Clinical inertia is the enemy of therapeutic success in the management of diabetes and its complications: a narrative literature review.

Diabetes mellitus is a chronic disease characterized by high social, economic and health burden, mostly due to the high incidence and morbidity of diabetes complications. Numerous studies have shown that optimizing metabolic control may reduce the risk of micro and macrovascular complications related to the disease, and the algorithms suggest that an appropriate and timely step of care intensification should be proposed after 3 months from the failure to achieve metabolic goals. Nonetheless, many population studies show that glycemic control in diabetic patients is often inadequate. The phenomenon of clinical inertia in diabetology, defined as the failure to start a therapy or its intensification/de-intensification when appropriate, has been studied for almost 20 years, and it is not limited to diabetes care, but also affects other specialties. In the present manuscript, we have documented the issue of inertia in its complexity, assessing its dimensions, its epidemiological weight, and its burden over the effectiveness of care. Our main goal is the identification of the causes of clinical inertia in diabetology, and the quantification of its social and health-related consequences through the adoption of appropriate indicators, in an effort to advance possible solutions and proposals to fight and possibly overcome clinical inertia, thus improving health outcomes and quality of care.

Follow-up of varicocele treated with percutaneous retrograde sclerotherapy: technical, clinical and seminal aspects.

Varicocele is a common cause of male infertility; it can be treated by percutaneous retrograde embolization of the internal spermatic vein in order to improve sperm parameters and male fertility. The aim of this study was to verify the improvement of semen parameters after varicocele retrograde sclerotherapy. We evaluated 223 patients with left (206) or bilateral (17) varicocele (mean age +/- SD, 27.3 +/- 4.7 yr, range 18-37) by clinical, Doppler and seminal examinations; all the patients underwent phlebography, using 5F Cobra catheter from the right femoral vein access to the internal spermatic vein and varicocele sclerosing with Hydroxy-polyaethoxydodecanol. Doppler and seminal examinations 6 months after sclerotherapy were requested for the follow-up. Sixty-seven patients with left or bilateral varicocele who did not undergo sclerotherapy were studied as controls. Six months after sclerotherapy, a complete resolution of left varicocele was present in 172 patients (77.1%), while a partial improvement was obtained in 34 patients (15.3%). In these 206 patients seminal examination showed a significant improvement of sperm concentration (mean +/- SEM, 52.1 +/- 4.1 vs 44.2 +/- 3.6 million/ml, p = 0.002) and progressive motility (40.5 +/- 2.2 vs 33.3 +/- 2.0%, p = 0.0001), but not of normal sperm morphology (38.9 +/- 2.3 vs 37.4 +/- 2.1%, ns). In the control group no significant variations of seminal parameters were observed 6 months after the basal examination. In conclusion, varicocele retrograde sclerotherapy is a well-tolerated technique with a low cost-benefit ratio, able to improve semen parameters.

Gonadotroph cell pituitary adenomas in males.

BACKGROUND: Considered exceptional in the past, gonadotroph cell pituitary adenomas account for 3.5-6.4% of total surgically excised pituitary adenomas when examined with immunospecific staining. The aim of this study was to describe the clinical, hormonal, radiological and immunohistochemical features, the management and the follow-up of our patients with gonadotroph adenoma. METHODS: In this retrospective study we describe 14 male subjects aged 19-70 yrs affected by gonadotroph cell pituitary adenomas; the patients were studied by hormonal, radiological and immunohistochemical investigations and followed up for 3-13 yrs by ambulatory and/or hospitalized care. RESULTS: Visual impairment and/or decreased libido and erectile dysfunction were the symptoms at presentation. Increased serum gonadotropin concentrations were shown in 3 patients. Reduced levels of testosterone were present in 9 patients, and normal in the remainder. At diagnosis all patients had pituitary macroadenomas, with wide extrasellar extension in 12. All patients underwent trans-sphenoidal surgery and immunohistochemical staining of surgically excised specimens showed the presence of gonadotroph and alpha-subunit cells in all pituitary adenomas. After surgery 3 patients had clear radiological evidence of normal pituitary; in the others a doubtful MRI picture or a residual adenomatous tissue were present. In the patients who did not undergo radiotherapy immediately after surgery, a regrowth of tumoral tissue was shown in 1-10 yrs. CONCLUSIONS: We stress the importance of a close follow-up of patients with gonadotroph adenomas after surgery, and we raise the question of whether radiotherapy may be useful for avoiding any further adenomatous regrowth.

Postmenopausal virilization in a woman with gonadotropin dependent ovarian hyperthecosis.

We report a case of a 66-yr-old woman with progressive hair balding, hirsutism and virilization. Gonadotropins and estradiol levels were in the postmenopausal range; total testosterone (TT), free testosterone (FT) and 17-hydroxyprogesterone (17-OHP) were elevated with dehydroepiandrosterone sulphate, androstendione and cortisol serum levels in the normal range, as 24-hr free urinary cortisol. TT, FT and 17-OHP were normalized, and FSH and LH fell to premenopausal levels on 18th day after a single i.m. injection of the GnRH analogue (GnRHa), triptorelin. Then, a diagnosis of hyperandrogenism of ovarian origin was made and bilateral ovariectomy was performed. Histological study of gonadal tissue revealed diffuse stromal hyperplasia of both ovaries with occasional nests of luteinized cells. With immunoperoxidase techniques these cells stained positively for testosterone and progesterone. One month after surgery, androgen levels were normalized together with regression of most of the clinical signs of virilization. In conclusion, our patient showed a severe virilization developed after menopause; hormonal investigations suggested a gonadotropin dependent ovarian hyperandrogenism, confirmed by histological examination; the presence of luteinized cells in the ovarian stroma was responsible for hyperandrogenism, as confirmed by the immunoperoxidase technique.

Calcium blood level modulates endogenous nitric oxide action: effects of parathroidectomy in patients with hyperparathyroidism.

UNLABELLED: Platelet cyclic guanosine monophosphate (cGMP) is produced by soluble guanylate cyclase (sGC), the activity of which is modulated by the activity of nitric oxide (NO) constitutive synthase (cNOS) which, in turn, is activated by a calcium/calmodulin complex. In primary hyperparathyroidism (H-PTH) an increase in platelet free calcium levels is present. In this study we evaluate the platelet cGMP levels, as an expression of NO production, in the presence of 3-isobutyl-1-methylxanthine (IBMX) alone (IBMXcGMP) and after stimulation by ionomycine (IONO; IONOcGMP) and sodium nitroprusside (SNP; SNPcGMP), in eight subjects affected by H-PTH before and after removal of adenoma. Platelet cGMP levels were also measured in seven normal subjects. IBMXcGMP and IONOcGMP were elevated in H-PTH patients compared with normal subjects (1.9 +/- 0.3 vs 0.8 +/- 0.2 fmol/10(6) platelets and 2.7 +/- 0.4 vs 1.4 +/- 0.3; P < 0.02 and P < 0.05 respectively) but SNPcGMP was unaffected (3.9 +/- 0.6 vs 2.5 +/- 0.5). After parathyroidectomy, blood levels of intact parathyroid hormone (i-PTH), total calcium (t-Ca), IBMXcGMP and IONOcGMP all decreased (177.5 +/- 23.9 vs 45.0 +/- 8.8 pg/ml, P < 0.005; 6.5 +/- 0.5 vs 4.6 +/- 0.1 mEq/1, P < 0.005; 1.9 +/- 0.3 vs 0.8 +/- 0.2, P < 0.005; 2.7 +/- 0.4 vs 1.8 +/ 0.3, P < 0.05 respectively), while SNPcGMP was not modified (3.9 +/- 0.6 vs 4.3 +/- 0.9). t-Ca and i-PTH were directly correlated with IBMXcGMP (P < 0.02, rs = 0.613; P < 0.02, rs = 0.576 respectively) and i-PTH was also correlated with t-Ca (P < 0.001), rs = 0.840). IN CONCLUSION: (1) levels of IBMXcGMP and IONOcGMP are high in subjects with H-PTH; (2) after surgery both IBMXcGMP and IONOcGMP decrease to normal values. As IBMXcGMP expresses basal cGMP and IONOcGMP expresses the cGMP after cNOS stimulation, it can be speculated that the increase in NO production could be a mechanism to downregulate the vasoconstriction which may be caused by the high calcium levels in smooth muscle cells. After surgery, together with the normalization of calcium levels, NO production also returned to normal values.

[Hormonal control of sexual behavior in males and endocrinologic causes of sexual dysfunction]. / Il controllo ormonale del comportamento sessuale nel maschio e cause endocrinologiche di disfunzione sessuale.

The role of androgens in the male sex differentiation, in the genesis and preservation of the erectile function is summarized. In sex differentiation, testosterone acts on genitalia and central nervous system (CNS). In CNS sexual steroids exert a morphogenetic action during neuronal development. At the pubertal age, the increase of testosterone leads to the development of sex characteristics, the onset of libido and the beginning of the nocturnal spontaneous erectile function. Spontaneous erections are androgen-dependent, and they are impaired in androgen deficiency. Normal androgen levels lead to make voluntary erections. However, in the human species, cortical influences may greatly affect what could be possible to occur in relation to the hormonal situation. Endocrine causes of sexual dysfunction are responsible for about 20-25% of the total; among these primary and secondary hypogonadisms are the most frequent and they are to be managed with causal treatments and androgen replacement therapy. Therefore, androgen treatments are not useful in functional sex disorders and they may be at risk on prostatic tissue. Andropause is related to a progressive reduction of testicular function, principally due to vascular disorders, with low-normal androgen levels. On the basis of these observations it is underlined that in the human species the androgen presence is a necessary but not sufficient condition for a correct sex function.

Clinical and genetic variability in XX sex-reversed patients.

Three 46, XX hypogonadal subjects are described who exhibited different clinical and genetic characteristics. Two patients, with complete sex-reversal, are sterile males with hypogonadal features; the third patient, with partial sex-reversal, presented with a eunuchoid appearance and with ambiguous genitalia. Polymerase chain reaction (PCR) amplification of DNA from these patients showed the presence of a translocation of the sex-determining region of the Y chromosome (Sry) only in the first two patients described.

A new approach in the evaluation of gonadotropins for the diagnosis of polycystic ovary syndrome.

The new immunometric methods using monoclonal antibodies to detect gonadotropins revealed a reduction in the absolute values of these hormones, especially LH, due to a decrease in cross-reaction between gonadotropin subunits. Therefore, reference values of the LH/FSH ratio and their diagnostic significance in the polycystic ovary syndrome (PCOS) need to be defined again. We evaluated the LH/-FSH ratio in basal conditions and after administration of GnRH (100 micrograms as i.v. bolus) in seventy patients with PCOS employing an immunoenzymatic method. In PCOS patients the LH/FSH ratio was greater than 1 in 70% when evaluated on a single sample and in 88% when evaluated on a pooled serum from four samples every 30 minutes; in the control group the ratio was always lower than 1. The LH/-FSH ratio evaluated on the peak values in response to GnRH was greater than 2 in all patients and lower than 2 in the control group. Our results indicate that the LH/FSH ratio is still an important diagnostic tool in PCOS, especially when evaluated on the peak values in response to GnRH, even if its reference values are lower using these new monoclonal methods.

Naltrexone must not be considered a real therapy in functional hypothalamic amenorrhea. The results of a double blind controlled study.

Endogenous opioids exert a tonic inhibitory control on GnRH pulsatility at the hypothalamic level and it must be responsible for some hypogonadotropic hypogonadic syndromes such as functional hypothalamic amenorrhea (FHA). We treated 22 patients suffering from FHA with an oral anti-opioid drug, Naltrexone Hydrochloridrate (NH), 50 mg once a day or placebo, in a double blind controlled study. Six patients exhibited a regular resumption of their menstrual cycles (4 on placebo and only 2 on NH). There was an increase of 17BE2 in 3 of these 6 patients; progesterone levels did not change at all. Gynaecological echography demonstrated folliculogenesis in 4 of these 6 patients (only 1 on NH). The results show that NH is not a real therapy in patients suffering from FHA. Furthermore placebo, useful to the resumption of menstrual bleeding in 4 patients, underlines the importance of psychosomatic effects in the therapeutic management of FHA.

[Male fertility in the elderly]. / La fertilità maschile nella terza età.

Fertility in the elderly is still a less known argument. We report some news about seminal parameters (SP) and testicular hystological parameters (THP) in this age. About SP: the volume of the ejaculate, the number and the motility of spermatozoa are reduced. The morphology is typical: spermatozoa with coiled tails are common. About THP: some testes show a normal hystological architecture; others show a reduced volume and some aspects of hypospermatogenesis or maturative arrest; others show a very reduced volume, thickness of the tubular basal membrane and other signs of cellular regression. These signs are dependent upon the vascular insufficiency and the hormonal alterations which may occur in the elderly.