorphic sites in exon 1, with different numbers of CAG and GGC repeats, resulting in variable lengths of polyglutamine and polyglycine stretches. Longer CAG repeats result in a reduced androgen receptor transcriptional activity, but the role of the GGC triplets is less clear. In this study we analysed CAG and GGC repeat lengths in men with a history of cryptorchidism, associated or not with impairment of sperm production, in comparison with normal fertile subjects. METHODS: We analysed CAG and GGC repeat lengths in a group of 105 ex-cryptorchid men in comparison with 115 fertile non-cryptorchid men. RESULTS: No difference was found between patients and controls in the mean and median values, and in distribution of CAG and GGC, when considered separately. However, the analysis of the joint distribution of CAG and GGC showed that some combinations are significantly more frequent in men with bilateral cryptorchidism (who frequently presented severe testiculopathies), in a manner similar to that found in idiopathic infertile subjects. CONCLUSIONS: Although further studies are needed to elucidate the possible role of specific CAG/GGC combinations as a causative factor, these data suggest a possible association between androgen receptor gene polymorphisms and cryptorchidism.

A novel circulating hormone of testis origin in humans.

Insulin-like factor 3 (INSL3) is a member of the relaxin-insulin family, and it is expressed in pre- and postnatal Leydig cells of the testis. This peptide affects testicular descent during embryonic development, and mutations in INSL3 gene or its receptor LGR8 (leucine-rich repeat-containing G protein-coupled receptor 8)/GREAT (G protein-coupled receptor affecting testicular descent) cause cryptorchidism in humans. The expression of LGR8/GREAT in different tissues and the production of INSL3 also by adult-type Leydig cells suggest additional roles of this hormonal system in adulthood. In this preliminary report we performed the first analysis in humans of INSL3 using a novel RIA kit to measure INSL3 concentrations in serum of normal men and with different testicular pathologies. The results show that INSL3 is circulating in adult men, and it is almost exclusively of testicular origin. Subjects with severe testicular damage, such as men with severe infertility, produce low amount of INSL3, and the concentrations of this hormone seem to reflect the functional status of the Leydig cells. In particular, INSL3 concentrations may be an even more sensitive marker of Leydig cell function than testosterone itself. Analysis of men treated with different combinations of hormones of the hypothalamus-pituitary-testis axis suggests that the production of INSL3 is related to LH in a manner similar to that of the LH-testosterone axis.

The INSL3-LGR8/GREAT ligand-receptor pair in human cryptorchidism.

Testicular descent is a complex multistep embryonic process requiring the interaction between anatomical and hormonal factors. Failure in any of these steps results in cryptorchidism, the most frequent congenital anomaly of the urogenital tract in human males. Evidence for a genetic cause for cryptorchidism is numerous and supported by animal models. In particular, INSL3 and LGR8/GREAT proteins seem to act as ligand and receptor, respectively, and to have a role in gubernaculum development involved in testicular descent. In a cohort of 87 ex-cryptorchid patients and 80 controls, we looked for mutations in INSL3 and LGR8/GREAT genes by sequencing. Patients were classified on the basis of seminal, hormonal, and testicular cytological analyses. We found three mutations in the INSL3 gene in four patients and one LGR8/GREAT mutation in four patients (8 of 87, 9.2%). The eight patients show different phenotypes, ranging from normozoospermia to complete azoospermia, and from bilateral cryptorchidism to retractile testes. Furthermore, the endocrine function of the testis appears normal in all subjects. The findings of our study demonstrate that INSL3-LGR8/GREAT mutations are frequently associated with human cryptorchidism and are maternally inherited. The only clinical consequence of alterations of the INSL3-LGR8/GREAT system seems to be failure of the testis to normally descend in the scrotum during embryonic development, without affecting the spermatogenic and endocrine components of the testis itself.

Inhibin B plasma concentrations in infertile patients with DAZ gene deletions treated with FSH.

OBJECTIVE: The DAZ (deleted in azoospermia) gene family on the Y chromosome long arm is the major candidate for the AZFc (azoospermia factor c) phenotype of male infertility and it is expressed only in germ cells. The aim of the study was to assess Sertoli cell function in subjects with AZFc deletions. DESIGN: Case-control, prospective study. METHODS: We have studied six severely oligozoospermic subjects with AZFc-DAZ deletions, and looked whether they responded in terms of inhibin B production to a 1 month FSH treatment. These patients were compared with three groups of patients affected by different spermatogenic alterations not related to deletions on the Y chromosome. RESULTS: Although affected by severe testiculopathy, patients with AZFc-DAZ deletions had only slightly elevated FSH, and normal inhibin B plasma concentrations. Inhibin B responded normally during FSH treatment, supporting the hypothesis that Sertoli cells are not altered. On the contrary, other severe testiculopathies not related to Y chromosome deletions showed high FSH and low inhibin B concentrations, with no response to FSH treatment. In these cases the cause of the spermatogenic defect probably damaged both germ and Sertoli cells. Finally, idiopathic patients with a hormonal status similar to Y-deleted patients (slightly elevated FSH and normal inhibin B concentrations) did not respond to FSH treatment, suggesting that Sertoli cells were already at their maximal functional capability. CONCLUSIONS: These data confirm that Sertoli cell function is not damaged in patients with AZFc-DAZ deletions and that the strong reduction of germ cells does not affect the FSH-inhibin B feedback loop.

Analysis of the DAZ gene family in cryptorchidism and idiopathic male infertility.

OBJECTIVE: To investigate whether partial deletions of the DAZ gene family on the Y chromosome are associated with cryptorchidism, similar to that found for complete AZF deletions. DESIGN: Prospective study. SETTING: University hospital. PATIENT(S): A total of 193 azoospermic and severely oligozoospermic men: 95 with a history of cryptorchidism and 98 classified as idiopathic. INTERVENTION(S): A two-part study for Y chromosome microdeletions was performed: a polymerase chain reaction (PCR)-based analysis for complete AZF deletions and partial DAZ gene analysis by PCR-restriction digestion assay for single-family variants. MAIN OUTCOME MEASURE(S): Presence and type of AZF deletions and number of DAZ genes present. RESULT(S): The frequency of complete AZF deletions was similar in idiopathic (13.3%) and cryptorchid men (11.6%), but partial DAZ deletions were found only in infertile subjects without cryptorchidism (7.1%). The testicular phenotype was similar in men with complete AZF deletions and partial DAZ deletions, therefore the contribution of the other AZF genes in determining the spermatogenic impairment is still unclear. CONCLUSION(S): Our findings suggest that the loss of only some copies of DAZ is sufficient to lead to severe male infertility, but it is not a frequent finding in cryptorchid men.

Use of recombinant human follicle-stimulating hormone in the treatment of male factor infertility.

OBJECTIVE: To evaluate the effects of treatment with recombinant human FSH (r-hFSH) on seminal parameters and seminiferous epithelium in idiopathic patients with oligozoospermia with normal FSH plasma levels. DESIGN: Randomized single-blind study. SETTING: Academic setting. PATIENT(S): Forty-five subjects with idiopathic oligozoospermia (sperm count <10 x 10(6)/mL) and normal FSH and inhibin B plasma levels. INTERVENTION(S): Three months of treatment with r-hFSH 50 IU (15 patients) or with r-hFSH 100 IU on alternate days (15 patients) or no treatment (15 patients); bilateral testicular fine-needle aspiration (FNA) performed before and after therapy; FSH and inhibin B plasma levels evaluated during treatment. MAIN OUTCOME MEASURE(S): Seminal parameters; testicular cytological features evaluated by FNA; plasma levels of FSH, LH, T, and inhibin B. RESULT(S): Treatment with r-hFSH at a dose of 50 IU induced no increase in sperm concentration, while treatment with r-hFSH at a dose of 100 IU induced a significant increase in sperm concentration. In particular, in 11/15 patients a doubling of the pretreatment sperm concentration was observed. No significant increase in sperm parameters was observed in the control group. In both groups of patients treated with r-hFSH, the cytological analysis before treatment showed hypospermatogenesis. An increase in the percentage of spermatogonia and spermatocytes was observed only after the treatment with r-hFSH at a dose of 100 IU. CONCLUSION(S): The findings of this study demonstrate that r-hFSH at a dose of 100 IU, as previously seen with highly purified FSH, increases the spermatogonial population and sperm production in idiopathic patients with oligozoospermia with normal FSH and inhibin B plasma levels and a cytological picture of hypospermatogenesis.

Immunostaining for placental alkaline phosphatase on fine-needle aspiration specimens to detect noninvasive testicular cancer: a prospective evaluation in cryptorchid men.

OBJECTIVE: To assess, in a 12-year prospective study, the potential for early detection of testicular carcinoma in situ (CIS) by immunocytochemistry, using anti-placental alkaline phosphatase (PLAP) monoclonal antibodies on testicular fine-needle aspiration cytology (FNAC) specimens taken from a group of formerly cryptorchid patients, as such men are at greater risk of developing testicular cancer. PATIENTS AND METHODS: Sixty-eight men who had had orchidopexy at the Urological Department of the University of Padova between 1975 and 1983 were evaluated first in 1993, by a protocol including a history, physical examination, testicular ultrasonography and serum tumour markers, to eliminate the presence of testicular cancer. In 57 of the 68 men, specimens taken from bilateral testicular FNAC were stained immunocytochemically using anti-PLAP monoclonal antibodies. After 8 years, the same protocol was repeated on the 57 men, and the follow-up was prolonged until March 2005 for men with previous positive PLAP immunostaining. RESULTS: In 1993, six of the 57 men, (10.5%) had unilateral positive immunostaining for PLAP. By 2001, none of these men had developed testicular cancer, while of the other 51 men, only one developed a nonseminomatous tumour. The uninterrupted surveillance of PLAP-positive men showed no overt cancer until March 2005. CONCLUSION: The present findings do not seem to confirm the reliability of PLAP immunostaining of testicular specimens from FNAC for detecting CIS. These findings might depend on the geographical variability of both CIS and testicular cancer incidence, as well as on the variable relationship between CIS and successive occurrence of invasive testis cancer.

Treatment of male idiopathic infertility with recombinant human follicle-stimulating hormone: a prospective, controlled, randomized clinical study.

OBJECTIVE: To evaluate the effects of treatment with FSH on seminal parameters and spontaneous pregnancy in male infertility. DESIGN: Prospective, controlled, randomized clinical study. SETTING: Infertility center at a university hospital. PATIENT(S): One hundred twelve men affected by idiopathic oligozoospermia. INTERVENTION(S): Patients were randomized into two groups: 62 subjects were treated with 100 IU of recombinant human FSH on alternate days for 3 months, and 50 patients did not receive any treatment. Semen analysis was performed in all subjects at the end of this period of treatment and after the following 3 months. Subjects who had not reached spontaneous pregnancy underwent assisted reproductive techniques. MAIN OUTCOME MEASURE(S): Seminal parameters, testicular cytologic analysis, FSH, LH, T, and inhibin B concentrations. RESULT(S): The treatment group considered as a whole did not show modifications in sperm parameters. However, a subgroup of these (30, 48.4%) had a significant increase of sperm count (responder group). In the period including 3 months after the withdrawal of FSH therapy, we observed a significantly higher spontaneous pregnancy rate in the responder group (5 of 30 [16.7%]) with respect to nonresponder and nontreated groups (1 of 32 [3.1%] and 2 of 50 [4.0%], respectively). Furthermore, the improvement of seminal parameters in the responder group allowed these patients to undergo less frequent IVF-ET/intracytoplasmic sperm injection. CONCLUSION(S): Results from this controlled, randomized clinical trial show that FSH therapy does not improve sperm concentration or pregnancy rate when infertile male patients are chosen solely by the clinical criteria of idiopathic oligospermia and normal FSH concentration. Subgroup analysis, however, does indicate that patients without maturation arrest in addition to the clinical scenario do benefit from medical therapy.